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vol. 2  q 3  2014

UPPER EXTREMITY PAIN SYNDROMESP.18 THE MADWOMAN IN THE ATTIC: PAIN AND BORDERLINE PERSONALITY DISORDERP.22 PAIN & SUICIDE: A HIDDEN EPIDEMICP.30 IF 13 CLINICIANS CAN’T AGREE ON YOUR DIAGNOSIS…YOU’VE GOT A PROBLEM!P.38 RESTLESS LEGS SYNDROMEP.58 CHRONIC PAIN IN CHILDREN: ARE THEY A POPULATION AT RISK?P.64


NEW

Butrans 7.5 mcg/hour Coming Soon Available in October

Butrans — 7 Days of Buprenorphine Delivery

Butrans is a Schedule III extended-release opioid analgesic WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; and NEONATAL OPIOID WITHDRAWAL SYNDROME Addiction, Abuse, and Misuse Butrans exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Butrans, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1) and Overdosage (10)]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Butrans. Monitor for respiratory depression, especially during initiation of Butrans or following a dose increase. Misuse or abuse of Butrans by chewing, swallowing, snorting or injecting buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death [see Warnings and Precautions (5.2)]. Accidental Exposure Accidental exposure to even one dose of Butrans, especially by children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions (5.2)]. Neonatal Opioid Withdrawal Syndrome Prolonged use of Butrans during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)]. Parentheses refer to sections in the Full Prescribing Information.


Butrans® (buprenorphine) Transdermal System is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Use: Because of the risks of addiction, abuse and misuse with opioids, even at recommended doses, and because of the greater risk of overdose and death with extended-release opioid formulations, reserve Butrans for use in patients for whom alternative treatment options (eg, non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Butrans is not indicated as an as-needed (prn) analgesic. CONTRAINDICATIONS ■

Butrans is contraindicated in patients with: significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; known or suspected paralytic ileus; hypersensitivity (eg, anaphylaxis) to buprenorphine

WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse ■ Butrans contains buprenorphine, a Schedule III controlled substance. Butrans exposes users to the risks of opioid addiction, abuse, and misuse. As modified-release products such as Butrans deliver the opioid over an extended period of time, there is a greater risk for overdose and death, due to the larger amount of buprenorphine present. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Butrans, and monitor all patients during therapy for the development of these behaviors or conditions. Abuse or misuse of Butrans by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose and death Life-Threatening Respiratory Depression ■ Serious, life-threatening, or fatal respiratory depression has been reported with modifiedrelease opioids, even when used as recommended, and if not immediately recognized and treated, may lead to respiratory arrest and death. The risk of respiratory depression is greatest during the initiation of therapy or following a dose increase; therefore, closely monitor patients for respiratory depression. Proper dosing and titration of Butrans are essential. Overestimating the Butrans dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental exposure to Butrans, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine

Neonatal Opioid Withdrawal Syndrome ■ Prolonged use of Butrans during pregnancy can result in neonatal opioid withdrawal syndrome which may be life-threatening to the neonate if not recognized and treated, and requires management according to protocols developed by neonatology experts Interactions with Central Nervous System Depressants ■ Hypotension, profound sedation, coma, respiratory depression, or death may result if Butrans is used concomitantly with other CNS depressants, including alcohol or illicit drugs that can cause CNS depression. Start with Butrans 5 mcg/hour patch, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant Use in Elderly, Cachectic, and Debilitated Patients and Patients with Chronic Pulmonary Disease ■ Closely monitor elderly, cachectic, and debilitated patients, and patients with chronic obstructive pulmonary disease because of the increased risk of life-threatening respiratory depression. Consider the use of alternative non-opioid analgesics in patients with chronic obstructive pulmonary disease if possible QTc Prolongation ■ Avoid in patients with Long QT Syndrome, family history of Long QT Syndrome, or those taking Class IA or Class III antiarrhythmic medications Hypotensive Effects ■ Butrans may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. Monitor patients during dose initiation or titration Use in Patients with Head Injury or Increased Intracranial Pressure ■ Monitor patients taking Butrans who may be susceptible to the intracranial effects of CO2 retention for signs of sedation and respiratory depression. Avoid the use of Butrans in patients with impaired consciousness or coma

Please read Brief Summary of Full Prescribing Information on the following pages.

Application Site Skin Reactions ■ In rare cases, severe application site skin reactions with signs of marked inflammation including “burn,” “discharge,” and “vesicles” have occurred Anaphylactic/Allergic Reactions ■ Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post-marketing experience Application of External Heat ■ Avoid exposing the Butrans application site and surrounding area to direct external heat sources. There is a potential for temperature-dependent increases in buprenorphine released from the system resulting in possible overdose and death Use in Patients with Gastrointestinal Conditions ■ Avoid the use of Butrans in patients with paralytic ileus and other GI obstructions. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms

ADVERSE REACTIONS ■

Most common adverse reactions (≥5%) reported by patients treated with Butrans in the clinical trials were nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash

Visit Butrans.com for more information or to print the Butrans Trial Offer and Butrans Savings Cards

The first transdermal system to deliver 7 days of buprenorphine

©2014 Purdue Pharma L.P. Stamford, CT 06901-3431 I8365-A 7/14


for transdermal administration BRIEF SUMMARY OF PRESCRIBING INFORMATION (For complete details please see the Full Prescribing Information and Medication Guide.) WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; and NEONATAL OPIOID WITHDRAWAL SYNDROME Addiction, Abuse, and Misuse BUTRANS® exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing BUTRANS, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1) and Overdosage (10)]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of BUTRANS. Monitor for respiratory depression, especially during initiation of BUTRANS or following a dose increase. Misuse or abuse of BUTRANS by chewing, swallowing, snorting or injecting buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death [see Warnings and Precautions (5.2)]. Accidental Exposure Accidental exposure to even one dose of BUTRANS, especially by children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions (5.2)]. Neonatal Opioid Withdrawal Syndrome Prolonged use of BUTRANS during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)]. 4 CONTRAINDICATIONS BUTRANS is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected paralytic ileus • Hypersensitivity (e.g., anaphylaxis) to buprenorphine [see Warnings and Precautions (5.12) and Adverse Reactions (6)] 5 WARNINGS AND PRECAUTIONS 5.1 Addiction, Abuse, and Misuse BUTRANS contains buprenorphine, a Schedule III controlled substance. As an opioid, BUTRANS exposes users to the risks of addiction, abuse, and misuse. As modified-release products such as BUTRANS deliver the opioid over an extended period of time, there is a greater risk for overdose and death, due to the larger amount of buprenorphine present. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed BUTRANS and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused [see Drug Abuse and Dependence (9)]. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing BUTRANS, and monitor all patients receiving BUTRANS for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as BUTRANS, but use in such patients necessitates intensive counseling about the risks and proper use of BUTRANS, along with intensive monitoring for signs of addiction, abuse, or misuse. Abuse or misuse of BUTRANS by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose and death [see Overdosage (10)]. Opioid agonists such as BUTRANS are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing BUTRANS. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, lifethreatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression, from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of BUTRANS, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with BUTRANS and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of BUTRANS are essential [see Dosage and Administration (2)]. Overestimating the BUTRANS dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental exposure to BUTRANS, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of BUTRANS during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. 5.4 Interactions with Central Nervous System Depressants Hypotension,

profound sedation, coma, respiratory depression, and death may result if BUTRANS is used concomitantly with alcohol or other (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of BUTRANS in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin BUTRANS therapy is made, start with BUTRANS 5 mcg/hour patch, monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.2)]. 5.5 Use in Elderly, Cachectic, and Debilitated Patients Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating BUTRANS and when BUTRANS is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)]. 5.6 Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with BUTRANS, as in these patients, even usual therapeutic doses of BUTRANS may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in these patients if possible. 5.7 QTc Prolongation A positive-controlled study of the effects of BUTRANS on the QTc interval in healthy subjects demonstrated no clinically meaningful effect at a BUTRANS dose of 10 mcg/hour; however, a BUTRANS dose of 40 mcg/hour (given as two BUTRANS 20 mcg/hour Transdermal Systems) was observed to prolong the QTc interval [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2)]. Consider these observations in clinical decisions when prescribing BUTRANS to patients with hypokalemia or clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia. Avoid the use of BUTRANS in patients with a history of Long QT Syndrome or an immediate family member with this condition, or those taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide). 5.8 Hypotensive Effects BUTRANS may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7.2)]. Monitor these patients for signs of hypotension after initiating or titrating the dose of BUTRANS. 5.9 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking BUTRANS who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with BUTRANS. BUTRANS may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of BUTRANS in patients with impaired consciousness or coma. 5.10 Hepatotoxicity Although not observed in BUTRANS chronic pain clinical trials, cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual buprenorphine for the treatment of opioid dependence, both in clinical trials and in post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injection drug abuse may have played a causative or contributory role. For patients at increased risk of hepatotoxicity (e.g., patients with a history of excessive alcohol intake, intravenous drug abuse or liver disease), obtain baseline liver enzyme levels and monitor periodically and during treatment with BUTRANS. 5.11 Application Site Skin Reactions In rare cases, severe application site skin reactions with signs of marked inflammation including “burn,” “discharge,” and “vesicles” have occurred. Time of onset varies, ranging from days to months following the initiation of BUTRANS treatment. Instruct patients to promptly report the development of severe application site reactions and discontinue therapy. 5.12 Anaphylactic/Allergic Reactions Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post-marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine is a contraindication to the use of BUTRANS. 5.13 Application of External Heat Advise patients and their caregivers to avoid exposing the BUTRANS application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds while wearing the system because an increase in absorption of buprenorphine may occur [see Clinical Pharmacology (12.3)]. Advise patients against exposure of the BUTRANS application site and surrounding area to hot water or prolonged exposure to direct sunlight. There is a potential for temperature-dependent increases in buprenorphine released from the system resulting in possible overdose and death. 5.14 Patients with Fever Monitor patients wearing BUTRANS systems who develop fever or increased core body temperature due to strenuous exertion for opioid side effects and adjust the BUTRANS dose if signs of respiratory or central nervous system depression occur. 5.15 Use in Patients with Gastrointestinal Conditions BUTRANS is contraindicated in patients with paralytic ileus. Avoid the use of BUTRANS in patients with other GI obstruction. The buprenorphine in BUTRANS may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase. 5.16 Use in Patients with Convulsive or Seizure Disorders The buprenorphine in BUTRANS may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during BUTRANS therapy. 5.17 Driving and Operating Machinery BUTRANS may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of BUTRANS and know how they will react to the medication. 5.18 Use in Addiction Treatment BUTRANS has not been studied and is not approved for use in the management of addictive disorders. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling:

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)] • QTc Prolongation [see Warnings and Precautions (5.7)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)] • Hypotensive Effects [see Warnings and Precautions (5.8)] • Interactions with Other CNS Depressants [see Warnings and Precautions (5.4)] • Application Site Skin Reactions [see Warnings and Precautions (5.11)] • Anaphylactic/Allergic Reactions [see Warnings and Precautions (5.12)] • Gastrointestinal Effects [see Warnings and Precautions (5.15)] • Seizures [see Warnings and Precautions (5.16)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 5,415 patients were treated with BUTRANS in controlled and open-label chronic pain clinical trials. Nine hundred twenty-four subjects were treated for approximately six months and 183 subjects were treated for approximately one year. The clinical trial population consisted of patients with persistent moderate to severe pain. The most common serious adverse drug reactions (all <0.1%) occurring during clinical trials with BUTRANS were: chest pain, abdominal pain, vomiting, dehydration, and hypertension/blood pressure increased. The most common adverse events (≥2%) leading to discontinuation were: nausea, dizziness, vomiting, headache, and somnolence. The most common adverse reactions (≥5%) reported by patients in clinical trials comparing BUTRANS 10 or 20 mcg/hour to placebo are shown in Table 2, and comparing BUTRANS 20 mcg/hour to BUTRANS 5 mcg/hour are shown in Table 3 below: Table 2: Adverse Reactions Reported in ≥5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Naïve Patients Open-Label Double-Blind Titration Period Treatment Period BUTRANS BUTRANS Placebo MedDRA (N = 1024) (N = 256) (N = 283) Preferred Term Nausea 23% 13% 10% Dizziness 10% 4% 1% Headache 9% 5% 5% Application site 8% 4% 7% pruritus Somnolence 8% 2% 2% Vomiting 7% 4% 1% Constipation 6% 4% 1% Table 3: Adverse Reactions Reported in ≥5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Experienced Patients Open-Label Double-Blind Titration Period Treatment Period BUTRANS BUTRANS 20 BUTRANS 5 MedDRA (N = 1160) (N = 219) (N = 221) Preferred Term Nausea 14% 11% 6% Application site 9% 13% 5% pruritus Headache 9% 8% 3% Somnolence 6% 4% 2% Dizziness 5% 4% 2% Constipation 4% 6% 3% Application site 3% 10% 5% erythema Application 3% 8% 6% site rash Application 2% 6% 2% site irritation The following table lists adverse reactions that were reported in at least 2.0% of patients in four placebo/active-controlled titration-to-effect trials. Table 4: Adverse Reactions Reported in Titration-to-Effect Placebo/ Active-Controlled Clinical Trials with Incidence ≥2% MedDRA Preferred Term BUTRANS (N = 392) Placebo (N = 261) Nausea Application site pruritus Dizziness Headache Somnolence Constipation Vomiting Application site erythema Application site rash Dry mouth Fatigue Hyperhidrosis Peripheral edema Pruritus Stomach discomfort

21% 15% 15% 14% 13% 13% 9% 7% 6% 6% 5% 4% 3% 3% 2%

6% 12% 7% 9% 4% 5% 1% 2% 6% 2% 1% 1% 1% 0% 0%

The adverse reactions seen in controlled and open-label studies are presented below in the following manner: most common (≥5%), common (≥1% to <5%), and less common (<1%). The most common adverse reactions (≥5%) reported by patients treated with BUTRANS in the clinical trials were nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash. The common (≥1% to <5%) adverse reactions reported by patients treated with BUTRANS in the clinical trials organized by MedDRA (Medical Dictionary for Regulatory Activities) System Organ Class were: Gastrointestinal disorders: diarrhea, dyspepsia, and upper abdominal pain General disorders and administration site conditions: fatigue, peripheral edema, application


site irritation, pain, pyrexia, chest pain, and asthenia Infections and infestations: urinary tract infection, upper respiratory tract infection, nasopharyngitis, influenza, sinusitis, and bronchitis Injury, poisoning and procedural complications: fall Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: back pain, arthralgia, pain in extremity, muscle spasms, musculoskeletal pain, joint swelling, neck pain, and myalgia Nervous system disorders: hypoesthesia, tremor, migraine, and paresthesia Psychiatric disorders: insomnia, anxiety, and depression Respiratory, thoracic and mediastinal disorders: dyspnea, pharyngolaryngeal pain, and cough Skin and subcutaneous tissue disorders: pruritus, hyperhidrosis, rash, and generalized pruritus Vascular disorders: hypertension Other less common adverse reactions, including those known to occur with opioid treatment, that were seen in <1% of the patients in the BUTRANS trials include the following in alphabetical order: Abdominal distention, abdominal pain, accidental injury, affect lability, agitation, alanine aminotransferase increased, angina pectoris, angioedema, apathy, application site dermatitis, asthma aggravated, bradycardia, chills, confusional state, contact dermatitis, coordination abnormal, dehydration, depersonalization, depressed level of consciousness, depressed mood, disorientation, disturbance in attention, diverticulitis, drug hypersensitivity, drug withdrawal syndrome, dry eye, dry skin, dysarthria, dysgeusia, dysphagia, euphoric mood, face edema, flatulence, flushing, gait disturbance, hallucination, hiccups, hot flush, hyperventilation, hypotension, hypoventilation, ileus, insomnia, libido decreased, loss of consciousness, malaise, memory impairment, mental impairment, mental status changes, miosis, muscle weakness, nervousness, nightmare, orthostatic hypotension, palpitations, psychotic disorder, respiration abnormal, respiratory depression, respiratory distress, respiratory failure, restlessness, rhinitis, sedation, sexual dysfunction, syncope, tachycardia, tinnitus, urinary hesitation, urinary incontinence, urinary retention, urticaria, vasodilatation, vertigo, vision blurred, visual disturbance, weight decreased, and wheezing. 7 DRUG INTERACTIONS 7.1 Benzodiazepines There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists. Closely monitor patients with concurrent use of BUTRANS and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking BUTRANS, and warn patients to use benzodiazepines concurrently with BUTRANS only as directed by their physician. 7.2 CNS Depressants The concomitant use of BUTRANS with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and BUTRANS for signs of respiratory depression, sedation, and hypotension. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)]. 7.3 Drugs Affecting Cytochrome P450 Isoenzymes Inhibitors of CYP3A4 and 2D6 Because the CYP3A4 isoenzyme plays a major role in the metabolism of buprenorphine, drugs that inhibit CYP3A4 activity may cause decreased clearance of buprenorphine which could lead to an increase in buprenorphine plasma concentrations and result in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of CYP2D6 and 3A4 inhibitors. If co-administration with BUTRANS is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)]. Inducers of CYP3A4 CYP450 3A4 inducers may induce the metabolism of buprenorphine and, therefore, may cause increased clearance of the drug which could lead to a decrease in buprenorphine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to buprenorphine. After stopping the treatment of a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. If co-administration or discontinuation of a CYP3A4 inducer with BUTRANS is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)]. 7.4 Muscle Relaxants Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients receiving muscle relaxants and BUTRANS for signs of respiratory depression that may be greater than otherwise expected. 7.5 Anticholinergics Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when BUTRANS is used concurrently with anticholinergic drugs. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Clinical Considerations Fetal/neonatal adverse reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see Warnings and Precautions (5.3)]. Teratogenic Effects - Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. BUTRANS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In animal studies, buprenorphine caused an increase in the number of stillborn offspring, reduced litter size, and reduced offspring growth in rats at maternal exposure levels that were approximately 10 times that of human subjects who received one BUTRANS 20 mcg/hour, the maximum recommended human dose (MRHD). Studies in rats and rabbits demonstrated no evidence of teratogenicity following BUTRANS or subcutaneous (SC) administration of buprenorphine during the period of major organogenesis. Rats were administered up to one BUTRANS 20 mcg/hour every 3 days (gestation days 6, 9, 12, & 15) or received daily SC buprenorphine up to 5 mg/kg (gestation days 6-17). Rabbits were administered four BUTRANS 20 mcg/hour every 3 days (gestation days 6, 9, 12, 15, 18, & 19) or received daily SC buprenorphine up to 5 mg/kg (gestation days 6-19). No teratogenicity was observed at any dose. AUC values for buprenorphine with BUTRANS application and SC injection were approximately 110 and 140 times, respectively, that of human subjects who received the MRHD of one BUTRANS 20 mcg/hour. Non-Teratogenic Effects In a peri- and post-natal study conducted in pregnant and lactating rats, administration of buprenorphine either as BUTRANS or SC buprenorphine was associated with toxicity to offspring. Buprenorphine was present in maternal milk. Pregnant

rats were administered 1/4 of one BUTRANS 5 mcg/hour every 3 days or received daily SC buprenorphine at doses of 0.05, 0.5, or 5 mg/kg from gestation day 6 to lactation day 21 (weaning). Administration of BUTRANS or SC buprenorphine at 0.5 or 5 mg/kg caused maternal toxicity and an increase in the number of stillborns, reduced litter size, and reduced offspring growth at maternal exposure levels that were approximately 10 times that of human subjects who received the MRHD of one BUTRANS 20 mcg/hour. Maternal toxicity was also observed at the no observed adverse effect level (NOAEL) for offspring. 8.2 Labor and Delivery Opioids cross the placenta and may produce respiratory depression in neonates. BUTRANS is not for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. 8.3 Nursing Mothers Buprenorphine is excreted in breast milk. The amount of buprenorphine received by the infant varies depending on the maternal plasma concentration, the amount of milk ingested by the infant, and the extent of first pass metabolism. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of buprenorphine is stopped. Because of the potential for adverse reactions in nursing infants from BUTRANS, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efficacy of BUTRANS in patients under 18 years of age has not been established. 8.5 Geriatric Use Of the total number of subjects in the clinical trials (5,415), BUTRANS was administered to 1,377 patients aged 65 years and older. Of those, 457 patients were 75 years of age and older. In the clinical program, the incidences of selected BUTRANS-related AEs were higher in older subjects. The incidences of application site AEs were slightly higher among subjects <65 years of age than those ≥65 years of age for both BUTRANS and placebo treatment groups. In a single-dose study of healthy elderly and healthy young subjects treated with BUTRANS 10 mcg/hour, the pharmacokinetics were similar. In a separate dose-escalation safety study, the pharmacokinetics in the healthy elderly and hypertensive elderly subjects taking thiazide diuretics were similar to those in the healthy young adults. In the elderly groups evaluated, adverse event rates were similar to or lower than rates in healthy young adult subjects, except for constipation and urinary retention, which were more common in the elderly. Although specific dose adjustments on the basis of advanced age are not required for pharmacokinetic reasons, use caution in the elderly population to ensure safe use [see Clinical Pharmacology (12.3)]. 8.6 Hepatic Impairment In a study utilizing intravenous buprenorphine, peak plasma levels (Cmax) and exposure (AUC) of buprenorphine in patients with mild and moderate hepatic impairment did not increase as compared to those observed in subjects with normal hepatic function. BUTRANS has not been evaluated in patients with severe hepatic impairment. As BUTRANS is intended for 7-day dosing, consider the use of alternate analgesic therapy in patients with severe hepatic impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance BUTRANS contains buprenorphine, a Schedule III controlled substance with an abuse potential similar to other Schedule III opioids. BUTRANS can be abused and is subject to misuse, addiction and criminal diversion [see Warnings and Precautions (5.1)]. 9.2 Abuse All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get “high”, or the use of steroids for performance enhancement and muscle build up. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. BUTRANS, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful recordkeeping of prescribing information, including quantity, frequency, and renewal requests, as required by state law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to reduce abuse of opioid drugs. Risks Specific to the Abuse of BUTRANS BUTRANS is intended for transdermal use only. Abuse of BUTRANS poses a risk of overdose and death. This risk is increased with concurrent abuse of BUTRANS with alcohol and other substances including other opioids and benzodiazepines [see Warnings and Precautions (5.4) and Drug Interactions (7.2)]. Intentional compromise of the transdermal delivery system will result in the uncontrolled delivery of buprenorphine and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions (5.1)]. Abuse may occur by applying the transdermal system in the absence of legitimate purpose, or by swallowing, snorting, or injecting buprenorphine extracted from the transdermal system. 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. BUTRANS should not be abruptly discontinued [see Dosage and Administration (2.3)]. If BUTRANS is abruptly discontinued in a physicallydependent patient, an abstinence syndrome may occur. Some or all of the

following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1)]. 10 OVERDOSAGE Clinical Presentation Acute overdosage with BUTRANS is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations. Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. Naloxone may not be effective in reversing any respiratory depression produced by buprenorphine. High doses of naloxone, 10-35 mg/70 kg, may be of limited value in the management of buprenorphine overdose. The onset of naloxone effect may be delayed by 30 minutes or more. Doxapram hydrochloride (a respiratory stimulant) has also been used. Remove BUTRANS immediately. Because the duration of reversal would be expected to be less than the duration of action of buprenorphine from BUTRANS, carefully monitor the patient until spontaneous respiration is reliably re-established. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects as buprenorphine continues to be absorbed from the skin. After removal of BUTRANS, the mean buprenorphine concentrations decrease approximately 50% in 12 hours (range 10-24 hours) with an apparent terminal half-life of approximately 26 hours. Due to this long apparent terminal half-life, patients may require monitoring and treatment for at least 24 hours. In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal. The severity of the withdrawal produced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient with an opioid antagonist, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Addiction, Abuse, and Misuse Inform patients that the use of BUTRANS, even when taken as recommended, can result in addiction, abuse, and misuse, which could lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share BUTRANS with others and to take steps to protect BUTRANS from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting BUTRANS or when the dose is increased, and that it can occur even at recommended doses [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Exposure Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store BUTRANS securely and to dispose of unused BUTRANS by folding the patch in half and flushing it down the toilet. Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of BUTRANS during pregnancy can result in neonatal opioid withdrawal syndrome, which may be lifethreatening if not recognized and treated [see Warnings and Precautions (5.3)]. Interaction with Alcohol and other CNS Depressants Inform patients that potentially serious additive effects may occur if BUTRANS is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a health care provider. Important Administration Instructions Instruct patients how to properly use BUTRANS, including the following: 1. To carefully follow instructions for the application, removal, and disposal of BUTRANS. Each week, apply BUTRANS to a different site based on the 8 described skin sites, with a minimum of 3 weeks between applications to a previously used site. 2. To apply BUTRANS to a hairless or nearly hairless skin site. If none are available, instruct patients to clip the hair at the site and not to shave the area. Instruct patients not to apply to irritated skin. If the application site must be cleaned, use clear water only. Soaps, alcohol, oils, lotions, or abrasive devices should not be used. Allow the skin to dry before applying BUTRANS. Hypotension Inform patients that BUTRANS may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position). Driving or Operating Heavy Machinery Inform patients that BUTRANS may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in BUTRANS. Advise patients how to recognize such a reaction and when to seek medical attention. Pregnancy Advise female patients that BUTRANS can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant. Disposal Instruct patients to refer to the Instructions for Use for proper disposal of BUTRANS. Patients can dispose of used or unused BUTRANS patches in the trash by sealing them in the Patch-Disposal Unit, following the instructions on the unit. Alternatively, instruct patients to dispose of used patches by folding the adhesive side of the patch to itself, then flushing the patch down the toilet immediately upon removal. Unused patches should be removed from their pouches, the protective liners removed, the patches folded so that the adhesive side of the patch adheres to itself, and immediately flushed down the toilet. Instruct patients to dispose of any patches remaining from a prescription as soon as they are no longer needed. Healthcare professionals can telephone Purdue Pharma’s Medical Services Department (1-888-726-7535) for information on this product. Distributed by: Purdue Pharma L.P., Stamford, CT 06901-3431 Manufactured by: LTS Lohmann Therapy Systems Corp., West Caldwell, NJ 07006 U.S. Patent Numbers 5681413; 5804215; 6264980; 6315854; 6344211; RE41408; RE41489; RE41571. © 2014, Purdue Pharma L.P. This brief summary is based on BUTRANS Prescribing Information 303385-0A, Revised 06/2014 (A)


GUEST EDITOR  SANFORD PUBLISHER  Aventine

M. SILVERMAN MD

Co.  6 Erie Street, Montclair, NJ 07042

ART DIRECTOR  DARRYL

FOSSA

EDITORIAL DIRECTOR  DEBRA EDITOR  HOLLY

WEINER

CASTER

EDITORIAL BOARD

Charles E. Argoff  MD, CPE Professor of Neurology Albany Medical College Department of Neurology Director Comprehensive Pain Center Albany Medical Center Department of Neurology Albany, NY

Peter A. Foreman  DDS, DAAPM Consultant Rotorua Hospital and Private Practice Rotorua, New Zealand

Steven D. Passik  PhD Director of Clinical Addiction Research and Education Millennium Laboratories San Diego, CA

Gary W. Jay  MD, FAAPM , DAAPM Medical Director DNA Center Daytona Beach, FL

John F. Peppin  DO, FACP Head of Global Medical Affairs, Pharmaceuticals Mallinckrodt Pharmaceuticals St. Louis, MO

Paul Arnstein  RN , PhD, ACNS - BC , FNP-C, FAAN Clinical Nurse Specialist for Pain Relief Massachusetts General Hospital Boston, MA

Mary Lynn McPherson  PharmD, BCPS, CPE, FASPE Professor and Vice Chair University of Maryland School of Pharmacy Department of Pharmacy Practice and Science Hospice Consultant Pharmacist Baltimore, MD

Joseph V. Pergolizzi  MD Adjunct Assistant Professor Johns Hopkins University School of Medicine Department of Medicine Baltimore, MD Senior Partner Naples Anesthesia and Pain Medicine Naples, FL

Said R. Beydoun  MD, FAAN Professor of Neurology Director of the Neuromuscular Program Keck Medical Center of University of Southern California Los Angeles, CA Jennifer Bolen  JD Founder Legal Side of Pain Knoxville, TN Paul J. Christo  MD, MBA Associate Professor Johns Hopkins University School of Medicine Department of Anesthesiology and Critical Care Medicine Baltimore, MD Michael R. Clark  MD, MPH, MBA Vice Chair, Clinical Affairs Johns Hopkins University School of Medicine Department of Psychiatry and Behavioral Sciences Director, Pain Treatment Programs Johns Hopkins Medical Institutions Department of Psychiatry and Behavioral Sciences Baltimore, MD Geralyn Datz  PhD Affiliate University of Southern Mississippi Department of Psychology Clinical Director Southern Behavioral Medicine Associates Hattiesburg, MS

Srinivas Nalamachu  MD Clinical Assistant Professor Kansas University Medical Center Department of Rehabilitation Medicine Kansas City, KS President and Medical Director International Clinical Research Institute Overland Park, KS Bruce D. Nicholson  MD Clinical Associate Professor Department of Anesthesia Penn State College of Medicine Hershey Medical Center Hershey, PA Director of Pain Specialists Lehigh Valley Health Network Department of Anesthesiology Allentown, PA Marco Pappagallo  MD Director of Medical Intelligence Grünenthal USA Bedminster, NJ Director Pain Management & Medical Mentoring New Medical Home for Chronic Pain New York, NY

Robert W. Rothrock  PA -C, MPA University of Pennsylvania Department of Anesthesiology and Critical Care Pain Medicine Division Philadelphia, PA Michael E. Schatman  PhD, CPE, DASPE Executive Director Foundation for Ethics in Pain Care Bellevue, WA Sanford M. Silverman  MD, PA CEO and Medical Director Comprehensive Pain Medicine Pompano Beach, FL Thomas B. Strouse  MD Medical Director Stewart and Lynda Resnick Neuropsychiatric Hospital at UCLA Los Angeles, CA Kevin L. Zacharoff  MD, FACPE, FACIP, FAAP Faculty Clinical Instructor SUNY Stony Brook School of Medicine Stony Brook, NY Director of Medical Affairs Inflexxion Inc. Newton, MA

PWJ is published by Aventine Co. Copyright © 2014, Aventine Co.

The opinions stated in the enclosed printed materials are those of the authors and do not necessarily represent the opinions of Aventine or its publication staff. Aventine Co. does not give guarantees or any other representation that the printed material contained herein is valid, reliable, or accurate. Aventine Co. does not assume any responsibility for injury arising from any use or misuse of the printed materials contained herein. The printed materials contained herein are assumed to be from reliable sources, and there is no implication that they represent the only, or best, methodologies or procedures for the pain condition discussed. It is incumbent upon the reader to verify the accuracy of any diagnosis and drug dosage information contained herein, and to make modifications as new information arises. All rights are reserved by Aventine Co. to accept, reject, or modify any advertisement submitted for publication. It is the policy of Aventine Co. to not endorse products. Any advertising herein may not be construed as an endorsement, either expressed or implied, of a product or service.


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/ PWJ / Q3 / 2014 11 | GUEST EDITOR’S LETTER by sanford m. Silverman

FEATURES

IF 13 CLINICIANS CAN’T AGREE ON YOUR DIAGNOSIS…YOU’VE GOT A PROBLEM!

by gary w. Jay

18 | REGIONAL PAIN SYNDROMES

UPPER EXTREMITY PAIN SYNDROMES

by sri Nalamachu / rohit

38 | CLINICAL CONUNDRUM

Nalamasu

58 | NEUROLOGY

RESTLESS LEGS SYNDROMES

by victor Rosenfeld

22 | EXPERT OPINION

64 | PEDIATRIC PAIN MANAGEMENT

by michael r. Clark

by kevin l. Zacharoff

THE MADWOMAN IN THE ATTIC: pain and borderline personality disorder

30 | KEY TOPIC

PAIN&SUICIDE: a hidden epidemic

CHRONIC PAIN IN CHILDREN: are they a population at risk?

70 | PUNDIT PROFILE with steven d. Passik

by martin d. Cheatle

8 | PWJ | www.painweek.org

Q3  | 2014


When 1st-line laxative therapy isn’t enough for patients with advanced illness,*

OPIOID-INDUCED CONSTIPATION MAY NEED RELISTOR-INDUCED RELIEF. • Opioid-induced constipation (OIC) is unique and

often unresponsive to laxative therapy1 • RELISTOR® (methylnaltrexone bromide) targets the

underlying cause of OIC without affecting analgesia2 • In a single-dose study, most patients experienced a

BM within 4 hours of the first dose and ≥3 weekly BMs when dosed every other day in a multi-dose study2,3 • The most common adverse reactions in clinical

trials with RELISTOR were abdominal pain, flatulence, nausea, dizziness, diarrhea, and hyperhidrosis 2 For more information, go to RELISTOR.com.

Indication RELISTOR is indicated for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Use of RELISTOR beyond four months has not been studied.

Important Safety Information about RELISTOR RELISTOR® (methylnaltrexone bromide) Subcutaneous Injection is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. Cases of gastrointestinal (GI) perforation have been reported in adult patients with opioid-induced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract (i.e., cancer, peptic ulcer,

Ogilvie’s syndrome). Perforations have involved varying regions of the GI tract (e.g., stomach, duodenum, or colon). Use RELISTOR with caution in patients with known or suspected lesions of the GI tract. Advise patients to discontinue therapy with RELISTOR and promptly notify their physician if they develop severe, persistent, or worsening abdominal symptoms. If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician. Use of RELISTOR beyond four months has not been studied. Safety and efficacy of RELISTOR have not been established in pediatric patients. The most common adverse reactions reported with RELISTOR compared with placebo in

clinical trials were abdominal pain (28.5%), flatulence (13.3%), nausea (11.5%), dizziness (7.3%), diarrhea (5.5%), and hyperhidrosis (6.7%). *Can include cardiovascular diseases, cancer, and COPD.

References 1. Thomas JR, Cooney GA. Palliative care and pain: new strategies for managing opioid bowel dysfunction. J Palliat Med. 2008;11(suppl 1):S1-S19. 2. RELISTOR (prescribing information). Raleigh, NC: Salix Pharmaceuticals, Inc. 3. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med. 2008;358(22):2332-2343.

Please see Brief Summary of complete Prescribing Information on the adjacent page. www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 For additional information, call: 1-866-669-SLXP (7597) To report adverse events, call: 1-800-508-0024

©2014 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. REL39-0314


The rates of discontinuation due to adverse events during the double-blind, placebo-controlled clinical trials (Study 1 and Study 2) were comparable between RELISTOR (1.2%) and placebo (2.4%). The following is a brief summary only. See complete Prescribing Information on www.Relistor.com or request complete prescribing information by calling 1-800-508-0024. INDICATIONS AND USAGE RELISTOR is indicated for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Limitation of use: Use of RELISTOR beyond four months has not been studied in the advanced illness population. CONTRAINDICATIONS RELISTOR is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. WARNINGS AND PRECAUTIONS Gastrointestinal Perforation Cases of gastrointestinal (GI) perforation have been reported in adult patients with opioid-induced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract (i.e., cancer, peptic ulcer, Ogilvie’s syndrome). Perforations have involved varying regions of the GI tract (e.g., stomach, duodenum, or colon). Use RELISTOR with caution in patients with known or suspected lesions of the GI tract. Advise patients to discontinue therapy with RELISTOR and promptly notify their physician if they develop severe, persistent, or worsening abdominal symptoms. Severe or Persistent Diarrhea If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician. ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The majority of patients had a primary diagnosis of incurable cancer; other primary diagnoses included end-stage COPD/emphysema, cardiovascular disease/heart failure, Alzheimer’s disease/dementia, HIV/AIDS, or other advanced illnesses. Patients were receiving opioid therapy (median daily baseline oral morphine equivalent dose = 172 mg), and had opioid-induced constipation (either <3 bowel movements in the preceding week or no bowel movement for 2 days). Both the methylnaltrexone bromide and placebo patients were on a stable laxative regimen for at least 3 days prior to study entry and continued on their regimen throughout the study. The safety of RELISTOR was evaluated in two, double-blind, placebo-controlled trials in patients with advanced illness receiving palliative care: Study 1 included a single-dose, double-blind, placebo-controlled period, whereas Study 2 included a 14-day, multiple-dose, double-blind, placebocontrolled period. The most common adverse reactions (>5%) in patients receiving RELISTOR are shown in the table below. Adverse Reactions from all Doses in Double-Blind, PlaceboControlled Clinical Studies of RELISTOR in Adult Patients with Opioid-Induced Constipation and Advanced Illness*

Adverse Reaction

RELISTOR N = 165

Placebo N = 123

Abdominal Pain

47 (28.5%)

12 (9.8%)

Flatulence

22 (13.3%)

7 (5.7%)

Nausea

19 (11.5%)

6 (4.9%)

Dizziness

12 (7.3%)

3 (2.4%)

Diarrhea

9 (5.5%)

3 (2.4%)

Hyperhidrosis

11 (6.7%)

8 (6.5%)

* Doses: 0.075, 0.15, and 0.30 mg/kg/dose

Postmarketing Experience The following additional adverse events have been identified during post-approval use of RELISTOR. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to RELISTOR, or a combination of these factors. Gastrointestinal Perforation, cramping, vomiting General Disorders and Administrative Site Disorders Diaphoresis, flushing, malaise, pain. Cases of opioid withdrawal have been reported. DRUG INTERACTIONS Drugs Metabolized by Cytochrome P450 Isozymes In healthy subjects, a subcutaneous dose of 0.30 mg/kg of methylnaltrexone did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate. In vitro methylnaltrexone did not significantly inhibit or induce the activity of cytochrome P450 (CYP) isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP3A4. In vitro, methylnaltrexone did not induce the enzymatic activity of CYP2E1. Drugs Renally Excreted Methylnaltrexone is actively secreted in the kidney. The potential of drug interactions between methylnaltrexone bromide and other drugs that are inhibitors of transporters in the kidney has not been fully investigated. Cimetidine Cimetidine given 400 mg three times daily did not significantly affect the systemic exposure to methylnaltrexone. The effect of a higher cimetidine dose (e.g., 800 mg) on the systemic exposure of methylnaltrexone has not been evaluated. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B Reproduction studies have been performed in pregnant rats at intravenous doses up to about 14 times the recommended maximum human subcutaneous dose of 0.3 mg/kg based on the body surface area and in pregnant rabbits at intravenous doses up to about 17 times the recommended maximum human subcutaneous dose based on the body surface area and have revealed no evidence of impaired fertility or harm to the fetus due to methylnaltrexone bromide. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, methylnaltrexone bromide should be used during pregnancy only if clearly needed. Labor and Delivery Effects of RELISTOR on mother, fetus, duration of labor, and delivery are unknown. There were no effects on the mother, labor, delivery, or on offspring survival and growth in rats following subcutaneous injection of methylnaltrexone bromide at dosages up to 25 mg/kg/day. Nursing Mothers Results from an animal study using [ 3H]-labeled methylnaltrexone bromide indicate that methylnaltrexone bromide is excreted via the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RELISTOR is administered to a nursing woman. Pediatric Use Safety and effectiveness of RELISTOR have not been established in pediatric patients. Geriatric Use In the phase 2 and 3 double-blind studies, a total of 77 (24%) patients aged 65-74 years (54 methylnaltrexone bromide, 23 placebo) and a total of 100 (31.2%) patients aged 75 years or older (61 methylnaltrexone bromide, 39 placebo) were enrolled. Pharmacokinetics of methylnaltrexone was similar between the elderly (mean age 72 years old) and young adults (mean age 30 years old). No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has

not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on pharmacokinetic data, and safety and efficacy data from controlled clinical trials, no dose adjustment based on age is recommended. Renal Impairment No dose adjustment is required in patients with mild or moderate renal impairment. Dose reduction by one-half is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault). In a study of volunteers with varying degrees of renal impairment receiving a single dose of 0.30 mg/kg methylnaltrexone bromide, renal impairment had a marked effect on the renal excretion of methylnaltrexone bromide. Severe renal impairment decreased the renal clearance of methylnaltrexone bromide by 8- to 9-fold and resulted in a 2-fold increase in total methylnaltrexone bromide exposure (AUC). Cmax was not significantly changed. No studies were performed in patients with end-stage renal impairment requiring dialysis. Hepatic Impairment No dose adjustment is required for patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of methylnaltrexone has not been studied. Patient Counseling Instruct patients not to continue taking RELISTOR and to promptly notify their physician if they experience severe, persistent, or worsening abdominal symptoms because these could be symptoms of gastrointestinal perforation [see Warnings and Precautions]. Instruct patients not to continue taking RELISTOR if they experience severe or persistent diarrhea. Inform patients that common side effects of RELISTOR include abdominal pain, flatulence, nausea, dizziness, and diarrhea. Advise patients to be within close proximity to toilet facilities once the drug is administered. Instruct patients with opioid-induced constipation and advanced illness to administer one dose subcutaneously every other day, as needed, but no more frequently than one dose in a 24-hour period. Instruct patients to discontinue RELISTOR if they stop taking their opioid pain medication. Instruct patients to use the RELISTOR single-use vial with a 27 gauge x ½-inch needle and 1 mL syringe. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/ medwatch or call 1-800-FDA-1088. To report adverse events, a product complaint, or for additional information, call: 1-800-508-0024. Manufactured for:

Salix Pharmaceuticals, Inc. Raleigh, NC 27615 Under License from: Progenics Pharmaceuticals, Inc. Tarrytown, NY 10591 REL-RALAB6-062013


e

SANFORD M.

SiLV RMAN

manage their pain? Without proper screening, controlled substances may be the means with which they implement suicide.

MD

A s we prepare for the PAINWeek conference, I am pleased to author the guest editor’s letter for PWJ. In this issue, we are reminded of the complexity and interdisciplinary nature of chronic pain. The primary care physician, who often first evaluates these patients, may be confronted with a myriad of symptoms and findings, which can be vexing at the very least. Making a diagnosis can be extremely challenging. In fact, we are also reminded in this issue that there is frequently not a diagnosis, but several with regard to the chronic pain patient. With the ever-increasing demands of our medical practices, sometimes we find ourselves focused on one aspect of the history and physical examination, yet we may be missing the global picture. The view from 30,000 feet is much different than up close. Dr. Gary Jay expounds upon these views in his article If 13 Clinicians Can’t Agree on Your Diagnosis…You’ve Got a Problem! He follows the course of a patient who, prior to seeing him, was sent to multiple physicians. Dr. Jay eventually evaluated the patient and, by spending a little more time listening and observing, was able to make the diagnosis and treat her successfully after years of frustration and dismissal by several prominent physicians. Perhaps you’ve heard this from your own chronic pain patients: “You’re the only doctor who actually examined me.” We as pain physicians have to look at the entire patient and integrate multiple findings, whereas specialists may be too focused on one aspect and of course don’t have enough time. None of us have enough time. This article truly illustrates that chronic pain patients are often shunted through the healthcare system and often not taken seriously.

Dr. Michael Clark reintroduces us to the borderline personality. All of us have seen and dealt with this patient in our practice. Borderline personality disorder (BPD), essentially a disorder of interpersonal functioning, is an enormously difficult condition to treat. The patient may present with exceptionally complementary behavior, but when refused a request, may turn on the physician with extreme anger and disruptive behavior. Dr. Clark states that yielding to the demands of these patients simply reinforces this behavior and ultimately their BPD. The patient must be made to realize that treatment is a collaborative effort and that their painful condition can be managed only if there is a concomitant modification of their behavior. Dr. Nalamachu and his coauthor Rohit Nalamasu offer a summary of Upper Extremity Pain Syndromes. When a patient presents with upper extremity pain, the practitioner must be systematic in their diagnostic approach. From the spine to the fingers, careful evaluation will often yield the appropriate pain generator. Diagnostic testing and specific techniques in physical examination are presented and provide valuable information to the frontline pain practitioner. Dr. Victor Rosenfeld discusses a common disorder seen in approximately 15% of the population—Restless Legs Syndrome. This interesting and frequently problematic syndrome is often overlooked and discarded by physicians, yet the National Institutes of Health has developed specific criteria for it. Although there are no formal tests for RLS, other etiologies for neuropathic pain syndromes and neuropathies should be ruled out. Diagnosis and treatment of RLS are discussed, which is important since RLS may be associated with various other commonly encountered pain syndromes such as peripheral neuropathy, lumbar radiculopathy, and fibromyalgia. Dr. Kevin Zacharoff discusses chronic pain in children and their relative risk of aberrant drug related behaviors. The lack of education regarding pain assessment in children still plagues our medical community. One question we all need to address is, why do we treat children differently? Dr. Zacharoff points out that the nonmedical use of prescription opioids is quite real in adolescents and should be taken seriously. Although chronic pain patients as a whole are at significant risk for psychiatric disorders, substance use disorders, and even suicide, it appears that the adolescent population may be leading the way with respect to prescription drug misuse, which may be a direct result of the undertreatment and assessment of their pain.

Dr. Martin Cheatle discusses the relationship between pain and suicide. He presents well-known data with regard to prescription drug overdose and also points out that pain patients are uniquely at risk for We would like to thank all of our contributing authors to PWJ. These suicide. Patients with anxiety disorders have a greater than 50% rate articles once again emphasize the complexity of our patients and of concurrent substance use disorder, a fact repeatedly overlooked the difficulty that practitioners often face in making diagnoses and by many pain practitioners when prescribing controlled substances appropriate treatment plans. for pain. Dr. Cheatle emphasizes that risk stratification and mental health screening should be done in all chronic pain patients, and Chronic pain patients, and their comorbidities, should never be that pain duration, pain intensity, and catastrophic thinking are all underestimated. independent risk factors for suicide. Are pain physicians responsible for morbidity in this group of patients when we prescribe opioids to —SANFORD M. SILVERMAN MD Q3  | 2014

www.painweek.org  | PWJ | 11


Martin D. Cheatle PhD

P.30

Michael R. Clark MD, MPH, MBA

P.22

Gary W. Jay  MD, DAAPM, FAAPM

P.38

Sri Nalamachu MD

P.18

Victor Rosenfeld MD

P.58

Kevin L. Zacharoff MD, FACIP, FACPE, FAAP

P.64

Martin Cheatle is Director of the Pain and Chemical Dependency Program at the Center for Studies of Addiction, and Clinical Assistant Professor of Psychiatry, Perelman School of Medicine, at the University of Pennsylvania. Dr. Cheatle’s main focus of research is pain management and opioid abuse in vulnerable populations, such as HIV/ AIDS and psychiatric patients.

Michael Clark is Vice Chair of Clinical Affairs, Johns Hopkins University School of Medicine, the Director of the Adolf Meyer Chronic Pain Treatment Programs in the Department of Psychiatry and Behavioral Medicine and has joint appointments in the Departments of Otolaryngology-Head & Neck Surgery in the School of Medicine and of Mental Hygiene in the Bloomberg School of Hygiene and Public Health. Dr. Clark specializes in the care of patients with chronic medical illnesses. He is a member of the Blaustein Pain Treatment Center and the Vestibular & Balance Disorders Center at the Johns Hopkins Medical Institutions.

Gary Jay is Medical Director of DNA Center in Daytona Beach, Florida. During his first 25 years of clinical work, he served as a principal investigator, key opinion leader, and pharmaceutical industry advisor and consultant while he was seeing over 30,000 patients. Dr. Jay was one of the original 30 founding members of the American Academy of Algology, now the American Academy of Pain Medicine (AAPM ) in 1983, and helped develop the subspecialty of pain medicine. He was instrumental in establishing the AAPM and has spent a good part of his professional career working with and supporting this organization until PAINWeek was started. He is currently the President of the Eastern Pain Association.

Sri Nalamachu is President and Medical Director of the International Clinical Research Institute in Overland Park, Kansas. He is Clinical Assistant Professor at Kansas University Medical Center Department of Rehabilitation Medicine in Kansas City. Dr. Nalamachu coauthored his article with Rohit Nalamasu, MS, Touro University College of Osteopathic Medicine, Vallejo, California.

Victor Rosenfeld is board certified in neurology and sleep medicine. He is currently Neurology Department Head and Medical Director of the Sleep Center at SouthCoast Health in Savannah, Georgia. He received his medical degree from Emory University and completed internal medicine at Alton Oschner Medical Foundation, followed by a neurology residency at University of Miami where he was Chief Resident. Dr. Rosenfeld then completed a Fellowship in Electrophysiology at UCLA . He has served as Chairman, Department of Neurology and Neurosurgery, and Medical Director, Neurophysiology, at Cottage Hospital as well as Medical Director, Sleepmed, Santa Barbara.

Kevin Zacharoff is a board certified anesthesiologist with over 25 years of clinical experience in anesthesiology and pain medicine. He is a Fellow of the American Academy of Pediatrics, and a faculty member and Clinical Instructor at the SUNY Stony Brook School of Medicine, Department of Preventive Medicine in New York. He is the Vice President of Medical Affairs at Inflexxion Inc. in Newton, Massachusetts, a member of the board of directors of the American Society of Pain Educators, and the Medical Director of the pain education programs, Pain EDU.org and pain ACTION.com. Dr. Zacharoff has been a faculty member and presented at PAINWeek since 2007.

12 | PWJ | www.painweek.org

Q3  | 2014


NOW APPROVED


NOW APPROVED The onset you expect. The duration they deserve. XARTEMISTM XR is the first and only FDA-approved oxycodone/acetaminophen combination to provide immediate- and extended-release analgesia.1

INDICATIONS AND USAGE XARTEMIS XR (oxycodone HCl and acetaminophen) Extended-Release Tablets (CII) is indicated for the management of acute pain severe enough to require opioid treatment and for which alternative treatment options are inadequate. Because of the risks of addiction, abuse, misuse, overdose, and death with opioids, even at recommended doses, reserve XARTEMIS XR for use in patients for whom alternative treatment options (e.g., non-opioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate.

NEW


XARTEMIS™ XR (oxycodone HCl and acetaminophen) Extended-Release Tablets (CII)

The onset you expect. The duration they deserve. XARTEMIS™ XR is the first and only FDA-approved oxycodone/acetaminophen combination to provide immediate- and extended-release analgesia.1 Delivers onset of pain relief in less than an hour and lasts up to 12 hours.1,2 •

In the clinical trial, supplemental analgesia was available to patients in the XARTEMIS XR and placebo groups.

Supplemental ibuprofen was used by less than 50% of the XARTEMIS XR-treated patients after the first dose interval.

NEW

Dosed as 2 tablets, twice a day.1 •

On the first day of treatment, an additional dose may be taken at 8 hours after initial dose if pain intensity requires it.

Visit xartemisxr.com/pwj

to discover a new approach to managing acute pain.

IMPORTANT RISK INFORMATION WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and HEPATOTOXICITY See full prescribing information for complete boxed warning. •

XARTEMIS XR exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions.

Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow tablets whole to avoid exposure to a potentially fatal dose of oxycodone.

Accidental consumption of XARTEMIS XR, especially in children, can result in fatal overdose of oxycodone.

Prolonged use of XARTEMIS XR during pregnancy can result in neonatal opioid withdrawal syndrome, which may be lifethreatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

XARTEMIS XR contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the maximum daily limit, and often involve more than one acetaminophen-containing product.

CONTRAINDICATIONS •

ADVERSE REACTIONS

XARTEMIS XR is contraindicated in patients with:

- known hypersensitivity to oxycodone, acetaminophen, or any other component of this product.

Serious adverse events may include respiratory depression and hepatotoxicity.

Common adverse events may include nausea, dizziness, headache, vomiting, constipation and somnolence.

- significant respiratory depression. - acute or severe bronchial asthma or hypercarbia. - known or suspected paralytic ileus.

See Brief Summary of Full Prescribing Information on the following pages. For additional Important Risk Information, including full boxed warning, visit xartemisxr.com. References: 1. XARTEMIS XR [package insert]. Hazelwood, MO: Mallinckrodt Brand Pharmaceuticals, Inc; 2014. 2. Singla N, Barrett T, Sisk L, Kostenbader K, Young J, Giuliani M. A randomized, double-blind, placebo-controlled study of the efficacy and safety of MNK-795, a dual-layer, biphasic, immediate-release and extended-release combination analgesic for acute pain. Curr Med Res Opin. 2014;30(3):349-359.

Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. © 2014 Mallinckrodt. March 2014


BRIEF SUMMARY - Consult full prescribing information before use.

XARTEMIS XR (oxycodone hydrochloride and acetaminophen) Extended-Release Tablets, for oral use, CII Initial U.S. Approval: 1976 WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and HEPATOTOXICITY Addiction, Abuse, and Misuse XARTEMIS XR exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing XARTEMIS XR, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)]. Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of XARTEMIS XR. Monitor for respiratory depression, especially during initiation of XARTEMIS XR or following a dose increase. Instruct patients to swallow XARTEMIS XR tablets whole; crushing, chewing, or dissolving XARTEMIS XR can cause rapid release and absorption of a potentially fatal dose of oxycodone [see Warnings and Precautions (5.2)]. Accidental Exposure Accidental ingestion of XARTEMIS XR, especially in children, can result in a fatal overdose of oxycodone [see Warnings and Precautions (5.2)]. Neonatal Opioid Withdrawal Syndrome Prolonged use of XARTEMIS XR during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)]. Hepatotoxicity XARTEMIS XR contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the maximum daily limit, and often involve more than one acetaminophen-containing product [see Warnings and Precautions (5.7, 5.11)]. CONTRAINDICATIONS XARTEMIS XR tablets are contraindicated in patients with • Known hypersensitivity to oxycodone, acetaminophen, or any other component of this product [see Warnings and Precautions (5.12)]. • Significant respiratory depression • Acute or severe bronchial asthma or hypercarbia • Known or suspected paralytic ileus WARNINGS AND PRECAUTIONS XARTEMIS XR is not interchangeable with other oxycodone/ acetaminophen products because of differing pharmacokinetic profiles that affect the frequency of administration. Addiction, Abuse, and Misuse XARTEMIS XR contains oxycodone, a Schedule II controlled substance. As an opioid, XARTEMIS XR exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed XARTEMIS XR and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing XARTEMIS XR, and monitor all patients receiving XARTEMIS XR for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of XARTEMIS XR for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as XARTEMIS XR, but use in such patients necessitates intensive counseling about the risks and proper use of XARTEMIS XR along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of XARTEMIS XR by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the oxycodone and can result in overdose and death [see Overdosage (10)]. Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of XARTEMIS XR, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with XARTEMIS XR and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of XARTEMIS XR are essential [see Dosage and Administration (2)]. Overestimating the XARTEMIS XR dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental consumption of XARTEMIS XR, especially by children, can result in respiratory depression and death due to an overdose of oxycodone.

Neonatal Opioid Withdrawal Syndrome Prolonged use of XARTEMIS XR during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Interactions with Central Nervous System Depressants Hypotension, profound sedation, coma, respiratory depression, and death may result if XARTEMIS XR is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of XARTEMIS XR in a patient taking a CNS depressant, assess the duration use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin XARTEMIS XR is made, start with XARTEMIS XR 1 tablet every 12 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.1)]. Elderly, Cachectic, and Debilitated Patients Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating XARTEMIS XR and when XARTEMIS XR is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)]. Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression for respiratory depression, particularly when initiating therapy and titrating with XARTEMIS XR, as in these patients, even usual therapeutic doses of XARTEMIS XR may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in these patients if possible. Hepatotoxicity XARTEMIS XR contains oxycodone and acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products. The typical daily acetaminophen contribution from XARTEMIS XR is 1300 mg. The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well. Serious Skin Reactions Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Inform patients about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Head Injury and Increased Intracranial Pressure The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries. Hypotensive Effect Oxycodone may cause severe hypotension particularly in individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs which compromise vasomotor tone such as phenothiazines. Administer XARTEMIS XR with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. XARTEMIS XR may produce orthostatic hypotension in ambulatory patients [see Drug Interactions (7.1)]. Use With Other Acetaminophen-containing Products The typical daily acetaminophen-contribution from XARTEMIS XR is 1300 mg. Due to the potential for acetaminophen hepatotoxicity at doses higher than 4000 milligrams/day, XARTEMIS XR should not be used concomitantly with other acetaminophen-containing products. Hypersensitivity/Anaphylaxis There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue XARTEMIS XR immediately and seek medical care if they experience these symptoms. Do not prescribe XARTEMIS XR for patients with acetaminophen allergy.

Difficulty Swallowing Due to characteristics of the formulation that cause the tablets to swell and become sticky when wet, consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying GI disorders resulting in a small gastrointestinal lumen. Instruct patients not to pre-soak, lick or otherwise wet XARTEMIS XR tablets prior to placing in the mouth, and to take one tablet at a time with enough water to ensure complete swallowing immediately after placing in mouth. Gastrointestinal Effects XARTEMIS XR is contraindicated in patients with known or suspected paralytic ileus. Opioids diminish propulsive peristaltic waves in the gastrointestinal tract and decrease bowel motility. Monitor for decreased bowel motility in postoperative patients receiving opioids. The administration of XARTEMIS XR may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Oxycodone may cause spasm of the Sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis. Cytochrome P450 3A4 Inhibitors and Inducers Since the CYP3A4 isoenzyme plays a major role in the metabolism of XARTEMIS XR, drugs that alter CYP3A4 activity may cause changes in clearance of oxycodone which could lead to changes in oxycodone plasma concentrations. Inhibition of CYP3A4 activity by its inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid effects. These effects could be more pronounced with concomitant use of CYP 2D6 and 3A4 inhibitors. Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism of oxycodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in oxycodone plasma concentrations, resulting in a potential lack of efficacy. If co-administration is necessary, caution is advised when initiating XARTEMIS XR treatment in patients currently taking, or discontinuing CYP3A4 inhibitors or inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Drug Interactions (7.4)]. Driving and Operating Machinery XARTEMIS XR may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly. ADVERSE REACTIONS The following treatment-emergent adverse reactions are discussed in more detail in other sections of the labeling: • Respiratory Depression [see Contraindications (4), Warnings and Precautions (5.2), and Overdosage (10)] • Hepatotoxicity [see Warnings and Precautions (5.7)] • Use With Other Acetaminophen-containing Products [see Warnings and Precautions (5.11)] • Interactions with Other CNS Depressants [see Warnings and Precautions (5.4)] Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. In safety data from two Phase 3 (one placebo-controlled, one open-label) trials where multiple doses of XARTEMIS XR were administered for up to 42 days, the most common adverse reactions (reported by ≥10% in any XARTEMIS XR dose group) were: nausea, dizziness and vomiting. The most common reasons for discontinuation due to AEs in these 2 studies (reported by ≥1% in any XARTEMIS XR dose group) were vomiting (4.8%) and nausea (4.1%); there were no reports of these adverse reactions in the placebo-treated patients. A total of 1028 subjects in 14 clinical studies were treated with XARTEMIS XR during the clinical development program, including 892 subjects treated with 15 mg oxycodone and 650 mg acetaminophen. This dosage regimen of XARTEMIS XR was administered to 607 patients in two Phase 3 studies (one placebo-controlled and one open-label). In a placebo-controlled post-bunionectomy acute pain trial, 329 patients were dosed with 15 mg oxycodone and 650 mg acetaminophen XARTEMIS XR or placebo orally every 12 hours, for approximately 48 hours (blinded period) [see Clinical Studies (14)]. Table 1 lists the adverse reactions reported by ≥1% of XARTEMIS XR-treated patients and more frequently in XARTEMIS XR-treated patients compared with placebo. Table 1. Treatment-Emergent Adverse Reactions* Reported by ≥1% of XARTEMIS XR-Treated Patients and More Frequently than Placebo in XARTEMIS XR-Treated Patients with Postoperative Bunionectomy Pain (blinded period) Preferred Term

Nausea Dizziness Headache Vomiting Constipation Somnolence Rash Blister Dysuria Edema peripheral Erythema Excoriation Hot flush Pruritus generalized

XARTEMIS XR (N = 166) % 31 13 10 9 4 4 2 1 1 1 1 1 1 1

Placebo (N = 163) % 6 1 5 0 3 <1 1 <1 0 0 0 0 <1 0

* A treatment-emergent adverse reaction refers to any untoward medical event associated with the use of the drug in humans, whether or not considered drug-related.

Other Adverse Reactions Observed During the Premarketing Evaluation of XARTEMIS XR The following adverse drug reactions not listed above occurred in ≥1% of XARTEMIS XR-treated patients in the pooled safety data from two Phase 3 studies (including a placebocontrolled and an open-label non-controlled safety study) where multiple-doses of XARTEMIS XR were administered every 12 hours for up to 42 days: Gastrointestinal disorders: dry mouth, dyspepsia, diarrhea General disorders and administration site conditions: fatigue Investigations: hepatic enzyme increased Psychiatric disorders: insomnia Respiratory, thoracic and mediastinal disorders: cough The following adverse drug reactions occurred in <1% of XARTEMIS XR-treated patients in the pooled safety data from the two Phase 3 studies described above: Cardiac disorders: palpitations Eye and ear disorders: tinnitus, vision blurred Gastrointestinal disorders: abdominal discomfort, abdominal pain, esophageal spasm General disorders and administration site conditions: asthenia, chest discomfort, chills, contusion, fall, feeling jittery, malaise, non-cardiac chest pain, thirst Immune system disorders: hypersensitivity Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood lactate dehydrogenase increased, blood pressure increased, gammaglutamyltransferase increased, liver functional test abnormal Metabolic and nutritional: decreased appetite Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal stiffness Nervous system disorders: cognitive disorder, memory impairment, migraine, myoclonus, paraesthesia, sedation, tremor Psychiatric disorders: anxiety, confusional state, disorientation, euphoric mood, mood altered, sleep disorder, withdrawal syndrome Renal and urinary disorders: urine flow decreased Respiratory, thoracic and mediastinal disorders: dyspnea, hiccups, hypopnea, oropharyngeal pain, throat irritation Skin and subcutaneous tissue disorders: dermatitis, ecchymosis, hyperhidrosis, urticaria Vascular disorders: flushing, hypertension DRUG INTERACTIONS CNS Depressants The concomitant use of XARTEMIS XR with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and XARTEMIS XR for signs of respiratory depression, sedation and hypotension. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)]. Neuromuscular Blocking Agents Oxycodone, as well as other opioid analgesics, may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monoamine Oxidase Inhibitors Monoamine Oxidase Inhibitors (MAOIs) have been reported to intensify the effects of at least one opioid drug causing anxiety, confusion, and significant depression of respiration or coma. The use of XARTEMIS XR is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Agents Affecting Cytochrome P450 Enzymes CYP3A4 Inhibitors Because the CYP3A4 isoenzyme plays a major role in the metabolism of oxycodone, drugs that inhibit CYP3A4 activity may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations and result in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of CYP2D6 and 3A4 inhibitors. If co-administration with XARTEMIS XR is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)]. CYP3A4 Inducers CYP450 3A4 inducers may induce the metabolism of oxycodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in oxycodone plasma concentrations, lack of efficacy or, possibly, development of a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. If co-administration with XARTEMIS XR is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)]. CYP2D6 Inhibitors Oxycodone is metabolized in part to oxymorphone via the Cytochrome P450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs, including amiodarone and quinidine, and antidepressants), such blockade has not yet been shown to be of clinical significance with this agent. However, clinicians should be aware of this possible interaction [see Clinical Pharmacology (12.3)]. Mixed Agonist/Antagonist Opioid Analgesics Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) should be administered with caution to patients who have received or are receiving a course of therapy with an opioid agonist analgesic such as XARTEMIS XR. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of XARTEMIS XR and/or may precipitate withdrawal symptoms in these patients.

See Brief Summary of Full Prescribing Information continued on adjacent page.


Anticholinergics Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of XARTEMIS XR tablets or oxycodone/acetaminophen in pregnant women. Epidemiological data on oral acetaminophen use in pregnant women show no increased risk of major congenital malformations. The incidence of malformations in human pregnancies has not been established for oxycodone as the data are limited. All pregnancies, regardless of drug exposure, have a background risk of 2 to 4% for major birth defects, and 15 to 20% for pregnancy loss. No animal reproductive or developmental studies were conducted with the combination of oxycodone and acetaminophen, the components of XARTEMIS XR. The following data are based on findings from studies performed with the individual components. Reproductive and developmental studies in rats and mice from the published literature identified adverse events at clinically relevant doses with acetaminophen. Treatment of pregnant rats with doses of acetaminophen approximately equal to the maximum human daily dose (MHDD) showed evidence of fetotoxicity and increases in bone variations in the fetuses. In another study, necrosis was observed in the liver and kidney of both pregnant rats and fetuses at doses approximately equal to the MHDD. In mice treated with acetaminophen at doses within the clinical dosing range, a reduction in number of litters of the parental mating pair was observed as well as retarded growth and abnormal sperm in their offspring and reduced birth weight in the next generation. Reproductive studies in rats and rabbits with doses of oxycodone greater than clinical doses did not show any teratogenic or embryo-fetal toxic effects. XARTEMIS XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged maternal use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see Warnings and Precautions (5.3)]. Labor and Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. XARTEMIS XR is not recommended for use in women during or immediately prior to labor. Neonates, whose mothers received opioid analgesics during labor, must be observed closely for signs of respiratory depression. An opioid antagonist such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Data Human Data Two large population based studies have evaluated the safety of acetaminophen in pregnant women during the first trimester; neither study showed an increased risk of congenital malformations. Available published data on oxycodone exposure during pregnancy and risk for malformations are limited and do not allow conclusions regarding a possible association. Animal Data No reproductive or developmental studies were conducted with the combination of oxycodone and acetaminophen, the components of XARTEMIS XR. The following data are based on findings from studies performed with the individual components. Studies in pregnant rats that received oral acetaminophen during organogenesis at doses up to 0.85 times the maximum human daily dose (MHDD = 4 grams/day, based on a body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations (reduced ossification and rudimentary rib changes). Offspring had no evidence of external, visceral, or skeletal malformations. When pregnant rats received oral acetaminophen throughout gestation at doses of 1.2-times the MHDD (based on a body surface area comparison), areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses. These effects did not occur in animals that received oral acetaminophen at doses 0.3-times the MHDD, based on a body surface area comparison. In a continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the diet (357, 715, or 1430 mg/kg/day). These doses are approximately 0.43, 0.87, and 1.7 times the MHDD, respectively, based on a body surface area comparison. A dose-related reduction in body weights of fourth and fifth litter offspring of the treated mating pair occurred during lactation and post-weaning at all doses. Animals in the high dose group had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next generation pups. Reproduction studies in Sprague-Dawley rats and New Zealand rabbits revealed that when oxycodone was administered orally at doses up to 16 mg/kg (approximately 2 times the daily oral dose of 90 mg for adults based on a body surface area comparison) and 25 mg/kg (approximately 5 times the daily oral dose of 90 mg based on body surface area comparison), it was non teratogenic or embryo-fetal toxic. Nursing Mothers Oxycodone is present in human milk and may result in accumulation and toxicities such as sedation and respiratory depression in some infants. Acetaminophen is present in human milk in small quantities. Based on data from more than 15 nursing mothers, the calculated infant daily dose of acetaminophen is approximately 1 to 2% of the maternal dose. There is one well-documented report of a rash in a breast-fed infant that resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen use.

Because of the potential for serious adverse reactions in nursing infants from XARTEMIS XR, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XARTEMIS XR in pediatric patients under the age of 18 years have not been established. Geriatric Use Of the 607 subjects in the Phase 3 studies treated with XARTEMIS XR, 63 (10.3%) were older than age 65, of which 10 (1.6%) were older than age 75. No untoward or unexpected adverse reactions were seen in the elderly patients who received oxycodone hydrochloride/acetaminophen extendedrelease tablets. However, special precaution should be given when determining the dosing amount and frequency of XARTEMIS XR for geriatric patients, since a greater sensitivity to oxycodone may be observed in this patient population when compared to younger patients. Hepatic Impairment XARTEMIS XR contains oxycodone and acetaminophen, which are extensively metabolized in the liver. Their clearance may be decreased in patients with hepatic impairment. In patients with hepatic impairment start with one tablet and adjust the dosage as needed. Monitor closely for respiratory depression [see Clinical Pharmacology (12.3)]. Renal Impairment Information from oxycodone HCl indicates that patients with renal impairment (defined as a creatinine clearance <60 mL/min) had higher plasma concentrations of oxycodone than subjects with normal renal function. In patients with renal impairment start with one tablet and adjust the dosage as needed. Monitor closely for respiratory depression [see Clinical Pharmacology (12.3)]. DRUG ABUSE AND DEPENDENCE Controlled Substance XARTEMIS XR contains oxycodone, a mu-opioid agonist of the morphine type and is a Schedule II controlled substance. XARTEMIS XR is subject to misuse, abuse, addiction and criminal diversion [see Warnings and Precautions (5.1)]. Abuse All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Drug abuse is the intentional non-therapeutic use of an overthe-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get “high,” or the use of steroids for performance enhancement and muscle build-up. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common in persons with substance abuse disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of true addiction. XARTEMIS XR, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to the Abuse of XARTEMIS XR XARTEMIS XR is intended for oral use only. Abuse of XARTEMIS XR poses a risk of overdose and death. Abuse may occur by taking intact tablets in quantities greater than prescribed or without legitimate purpose, by crushing and chewing, or snorting the crushed formulation, or by injecting a solution made from the crushed formulation. The risk of overdose and death is increased with concurrent abuse of alcohol or other central nervous system depressants. With intravenous abuse, the inactive ingredients in XARTEMIS XR can result in death, local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Dependence Patients may exhibit tolerance to some of the effects of oxycodone. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In patients suspected of having significant physical dependence, withdrawal symptoms may be reduced by tapering therapy. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1, 8.2)]. OVERDOSAGE Signs and Symptoms Following an acute overdosage, toxicity may result from the oxycodone or the acetaminophen. Oxycodone Acute overdosage with opioids is often characterized by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, sometimes, pulmonary edema, bradycardia, hypotension, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations [see Clinical Pharmacology (12.2)]. Acetaminophen In acetaminophen overdosage, dose-dependent potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. Treatment A single or multiple drug overdose with oxycodone and acetaminophen is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended. Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Oxygen, intravenous fluids, vasopressors, assisted ventilation, and other supportive measures should be employed as indicated. Oxycodone Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The opioid antagonist naloxone hydrochloride is a specific antidote against respiratory depression which may result from overdose or unusual sensitivity to opioids, including oxycodone. Since the duration of action of oxycodone may exceed that of the antagonist, the patient should be kept under continued surveillance, and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression. Administer opioid antagonists cautiously to persons who are known, or suspected to be, physically dependent on XARTEMIS XR. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. In an individual physically dependent on opioids, administration of the usual dose of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the agonist should be begun with care and by titration with smaller than usual doses of the agonist. Acetaminophen Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration. Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dosedependent and occurs early in the course of intoxication.

Inform patients not to adjust the dose of XARTEMIS XR without consulting with a physician or other healthcare professional. Inform patients not to not take more than 4000 milligrams of acetaminophen per day and to call their doctor if they took more than the recommended dose. Addiction, Abuse, and Misuse Inform patients that the use of XARTEMIS XR , even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see Warnings and Precautions (5.1)]. Instruct patients not to share XARTEMIS XR with others and to take steps to protect XARTEMIS XR from theft or misuse. Life-threatening Respiratory Depression Inform patients of the risk of life-threatening of respiratory depression, including information that the risk is greatest when starting XARTEMIS XR or when the dose is increased, and that it can occur even at recommended doses [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Consumption Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store XARTEMIS XR securely and to dispose of unused XARTEMIS XR by flushing the tablets down the toilet. Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of XARTEMIS XR during pregnancy can result in neonatal opioid withdrawal syndrome, which may be lifethreatening if not recognized and treated [see Warnings and Precautions (5.3)]. Interactions with Alcohol and other CNS Depressants Inform patients that potentially serious additive effects may occur if XARTEMIS XR is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a health care provider. Impairment of Mental or Physical Ability Inform patients that XARTEMIS XR may cause drowsiness, dizziness, or lightheadedness and may impair mental and/ or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery). Advise patients started on XARTEMIS XR or patients whose dose has been adjusted to refrain from any potentially dangerous activity until it is established that they are not adversely affected. Use During Pregnancy Instruct females of reproductive potential who become or are planning to become pregnant to consult a physician prior to initiating or continuing therapy with XARTEMIS XR. Advise patients that safe use in pregnancy has not been established. Information Regarding Nursing Advise women to not breastfeed as breastfeeding may cause sedation in the infant. Cessation of Therapy If patients have been receiving treatment with XARTEMIS XR for more than a few weeks and cessation of therapy is indicated, counsel them on the possibility of withdrawal and provide medical support for safe discontinuation of the product. Common Side Effects Advise patients taking XARTEMIS XR of the potential for severe constipation; appropriate laxatives and/or stool softeners as well as other appropriate treatments should be initiated from the onset of opioid therapy. Advise patients of the most common adverse reactions that may occur while taking XARTEMIS XR: nausea, dizziness, headache, vomiting, constipation and somnolence. XARTEMIS is a trademark of Mallinckrodt LLC. Mallinckrodt, the “M” brand mark, and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company. © 2014 Mallinckrodt LLC Issue: 03/2014 Manufactured for: Mallinckrodt Brand Pharmaceuticals, Inc. Hazelwood, MO 63042

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) Provide the following information to patients receiving XARTEMIS XR or their caregivers: Proper Administration Inform patients that XARTEMIS XR is not interchangeable with other forms of oxycodone/acetaminophen. Inform patients XARTEMIS XR is a narcotic pain reliever and must be taken only as directed. Inform patients to take each tablet with enough water to ensure complete swallowing immediately after placing in the mouth, and not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth. Inform patients that XARTEMIS XR tablets must be swallowed whole. Do not crush or dissolve. Do not use XARTEMIS XR for administration via nasogastric, gastric, or other feeding tubes as it may cause obstruction of feeding tubes. Inform patients that if they miss a dose to take it as soon as possible. If it is almost time for the next dose, skip the missed dose and take the next dose at the regularly scheduled time. Do not take more than 2 tablets at once unless instructed by their healthcare provider. If they are not sure about their dosing, call their healthcare provider.

For additional Important Risk Information, including full boxed warning, visit xartemisxr.com.


SRI NALAMACHU MD/ROHIT NALAMASU MS

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R GiONAL PAIN SYNDROM S

Upper Extremity Pain Syndromes: Tests

Adson’s test: The patient is examined standing. The examiner palpates the radial pulse while moving the upper extremity in abduction, extension, and external rotation. The patient rotates his head towards the involved side while taking a deep breath and holding it. A diminished or absent radial pulse = a positive test for thoracic outlet syndrome. Finkelstein’s test: The thumb is folded across the palm with the fingers flexed over the thumb as the hand is pulled away from the involved wrist area. Pain = a positive test for De Quervain’s tenosynovitis. Phalen’s test: The patient flexes both wrists together, and the examiner holds the wrists in this position for at least a minute. Numbness or parasthesia in the median nerve distribution = a positive test for carpal tunnel syndrome. Tinel’s test: The examiner taps over the carpal tunnel. Tingling or parasthesia distal to the site of pressure = a positive test for carpal tunnel syndrome.

abstract: “Upper extremity” is defined as the extension of the body from shoulder to the digits and includes the digits, arm, forearm, hand, as well as shoulder, elbow, wrist, and metacarpophalangeal and carpometacarpal joints. Upper extremity is ideally designed for motion, not to carry heavy loads. Technological advancements have shown us a significant increase in upper extremity pain syndromes with repetitive motion. We describe in this article some of the most common pain syndromes seen in orthopedic, sports, and occupational medicine as well as in primary care clinics. This is a brief overview of the diagnosis and treatment of these syndromes in an outpatient setting; we recommend readers refer to orthopedic and sports medicine literature for further reading.

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CARPAL TUNN L SYNDROM

D QU RVAiN’S T NOSYNOViTiS

Etiology: Carpal tunnel syndrome (CTS) is the entrapment of the median nerve at the wrist, which results in paresthesia of the lateral 3-and-a-half fingers. It can present with moderately severe pain, but paresthesia is the hallmark for diagnosis. One of the common complaints of patients with carpal tunnel is clumsiness. Recent years have seen a rise in incidence rates due to the increase in computer and mobile technology usage.

Etiology: De Quervain’s tenosynovitis is inflammation of the extensor pollicis brevis and the abductor pollicis longus tendons on the side of the wrist at the base of the thumb. It is typically caused by heavy lifting. Diagnosis: De Quervain’s tenosynovitis causes pain and tenderness at the site of the wrist beneath the base of the thumb, with occasional slight swelling and redness in the area. Diagnosis is purely based on the location of pain, and the tenderness of the affected wrist. A positive Finkelstein’s test suggests De Quervain’s tenosynovitis.

Diagnosis: Pain and paresthesia in the lateral 3 to 4 fingers is the common clinical presentation, with the pinky spared. Symptoms usually get worse at night. Physical exam usually reveals a positive Phalen’s test and Tinel’s test at the wrist. Phalen’s test has a higher sensitivity and specificity than Tinel’s test, which has a moderate sensitivity and specificity for CTS. Nerve conduction studies can also be used for diagnosis of CTS, with varying sensitivity for motor vs sensory nerve testing.

CUBiTAL TUNN L SYNDROM

Treatment: Mild CTS can be treated with ergonomic changes, splinting, and symptomatic treatment using oral NSAIDs, topical NSAIDs, and topical local anesthetics. Moderate CTS may respond to cortisone injections, while surgical release is usually reserved for moderately severe to severe CTS.

Etiology: Cubital tunnel syndrome is caused by ulnar nerve entrapment at the elbow resulting from increased pressure usually secondary to leaning on the elbow or sleeping on the elbow. The ulnar nerve lies directly under the skin, near the medial epicondyle, and is easily susceptible to pressure.

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Treatment: Treatment involves a combination of rest, splinting, ice, NSAIDs, and/or cortisone injections. Injections are extremely effective, and surgery is rarely necessary.

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REGIONAL PAIN SYNDROMES

Diagnosis: Symptoms include pain and paresthesia in the medial 1-and-a-half fingers. Atrophy of intrinsic muscles is noticed in the advanced stages. Treatment: Avoiding pressure on the nerve at the elbow, along with wearing an elbow pad, will help in cases with minimal entrapment. Symptomatic treatment includes the use of topical NSAIDs; topical anesthetic patches may also be of value. Moderate cases may respond to cortisone injections, but severe cases will require surgical intervention with ulnar nerve transposition.

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PiCONDYLiTiS ●  Lateral Epicondylitis Etiology: Lateral epicondylitis, also known as tennis elbow, is a painful condition involving the extensor muscles of the elbow, primarily the extensor carpi radialis brevis. Extensor tendons attach to the lateral part of the elbow and help extend the elbow and stabilize the wrist. Degeneration of the tendon attachment places greater stress on the area, leading to pain with activities where the extensors are active; for example, lifting, gripping, and/or grasping. Tennis and similar sports are commonly associated with this, but the problem can occur with many different types of activities, athletic or otherwise. Trauma can also cause lateral epicondylitis, often resulting in degeneration and pain. ●  Medial Epicondylitis Etiology: Medial epicondylitis, also known as golf elbow, is an overuse injury affecting the flexor-pronator muscle origin at the anterior medial epicondyle of the humerus. Repetitive stress at the musclotendinous junction and its origin at the medial epicondyle lead to tendonitis. Medial epicondylitis is less frequent compared to lateral epicondylitis. Diagnosis (Lateral/Medial): Diagnosis is based purely on physical examination, but imaging and electrodiagnostic tests can help rule out other causes of pain. Treatment (Lateral/Medial): Conservative treatment involves NSAIDs, activity modification, bracing, shock wave, and physical therapy. Those refractory to conservative treatment require cortisone and PRP (platelet-rich plasma) injections. There are small scale studies showing positive results with botulinum toxin injections into the muscles. More severe cases may require surgical intervention—removing degenerated tissue and reattaching healthy muscle to the bone.

swimming, and tennis. It can also be caused by overuse of the rotator cuff tendons of the shoulder: supraspinatus, infraspinatus, teres minor, and subscapularis, also referred to as the SITS muscles. Other common causes of rotator cuff syndrome include trauma, shoulder instability, impingement of the rotator cuff tendons, and abnormally shaped acromion. Rotator cuff syndrome is uncommon in children, teenagers, and women, and affects around 5% to 10% of the population at some point in their life. Diagnosis: Common clinical features of rotator cuff syndrome include weak and painful abduction (during 70 to 120 degrees), weak forward flexion, and anterolateral shoulder pain. Rotator cuff syndrome is, however, very difficult to distinguish from other shoulder pain causes like calcific tendinitis and subacromial bursitis. MRI of the shoulder is recommended prior to considering surgical options. Treatment: Mild rotator cuff syndrome can be treated with relative rest and rehabilitation involving the rotator cuff, periscapular, and trunk muscles. As it progresses to moderate levels, however, the use of corticosteroid injections to the subacromial space may be advised. Surgery is only suggested for refractory cases as well as severe rotator cuff tears. A tear of the rotator cuff should be a concern if the patient cannot abduct the arm or if there is significant pain.

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THORACiC OUTL T SYNDROM

Etiology: Thoracic outlet syndrome encompasses a group of disorders affecting the brachial plexus and blood vessels in the thoracic outlet, between the clavicle and the first rib. Compression of these structures leads to numbness in the fingers as well as shoulder and neck pain. Common causes of thoracic outlet syndrome include trauma, job- or sports-related repetitive injuries; anatomical abnormalities such as an extra rib; and pregnancy. It is generally classified into neurogenic vs vascular based on the symptomatology and the involvement of nerves vs blood vessels, respectively. The disease is more often seen in women, and is aggravated by poor posture and obesity. Diagnosis: Adson’s test is used to assess for the presence of thoracic outlet syndrome at the scalene triangle. Other diagnostic tests include X-rays to look for an extra rib. CT scans, MRIs, diagnostic ultrasound, and nerve conduction studies may be of diagnostic value. Treatment: Thoracic outlet syndrome is treated with physical therapy and NSAIDs for symptomatic treatment. Weight loss and lifestyle changes are recommended. Surgery is reserved for severe cases.

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ROTATOR CUFF SYNDROM

Etiology: Rotator cuff syndrome is a spectrum of disorders commonly referred to as shoulder impingement syndrome, painful arc syndrome, supraspinatus syndrome, etc. It is commonly caused by repetitive overhead activities including sports such as basketball,

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“No, I said ‘Mu’.” Opioids play an important role in chronic pain relief by binding to mu-receptors in the brain and blocking pain signals.1 But they also bind to mu-receptors in the bowel. That’s why patients taking opioids for chronic pain can develop opioid-induced constipation (OIC). The incidence of OIC varies and has been reported as high as 81%.* To start the OIC conversation, call 1-800-601-9063 and request an educational poster for your office.

Opioid-Induced Constipation is µ-nique *Published estimates of the incidence of OIC in patients receiving opioids for chronic pain vary due to differences in the studies conducted (eg, study design, definition of constipation, opioids used). Meta-analyses of randomized controlled trials suggest that 15%–41%2-4 of these patients develop OIC, while observational and survey-based studies suggest that 37%–81%5-9 develop OIC. 1. Camilleri M. Am J Gastroenterol. 2011;106(5):835-842. 2. Kalso E et al. Pain. 2004;112(3):372-380. 3. Papaleontiou M et al. J Am Geriatr Soc. 2010; 58(7):1353-1369. 4. Moore RA et al. Arthritis Res Ther. 2005;7(5):R1046-1051. 5. Bell TJ et al. Pain Med. 2009;10(1):35-42. 6. Anastassopoulos KP et al. J Manag Care Pharm. 2012;18(8):615-626. 7. Cook SF et al. Aliment Pharmacol Ther. 2008;27(12):1224-1232. 8. Tuteja AK et al. Neurogastroenterol Motil. 2010;22(4):424-430, e96. 9. Mahowald ML et al. Arthritis Rheum. 2005;52(1):312-321.

©2014 AstraZeneca.

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“The life of the patient with borderline personality disorder is a life of chaos.”


Michael R. Clark MD, MPH, MBA by


eXPeRT OPINION

THE iNDiViDUAL WiTH A PERSONALiTY DiSORDER WiLL MAKE THEMSELVES KNOWN TO OTHERS BECAUSE THERE iS CLiNiCALLY SiGNiFiCANT DiSTRESS OR iMPAiRMENT iN ALL AREAS OF FUNCTiONiNG.

abstract: Patients with chronic pain present a spectrum of complexity. The more complex patient is often formulated as having a personality disorder. The most dramatic and frustrating patients are usually diagnosed with borderline personality disorder (BPD). Studies investigating BPD in patients with chronic pain showed an average prevalence of 30%, highlighting the importance of being able to effectively treat this patient population. These patients deserve a comprehensive evaluation,

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individual formulation, and tailored treatment plan. The patient should be engaged and not banned from treatment. A patient-centered approach promotes expertise in management and preserving the patient-practitioner relationship. Appropriate treatment of these patients should aim for a collaboration to practice productive behaviors despite intense emotional distress. Longitudinal research supports an orientation of therapeutic optimism that forms the foundation for this rehabilitative approach.

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INTRODUCTiON Personality Disorder Criteria

to difficulty controlling anger and disappointment (eg, displays of temper, physical fights). The daily existence of the person with BPD becomes one filled by chronic feelings of emptiness with stress-related paranoid ideation or dissociative symptoms.

The Diagnostic and Statistical Manual ( DSM ) defines a personality The behavior of a patient with BPD is primarily the manifestation of disorder as having several key criteria.1 First, the inner experience emotional instability and extraversion.2 For patients with this comand behavior of the person deviates to such an extent from the expec- bination of personality traits, a small emotional stimulus typically tations of the individual’s culture that they are obviously an outlier produces a disproportionate response. In addition, the responses to beyond usual norms. This pattern of thinking, feeling, and acting is emotionally laden stimuli are unpredictable and inconsistent over enduring, inflexible, and pervasive across the person’s lifespan longi- time. Even the range of emotional responses for any given stimulus tudinally and a spectrum of life circumstances cross-sectionally. The is large. While they are endowed with these inherent vulnerabiliindividual with a personality disorder will make themselves known ties, these negative behaviors have usually been unintentionally reinto others because there is clinically significant distress or impair- forced by good intentions. Practitioners as well as family, friends, and ment in all areas of functioning. This disability is the manifestation coworkers have tried to help the patient by engaging with them and of dysfunctional impulse control; the range, intensity, lability, and trying to meet their demands. Unfortunately, the patient is focused appropriateness of emotional responses; and ways of perceiving and on pursuing an immediate reward (attention, comfort, relief) for interpreting self, other people, and events. A personality disorder is negative feelings that emerge from their emotional sensitivity and essentially a disorder of interpersonal functioning. This diagnosis craving for interaction with others. In summary, interacting with a should only be made after consideration that the pattern of dysfunc- BPD is upsetting and unsatisfying because they are so unstable and tion is of long duration present since adolescence, and that another unpredictable in the extreme. mental disorder, medical condition, or effects of a substance does not offer a better explanation.

The Relationship Between BPD and Chronic Pain

Types of Personality Disorders The DSM offers clusters of personality disorder diagnoses based on certain common themes or shared primary characteristics.1 The Cluster A personality disorders are noted as “odd,” with the Paranoid being primarily suspicious in contrast to the Schizoid who is detached and the Schizotypal who is eccentric. The Cluster B personality disorders are more “dramatic”: the Antisocial who shows reckless disregard for others, the Borderline who is emotionally unstable, the Histrionic who seeks attention, and the Narcissistic who sees herself as superior. Finally, the Cluster C disorders share a quality of “anxiousness”: the Avoidant usually feels inadequate whereas the Dependent is fearful and the Obsessive-Compulsive inflexible.

Often the patient with chronic pain is described as difficult and frustrating. Practitioners usually wonder at some point if this subset of patients has a personality disorder and, specifically, BPD because the interactions are characterized by heightened negative emotions in both patient and practitioner.3 Research is limited but estimates of the prevalence of BPD in patients with chronic pain averages 30%.4 However, caution must be exercised because these difficult interactions may be the result of another mental disorder. For example, when controlling for major depression, no association was found between increased pain severity and increased BPD symptomatology.5 Personality traits act as modifying factors that have the potential to complicate the treatment process rather than serve as the sole explanation for chronic pain.6 Diagnosing the difficult patient with BPD is usually premature and ultimately incorrect.

Borderline Personality Disorder

Utilizing a combination of direct evaluation of the patient to see if they meet DSM criteria and critical collateral and longitudinal The patient with borderline personality disorder ( BPD) presents information determining that the symptoms and impairment have a special case,1 one that is particularly difficult because of a per- been consistently present over time and that other disorders have vasive pattern of instability which infuses interpersonal relation- been ruled out as their cause, a diagnosis of BPD can be made. Once ships, self-image, moods, and impulsive decision-making. Typically the diagnosis of BPD in the patient with chronic pain is made, manpatients with BPD live lives of chaos with frantic efforts to avoid real aging the patient effectively becomes the goal.7 Their traits do serve or imagined abandonment, with unstable and intense interpersonal a useful purpose for them: they garner attention from others when relationships that fluctuate from the extreme of idealization to that ill, protect themselves from misuse when vulnerable, and obtain of devaluation. These people possess fragile identities with a sense assistance during convalescence. The problem with managing the of self or self-image that is unstable and easily undermined either BPD patient is not that their emotions are foreign but simply too through self-damaging impulsive acts (eg, excessive spending, sexual much of a good thing. This excess of emotion is a form of catastrobehavior, substance abuse, recklessness) or recurrent self-mutilation phizing that becomes increasingly maladaptive and characterized by and suicidal behaviors. Generally, BPD is characterized by an under- an overwhelming amplification of negative feelings and worries that lying affective instability with intense and quick-changing emotional undermine their capacity to function with any form of discomfort.8 states that are distressing (eg, dysphoria, irritability, anxiety) and lead This conceptualization may explain why research demonstrates that Q3  | 2014

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EXPERT OPINION

THE PROBLEM WiTH MANAGiNG THE BPD PATiENT iS NOT THAT THEiR EMOTiONS ARE FOREiGN BUT SiMPLY TOO MUCH OF A GOOD THiNG. THiS EXCESS OF EMOTiON iS A FORM OF CATASTROPHiZiNG THAT BECOMES iNCREASiNGLY MALADAPTiVE…

patients with chronic pain who also have BPD use more pain medications than those patients with chronic pain without BPD. Patients with both may be unable to regulate pain. Also, these patients have family members with higher rates of somatoform pain disorders suggesting inherited traits or learned behaviors relating to eliciting care and attention from others.4

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TR ATM NT FOR BORD RLiN P RSONALiTY DiSORD R Treat the Untreatable

The management of BPD begins with understanding the course and prognosis of this disorder. Although usually conceived of as chronic and deteriorating, in fact, the majority of patients with BPD enter remission and no longer meet criteria for the diagnosis.9 At 2 years after diagnosis, less than 44% of BPD patients retained the diagnosis.10 In a longer follow-up study, 88% of patients with BPD were found to be in remission after 10 years.11 Over time, the most dramatic manifestations of suicidality, self-injury, and psychotic-type symptoms resolve more quickly. A 10-year meta-analysis showed a nonlinear number of diagnostic criteria decreasing within the first few years, with persistence of a smaller number over the remaining longer period of follow-up.12 The long-term management of BPD shifts from remaining safe amidst the chaos to coping with the generalized feelings of abandonment, emptiness, vulnerability, and dysphoria that are likely to persist. In the special circumstance of BPD in patients with chronic pain, no relationship has been found between BPD symptoms and receiving medical disability.13 The next step in management defines specific targets of therapy.14 Patients with BPD are characterized by 3 domains of dysfunction: affective dysregulation, impulsive-behavioral dyscontrol, and cognitive-perceptual symptoms. Often patients suffer from comorbid affective disorders that produce or amplify these types of symptoms.15 The pharmacotherapy of BPD utilizes all the options for stabilizing mood (antidepressants, anticonvulsants, lithium), second-generation

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antipsychotics, and omega-3 fatty acids.16 Medications are helpful to diminish severe symptoms and create a more stable foundation for psychotherapy.17 The medications help to decrease intense and rapid emotional responses and reactive impulsive behaviors that lead to interpersonal psychopathology.18 Then, the focus in psychotherapy can begin to address how to cope with this dysfunction.19 Dialectical behavior therapy encompasses the themes that strong emotions are acknowledged and validated, frustration is accepted but self-harm is limited, and altering behaviors can improve functioning.20 The environment of psychotherapy offers a therapeutic relationship in which the patient can experience affirmation rather than rejection and invalidation.21

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TR ATM NT OF BORD RLiN P RSONALiTY DiSORD R iN PATi NTS WiTH CHRONiC PAiN

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The Essential Principles of Pain Management Jensen and colleagues22 addressed the critical elements of pain management in the form of 3 questions: Is the patient doing more? Is the patient feeling better? Is there less focus on pain and emotional distress? More recently the clinical model of Acceptance and Commitment Therapy laid out the following tenets: accepting things as they come, perceiving things as they are, being in the present moment, observing yourself in context, identifying your values, and committing to actions towards your goals.23,24 The goals for patients with BPD and those with chronic pain are similar.25 Both groups are working toward improved functioning with the ability to tolerate discomfort, develop coping skills for difficult situations, and emphasize behaviors based on thoughts rather than feelings.

Initiating Treatment Many schema exist for how to initiate treatment. Generally, the individual case must be formulated into a structure that facilitates efficiency and economy but avoids the errors of reductionist and categorical thinking. The more objective classifications utilize the Q3  | 2014


behaviors that the patient is doing as opposed to the more subjective assessment of what the patient is thinking or feeling. For example, the patient with BPD and chronic pain can generally be characterized as demanding, noncompliant, or high-utilizing.

their inability. The most common conditions that render a patient unable to follow directions are psychiatric or cognitive. For example, depressive and anxiety disorder or even psychotic syndromes impair the patient’s compliance. And, if the patient has a dementia, delirium, low IQ, or cognitive impairment from intoxication, compliance with a practitioner’s recommendations is unlikely. Once the cause of noncompliance is understood, appropriate psychiatric treatment can be implemented, aid of caregivers elicited, or strategies for educating and engaging patients implemented.

The demanding patient is angry and wants the practitioner to “just fill my order.” In other words, they do not understand “no” when stated by the practitioner in the face of an unreasonable request. These patients usually try to intimidate with confrontation and threats. If the practitioner gives in, they are reinforcing the behavior for future interactions and beginning to recognize that filling orders is boring The high-utilizing patient is a special subset that exhibits significant and not good for the patient. If the practitioner takes charge of the distress with multiple unexplained physical symptoms, an overinteraction, the patient has the opportunity to benefit from treatment whelming medical history, and extensive treatment failures. The and the practitioner avoids the classic “burn-out.” The opportunity approach to caring for this type of patient begins with recognizing for the patient is to stop being a customer who is simply procuring the distress and validating it for the patient. The major goal is to stop products and services and become a person who is under medical the unexpected calls, office visits, and requests for more consults, care. The practitioner can facilitate this transformation by explain- tests, and interventions. To do this, the sustaining and reinforcing ing the patient-practitioner relationship as one in which treatment is factors of the patient’s abnormal illness behavior must be removed a collaboration, and the treatment plan is modified when appropri- and the specific causes of their distress must be treated. Studies have ate. Given the demanding patient’s initial behavior, the practitioner demonstrated that patients with BPD are likely to suffer from other will need to define consequences for inappropriate acts, noting that psychiatric disorders. In 1 study, 85% of patients met these criteria.26 offensive behavior will not be tolerated and, if the behavior does not Expanding the assessment of the high-utilizing patient will likely improve, discharge from care will result. This is perhaps the hardest yield an additional diagnosis that is driving the seeking of health step for a practitioner because they want to help and feel that they care and, when appropriately treated, the utilization will decrease are abandoning the patient. In contrast, they are not giving in to the back to expected levels. temptation to “help” the patient by giving them what they want even when it is not good for them. The demanding patient will usually try to evoke the fear of abandonment by stating that the practitioner will Sustaining Treatment not help them or is rejecting them. In fact, the appropriate response by the practitioner is that the patient is rejecting treatment by their While the initiation of therapy requires distinct approaches tailored repeated requests for something else and unwillingness to follow the to the formulation of whether the patient is primarily demanding, noncompliant, or high-utilizing, the long-term phase of treatment practitioner’s recommendations. has a similar outline for all 3 types. The patient must be engaged The noncompliant patient is disengaged and offers a different challenge in longitudinal care to benefit from it. The patient is entitled to that can usually be sorted into those patients who will not follow her diagnosis and a general description of the goals of therapy. The directions and those who cannot follow directions. The patient who patient should be introduced to the diagnosis of BPD as a problem will not follow directions is misbehaving. This willful noncompli- that results from an excessive endowment of feelings and that those ance needs an explanation and the practitioner must figure it out. feelings are influencing their behaviors. The goals of treatment are The patient generally has different beliefs about or different goals for based on optimism about a good outcome and that helping the patient the treatment. For example, the patient may believe the diagnosis is change their behaviors will then change their feelings with the resulwrong and therefore the treatment prescribed does not make sense tant improvement in their function and quality of life. to them, or that the likely risks of treatment outweigh the potential benefits or that they do not possess the self-efficacy (confidence, This approach to actively engage the patient in treatment focuses skills) necessary to engage in treatment. The patient may have a first on the patient’s behaviors, not their distressing feelings. In fact, different goal for treatment: in the management of chronic pain, the the patient’s intense emotions are recast as a talent for both reading patient is often focused on being comfortable and the practitioner and evoking emotions in others. Patients with BPD are extremely is focused on making changes to increase function. Other examples sensitive to the emotional states of others and the attention they are include the patient seeking medications for the purpose of abuse or receiving from others. Therefore, the practitioner is in the unenviable diversion rather than their prescribed benefits or a patient who is position of minimizing their own negative feelings about the patient seeking attention and by way of noncompliance ends up with more and remaining available to them. This process requires a balance of frequent contact with the practitioner. For these patients, the feeling rewarding progress for mastering skills with generous amounts of of isolation can occur when progress is achieved and less frequent attention (positive reinforcement) and ignoring most maladaptive appointments are the result. behaviors (extinction) with confrontation of only the most inappropriate actions to provide the patient with specific steps for avoiding The noncompliant patient who cannot follow directions is more negative outcomes in the future (negative reinforcement). Medicastraightforward and a matter of making the diagnosis that explains tions such as opioids and benzodiazepines should not be prescribed Q3  | 2014

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EXPERT OPINION

because of their powerful reinforcing effects that occur when an upset patient takes them and receives immediate comfort. In effect, a negative emotional state coupled with a poor choice is rewarded and more likely to occur in the future. In addition, becoming angry with the patient and scolding them for poor choices (punishment) is ineffective and only serves to inadvertently deliver more attention to the patient. Once again, a negative behavior is reinforced and more likely to occur. The message to both practitioners and patients alike is that we cannot help how we feel but can decide what we do.

can demonstrate those strengths and not evoke their vulnerabilities. Helping the patient to make choices about what situations they place themselves in will optimize their chances for a more successful interaction and outcome. Finally, the patient will need to be reminded that a successful outcome requires practice and practice requires tolerating less than perfection in both themselves and others.

The practitioner should therefore plan for the patient’s failure and be prepared, not angry. Inappropriate behavior, likely the result of provoked negative feelings, should be ignored as much as possible and if unable to be ignored should be responded to immediately. GenThe Specific Components of Treatment erally, the immediate response should be simple and straightforward with the setting of limits and the description of a more appropriate The strategic reinforcement of better choices to engage in health- alternative behavior with the commitment to discuss larger issues in ier behaviors that produce more positive outcomes for the patient more detail in the future after the distress has dissipated. Similarly, involves helping the patient by guiding their choices and scripting appropriate and desired behaviors should be immediately rewarded. their actions.7 First, the basic behaviors of health care are emphasized Early in treatment, successes many be of minimal significance but with concrete instructions provided to the patient such as coming should be applauded. Making a fuss over the patient’s progress will to scheduled appointments on time, staying sober, and trying new satisfy their need for attention. The patient will sense and respond productive behaviors. In addition, the practitioner must describe the favorably to the practitioner’s enthusiasm and interest. And, now is consequences for not following these directions. Emergency appoint- the time to provide the ultimate reward of discussing the patient’s ments will not be scheduled to make up for missed regular appoint- feelings because they will be positive and that will be the result of ments. The patient will not be seen when intoxicated. Self-injury or making better choices and engaging in more healthy behaviors. threats of self-harm will be ignored beyond insuring safety. In other words, no extra attention will be given for negative emotions, poor Because the patient will not have instant success and behave perfectly choices, and unhealthy behaviors. as desired, the practitioner must guard against some common pitfalls in treatment. Despite the patient’s repeated difficulties in meeting The life of the patient with BPD is a life of chaos. That chaos produces the stated goals of treatment, the practitioner should not lower their many problems for the patient. However, the theme in treatment is to expectations for the patient because this will begin a downward spiral step back from the chaos and make the point that emotional distress of lower and lower expectations and the patient deserves better. The has many causes. As noted before, the psychiatric comorbidity in both end result will be an unsatisfying patient-practitioner relationship patients with BPD and chronic pain is high.27 One would expect that in which the patient is basically given what they want to keep them affective and anxiety disorders are likely to be underdiagnosed and quiet and the practitioner becomes increasingly frustrated with the treatment often never occurs. The benefits of even overdiagnosing patient’s lack of progress and their own feelings of being trapped, major depressive disorder greatly outweigh the risks, and treating providing an ineffective treatment just to avoid experiencing the major depressive disorder serves many purposes. Perhaps the condi- patient’s outbursts. In other words, the practitioner should not offer tion that is more difficult to diagnose in this population is addiction. less than their full expertise. The practitioner must remain confident While these patients are at increased risk for substance use disorders, in the principles of treatment and the long-term success that will aberrant drug-taking behaviors are common but not equivalent to result if both parties remain engaged in practice and the processsubstance abuse. These behaviors are more likely to signal a lack of ing of less than ideal outcomes by rewarding effort and incremental efficacy of the prescribed medication, inadequate treatment, or more progress. benign forms of noncompliance. The practitioner should not accept the patient’s feelings as excuses. The patient may say she could have acted better if only she didn’t feel What to Expect Over a Course of Treatment so bad. The practitioner will need to repeatedly remind the patient that her actions will dictate her feelings, not vice-versa. Therefore, The key to working with a patient with a personality disorder like she will still need to choose appropriate acts and then the practiBPD is to work with the traits, not against them. In other words, the tioner will review with her the feelings that resulted. Finally, the practitioner must understand the trait composition of the individual practitioner must not quit on the patient unless the patient makes patient. Knowing the amount of a given trait possessed by a patient the unfortunate decision to fire the practitioner. While not the allows the practitioner to identify the strengths of that trait and desired outcome and a very poor choice by the patient, the pracbuild on them. The practitioner must reframe the vulnerabilities of titioner should keep the focus on the patient’s actions. The point specific traits as assets and not emphasize or give in to the pressure should be made that the patient is rejecting the practitioner and to describe them as liabilities. A particular trait does not make the not that the practitioner is rejecting the patient—the implications patient good or bad. The goal of guidance is to help the patient being that the practitioner remains interested and willing to help the match the inherent strengths of their traits to a context in which they patient and that when the patient experiences the negative feelings

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and consequences of having fired the practitioner she is welcome to return to treatment. The practitioner is constantly reminding the patient that he is optimistic about the outcome of treatment and believes that the patient can achieve that success.

CONCLUSiONS Treating patients with both BPD and chronic pain does not have to be a Sisyphean task. The practitioner must remember that the patient must do the work of treatment. When the patient says they think something, it really means they are feeling something—usually negative. When the patient says they need something, it really means they want something—usually something they should not have. And, when the patient says they cannot do something, it really means they will not do something—usually something they should do. The practitioner does have to remain engaged with the patient and should never put off for tomorrow what he can confront today. It is easier for the practitioner to change than for the patient to change but that approach will not work and reinforces the patient’s underlying belief in a pessimistic future. The practitioner’s commitment to therapeutic optimism will be eventually rewarded. The patient with BPD and chronic pain is manageable. These patients seeking medical care need help. If appropriate care is not offered, they will accept inappropriate care and suffer for it. Look for creative options to solve their problems. The practitioner can always get help and team-based treatment diffuses the burden and frustration that will be inevitable. However, comprehensive treatment is effective and the satisfaction of helping such patients turn such dysfunctional lives into productive ones is unmatched.  References 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Washington, DC: American Psychiatric Press Inc.; 2013. 2. NICE: National Institute for Health and Clinical Excellence. Borderline personality disorder: treatment and management. London, England: 2009. Available at: http:// www.nice.org.uk/. 3. Conrad R, Schilling G, Bausch C, et al. Temperament and character personality profiles and personality disorders in chronic pain patients. Pain. 2007;133:197–209. 4. Sansone RA , Sansone LA . Chronic pain syndromes and borderline personality. Innov Clin Neurosci. 2012;9(1):10–14. 5. Tragesser SL , Bruns D, Disorbio JM . Borderline personality disorder features and pain: the mediating role of a negative affect in a pain patient sample. Clin J Pain. 2010;26:348–353.

10. Grilo CM , Sanislow CA , Gunderson JG, et al. Two-year stability and change of schizotypal, borderline, avoidant, and obsessive-compulsive personality disorders. J Consult Clin Psychol. 2004;2(5):767–775. 11. Zanarini MC , Frankenburg FR , Hennen J, et al. Prediction of the 10-year course of borderline personality disorder. Am J Psychiatry. 2006;163:827–832. 12. Gunderson JG. Borderline personality disorder: ontogeny of a diagnosis. Am J Psychiatry. 2009;166:530–539. 13. Sansone RA , Sinclair JD, Wiederman MW. Disability and borderline personality in chronic pain patients. Pain Res Manag. 2010;15:369–370. 14. American Psychiatric Association. Practice guidelines for the treatment of patients with borderline personality disorder. Arlington, VA: American Psychiatric Association; 2001. 15. Stein DJ, Hollander E, Liebowitz MR . Neurobiology of impulsivity and the impulse control disorders. J Neuropsychiatry Clin Neurosci. 1993;5(1):9–17. 16. Bellino S, Rinaldi C, Bozzatello P, et al. Pharmacotherapy of borderline personality disorder: a systematic review for publication purpose. Curr Med Chem. 2011;18(22):3322–3329. 17. Stoffers JM , Völlm BA , Rücker G, et al. Psychological therapies for people with borderline personality disorder. Cochrane Database Syst Rev. 2012 Aug 15;8:CD 005652. 18. Rifkin A, Quitkin F, Carrillo C, et al. Lithium carbonate in emotionally unstable character disorders. Arch Gen Psychiatry. 1972;27:519–523. 19. Moen R, Freitag M, Miller M, et al. Efficacy of extended-release divalproex combined with “condensed” dialectical behavior therapy for individuals with borderline personality disorder. Ann Clin Psychiatry. 2012;24(4):255–260. 20. Rizvi SL . Treatment failure in dialectical behavior therapy. Cogn Behav Pract. 2011;18:403–412. 21. Bedics JD, Atkins DC , Comtois KA , et al. Treatment differences in the therapeutic relationship and introject during a 2-year randomized controlled trial of dialectical behavior therapy versus nonbehavioral psychotherapy experts for borderline personality disorder. J Consult Clin Psychol. 2012;80(1):66–77. 22. Jensen MP, Turner JA , Romano JM , et al. Coping with chronic pain: a critical review of the literature. Pain. 1991;47:249–283. 23. Hayes SC , Strosahl K, Wilson KG. Acceptance and commitment therapy: an experiential approach to behavior change. New York, NY: Guilford; 1999. 24. McCracken LM . Learning to live with the pain: acceptance of pain predicts adjustment in persons with chronic pain. Pain. 1998;74:21–27. 25. Wasan AD, Wootton J, Jamison RN . Dealing with difficult patients in your pain practice. Reg Anesth Pain Med. 2005;30:184–192. 26. Grant BF, Chou SP, Goldstein RB, et al. Prevalence, correlates, disability, and comorbidity of DSM - IV borderline personality disorder: results from the WAVE 2 National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2008;69(4):533–545. 27. Lieb K, Zanarini MC , Schmahl C, et al. Borderline personality disorder. Lancet. 2004;364:453-461.

6. Vendrig AA . The Minnesota Multiphasic Personality Inventory and chronic pain: a conceptual analysis of a long-standing but complicated relationship. Clin Psychol Rev. 2000;20:533–559. 7. Kalira V, Treisman GJ, Clark MR . Borderline personality disorder and chronic pain: a practical approach to evaluation and treatment. Curr Pain Headache Rep. 2013;17(8):350. 8. Sullivan MJ, Thorn B, Haythornthwaite JA , et al. Theoretical perspectives on the relation between catastrophizing and pain. Clin J Pain. 2001;17:52–64. 9. Karaklic D, Bungener C. Course of borderline personality disorder: literature review. Encephale. 2010;36(5):373–379.

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by Martin

D. Cheatle PhD

a hidden epidemic


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K Y TOPIC

Patients that experience chronic pain are more likely to develop depression than patients without pain.

Patients suffering from chronic pain frequently develop concomitant medical and psychological disorders. While there has been a great deal of focus on the escalating prevalence of “unintentional� opioid-related overdose fatalities, there has been less attention devoted to a silent epidemic in this patient population, that of suicide. There is a high prevalence of depression in the pain population and a significant subgroup of patients with pain experience suicidal ideation. It is critical to evaluate both depression and the potential for suicidal ideation and develop strategies to mitigate risk. This article reviews the current literature on pain, depression, and suicide and outlines effective assessment and early intervention techniques that can be employed in the clinic setting. abstract:


KEY TOPIC

atients with chronic pain (CP) are complex and commonly experience noteworthy psychiatric and medical comorbidities, including mood disorders, anxiety disorders, posttraumatic stress disorders (PTSD), and substance use disorders. For example, a study employed data from the National Comorbidity Survey with a sample size of 5877 and discovered that individuals with CP, as compared to the general population, had a significantly higher level of depression (20.2% vs 9.3%), PTSD (10.7% vs 3.3%), and any anxiety disorder (35.1% vs 18.1%).1 Another study revealed that patients that experience CP are more likely to develop depression than patients without pain.2 There has also been great concern regarding the increasing preva- Several recent studies have also shown a particularly high prevalence lence of opioid abuse and opioid-related fatal overdoses. For example, of suicidal ideation in subgroups of patients with chronic pain. One there were 38,329 medication-related deaths in 2010 in the United study by Lee et al evaluated psychiatric symptoms in patients diagStates and, of those deaths, 16,651 were related to opioids alone or in nosed with complex regional pain syndrome (CRPS). In this sample, combination with other drugs, the most common drug being ben- 74.4% of the 39 patients with CRPS Type I or II were determined to zodiazepines.3 While many of these overdoses are considered to be be at high risk for suicidal ideation. Risk factors associated with suiunintentional in nature, most likely a subgroup of these individuals cidal ideation included the co-occurrence of depression, the severity intentionally overdosed for purposes of committing suicide, as sui- of the pain, and low scores on the Global Assessment of Functioning cidal ideation is highly prevalent in patients with chronic pain.4-14 scale.18 Calandre et al assessed pain, sleep disorders, and depression in 373 patients diagnosed with fibromyalgia. Of these patients, 48% A recent study by Racine et al14 evaluated 88 patients with CP during reported suicidal ideation—39.7% passive ideation and 8.3% active an intake evaluation at several pain clinics and compared patients ideation. Suicidal ideation was associated with depression, anxiety, who reported active or passive suicidal ideation with patients expe- sleep, and global mental health.19 riencing no suicidal ideation. Twenty-four percent of the patients reported having suicidal ideation. Identified risk factors included being unemployed or disabled, poor sleep quality, the patient’s per- RiSK ASS SSM NT ceived mental health status, a pain-related sense of helplessness, and history of using illicit drugs. This rate of suicidal ideation has been Two components of risk assessment are identifying common and identified in other studies including a study by Smith et al who exam- pain-specific risk factors and the utilization of mental health screenined 153 subjects with chronic noncancer pain and discovered that ing tools. 19% of this sample reported current passive suicidal ideation, 13% reported active ideation, 5% had a plan for suicide, and 5% reported a past history of suicide attempt.8 RiSK FACTORS Risk assessment consists fi rst of being cognizant of the general and A systematic review by Tang and Crane revealed that the risk of suc- pain-specific risk factors for suicide. Risk factors characteristic of cessful suicide was doubled in patients with CP as compared to non- suicide, both general and pain-specific, are outlined in Table 1. The pain controls and that risk factors included family history of suicide, Centers for Disease Control and Prevention and the National Center previous suicide attempts, female gender, and experiencing comorbid for Injury Prevention and Control outline various risk factors for suidepression. Risk factors that were pain-specific included pain loca- cide in the general population.20 These risk factors include family histion (low back and widespread pain), pain intensity (high), duration tory of suicide, history of childhood abuse, previous suicide attempts, of pain complaints, and the presence of concomitant insomnia.13 history of mental disorder (particularly depression), sense of feeling hopeless, history of substance use disorder, impulsive and aggressive Another study examined 466 patients referred to a behaviorally-based behaviors, losses such as work and family roles, isolation, and experipain program from a community health system. There was a high encing a chronic illness. Of these general risk factors, many are parrate of suicidal ideation in this sample (28%) and potential predic- ticularly relevant to the pain population such as hopelessness, history tors of suicide included pain location (extremity and generalized), of mental disorder (particularly depression), history of substance use work disruption, becoming socially withdrawn, pre-pain history of disorder, recent losses, isolation, and physical illness. depression, family history of depression, and history of sexual/physical abuse. Logistic regression revealed that the history of sexual/ Pain-specific risk factors for suicide include pain location (generalphysical abuse, family history of depression, and being socially ized pain, migraine, low back pain), pain type (fibromyalgia, CRPS), withdrawn were predictive of suicidal ideation.15 Other studies have high pain intensity, duration of the pain complaints, insomnia, and demonstrated that catastrophizing16 and burdensomeness (“I am a pain catastrophizing. Specific behaviors that may be suggestive of burden”)17 are also factors that are associated with suicidal ideation an increased risk for suicide include dispensing of personal property, having no future goals, and making a will. in the pain population.

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Patients with CP are particularly vulnerable to an increasing risk for suicide as oftentimes they are unable to return to gainful employment; they are more isolated and perceive that they are a burden on family and society due to their pain-related disability; they have lost important family and societal roles; they have a high rate of depression; and a subgroup have a recent or current substance use disorder.

Table 1. Risk Factors for Suicide Not Pain Specific

Pain Specific

Unemployed/disabled

Pain location (low back, generalized)

Poor sleep quality

High pain intensity

History of illicit drug use

Pain duration

Family history of suicide

History of depression before pain

Previous suicide attempts

Pain etiology (CRPS, fibromyalgia)

Concomitant mental health history (especially depression)

Catastrophizing

History of sexual/ physical abuse

Pain-related helplessness

assessment of depression in the medical population that excludes somatic symptoms, possibly more accurately assessing depression in the pain population. The POMS evaluates 6 mood states including depression, anxiety, and anger, considered most relevant in pain. The BDI, BDIFS, and the POMS are all proprietary. Other assessment tools for depression include the Zung Self-rating Depression Scale,26 the Center for Epidemiologic Studies (CES) Depression Scale with both a short and full version,27 and the Patient Health Questionnaire ( PHQ) that is derived from the Primary Care Evaluation of Mental Disorders ( PRIME -MD).28 The PHQ has 2 versions for depression: the PHQ -9,29 which measures 9 symptoms of depression based on the Diagnostic and Statistical Manual of the Mental Disorders, 4th edition, text revision ( DSM-IV TR), and the PHQ -2,30 which has 2 items. The PHQ -2 can be utilized to screen for depression, but the PHQ -9 is required to render the diagnosis of depressive disorder. The Zung, the CES, and the PHQ-9 and PHQ-2 are all free access.

Table 2. Self-Report Depression Screening Tools Tool Beck Depression Inventory ®–II

Social isolation

Number of Items

Time to Complete

21

5–10 minutes

7

<5 minutes

60 35

10–15 minutes 5–10 minutes

20

10 minutes

20 10

5–10 minutes 5 minutes

9 2

5 minutes <5   minutes

(Beck et al, 199624 )

Beck Depression Inventory ®– Fast Screen for Medical Patients (Beck et al, 2000 25)

Family history of depression Hopelessness

Profile of Mood States 2® »» Full-Length Version »» Short Version (McNair et al, 197123 )

Burdensomeness (“I am a burden”)

Zung Self-Rating Depression Scale (Zung 196526)

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M NTAL H ALTH SCR NiNG TOOLS A number of mental health screening tools have been developed for depression and have adequate validity and reliability. Examples of the various depression screening tools, including number of items and time to take the assessment, are outlined in Table 2. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials ( IMMPACT ) consisted of an expert consensus group that evaluated the various tools for measuring emotional functioning in chronic pain trials.21 They concluded that the Beck Depression Inventory ( BDI )22 and the Profile of Mood States ( POMS)23 were the most relevant in the CP population. The BDI is a 21-item, self-report measure of the severity of depression symptoms assessed over the past week. The BDI-II 24 is a revised version of the BDI and is widely used in measuring depression. The BDI-Fast Screen for Medical Patients ( BDIFS)25 is a 7-item Q3  | 2014

Center for Epidemiologic Studies Depression Scale–Revised »» Full »» Short (Radloff 1977 27 )

Patient Health Questionnaire »» PHQ-9 »» PHQ-2 (Kroenke et al 200129, 200330 )

In a busy practice, it is recommended to select an assessment tool that fits the clinic structure with regards to cost, time to complete, and ease of interpretation. Documentation of the depression score is critical in measuring the efficacy of prescribed treatments, such as an antidepressant and if there is endorsement of suicidal ideation. Many of these scales can be completed in the waiting room and www.painweek.org  | PWJ | 33


KEY TOPIC

If the patient admits to acute suicidal ideation and is unwilling to contract for safety and has plans for how they are going to commit suicide, inpatient admission is warranted. integrated into the electronic health record system for real time assessment and monitoring.

RiSK STRATiFiCATiON AND

eARLY iNTeRVeNTiON

patient admits to acute suicidal ideation and is unwilling to contract for safety and has plans for how they are going to commit suicide, inpatient admission is warranted. Maximizing a psychopharmacologic regimen targeting depression, sleep, and pain can be helpful in mitigating or reducing the risk of suicide. If the patient is treated as an outpatient and opioids are part of the pain treatment strategies, the opioids should be prescribed in small amounts with family members dispensing the medications. Frequent urine drug screenings should be performed to ensure that they are adhering to using their opioids appropriately and not hoarding for a subsequent attempt.32

Risk stratification is based on the clinical evaluation of risk factors and results of the screening tool. Patients can be stratified into lowor high-risk patients based on whether they have specific plans for suicide; do they have the means (access to guns, lethal supply of medications); whether they have a history of suicidal attempts; their There are patients who have chronic depression and chronic suilevel of social support; do they demonstrate effective coping skills; cidal ideation with no active plans, but these patients could become do they have a positive relationship with their healthcare provider (is acutely suicidal if there are new stressors, such as divorce, finanthe patient open in the way that they communicate their emotional cial losses, or poorly controlled pain. These patients should be status and life stressors); and whether they are willing to contract under psychiatric and psychological care as part of an overall pain for safety. Whether patients are low- or high-risk, if they screen as management strategy, with ongoing mental health screening and moderate-high in level of depression, referral to local behavioral close monitoring of their medication use, particularly opioids and benzodiazepines. health specialists is absolutely indicated. Locating a qualified behavioral health specialist can be challenging. The Substance Abuse and Mental Health Service Administration (SAMHSA) has developed a website to facilitate locating both mental health and substance abuse treatment services in or near your community (findtreatment.samhsa.gov).31Proactively, a clinic should maintain an active list of both crises centers and local behavioral health practitioners and the type of insurance they accept. If the

34 | PWJ | www.painweek.org

Basic strategies to reduce risk of suicidal ideation in the pain population are to target some of the potential mediators of pain and suicide such as inadequate pain control, poor pain coping skills, and sleep disorders. Strongly encourage these patients to structure out of house time and to be productive in some manner, such as volunteering in the community. This can reduce isolation and promote a sense of belonging and purpose. Q3  | 2014


CONCLUSiON Chronic pain is a significant healthcare problem. Many of the patients that suffer from CP also experience concomitant medical and psychiatric disorders, including depression, and suicidal ideation occurs in a substantial number of these individuals. Pain in itself is a potentially independent risk factor for suicide. A number of risk factors have been identified and clinicians who are actively involved in treating patients with CP should be cognizant of these risk factors and monitor for any significant, stressful changes in the patient’s life that could alter risk for suicide. There are also a number of potentially modifiable mediators of pain and suicidal risk, including insomnia, depression, substance use disorder, and poor stress coping abilities. Being proactive in developing resources for this population of patients is important. Lastly, maintaining an open, nonjudgmental dialogue with the patient that strengthens the clinician/patient relationship will provide the ongoing opportunity to effectively monitor and intervene, thus mitigating risk and promoting improvement in quality of life.

22. Beck A, Ward C, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561–571.

References

23. McNair D, Lorr M, Droppleman L. Manual Profile of Mood States. San Diego, CA: Educational and Industrial Testing Service; 1971.

1. McWilliams LA , Cox BJ, Enns MW. Mood and anxiety disorders associated with chronic pain: an examination in a nationally representative sample. Pain. 2003;106:127–133. 2. Magni G, Marchetti M, Moreschi C, et al. Chronic musculoskeletal pain and depressive symptoms in the National Health and Nutrition Examination, I: epidemiologic follow-up study. Pain. 1993;53(2):163–168.

with chronic noncancer pain referred to a behaviorally based pain program. Pain Phys. 2014;17(3):E359–E367. 16. Edwards RR , Smith MT, Kudel I, et al. Pain-related catastrophizing as a risk factor for suicidal ideation in chronic pain. Pain. 2006;126:272–279. 17. Kanzler KE, Bryan CJ, McGeary DD, et al. Suicidal ideation and perceived burdensomeness in patients with chronic pain. Pain Pract. 2012;12:602–609. 18. Lee D, Noh E, Kim Y, et al. Risk factors for suicidal ideation among patients with complex regional pain syndrome. Psychiatry Investig. 2014;11(1):32–38. 19. Calandre E, Navajas-Rojas M, Ballesteros J, et al. Suicidal ideation in patients with fibromyalgia: a cross-sectional study. Pain Pract. 2014;Jan 17. Epub ahead of print. 20. Centers for Disease Control and Prevention. National Center for Injury Prevention and Control; 2010. Available at: www.cdc.gov/violenceprevention/suicide/ statistics. 21. Dworkin R, Turk DC , Farrar JT, et al. IMMPACT. Core outcome measures for chronic pain trials: IMMPACT recommendations. Pain. 2005;113(1–2):9–19.

24. Beck A, Steer RA , Brown GK . Manual for Beck Depression Inventory–II . San Antonio, TX: Psychological Corporation; 1996. 25. Beck A, Steer R, Brown C. Beck Depression Inventory-Fast Screen for Medical Patients Manual. San Antonio, TX: Psychological Corporation; 2000. 26. Zung W. A self-rating depression scale. Arch Gen Psychiatry. 1965;12:63–70.

3. Jones CM , Mack KA , Paulozzi LJ . Pharmaceutical overdose deaths, United States, 2010. JAMA . 2013;309:657–659.

27. Radloff L. The CES -D scale: a self-report depression scale for research in the general population. Appl Psychol Meas. 1977;1:385–401.

4. Hitchcock L, Ferrell B, McCaffery M. The experience of chronic nonmalignant pain. J Pain Symptom Manage. 1994;9:312–318.

28. Spitzer RL , Williams JB, Kroenke K, et al. Utility of a new procedure for diagnosing mental disorders in primary care. The PRIME- MD 1000 study. JAMA . 1994;272(22):1749–1756.

5. Stenager EN, Stenager E, Jensen K. Attempted suicide, depression and physical diseases: a 1-year follow-up study. Psychother Psychosom. 1994;61:65–73. 6. Fishbain DA , Goldberg M, Rosomoff RS, et al. Completed suicide in chronic pain. Clin J Pain. 1991;7:29–36. 7. Fishbain DA . The association of chronic pain and suicide. Semin Clin Neuropsychiatry. 1999;4:221–227. 8. Smith MT, Edwards RR , Robinson RC , et al. Suicidal ideation, plans and attempts in chronic pain patients: factors associated with increased risk. Pain. 2004;111:201–208.

29. Kroenke K, Spitzer RL , Williams JB . The PHQ -9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606–613. 30. Kroenke K, Spitzer RL , Williams JB . The Patient Health Questionnaire-2: validity of a two-item depression screener. Med Care. 2003;41(11):1284–1292. 31. Substance Abuse and Mental Health Services Administration Substance Abuse Treatment Facility Locator. Available at: http://findtreatment.samhsa.gov. 32. Cheatle MD. Depression, chronic pain, and suicide by overdose: on the edge. Pain Med. 2011;12 suppl 2:S43-S48.

9. Braden JB, Sullivan MD. Suicidal thoughts and behavior among adults with self-reported pain conditions in the national comorbidity survey replication. J Pain. 2008;9:1106–1115. 10. Ilgen MA , Zivin K, McCammon RJ, et al. Pain and suicidal thoughts, plans and attempts in the United States. Gen Hosp Psychiatry. 2008;30:521–527. 11. Ratcliffe GE, Enns MW, Belik SL, et al. Chronic pain conditions and suicidal ideation and suicide attempts: an epidemiologic perspective. Clin J Pain. 2008;24:204–210. 12. Substance Abuse and Mental Health Services Administration Office of Applied Studies. Drug Abuse Warning Network, 2007: estimates of drug-related emergency department visits. Rockville, MD; 2010. 13. Tang NK , Crane C. Suicidality in chronic pain: a review of the prevalence, risk factors and psychological links. Psychol Med. 2006;36:575–586. 14. Racine M, Choinière M, Nielson WR . Predictors of suicidal ideation in chronic pain patients: an exploratory study. Clin J Pain. 2014;30(5):371–378. 15. Cheatle M, Wasser T, Foster C, et al. Prevalence of suicidal ideation in patients

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from acute or chronic pain every year and it is the leading reason for those seeking medical care. Mild to moderate musculoskeletal injuries—sprains, strains, contusions, repetitive use, and minor trauma—are the most common acute causes of pain. Therapeutic options are typically limited to over-the-counter (OTC) medications, such as nonsteroidal anti-inflammatory medications (also known as NSAIDs), counter irritants, and prescription strength drugs such as higher dose NSAIDs and, to a lesser extent, muscle relaxants and opioids.

NSAID medications are the most widely used treatment for pain and inflammation in the US. It is estimated that every day, more than 30 million Americans use NSAIDs for pain from headaches, arthritis, and other conditions. These drugs work by interrupting the inflammatory cascade and prostaglandin synthesis resulting in decreased pain and tissue inflammation. However, as effective as these drugs are, they are associated with many drug interactions and adverse effects. In 2005, the FDA put a black box warning on all NSAIDs discussing cardiovascular and gastrointestinal (GI) risks.


“What is needed is a safer and effective alternative for initial treatment of mild to moderate musculoskeletal injuries. A recently introduced product may be a candidate for the job.” A meta-analysis, published in May 2013 in The Lancet, included more than 600 clinical trials that evaluated about 353,000 patients. Researchers wanted to provide more reliable estimates of the effect that NSAIDs have on vascular and coronary events such as heart attacks, strokes, and death as well as on GI complications including perforations, obstructions, or bleeding. All of the NSAIDs studied, including naproxen, roughly doubled the risk of being hospitalized because of congestive heart failure. All NSAID s were linked with a 2- to 4-fold increased risk of GI complications, primarily bleeding. The lowest risk was associated with using COX-2 inhibitors. The high incidence of GI bleeding resulted in the addition of gastroprotective medications, such as omeprazole, to many NSAID treatment regimens. This common strategy increases both the cost of treatment and the potential for further drug interactions and adverse effects associated with the added medication. The overall results mean that, compared with placebo, about 3 excess major vascular events, including 1 death, could be expected annually per 1000 patients taking high-dose diclofenac or a COX-2 inhibitor. But for every 1000 patients at high risk of major vascular events, taking a COX-2 inhibitor or high-dose diclofenac would result in an additional 7 or 8 of those events occurring, with approximately 2 fatalities. A meta-analysis published in the British Medical Journal in January 2011 noted NSAIDs have been linked to about 30% of drug-related hospital admissions, and it estimated that 12,000 to 16,000 Americans die annually as a result of GI bleeding caused by NSAIDs. Other than NSAIDs, counter irritants are the mainstay of OTC treatment of muscle injury and pain. Counter irritants, including preparations containing camphor, mint oil, capsaicin, or menthol, cause irritation or mild inflammation of the skin at the site of application producing a

temporary paradoxical pain-relieving effect that masks pain in muscles, joints, and other tissues distal to the site of application. These compounds do not treat the underlying muscle injury and inflammation. Potential adverse effects include local skin reactions, such as redness, rash, burning, and stinging. Serious injuries such as first- to third-degree chemical burns associated with products containing menthol, methyl salicylate, and capsaicin have been reported frequently enough for the FDA to issue a drug safety communication to consumers and healthcare professionals. What is needed is a safer and effective alternative for initial treatment of mild to moderate musculoskeletal injuries. A recently introduced product may be a candidate for the job. Gensco Laboratories, an innovative pharmaceutical company specializing in novel topical medications, has added SpeedGel Rx to the list of prescription alternatives for both patients and retail pharmacies. This prescription product is a combination of several natural ingredients in a patented transdermal base. Gensco states that this medication will reduce inflammation, bruising, and associated pain. Company supplied study data supports this assertion but more importantly, patients have consistently reported positive outcomes. The company reports that larger trials are underway evaluating SpeedGel Rx efficacy in more chronic conditions, such as osteoarthritis. Since this product is topical, it can be applied directly to the site of injury for local effects and, because it does not contain NSAIDs, aspirin, or APAP, there is a much lessened incidence of adverse drug effects. These features, along with the positive patient experiences, make SpeedGel Rx a suitable consideration as a first step in the treatment of musculoskeletal pain especially in those patient populations at risk for ADRs from NSAIDs as well the comorbidities associated with anticoagulation drugs and GI distress. — Robert

Wilbur, PharmD, CPh


by Gary

W. Jay MD, DAAPM, FAAPM


CLiNiCAL  CONUNDRUM

abstract: There are things that should be done when seeing a patient, and things that shouldn’t be done, and, finally, there are things that are not considered secondary to conditioning. This is the history of a patient I saw in the 1990s. I kept her chart as I found it remarkable for a number of reasons, the #1 being it has a lesson for all of us to remember! I have included a number of definitions of ENT terms and some medications, to give the reader a clearer understanding of what was going on. The definitions are gleaned from ENT textbooks accessed via Elsevier’s ClinicalKey software or from my training. Specifically regarding the medications mentioned, the Epocrates website or Goodman & Gilman were consulted.1,2

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www.painweek.org  | PWJ | 39


CLINICAL CONUNDRUM

e

e

TH PATi NT:

The patient was a 38-year-old left-handed Caucasian female, 5”1” tall, with a thin build, who worked as an RN. She went through a full-term pregnancy, delivering with epidural. No medications other than prescribed vitamins were taken during her pregnancy. She was a smoker and drank wine in moderation. The patient’s husband was a physician, a general practitioner. Three months after her son was born, the patient experienced extreme fatigue. She was seen by her PCP, an IM, who sent her to an endocrinologist. Her TSH was >10 mU/L. His diagnosis was hypothyroidism (not uncommon after pregnancy). She was started on Synthroid®. Later, Cytomel® was added. She began to feel better.

One month later the patient was awakened at night with severe bilateral otalgia; she got out of bed and was so dizzy she fell onto the floor; she also felt extremely nauseated. Her husband helped her back to bed and brought her ASA and water. She couldn’t keep it down. Over the next several weeks, she became bedbound and was unable to return to work.

↓ Primary otalgia: ear pain caused by disease in the external, middle, or inner ear; indistinguishable in terms of pain experienced. External ear pain may be mechanical or secondary to trauma or foreign bodies. It may be secondary to an infective etiology (otitis externa): Staphylococcus, Pseudomonas, Candida, herpes zoster, or viral myringitis. Middle ear pain may be mechanical: barotrauma (often iatrogenic), eustachian tube obstruction leading to acute otitis media. It may also be secondary to an inflammatory/infective etiology: acute otitis media or mastoiditis. The neuroanatomical basis of referred otalgia rests within 1 of 5 general neural pathways (see page 41). Vertigo: the sensation that the environment is spinning around relative to oneself (object vertigo) or vice versa (subjective vertigo). True vertigo indicates a rotary sensation of the patient or surroundings. This may result from disease of the inner ear or problems with vestibular centers or pathways in the central nervous system. Dizziness: a nonspecific term to indicate true vertigo, lightheadedness, imbalance, or possible syncope.

40 | PWJ | www.painweek.org

#1 CLiNiCiAN:

The PCP, an Internal Medicine Specialist

The internal medicine specialist checked her endocrine status; she was fine on her current medications. Her symptoms: severe bilateral otalgia, dizziness, and nausea. The examination showed mild bradycardia, which the patient insisted was normal for her. Her blood work was within normal limits with normal glucose. DIAGNOSIS: unknown. THE PLAN: start on Vicodin® for severe otalgia. The patient remained bedbound and was sent to the local ENT for consultation.

#2 CLiNiCiAN:

The ENT Specialist

The patient complained of bilateral otalgia, dizziness, and nausea, all constant. The ENT specialist did a routine exam. DIAGNOSIS: “vertigo of unknown etiology” even though in his notes he described her as having dizziness with no “rotational spin” or vertiginous aspects to her complaint. THE PLAN: cerebral MRI with and without enhancement. The MRI was negative. She was sent to see a neurologist.

#3 CLiNiCiAN: The Neurologist

The neurologist did a routine examination, including cold and warm calorics, the result of which he called “equivocal.” The rest of examination showed the patient to have difficulty walking a straight line. THE PLAN: have the patient evaluated by another local ENT. Q3  | 2014


↓ Calorics: a test that stimulates the inner ear and nearby nerves by delivering cold or warm water (or, rarely, air) to the ear canal at different times. The person doing the test should first examine the ear and especially the eardrum to make sure they are normal. One ear is tested at a time. When cold water enters the ear and the inner ear changes temperature, it should cause fast, side-to-side eye movements called nystagmus. The eyes should move away from the cold water and slowly back. Next, warm water is placed into the ear. The eyes should move toward the warm water and then slowly away. The eyes can be looked at directly. However, often this test is done as part of electronystagmography, which uses patches (electrodes) placed around the eyes to detect the movements. A computer records the results. Ice cold water may be used if there are no responses.

↓ Dysdiadochokinesia: impairment of the ability to perform rapidly alternating movements (a symptom of cerebellar impairment). Vestibulopathy/vestibulitis: a change or reduction in the function of 1 or both of the peripheral vestibular mechanisms, possibly caused by a labyrinthitis, vestibular neuronitis, Ménière’s disease, or even a surgical procedure such as a vestibular neurectomy. Bilateral vestibulopathy occurs when the balance portions of both inner ears are damaged; symptoms include imbalance and visual problems. The imbalance is worse in the dark or in situations where footing is uncertain. Spinning vertigo is unusual. The visual symptoms, called oscillopsia, only occur when the head is moving. Oscillopsia is often common during walking. Quick movements of the head are associated with transient visual blurring. Vestibular neuritis and labyrinthitis (defined on page 39) are sometimes used interchangeably. However, experts in the field now recommend that vestibular neuritis be confined to cases in which the vestibular nerve only is involved, whereas labyrinthitis should be used in cases in which the vestibular nerve and the labyrinth are affected. Zofran® (ondansetron): for prevention of nausea/vomiting, chemotherapy related. Compazine® (prochlorperazine maleate): for severe nausea and vomiting, anxiety related.

Q3  | 2014

#4     CLiNiCiAN: A Local ENT

An ENT affiliated with the local university medical center did a full evaluation in office. The patient showed no hearing deficits (nor did she complain of one). DIAGNOSIS: autoimmune disorder of bilateral inner ears. His recommendation was to immediately start on methotrexate and prednisone. The patient, at her physician husband’s urging, refused.

#5 CLiNiCiAN:

A General Surgeon The patient’s PCP recommended a general surgeon, specializing in gastroenterology, to evaluate her nausea. The examination was negative (she had mild bradycardia). DIAGNOSIS: cholysystitis, which he claimed caused her nausea. THE PLAN: cholecystectomy, which was done a week later. The patient remained bedbound, healing from the cholecystectomy, and continued to have severe bilateral otalgia, nausea, and difficulty walking secondary to dizziness, which hindered her recovery.

◉ DURATION UPDATE— It was now 15 months since symptoms began. The patient

and her husband were becoming desperate.

#6 CLiNiCiAN:

Chairman, Department of Otolaryngology

This physician was the Chairman of the otolaryngology department at a midwest medical center. As would be expected, the history and examination were done by a resident. The Chairman came in and saw the patient, talked to her for several minutes (<5) and told her that her symptoms “made no sense.” DIAGNOSIS: hysteria, and he told the patient to go back to work.

e

e

TH PATi NT: The patient and her husband felt devastated by the cavalier diagnosis of hysteria. The patient was still bedbound and unable to walk without falling. Otalgia made it difficult for her to concentrate and the pain made “thinking very difficult.” Her depression was growing; she refused a psychiatric consultation suggested by her husband. She remained on Vicodin, Synthroid, and multivitamins. THE PATIENT’S HUSBAND—He had been following the “Don’t Treat Your Family” rule but, now enraged, he began to call friends and pull strings.

#7 CLiNiCiAN: The Neurologist

This physician, a neurologist associated with a midwest medical center, called the examination essentially negative (mild bradycardia found). He did question hand movements (dysdiadochokinesia). He ordered another MRI with and without enhancement; it was negative. He repeated calorics and called the results equivocal. DIAGNOSIS: vestibulopathy, etiology unknown. The patient’s otalgia and nausea were thought to be secondary to the patient’s reaction to dizziness. He added Compazine® to the patient’s treatment, and later Zofran®. The Compazine caused sedation and increased problems with walking so she stopped taking it within several weeks, then started Zofran. www.painweek.org  | PWJ | 41


CLINICAL CONUNDRUM

e

e

TH PATi NT: She continued to have bilateral otalgia, her pain rated 8 to 9 on a 0 to 10 numeric rating scale. She continued to have dizziness but could walk with difficulty using a cane or crutches, but only sometimes. At other times she was too dizzy. Her nausea continued. Zofran helped more than other more common drugs but was extremely expensive. She continued on the Zofran, Vicodin (which on occasion would increase her nausea, leading to vomiting), multivitamins, Synthroid, and Cytomel. Her depression, which had been growing, grew even more severe. She still refused a psych consultation, afraid it would negate the reality of other symptoms if people thought she was “crazy.”

#8 CLiNiCiAN:

Chairman, ENT Department

The Chairman of an ENT department in a northeast medical school stated that he had read all the old records. He was the first to do a Nylen-Barany maneuver (per records), which was negative. Calorics were equivocal to negative. The patient’s hearing was normal except high tones increased. He was most impressed by her dizziness. DIAGNOSIS: cupulolithiasis. He had no explanation for her otalgia or nausea. The patient was sent to see a local ENT near her home for treatment.

#9 CLiNiCiAN: ↓ Nylen-Barany Maneuver (also called Dix–Hallpike): a diagnostic maneuver used to identify benign paroxysmal positional vertigo. Cupulolithiasis or benign paroxysmal positional vertigo or canalithiasis: a recurrent, brief or short-term form of positional vertigo occurring in clusters; believed to result from displaced remnants of utricular otoconia into the semicircular ducts, usually the posterior. Benign positional vertigo: brief attacks of paroxysmal vertigo and nystagmus that occur solely with certain head movements or positions, for example, with neck extension; due to labyrinthine dysfunction.

A Local ENT

A local ENT disagreed with the given diagnosis of cupulolithiasis and felt that the patient had Ménière’s disease, in spite of her normal hearing. Also, in spite of the patient’s description of otalgia the physician felt that the patient really had tinnitus. She questioned an association with hypothyroidism, but thyroid testing showed the patient’s thyroid studies to all be within normal limits. The patient and her husband walked out of the consultation secondary to the doctor’s attitude.

e

e

TH PATi NT: Desperation is too simple a word to describe her feelings. Her depression was becoming significant. She was becoming angrier, taking it out on her husband and her child’s nanny. Part of her anger was due to the fact that she hadn’t been able to take care of her child as she had dreamed of. She had almost dropped him once secondary to dizziness, as she was standing, and was afraid to pick him up or hold him, even when lying or sitting down. THE PATIENT’S HUSBAND—He was feeling ineffectual, growing more angry and frustrated. Worse, he was wondering what he was doing in a field—medicine—that could not help his wife.

#10 CLiNiCiAN: A Chiropractor

Out of desperation, and against the husband’s recommendations, the patient went to a chiropractor. She was treated 6 times in 2 weeks. The chiropractor offered no specific diagnosis and just did cervical adjustments. No change was noted to any symptom. Her husband forced her to stop.

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#11 CLiNiCiAN:

Chair, Internal Medicine

This physician was the Chair in internal medicine at a west coast medical center/university. He doubted Ménière’s disease, as well as labyrinthitis. However, he couldn’t come up with a diagnosis, and sent the patient to see the Chair of the department of neurology at the same university. The patient was seen the very next day.

#12 CLiNiCiAN:

Chair, Department Neurology

↓ Labyrinth: a structure of fluid-filled sacs and tubes just inside the skull containing the cochlea, which is necessary for hearing, and the balance organs (vestibular system), which tell people which way is up and down, even when their eyes are shut. Labyrinthitis: an inflammatory condition affecting the labyrinth in the cochlea and vestibular system of the inner ear. Vestibular neuronitis: inflammation of the bundle of nerves in the inner ear leading to the brain. Causes of labyrinthitis: often unknown, possibly related to a viral infection such as flu or a cold or, rarely, a bacterial infection such as a middle ear infection (otitis media) or meningitis. Labyrinthitis may rarely occur as part of an autoimmune disease or after a head or ear injury. Other more rare causes can include allergies, medications that can damage the inner ear, a stroke, or a tumor. Autoimmune abyrinthitis: labyrinthitis secondary to an autoimmune etiology.

The Chair’s examination was negative. He thought the patient’s dizziness was her primary symptom; however, she had a negative Romberg, negative cerebellar signs/symptoms, no dysdiadochokinesia. DIAGNOSIS: vestibulopathy/vestibulitis, unknown etiology. THE PLAN: prednisone for the vestibulopathy and Percocet® for her otalgia.   ◉ DURATION UPDATE— It was now 3 years since the symptoms began.

e

e

TH PATi NT: She was very depressed, angry, frustrated, and frightened that she might never get better. She was still unable to work, still had problems walking and had fallen several times. She still had constant pain from her otalgia. She was more deconditioned, and remained essentially bedbound, but could sit/lie on the couch in living room. She took prednisone for 3 months and discontinued it secondary to weight gain and no change in her symptoms/condition. She continued on Zofran, Percocet, Synthroid, Cytomel, and multivitamins.

#13 CLiNiCiAN: An ENT Professor

This professor of ENT, at another midwestern medical university, could not explain the patient’s otalgia, but he said the patient’s dizziness “felt neurological.” When the patient was seen, most of her complaints were of pain from otalgia. THE PLAN: send the patient to me, a pain specialist, to see if I could help her otalgia.

#14 CLiNiCiAN: The Author

I obtained all records and read them—all 6 inches worth—before my appointment with the patient. As per usual in my interdisciplinary clinic, I had an RN take a full history, then I repeated it with the patient and her husband. Her symptoms were unchanged: bilateral otalgia, dizziness (now with possible hint of vertigo), and nausea. We went through the history of the disorder and her medical odyssey. I did a full neurological examination—calorics: negative; negative Nylen-Barany; minimal cerebellar findings; gait, station unsteady, better with cane, held onto wall without it (also patient very deconditioned). On general examination she had tenderness to the L diaphragm anteriorly, as well as minimal bradycardia (normal for her, as stated by the patient). She continued on Zofran, Percocet, Synthroid, Cytomel, multivitamins, and Pepto-Bismol® for nausea. My diagnosis? I didn’t have one, but I did have one thought: every physician she had seen had looked through their looking glass at the symptom that they thought would be Q3  | 2014

www.painweek.org  | PWJ | 43


Tablets not actual size. Not actual patient.

WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and CYTOCHROME P450 3A4 INTERACTION Addiction, Abuse, and Misuse OxyContin Ž exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing OxyContin and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of OxyContin. Monitor for respiratory depression, especially during initiation of OxyContin or following a dose increase. Instruct patients to swallow OxyContin tablets whole; crushing, chewing, or dissolving OxyContin tablets can cause rapid release and absorption of a potentially fatal dose of oxycodone [see Warnings and Precautions (5.2)]. Accidental Ingestion Accidental ingestion of even one dose of OxyContin, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions (5.2)]. Neonatal Opioid Withdrawal Syndrome Prolonged use of OxyContin during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)]. Cytochrome P450 3A4 Interaction The concomitant use of OxyContin with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Monitor patients receiving OxyContin and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.14) and Clinical Pharmacology (12.3)].


Because your patients’ chronic pain treatment needs may change over time

Reassess at every step

Every-12-hour OxyContin Tablets

OxyContin 60 mg and 80 mg tablets, a single dose greater than 40 mg, or a total daily dose greater than 80 mg are for use in opioid-tolerant patients only. Use of these higher doses in patients who are not opioid-tolerant may cause fatal respiratory depression.

Indications and Usage OxyContin is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Use • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve OxyContin for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain • OxyContin is not indicated as an as-needed (prn) analgesic

Contraindications OxyContin is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected paralytic ileus and gastrointestinal obstruction • Hypersensitivity (e.g., anaphylaxis) to oxycodone Please see Additional Warnings and Precautions on the following page. Please read Brief Summary of Full Prescribing Information on the following pages, including Boxed Warning.

For information about or to print OxyContin Savings Cards for your eligible patients, please visit PurdueHCP.com/SavingsProgram


Additional Warnings and Precautions • OxyContin contains oxycodone, a Schedule II controlled substance. OxyContin exposes users to the risks of opioid addiction, abuse, and misuse. As modified-release products such as OxyContin deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of oxycodone present. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse or misuse prior to prescribing OxyContin and monitor all patients during therapy for the development of these behaviors or conditions. • Instruct patients to swallow the OxyContin tablets intact. Crushing, chewing, snorting, or injecting the dissolved product could result in overdose and death. • Serious, life-threatening, or fatal respiratory depression has been reported with modified-release opioids, even when used as recommended, and if not immediately recognized and treated, may lead to respiratory arrest and death. The risk of respiratory depression is greatest during initiation of therapy or following a dose increase; therefore, closely monitor patients for respiratory depression. Proper dosing and titration of OxyContin are essential. Overestimating the OxyContin dose when converting patients from another opioid product can result in fatal overdose with the first dose. • Accidental ingestion of even one dose of OxyContin, especially by children, can result in respiratory depression and death due to an overdose of oxycodone. • Prolonged use of OxyContin during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening to the neonate if not recognized and treated, and requires management according to protocols developed by neonatology experts. • Hypotension, profound sedation, coma, respiratory depression, or death may result if OxyContin is used concomitantly with other CNS depressants, including alcohol or illicit drugs that can cause CNS depression. Start with 1/3 to 1/2 the usual dose of OxyContin, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant. • Closely monitor elderly, cachectic, and debilitated patients, and patients with chronic obstructive pulmonary disease because of increased risk of life-threatening respiratory depression. Consider the use of alternative non-opioid analgesics in patients with chronic pulmonary disease if possible. • OxyContin may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. Monitor patients during dose initiation and titration. Avoid use of OxyContin in patients with circulatory shock. • Monitor patients taking OxyContin who may be susceptible to the intracranial effects of CO2 retention for signs of sedation and respiratory depression. Avoid the use of OxyContin in patients with impaired consciousness or coma. • OxyContin is contraindicated in patients with GI obstruction, including paralytic ileus. Use caution when prescribing OxyContin for patients who have difficulty swallowing, or have underlying GI disorders that may predispose them to obstruction. Consider use of an alternative analgesic in these patients. • OxyContin may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. • OxyContin may aggravate convulsions in patients with convulsive disorders and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control. • Avoid the use of mixed agonist/antagonist or partial agonist analgesics in patients who have received or are receiving OxyContin, as they may reduce the analgesic effect and/or precipitate withdrawal. Do not abruptly discontinue OxyContin. • OxyContin may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. • Concomitant use of CYP3A4 inhibitors may prolong opioid effects. Use with CYP3A4 inducers may cause lack of efficacy or development of withdrawal symptoms. If co-administration is necessary, evaluate patients frequently and consider dose adjustments until stable drug effects are achieved.

©2014 Purdue Pharma L.P., Stamford, CT 06901-3431

B8810-A 6/14


10 mg l 15 mg l 20 mg l 30 mg 40 mg l 60 mg* l 80 mg* *60 mg and 80 mg for use in opioid-tolerant patients only BRIEF SUMMARY OF PRESCRIBING INFORMATION (For complete details please see the Full Prescribing Information and Medication Guide.) WARNING: ADDICTION, ABUSE and MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and CYTOCHROME P450 3A4 INTERACTION Addiction, Abuse, and Misuse OXYCONTIN® exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing OXYCONTIN and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of OXYCONTIN. Monitor for respiratory depression, especially during initiation of OXYCONTIN or following a dose increase. Instruct patients to swallow OXYCONTIN tablets whole; crushing, chewing, or dissolving OXYCONTIN tablets can cause rapid release and absorption of a potentially fatal dose of oxycodone [see Warnings and Precautions (5.2)]. Accidental Ingestion Accidental ingestion of even one dose of OXYCONTIN, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions (5.2)]. Neonatal Opioid Withdrawal Syndrome Prolonged use of OXYCONTIN during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)]. Cytochrome P450 3A4 Interaction The concomitant use of OXYCONTIN with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Monitor patients receiving OXYCONTIN and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.14) and Clinical Pharmacology (12.3)]. 4 CONTRAINDICATIONS OXYCONTIN is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected paralytic ileus and gastrointestinal obstruction • Hypersensitivity (e.g., anaphylaxis) to oxycodone [see Adverse Reactions (6.2)] 5 WARNINGS AND PRECAUTIONS 5.1 Addiction, Abuse, and Misuse OXYCONTIN contains oxycodone, a Schedule II controlled substance. As an opioid, OXYCONTIN exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. As modified-release products such as OXYCONTIN deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of oxycodone present [see Drug Abuse and Dependence (9)]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OXYCONTIN. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse or misuse prior to prescribing OXYCONTIN, and monitor all patients receiving OXYCONTIN for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as OXYCONTIN, but use in such patients necessitates intensive counseling about the risks and proper use of OXYCONTIN along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse, or misuse of OXYCONTIN by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of oxycodone and can result in overdose and death [see Overdosage (10)]. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing OXYCONTIN. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s

clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioidinduced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of OXYCONTIN, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with OXYCONTIN and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of OXYCONTIN are essential [see Dosage and Administration (2)]. Overestimating the OXYCONTIN dose when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of OXYCONTIN, especially by children, can result in respiratory depression and death due to an overdose of oxycodone. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of OXYCONTIN during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. 5.4 Interactions with Central Nervous System Depressants Hypotension and profound sedation, coma, or respiratory depression may result if OXYCONTIN is used concomitantly with other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of OXYCONTIN in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that can cause CNS depression. If the decision to begin OXYCONTIN therapy is made, start with 1/3 to 1/2 the usual dose of OXYCONTIN, monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.1) and Dosage and Administration (2.2)]. 5.5 Use in Elderly, Cachectic, and Debilitated Patients Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating OXYCONTIN and when OXYCONTIN is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)]. 5.6 Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with OXYCONTIN, as in these patients, even usual therapeutic doses of OXYCONTIN may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in these patients if possible. 5.7 Hypotensive Effects OXYCONTIN may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7.1)]. Monitor these patients for signs of hypotension after initiating or titrating the dose of OXYCONTIN. In patients with circulatory shock, OXYCONTIN may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of OXYCONTIN in patients with circulatory shock. 5.8 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking OXYCONTIN who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with OXYCONTIN. OXYCONTIN may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of OXYCONTIN in patients with impaired consciousness or coma. 5.9 Difficulty in Swallowing and Risk for Obstruction in Patients at Risk for a Small Gastrointestinal Lumen There have been post-marketing reports of difficulty in swallowing OXYCONTIN tablets. These reports included choking, gagging, regurgitation and tablets stuck in the throat. Instruct patients not to pre-soak, lick or otherwise wet OXYCONTIN tablets prior to placing in the mouth, and to take one tablet at a time with enough water to ensure complete swallowing immediately after placing in the mouth. There have been rare post-marketing reports of cases of intestinal obstruction, and exacerbation of diverticulitis, some of which have required medical intervention to remove the tablet. Patients with underlying GI disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen are at greater risk of developing these complications. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying GI disorders resulting in a small gastrointestinal lumen. 5.10 Use in Patients with Gastrointestinal Conditions OXYCONTIN is contraindicated in patients with GI obstruction, including paralytic ileus. The oxycodone in OXYCONTIN may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase. 5.11 Use in Patients with Convulsive or Seizure Disorders The oxycodone in OXYCONTIN may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during OXYCONTIN therapy. 5.12 Avoidance of Withdrawal Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including OXYCONTIN. In these patients, mixed agonist/ antagonist and partial agonist analgesics may reduce the analgesic effect and/ or may precipitate withdrawal symptoms. When discontinuing OXYCONTIN, gradually taper the dose [see Dosage and Administration (2.4)]. Do not abruptly discontinue OXYCONTIN. 5.13 Driving and Operating Machinery

OXYCONTIN may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of OXYCONTIN and know how they will react to the medication. 5.14 Cytochrome P450 3A4 Inhibitors and Inducers Since the CYP3A4 isoenzyme plays a major role in the metabolism of OXYCONTIN, drugs that alter CYP3A4 activity may cause changes in clearance of oxycodone which could lead to changes in oxycodone plasma concentrations. Inhibition of CYP3A4 activity by its inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid effects. CYP450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism of oxycodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in oxycodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone. If co-administration is necessary, caution is advised when initiating OXYCONTIN treatment in patients currently taking, or discontinuing, CYP3A4 inhibitors or inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)]. 5.15 Laboratory Monitoring Not every urine drug test for “opioids” or “opiates” detects oxycodone reliably, especially those designed for in-office use. Further, many laboratories will report urine drug concentrations below a specified “cut-off” value as “negative”. Therefore, if urine testing for oxycodone is considered in the clinical management of an individual patient, ensure that the sensitivity and specificity of the assay is appropriate, and consider the limitations of the testing used when interpreting results. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)] • Interactions with Other CNS Depressants [see Warnings and Precautions (5.4)] • Hypotensive Effects [see Warnings and Precautions (5.7)] • Gastrointestinal Effects [see Warnings and Precautions (5.9, 5.10)] • Seizures [see Warnings and Precautions (5.11)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of OXYCONTIN was evaluated in double-blind clinical trials involving 713 patients with moderate to severe pain of various etiologies. In open-label studies of cancer pain, 187 patients received OXYCONTIN in total daily doses ranging from 20 mg to 640 mg per day. The average total daily dose was approximately 105 mg per day. OXYCONTIN may increase the risk of serious adverse reactions such as those observed with other opioid analgesics, including respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, or shock [see Overdosage (10)]. The most common adverse reactions (>5%) reported by patients in clinical trials comparing OXYCONTIN with placebo are shown in Table 1 below: TABLE 1: Common Adverse Reactions (>5%) Adverse Reaction

OXYCONTIN (n=227)

Placebo (n=45)

(%)

(%)

Constipation

(23)

(7)

Nausea

(23)

(11)

Somnolence

(23)

(4)

Dizziness

(13)

(9)

Pruritus

(13)

(2)

Vomiting

(12)

(7)

Headache

(7)

(7)

Dry Mouth

(6)

(2)

Asthenia

(6)

Sweating

(5)

(2)

In clinical trials, the following adverse reactions were reported in patients treated with OXYCONTIN with an incidence between 1% and 5%: Gastrointestinal disorders: abdominal pain, diarrhea, dyspepsia, gastritis General disorders and administration site conditions: chills, fever Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: twitching Psychiatric disorders: abnormal dreams, anxiety, confusion, dysphoria, euphoria, insomnia, nervousness, thought abnormalities Respiratory, thoracic and mediastinal disorders: dyspnea, hiccups Skin and subcutaneous tissue disorders: rash Vascular disorders: postural hypotension The following adverse reactions occurred in less than 1% of patients involved in clinical trials: Blood and lymphatic system disorders: lymphadenopathy Ear and labyrinth disorders: tinnitus Eye disorders: abnormal vision Gastrointestinal disorders: dysphagia, eructation, flatulence, gastrointestinal disorder, increased appetite, stomatitis General disorders and administration site conditions: withdrawal syndrome (with and without seizures), edema, peripheral edema, thirst, malaise, chest pain, facial edema Injury, poisoning and procedural complications: accidental injury Investigations: ST depression Metabolism and nutrition disorders: dehydration Nervous system disorders: syncope, migraine, abnormal gait, amnesia, hyperkinesia, hypesthesia, hypotonia, paresthesia, speech disorder, stupor, tremor, vertigo, taste perversion Psychiatric disorders: depression, agitation, depersonalization, emotional lability, hallucination Renal and urinary disorders: dysuria, hematuria, polyuria, urinary retention Reproductive system and breast disorders: impotence Respiratory, thoracic and mediastinal disorders: cough increased, voice alteration Skin and subcutaneous tissue disorders: dry skin, exfoliative dermatitis 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of controlled-release oxycodone: abuse, addiction, amenorrhea, cholestasis, death, dental caries, increased hepatic enzymes, hyperalgesia, hypogonadism, hyponatremia, ileus, muscular hypertonia, overdose, palpitations (in the context of withdrawal), seizures, syndrome of inappropriate antidiuretic hormone secre-


tion, and urticaria. Anaphylaxis has been reported with ingredients contained in OXYCONTIN. Advise patients how to recognize such a reaction and when to seek medical attention. In addition to the events listed above, the following have also been reported, potentially due to the swelling and hydrogelling property of the tablet: choking, gagging, regurgitation, tablets stuck in the throat and difficulty swallowing the tablet. 7 DRUG INTERACTIONS 7.1 CNS Depressants The concomitant use of OXYCONTIN and other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma, or death. Monitor patients receiving CNS depressants and OXYCONTIN for signs of respiratory depression, sedation, and hypotension. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)]. 7.2 Muscle Relaxants Oxycodone may enhance the neuromuscular blocking action of true skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients receiving muscle relaxants and OXYCONTIN for signs of respiratory depression that may be greater than otherwise expected. 7.3 Drugs Affecting Cytochrome P450 Isoenzymes Inhibitors of CYP3A4 and 2D6 Because the CYP3A4 isoenzyme plays a major role in the metabolism of oxycodone, drugs that inhibit CYP3A4 activity may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations and result in increased or prolonged opioid effects. These effects could me more pronounced with concomitant use of CYP2D6 and 3A4 inhibitors. If co-administration with OXYCONTIN is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)]. Inducers of CYP3A4 CYP450 3A4 inducers may induce the metabolism of oxycodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in oxycodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone. If co-administration with OXYCONTIN is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved. After stopping the treatment of a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression [see Clinical Pharmacology (12.3)]. 7.4 Mixed Agonist/Antagonist and Partial Agonists Opioid Analgesics Mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonist (buprenorphine) analgesics may reduce the analgesic effect of oxycodone or precipitate withdrawal symptoms. Avoid the use of mixed agonist/ antagonist and partial agonist analgesics in patients receiving OXYCONTIN. 7.5 Diuretics Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also lead to acute retention of urine by causing spasm of the sphincter of the bladder, particularly in men with enlarged prostates. 7.6 Anticholinergics Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when OXYCONTIN is used concurrently with anticholinergic drugs. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Clinical Considerations Fetal/neonatal adverse reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see Warnings and Precautions (5.3)]. Teratogenic Effects - Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. OXYCONTIN should be used during pregnancy only if the potential benefit justifies the risk to the fetus. The effect of oxycodone in human reproduction has not been adequately studied. Studies with oral doses of oxycodone hydrochloride in rats up to 8 mg/kg/day and rabbits up to 125 mg/kg/day, equivalent to 0.5 and 15 times an adult human dose of 160 mg/day, respectively on a mg/m2 basis, did not reveal evidence of harm to the fetus due to oxycodone. In a pre- and postnatal toxicity study, female rats received oxycodone during gestation and lactation. There were no long-term developmental or reproductive effects in the pups [see Nonclinical Toxicology (13.1)]. Non-Teratogenic Effects Oxycodone hydrochloride was administered orally to female rats during gestation and lactation in a pre- and postnatal toxicity study. There were no drug-related effects on reproductive performance in these females or any long-term developmental or reproductive effects in pups born to these rats. Decreased body weight was found during lactation and the early post-weaning phase in pups nursed by mothers given the highest dose used (6 mg/kg/day, equivalent to approximately 0.4-times an adult human dose of 160 mg/day, on a mg/m2 basis). However, body weight of these pups recovered. 8.2 Labor and Delivery Opioids cross the placenta and may produce respiratory depression in neonates. OXYCONTIN is not recommended for use in women immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics can prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. 8.3 Nursing Mothers Oxycodone has been detected in breast milk. Instruct patients not to undertake nursing while receiving OXYCONTIN. Do not initiate OXYCONTIN therapy while nursing because of the possibility of sedation or respiratory depression in the infant. Withdrawal signs can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 8.4 Pediatric Use Safety and effectiveness of OXYCONTIN in pediatric patients below the age of 18 years have not been established. 8.5 Geriatric Use In controlled pharmacokinetic studies in elderly subjects (greater than 65 years) the clearance of oxycodone was slightly reduced. Compared to young adults, the plasma concentrations of oxycodone were increased approximately 15% [see Clinical Pharmacology (12.3)]. Of the total number of subjects (445) in clinical studies of oxycodone hydrochloride controlled-release tablets, 148 (33.3%) were age 65 and older (including those age 75 and older) while 40 (9.0%) were age 75 and older. In clinical trials with appropriate initiation of therapy and dose titration, no untoward or unexpected adverse reactions were seen in the elderly patients who received oxycodone

hydrochloride controlled-release tablets. Thus, the usual doses and dosing intervals may be appropriate for elderly patients. However, reduce the starting dose to 1/3 to 1/2 the usual dosage in debilitated, non-opioid-tolerant patients. Respiratory depression is the chief risk in elderly or debilitated patients, usually the result of large initial doses in patients who are not tolerant to opioids, or when opioids are given in conjunction with other agents that depress respiration. Titrate the dose of OXYCONTIN cautiously in these patients. 8.6 Hepatic Impairment A study of OXYCONTIN in patients with hepatic impairment demonstrated greater plasma concentrations than those seen at equivalent doses in persons with normal hepatic function. Therefore, in the setting of hepatic impairment, start dosing patients at 1/3 to 1/2 the usual starting dose followed by careful dose titration [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment In patients with renal impairment, as evidenced by decreased creatinine clearance (<60 mL/min), the concentrations of oxycodone in the plasma are approximately 50% higher than in subjects with normal renal function. Follow a conservative approach to dose initiation and adjust according to the clinical situation [see Clinical Pharmacology (12.3)]. 8.8 Gender Differences In pharmacokinetic studies with OXYCONTIN, opioid-naïve females demonstrate up to 25% higher average plasma concentrations and greater frequency of typical opioid adverse events than males, even after adjustment for body weight. The clinical relevance of a difference of this magnitude is low for a drug intended for chronic usage at individualized dosages, and there was no male/female difference detected for efficacy or adverse events in clinical trials. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance OXYCONTIN contains oxycodone, a Schedule II controlled substance with a high potential for abuse similar to other opioids including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. OXYCONTIN can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)]. The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse. 9.2 Abuse All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to, the following examples: the use of a prescription or over-the-counter drug to get “high”, or the use of steroids for performance enhancement and muscle build up. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. OXYCONTIN, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful recordkeeping of prescribing information, including quantity, frequency, and renewal requests as required by state law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to reduce abuse of opioid drugs. Risks Specific to Abuse of OXYCONTIN OXYCONTIN is for oral use only. Abuse of OXYCONTIN poses a risk of overdose and death. The risk is increased with concurrent use of OXYCONTIN with alcohol and other central nervous system depressants. Taking cut, broken, chewed, crushed, or dissolved OXYCONTIN enhances drug release and increases the risk of overdose and death. With parenteral abuse, the inactive ingredients in OXYCONTIN can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases, such as hepatitis and HIV. Summary The in vitro data demonstrate that OXYCONTIN has physicochemical properties expected to make abuse via injection difficult. The data from the clinical study, along with support from the in vitro data, also indicate that OXYCONTIN has physicochemical properties that are expected to reduce abuse via the intranasal route. However, abuse of OXYCONTIN by these routes, as well as by the oral route, is still possible. Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of OXYCONTIN on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate. OXYCONTIN contains oxycodone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit, including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. OXYCONTIN can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.1)]. 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. OXYCONTIN should not be abruptly discontinued [see Dosage and Administration (2.4)]. If OXYCONTIN is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur. Some or all

of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)]. 10 OVERDOSAGE Clinical Presentation Acute overdosage with OXYCONTIN can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdose. Such agents should be administered cautiously to persons who are known, or suspected to be physically dependent on OXYCONTIN. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. Because the duration of reversal would be expected to be less than the duration of action of oxycodone in OXYCONTIN, carefully monitor the patient until spontaneous respiration is reliably reestablished. OXYCONTIN will continue to release oxycodone and add to the oxycodone load for 24 to 48 hours or longer following ingestion necessitating prolonged monitoring. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be administered as directed in the product’s prescribing information. In an individual physically dependent on opioids, administration of the usual dose of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. CAUTION DEA FORM REQUIRED 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Addiction, Abuse and Misuse Inform patients that the use of OXYCONTIN, even when taken as recommended can result in addiction, abuse and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share OXYCONTIN with others and to take steps to protect OXYCONTIN from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression including information that the risk is greatest when starting OXYCONTIN or when the dose is increased and that it can occur even at recommended doses [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Ingestion Inform patients that accidental ingestion, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store OXYCONTIN securely and to dispose of unused OXYCONTIN by flushing the tablets down the toilet. Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of OXYCONTIN during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.3)]. Interactions with Alcohol and other CNS Depressants Inform patients that potentially serious additive effects may occur if OXYCONTIN is used with other CNS depressants, and not to use such drugs unless supervised by a health care provider. Important Administration Instructions Instruct patients how to properly take OXYCONTIN, including the following: • OXYCONTIN is designed to work properly only if swallowed intact. Taking cut, broken, chewed, crushed, or dissolved OXYCONTIN tablets can result in a fatal overdose. • OXYCONTIN tablets should be taken one tablet at a time. • Do not pre-soak, lick or otherwise wet the tablet prior to placing in the mouth. • Take each tablet with enough water to ensure complete swallowing immediately after placing in the mouth. Hypotension Inform patients that OXYCONTIN may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position). Driving or Operating Heavy Machinery Inform patients that OXYCONTIN may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in OXYCONTIN. Advise patients how to recognize such a reaction and when to seek medical attention. Pregnancy Advise female patients that OXYCONTIN can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant. Disposal of Unused OXYCONTIN Advise patients to flush the unused tablets down the toilet when OXYCONTIN is no longer needed. Healthcare professionals can telephone Purdue Pharma’s Medical Services Department (1-888-726-7535) for information on this product. Purdue Pharma L.P. Stamford, CT 06901-3431 ©2014, Purdue Pharma L.P. U.S. Patent Numbers 6,488,963; 7,129,248; 7,674,799; 7,674,800; 7,683,072; 7,776,314; 8,114,383; 8,309,060; and 8,337,888. This brief summary is based on OXYCONTIN Prescribing Information 302940-0E, Revised 04/2014 (A)


CLINICAL CONUNDRUM

most important. The ENT looked at dizziness, otalgia possibly. The general surgeon looked at nausea, etc. My thought: as all symptoms began at once, could anything connect them? I had one idea, which I needed to research. The patient was asked to return the next day (she lived relatively locally). I felt that only one thing could be associated with all symptoms at once: the vagus nerve. But how and why did the symptoms start? The patient was seen the next day. As was my tendency, when I escorted the patient to my office from my waiting room, I walked behind her so I could observe her gait and station without doing it “officially.” The patient used a cane, but when she walked, she seemed to favor her left side. I had not seen that on the official examination the day before. I went over several historical points, particularly the origin of symptoms. The patient, her husband, and I went back over the history of her pregnancy and hypothyroidism. When the patient was in the examination room on the second day, with her husband and a female nurse, I began to look at her general body contours and noted one thing: she didn’t have much of a waist. I asked the patient about her lack of a waist, and she and her husband laughed. She commented that “it made it difficult for me when I was pregnant. I didn’t have a waist before the baby and it felt like he was pushing up into my lungs.” When I asked her if she was ever short of breath when she was pregnant, she looked at me like I was an idiot and said “Of course! I was carrying almost 40 pounds that was jamming me in the stomach.” BINGO! That was the “ah-ha!” moment.

Things fell into place. My diagnosis: vagal nerve neuropathy vs autonomic nervous system (ANS) neuropathy. The vagus nerve, the 10th cranial nerve, is a main aspect of the parasympathetic nervous system. The diagnosis made sense as it could be secondary to possible initial ischemia of left phrenic nerve/crural diaphragm by constant pressure of the enlarged uterus below her diaphragm (see Figure 1). AND the vagus nerve did “connect” the stomach to the 8th cranial nerve, which controlled the vestibular system as well. Could it cause otalgia? Yes, as I had found during my research the night before, in Gastroenterology and Gray’s Anatomy.

ee

e e

MY R S ARCH AND TH M DiCAL FACTS Found in Gastroenterology3

↓ The autonomic nervous system— sympathetic (SANS) and parasympathetic (PANS) branches: PANS and SANS exit at different sites in the central nervous system. The PANS exits via the midbrain, pons, medulla (cranial nerves III, VII, IX, and X), and the sacral level of the spinal cord. The SANS exits via the thoracic and lumbar segments of the spinal cord. There is a major sympathetic output (called the splanchnic outflow) between T5 and L2.

Abstract: Sensory and motor innervation of the crural diaphragm by the vagus nerves. Conclusion: Vagal sensory and motor neurons functionally innervate the crural diaphragm (CD) and phrenoesophageal ligament. CD vagal afferents show mechanosensitivity to distortion of the gastroesophageal junction, while vagal motor neurons innervate both CD and distal esophagus and may represent a common substrate for motor control of the reflux barrier. Note my assumption that the vagus nerve enervated the crural aspect of the diaphragm was made in 1996 when this patient was seen; the above noted research was done in 2010. Question: Was the patient’s bradycardia, seen throughout her ordeal, further stigmata of the parasympathetic autonomic nervous system issue? Answer: Yes, a possibly totally overlooked clue, but bradycardia alone is not terribly unusual. But it could be associated with the Vagus nerve.

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CLINICAL CONUNDRUM Figure 1. The Crural Diaphram ↓ The vagus nerve can induce otalgia (see Figure 2): The neuroanatomic basis of referred otalgia rests within 1 of 5 general neural pathways: via the trigeminal nerve (cranial nerve V), facial nerve (cranial nerve VII), glossopharyngeal nerve (cranial nerve IX), vagus nerve (cranial nerve X), or via the second and third spinal segments, C2 and C3. Another possibility is via referred myofascial pain from myofascial trigger points in the patient’s neck, in the sternocleidomastoid muscle.

Xiphoid process

The vagus nerve can produce nausea: Gastroparesis, also called delayed gastric emptying, is a disorder that slows or stops the movement of food from the stomach to the small intestine. Normally, the muscles of the stomach, which are controlled by the vagus nerve, contract to break up food and move it through the gastrointestinal tract. Gastroparesis can occur when the vagus nerve is damaged by illness or injury and the stomach muscles stop working normally. Food then moves slowly from the stomach to the small intestine or stops moving altogether. Most people diagnosed with gastroparesis have idiopathic gastroparesis, which means a healthcare provider cannot identify the cause, even with medical tests. Diabetes is the most common known cause of gastroparesis. The most common symptoms of gastroparesis are nausea, a feeling of fullness after eating only a small amount of food, and vomiting undigested food, sometimes several hours after a meal.

Last rib opening for  lesser splanchnic nerve

Figure 2. Cranial Nerve X—Vagus Nerve

Tympanic n and plexus and auricular n

Sup. vagal ganglion

CN X

Jugular foramen

C O R T E X

Inf. (nodose) vagal ganglion —Supraglottic larynx — Laryngeal and lingual surfaces of epiglottis — Lower pharynx

Internal laryngeal branch of sup. laryngeal nerve and the pharyngeal branch of the vagus nerve (CN X)

Primary and referred otalgia pathways of the vagus nerve (X). Cranial nerve X is involved with otalgia via the auricular nerve of Arnold. Adapted from Am J Clin Oncol. 2003;26:e157–162.

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e

e

TR ATM NT ↓ Medications: Carbamazepine ACM (an anticonvulsant medication), potentiates GABA receptors; stabilizes the inactivated state of voltage-gated sodium channels. Gabapentin binds to the α2 δ subunits (1 and 2) and has been found to reduce calcium currents after chronic but not acute application via an effect on trafficking of voltage-dependent calcium channels in the central nervous system. Bellergal ST, ergotamine, belladonna alkaloids, and phenobarbital combination for ANS relaxation (also used for both tension-type and frequent migraine headaches as well as menopausal symptom suppressant). The ergotamine, belladonna alkaloids, and phenobarbital combination has also been used for its autonomic effects in the treatment of various cardiovascular, gastrointestinal, and genitourinary disorders. Withdrawn from market when FDA took ergot combinations off of the market. Meclizine for motion sickness and vertigo, 25 to 100 mg BID or TID.

The patient was started on carbamazepine (remember that this was in mid-1990s) and titrated up to 200 mg TID. She was also started on Bellergal ST for autonomic nervous system “relaxation.” ( NOTE: the FDA has taken all partial ergot containing drugs, including Bellergal, off the market.) She was also placed on meclizine. I got the impression that the dizziness was more like car sickness. I recommended that she continue Zofran as needed, as well as the thyroid medications, Percocet, and multivitamins. Three weeks later, the patient was on carbamazepine 200 TID, Bellergal ST, and meclizine, and her symptoms were: otalgia 3–4/10 (down from 9/10); dizziness moderate towards mild (4/10); nausea, less (3/10 and taking less Zofran). I added gabapentin 300 mg BID (off label at the time). The patient started in clinical psychology for testing and treatment for depression as well as physical therapy for reconditioning. Lastly, the patient was started in biofeedback therapy for relaxation training. Why not do this earlier? After her experiences, I didn’t want her to think that I felt her symptoms were “all in her head.” She was not hysterical and it was only after she saw a significant decrease in her physiological symptoms that she became open to the idea that treatment of her depression and relaxation would be helpful. Within 2 more months, the patient’s otalgia was 1–2/10; her dizziness was minimal and nausea was minimal. She continued to go to PT, psych, and she especially loved biofeedback. She had returned to work on a part-time basis. She asked if she could go to see an acupuncturist, as she saw she was getting better and wanted to do whatever she could to hasten it. The patient was sent to a Doctor of Oriental Medicine ( DOM ) for acupuncture and, after a phone consultation during which I made certain that the DOM understood the medications the patient was taking, she also began a course of herbal medication. Six months after her initial presentation to me, the patient had returned to work full time. Her otalgia was negligible and she took Percocet rarely; her dizziness was gone and her nausea was gone. Over the course of the next several years, she had a return of her symptoms 3 times during menses that occurred in association with significant stress in her life. The patient’s medications were weaned off after a year, with the patient taking: Tegretol® 200 mg BID (no ECG changes); Bellergal ST 1–2/day, and Antivert®, rarely.

CONCLUSiON I am not certain whether the apparent neuropathy was either vagal motor/sensory or ANS, but the anticonvulsant medications obviously worked. My gut tells me it was vagal. Later, I was able to find one article that essentially proved my theory. It was written by Dr. Blau, a headache specialist I had known from the UK . Here are excerpts from the abstract for his article “Ear pain referred by the vagus”4: “Pain may be referred from a hiatus hernia to one ear and spread to the first division of the trigeminal nerve on the same side. …The pain, a severe deep seated ache, was felt inside his right ear (he pointed to the external auditory meatus with his index finger) radiating upwards and forward over the right parietal region to the right temple. He had tried various analgesics, deriving some benefit, but he had gained complete relief about 30 minutes after taking antacids, magnesium trisilicate, or a proprietary preparation containing light magnesium carbonate.” “His wife, who accompanied him, said that 2 doctors had curtly dismissed the idea that antacids could relieve headache.”

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CLINICAL CONUNDRUM

“  CHRONiC PAiN iS iNDeeD A BiOPSYCHOSOCiAL PROBLeM: iF YOU DON’T ATTeND TO ALL ASPeCTS THE PATieNT WON’T GeT BeTTeR.”

I called Dr. Blau and he agreed with my diagnosis. He had written of his own case: “This case supports the hypothesis that unilateral facial pain may be referred by the vagus… Pain in the ear or pressure across the bridge of the nose are ‘heart sinkers’ because usually there is no cause to be found and we are bereft of ideas on pathogenesis or treatment. This case report, however, shows that aural pain, albeit rarely, may arise from a hiatus hernia. Perhaps gastroenterologists have encountered this picture or might look out for this syndrome in the future.”

The purpose of this article is NOT in any way to focus on the author. It deals with and should resonate with the reader that “focused examinations” limited to a patient’s symptoms are not appropriate until you have done a full examination of the entire body and all systems and learned about the psychological and sociological aspects of the patient’s life. Chronic pain is indeed a biopsychosocial problem: if you don’t attend to all aspects the patient won’t get better. I believe that if these 13 physicians were not looking at the patient just through their monoculars, which were attuned to their specialties, the patient may have been correctly diagnosed and treated earlier.

References 1.

Epocrates website definitions. Available at: www.epocrates.com.

2. Brunton L, Chabner L, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition. New York, NY: McGraw-Hill Professional; 2010. 3. Young RL , Page AJ, Cooper NJ, et al. Sensory and motor innervation of the crural diaphragm by the vagus nerves. Gastroenterology. 2010;138(3):1091–1101. 4. Blau JN . Ear pain referred by the vagus. BMJ . 1989;299:1569–1570. 5. Scarbrough TJ, Day TA , Williams TE, et al. Referred otalgia in head and neck cancer: a unifying schema. Am J Clin Oncol. 2003;26:e157-162.

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(fenoprofen calcium capsules) 400 mg Fast and Effective, Move On With Nalfon Safety Information Nalfon® is indicated for relief of mild to moderate pain in adults and for relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis.

Cardiovascular Risk • Non-steroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS). • Nalfon® is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS). Nalfon® is contraindicated in patients who have shown hypersensitivity to fenoprofen calcium. Nalfon® should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. Nalfon® is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. Nalfon® is contraindicated in patients with a history of significantly impaired renal function. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. After observing the response to initial therapy with Nalfon, the dose and frequency should be adjusted to suit an individual patient's needs.

Request Information and Rx Co-pay Cards* Scan the QR code to request more information on Nalfon or to request co-pay cards. Your patients will pay no more than $15 on co-pays up to $50. *Valid for Initial Script and 5 Refills. View Complete Details.

Copyright © 2014, Xspire Pharma, Ridgeland, MS 39157

42195-308-09


(fenoprofen calcium capsules) 400 mg

What makes NALFON a unique and different non-steroidal anti-inflammatory patient option? NALFON is Safe... During clinical studies, Nalfon had less than 2% discontinuation rate due to gastrointestinal adverse reactions.

NALFON is Effective... • Nalfon has more clinician use and prescriptions than any other branded NSAID with over 40 years of use and in excess of 37 million prescriptions. • Nalfon reaches peak plasma levels within 2 hours of administration. Peak Levels (2 hours)

0

1

2

3

90% of a single oral dose is eliminated within 24-hours as fenoprofen glucuronicle and 4-hydroxfenoprofen glucuronide, the majority urinary metabolites of fenoprofen. 4

5

6

7

8

9

NALFON is Flexible... Unlike other commonly prescribed NSAIDs with QID dosing, Nalfon is dosed TID for better patient compliance.

NALFON is Cost Effective... • Nalfon is covered by 90% of all commercial plans with a patient co-pay. • Nalfon is covered by Medicare-D plans and Tri-Care. • Only Nalfon offers patients a “Pay No More Than $15” instant pharmacy rebate. Safety Information Nalfon® is indicated for relief of mild to moderate pain in adults and for relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis. Cardiovascular Risk • Non-steroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS). • Nalfon® is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS). For more information on Nalfon 400 mg, visit www.nalfon.com


(fenoprofen calcium capsules) 400 mg TM

Technology

• Nalfon is the only fenoprofen calcium available in a capsule preparation. • Nalfon is rapidly absorbed with a 30-minute onset of action. • Nalfon is readily bound to plasma proteins at 99%.

Recommended Dosing Carefully consider the potential benefits and risks of Nalfon and other treatment options before deciding to use Nalfon. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

Nalfon is indicated: • For relief of mild to moderate pain in adults. • For relief of the signs and symptoms of rheumatoid arthritis. • For relief of the signs and symptoms of osteoarthritis.

After observing the response to initial therapy with Nalfon, the dose and frequency should be adjusted to suit an individual patient's needs. • The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity of the symptoms. • Total daily dosage should not exceed 3200 mg. • Nalfon may be administered with meals or with milk. • The smallest dose that yields acceptable control should be employed.

(feno

profen calcium capsule s) 400 m

Disp

* NALFON 400 mg EP 123

*Not actual size

Use this Nalfon 400 mg capsule for identification.

g

90 C aps Take 1 Cap Q8 H PRN rs Pain Infla a n d mma tion

Contraindications Nalfon® is contraindicated in patients who have shown hypersensitivity to fenoprofen calcium. Nalfon® should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. Nalfon® is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. Nalfon® is contraindicated in patients with a history of significantly impaired renal function. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. After observing the response to initial therapy with Nalfon, the dose and frequency should be adjusted to suit an individual patient's needs.

Nalfon ©2011 is a registered trademark of Xspire Pharma. WraSer Pharmaceuticals R1NF0210ZJ02


NALFON ®

(fenoprofen calcium capsules, USP) 200 mg and 400 mg

Rx ONLY

Cardiovascular Risk • Non-Steroidal Anti-Inflammatory (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (See WARNINGS). • Nalfon® is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at great-er risk for serious gastrointestinal events (see WARNINGS). DESCRIPTION Nalfon® (fenoprofen calcium capsules, USP) is a nonsteroidal, anti-inflammatory, antiarthritic drug. Nalfon capsules contain fenoprofen calcium as the dihydrate in an amount equivalent to 200 mg (0.826 mmol) or 400 mg (1.65 mmol) of fenoprofen. The 200 mg capsules contain cellulose, gelatin, iron oxides, silicone, titanium dioxide, and other inactive ingredients. The 400mg capsules contain gelatin, sodium lauryl sulfate, iron oxide yellow, FD&C Blue 1, titanium dioxide, FD&C Red 40, crospovidone, talc, and magnesium stearate. Chemically, Nalfon is an arylacetic acid derivative. Nalfon is a white crystalline powder that has the structural formula C30H26CaO6•2H2O representing a molecular weight of 558.65. At 25°C, it dissolves to a 15 mg/mL solution in alcohol (95%). It is slightly soluble in water and insoluble in benzene. The pKa of Nalfon is a 4.5 at 25°C. CLINICAL PHARMACOLOGY Nalfon is a nonsteroidal, anti-inflammatory, antiarthritic drug that also possesses analgesic and antipyretic activities. Its exact mode of action is unknown, but it is thought that prostaglandin synthetase inhibition is involved. Results in humans demonstrate that fenoprofen has both antiinflammatory and analgesic actions. The emergence and degree of erythemic response were measured in adult male volunteers exposed to ultraviolet irradiation. The effects of Nalfon, aspirin, and indomethacin were each compared with those of a placebo. All 3 drugs demonstrated antierythemic activity. In all patients with rheumatoid arthritis, the anti-inflammatory action of Nalfon has been evidenced by relief of pain, increase in grip strength, and reductions in joint swelling, duration of morning stiffness, and disease activity (as assessed by both the investigator and the patient). The anti-inflammatory action of Nalfon has also been evidenced by increased mobility (i.e., a decrease in the number of joints having limited motion). The use of Nalfon in combination with gold salts or corticosteroids has been studied in patients with rheumatoid arthritis. The studies, however, were inadequate in demonstrating whether further improvement is obtained by adding Nalfon to maintenance therapy with gold salts or steroids. Whether or not Nalfon used in conjunction with partially effective doses of a corticosteroid has a “steroid-sparing” effect is unknown. In patients with osteoarthritis, the anti-inflammatory and analgesic effects of Nalfon have been demonstrated by reduction in tenderness as a response to pressure and reductions in night pain, stiffness, swelling, and overall disease activity (as assessed by both the patient and the investigator). These effects have also been demonstrated by relief of pain with motion and at rest and increased range of motion in involved joints. In patients with rheumatoid arthritis and osteoarthritis, clinical studies have shown Nalfon to be comparable to aspirin in controlling the aforementioned measures of disease activity, but mild gastrointestinal reactions (nausea, dyspepsia) and tinnitus occurred less frequently in patients treated with Nalfon than in aspirin-treated patients. It is not known whether Nalfon causes less peptic ulceration than does aspirin. In patients with pain, the analgesic action of Nalfon has produced a reduction in pain intensity, an increase in pain relief, improvement in total analgesia scores, and a sustained analgesic effect. Under fasting conditions, Nalfon is rapidly absorbed, and peak plasma levels of 50 μg/mL are achieved within 2 hours after oral administration of 600 mg doses. Good dose proportionality was observed between 200 mg and 600 mg doses in fasting male volunteers. The plasma half-life is approximately 3 hours. About 90% of a single oral dose is eliminated within 24 hours as fenoprofen glucuronide and 4'-hydroxyfenoprofen glucuronide, the major urinary metabolites of fenoprofen. Fenoprofen is highly bound (99%) to albumin. The concomitant administration of antacid (containing both aluminum and magnesium hydroxide) does not interfere with absorption of Nalfon. There is less suppression of collagen-induced platelet aggregation with single doses of Nalfon than there is with aspirin. INDICATIONS AND USAGE Carefully consider the potential benefits and risks of Nalfon and other treatment options before deciding to use Nalfon. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Nalfon is indicated: • For relief of mild to moderate pain in adults. • For relief of the signs and symptoms of rheumatoid arthritis. • For relief of the signs and symptoms of osteoarthritis. CONTRAINDICATIONS Nalfon is contraindicated in patients who have shown hypersensitivity to fenoprofen calcium. Nalfon should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS – Anaphylactoid Reactions, and PRECAUTIONS – Preexisting Asthma). Nalfon is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Nalfon is contraindicated in patients with a history of significantly impaired renal function (see WARNINGS – Advanced Renal Disease). WARNINGS - CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may give a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS - Gastrointestinal Effects). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS). Hypertension NSAIDs, including Nalfon, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Nalfon, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Nalfon should be used with caution in patients with fluid retention, compromised cardiac function or heart failure. The possibility of renal involvement should be considered. Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation NSAIDs, including Nalfon, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or de-bilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decomposition. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of Nalfon in patients with advanced renal disease. There-fore, treatment with Nalfon is not recommended in patients with advanced renal disease. (See CONTRAINDICATIONS). Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Nalfon. Nalfon should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS - Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Skin Reactions NSAIDs, including Nalfon, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hyper-sensitivity. Pregnancy Starting at 30-weeks gestation, Nalfon and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. Ocular Studies to date have not shown changes in the eyes attributable to the administration of Nalfon. However, adverse ocular effects have been observed with other anti-inflammatory drugs. Eye examinations, therefore, should be performed if visual disturbances occur in patients taking Nalfon. Central Nervous System Caution should be exercised by patients whose activities require alertness if they experience CNS side effects while taking Nalfon. Hearing Since the safety of Nalfon has not been established in patients with impaired hearing, these patients should have periodic tests of auditory function during prolonged therapy with Nalfon. PRECAUTIONS - General Nalfon cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of Nalfon in reducing inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Nalfon. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Nalfon. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Nalfon should be discontinued. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including Nalfon. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Nalfon, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Nalfon who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Nalfon should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Information for Patients - Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. 1. Nalfon, like other NSAIDs, may cause serious CV side effects, such as myocardial infarction (MI) or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). 2. Nalfon, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can oc-

cur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS - Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation). 3. Nalfon, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hy-persensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. 5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. 6. Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). 7. Starting at 30-weeks gestation, Nalfon and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Nalfon should be discontinued. Drug Interactions - ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. Aspirin The coadministration of aspirin decreases the biologic half-life of fenoprofen because of an increase in metabolic clearance that results in a greater amount of hydroxylated fenoprofen in the urine. Although the mechanism of interaction between fenoprofen and aspirin is not totally known, enzyme induction and displacement of fenoprofen from plasma albumin binding sites are possibilities. As with other NSAIDs, concomitant administration of fenoprofen calcium and aspirin is not generally recommended because of the potential of increased adverse effects. Diuretics Clinical studies, as well as post marketing observations, have shown that Nalfon can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has

been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS - Renal Effects), as well as to assure diuretic efficacy. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. Phenobarbital Chronic administration of phenobarbital, a known enzyme inducer, may be associated with a decrease in the plasma half-life of fenoprofen. When phenobarbital is added to or withdrawn from treatment, dosage adjustment of Nalfon may be required. Plasma Protein Binding In vitro studies have shown that fenoprofen, because of its affinity for albumin, may displace from their binding sites other drugs that are also albumin bound, and this may lead to drug interactions. Theoretically, fenoprofen could likewise be displaced. Patients receiving hydantoins, sulfonamides, or sulfonylureas should be observed for increased activity of these drugs and, therefore, signs of toxicity from these drugs. Drug/Laboratory Test Interactions Amerlex-M kit assay values of total and free triiodothyronine in patients receiving Nalfon have been reported as falsely elevated on the basis of a chemical cross-reaction that directly interferes with the assay. Thyroidstimulating hormone, total thyroxine, and thyrotropin-releasing hormone response are not affected. Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of fenoprofen. Studies have not been conducted to determine the effect of fenoprofen on mutagenicity or fertility. Pregnancy - Teratogenic Effects. Pregnancy Category - C Prior to 30-Weeks Gestation; Category D starting at 30-Weeks Gestation. Starting at 30-weeks gestation, Nalfon and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. Nalfon can cause fetal harm when administered to a pregnant woman starting at 30-weeks gestation. If this drug is used during this time period in pregnancy, the patient should be apprised of the potential hazard to a fetus. There are no adequate and well-controlled studies in pregnant women. Prior to 30-weeks gestation, Nalfon should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities when given daily oral doses of 50 or 100 mg/kg fenoprofen calcium, respectively (0.15 and 0.6 times the maximum human daily dose of 3,200 mg based on body surface area comparisons). However, animal reproduction studies are not always predictive of human response. Nonteratogenic Effects Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Labor and Delivery The effects of Nalfon on labor and delivery in pregnant women are unknown. In rat studies, maternal exposure to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, increased the incidence of dystocia, delayed parturition, and decreased pup survival. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Nalfon, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients under the age of 18 have not been established. Geriatric Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). ADVERSE REACTIONS During clinical studies for rheumatoid arthritis, osteoarthritis, or mild to moderate pain and studies of pharmacokinetics, complaints were compiled from a checklist of potential adverse reactions, and the following data emerged. These encompass observations in 6,786 patients, including 188 observed for at least 52 weeks. For comparison, data are also presented from complaints received from the 266 patients who received placebo in these same trials. During short-term studies for analgesia, the incidence of adverse reactions was markedly lower than that seen in longer-term studies. Adverse Drug Reactions Reported in >1% of Patients During Clinical Trials Digestive System— During clinical trials with Nalfon, the most common adverse reactions were gastrointestinal in nature and occurred in 20.8% of patients receiving Nalfon as compared to 16.9% of patients receiving placebo. In descending order of frequency, these reactions included dyspepsia (10.3% Nalfon vs. 2.3% placebo), nausea (7.7% vs. 7.1%), constipation (7% vs. 1.5%), vomiting (2.6% vs. 1.9%), abdominal pain (2% vs. 1.1%), and diarrhea (1.8% vs. 4.1%). The drug was discontinued because of adverse gastrointestinal reactions in less than 2% of patients during premarkeing studies. Nervous System —The most frequent adverse neurologic reactions were headache (8.7% vs. 7.5%) and somnolence (8.5% vs. 6.4%). Dizziness (6.5% vs. 5.6%), tremor (2.2% vs. 0.4%), and confusion (1.4% vs. none) were noted less frequently. Nalfon was discontinued in less than 0.5% of patients because of these side effects during premarketing studies. Skin and Appen-dages—Increased sweating (4.6% vs. 0.4%), pruritus (4.2% vs. 0.8%), and rash (3.7% vs. 0.4%) were reported. Nalfon was discontinued in about 1% of patients because of an adverse effect related to the skin during premarketing studies. Special Senses—Tinnitus (4.5% vs. 0.4%), blurred vision (2.2% vs. none), and decreased hearing (1.6% vs. none) were reported. Nalfon was discontinued in less than 0.5% of patients because of adverse effects related to the special senses during premarketing studies. Cardiovascular—Palpitations (2.5% vs. 0.4%). Nalfon was discontinued in about 0.5% of patients because of adverse cardiovascular reactions during premarketing studies. Miscellaneous—Nervousness (5.7% vs. 1.5%), asthenia (5.4% vs. 0.4%), peripheral edema (5.0% vs. 0.4%), dyspnea (2.8% vs. none), fatigue (1.7% vs. 1.5%), upper respiratory infection (1.5% vs. 5.6%), and nasopharyngitis (1.2% vs. none). Adverse Drug Reactions Reported in <1% of Patients During Clinical Trials Digestive System—Gastritis, peptic ulcer with/without perforation, gastrointestinal hemorrhage, anorexia, flatulence, dry mouth, and blood in the stool. Increases in alkaline phosphatase, LDH, SGOT, jaundice, and cholestatic hepatitis, aphthous ulcerations of the buccal mucosa, metallic taste, and pancreatitis (see PRECAUTIONS). Cardiovascular—Atrial fibrillation, pulmonary edema, electrocardiographic changes, and supraventricular tachycardia. Genitourinary Tract—Renal failure, dysuria, cystitis, hematuria, oliguria, azotemia, anuria, interstitial nephritis, nephrosis, and papillary necrosis (see WARNINGS). Hypersensitivity—Angioedema (angioneurotic edema). Hematologic—Purpura, bruising, hemorrhage, thrombocytopenia, hemolytic anemia, aplastic anemia, agranulocytosis, and pancytopenia. Nervous System—Depression, disorientation, seizures, and trigeminal neuralgia. Special Senses—Burning tongue, diplopia, and optic neuritis. Skin and Appendages—Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, and alopecia. Miscellaneous—Anaphylaxis, urticaria, malaise, insomnia, tachycardia, personality change, lymphadenopathy, mastodynia, and fever. OVERDOSAGE Signs and Symptoms—Symptoms of overdose appear within several hours and generally involve the gastrointestinal and central nervous systems. They include dyspepsia, nausea, vomiting, abdominal pain, dizziness, headache, ataxia, tinnitus, tremor, drowsiness, and confusion. Hyperpyrexia, tachycardia, hypotension, and acute renal failure may occur rarely following overdose. Respiratory depression and metabolic acidosis have also been reported following overdose with certain NSAIDs.Treatment—To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Con-trol Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal. Alkalinization of the urine, forced diuresis, peritoneal dialysis, hemodialysis, and charcoal hemoperfusion do not enhance systemic drug elimination. DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of Nalfon and other treatment options before deciding to use Nalfon. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with Nalfon, the dose and frequency should be adjusted to suit an individual patient's needs. Analgesia For the treatment of mild to moderate pain, the recommended dosage is 200 mg given orally every 4 to 6 hours, as needed. Rheumatoid Arthritis and Osteoarthritis For the relief of signs and symptoms of rheumatoid arthritis or osteoarthritis the recommended dose is 400 to 600 mg given orally, 3 or 4 times a day. The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity of the symptoms. Dosage adjustments may be made after initiation of drug therapy or during exacerbations of the disease. Total daily dosage should not exceed 3,200 mg. Nalfon may be administered with meals or with milk. Although the total amount absorbed is not affected, peak blood levels are delayed and diminished. Patients with rheumatoid arthritis generally seem to require larger doses of Nalfon than do those with osteoarthritis. The smallest dose that yields acceptable control should be employed. Although improvement may be seen in a few days in many patients, an additional 2 to 3 weeks may be required to gauge the full benefits of therapy. HOW SUPPLIED Nalfon® (fenoprofen calcium capsules, USP) are available in: The 200 mg* capsule is opaque yellow No. 97 cap and opaque white body, imprinted with “RX681” on the cap and body. NDC 42195-308-10 Bottles of 100. The 400 mg* capsule is opaque green cap and opaque blue body, imprinted with “NALFON 400 mg” on the cap and “EP 123” on the body. NDC 42195-308-09 Bottles of 90 *Equivalent to fenoprofen. Preserve in well-closed containers. Store at 20° - 25° C (68° - 77° F). (See USP Controlled Room Temperature). ATTENTION DISPENSER: Accompanying Medication Guide must be dispensed with this product.

NSAID medicines that need a prescription Generic Name Trade Name Celecoxib Diclofenac Diflunisal Etodolac Fenoprofen Flurbiprofen Ibuprofen Indomethacin Ketoprofen Ketorolac Mefenamic Acid Meloxicam Nabumetone Naproxen Oxaprozin Piroxicam Sulindac Tolmetin

Celebrex Cataflam, Voltaren, Arthrotec (combined with misoprostol) Dolobid Lodine, Lodine XL Nalfon, Nalfon 200 Ansaid Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with oxycodone) Indocin, Indocin SR, Indo-Lemmon, Indomethagan Oruvail Toradol Ponstel Mobic Relafen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole) Daypro Feldene Clinoril Tolectin, Tolectin DS, Tolectin 600

This Medication Guide has been approved by the U.S. Food and Drug Administration.

*Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke.

Manufactured by: Emcure Pharmaceuticals, USA East Brunswick, NJ 08896 Manufactured for: Xspire Pharma Ridgeland, MS 39157 Rev. 08/2012

References 1. Wk Prescription Sales Data, 2012 2. Podiatry Today, Vol. 19, Issue 3 3. Nalfon Package Insert, July 2009 4. Medispan, 2012


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TH SiNGL POiNT OF ACC SS FOR FRONTLiN PRACTiTiON RS

PAINWeek is now the single point of access for busy practitioners, spanning live, digital, and print communications. You can now look to PAINWeek for timely coverage of the vast array of issues in pain management—diagnosis, research, and the evolving legal/ regulatory landscape for prescribing clinicians. Go to www.painweek.org and click “JOiN”

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●● One-Minute Clinician F ATUR S: “BRAINFOOD” that you can put to use right away, ●● PAINWeek eNewsletter News in pain management and information on upcoming every day PAINWeek activities. ●● PWJ — PAINWeek Journal Feature Highlight ●● Conference Registration News Excerpts and links to articles from our quarterly pain Alerts on discounts and special deals on PAINWeek and management publication. PAINWeekEnd conferences. ●● Pundit Profile ●● Expert Opinion What makes our faculty tick—who inspired them, their Video interviews with PAINWeek faculty on key topics greatest achievements, and the legacies they hope to like risk assessment, rational polypharmacy, differential leave behind. Find out in these insightful interviews with diagnosis of migraine headache and more! PAINWeek faculty.

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Rosenfeld MD

by Victor


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N UROLOGY

Restless legs syndrome is a common disorder seen in approximately 15% of the population. It can have a myriad of symptoms and is diagnosed on clinical grounds established by the National Institutes of Health. This article focuses on the history, pathophysiology, and diagnosis of restless legs syndrome, as well as the genetics, epidemiology, laboratory, and other testing that can be used in its workup. abstract:

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NEUROLOGY

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HiSTORY OF R STL SS L GS SYNDROM The original description of restless legs syndrome ( RLS) probably dates back to 1652. Sir Thomas Willis, a physician and neuroanatomist most famously associated with the cerebral vascular term Circle of Willis, described “Night-Crawler Syndrome” or akathisia.1 It was later discussed by Dr. Karl Axel Ekbom who coined the term RLS in the 1950s.2 Ekbom produced extensive publications on the subject and predicted an incidence of 5% to 15% of the population, which is in line with what we think today. In addition he correlated RLS with iron deficiency, which we know now is related to both the primary and secondary pathogenesis of RLS.3-5

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CLiNiCAL SYMPTOMS AND CRiT RiA The current National Institutes of Health ( NIH ) criteria for RLS has 4 cardinal symptoms, remembered by the acronym URGE —Urge to move legs associated with unpleasant sensation. Worsening of symptoms with Rest. Improvement of symptoms with movement or Getting up. Symptoms tend to increase in Evening and night.6 All 4 must be positive for patients to meet the criteria. Restless legs is a clinical diagnosis; there is no biomarker, exam finding, or electrophysiologic testing required to confirm the diagnosis. Patients with RLS describe many other symptoms besides the classic restlessness and need to move, such as creepy-crawly sensations, or even neuropathic symptoms such as burning and tingling. In more severe cases symptoms can also include the upper extremities and, rarely, can be lateralized confounding the differential diagnosis with peripheral and central nervous system diseases. In current studies, approximately 10% to 15% of the northern European population suffers from RLS, but accurate demographics in other populations are not yet clear.7 Family history of RLS is seen in approximately 50% of patients and can occur in both a sporadic as well as autosomal dominant pattern.8 Usually those with early onset symptoms, before age 45, will have a strong family history of RLS and tend to have more pronounced symptoms. However, the clinician will need to be vigilant for the secondary causes of RLS that can be tested and treated accordingly and will be discussed below.

an overnight sleep study.9 However, PLMD may or may not be clinically relevant as patients with PLMD may not suffer with RLS symptoms and, vice-versa, patients with RLS may not have PLMD seen on a sleep study. PLMD involves excessive movement during sleep. Polysomnography scoring criteria for PLMD requires stereotyped limb movements that are over .5 seconds, at least 4 movements, separated by more than 5 seconds, for less than 90 seconds. Over 15 periodic limb movements per hour in adults, or over 5 per hour in pediatric patients, is considered to be significant, especially if they are associated with disturbed sleep or resulting in daytime sleepiness or fatigue. Interestingly medications for the treatment of PLMD are the same as those used to treat RLS and are listed in the Table, but there is no FDA-approved medication for the treatment of PLMD.

Table. Medications Commonly Used in RLS and PLMD Medication

Dosage*

Clonazepam

.5–2 mg

Valproate

500–2000 mg

Topiramate

50–200 mg

Gabapentin

300–1200 mg

Pregabalin

50–200 mg

Hydrocodone

5–10 mg

Pramipexole

.25–1 mg

Ropinirole

.5–3 mg

Gabapentin enacarbil

600 mg at 6 PM

Rotigotine transdermal

1–4 mg daily

*  every night at bedtime unless otherwise indicated

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T STiNG As previously mentioned, RLS is a clinical diagnosis and does not require any formal testing. It has been suggested that RLS can be “tested” by using the suggested immobilization test, or SIT, a polysomnogram format utilizing leg electromyogram ( EMG) leads during the day for 1 hour. The subject sits comfortably awake and upright in bed with legs outstretched. RLS is supported when more than 40 periodic leg movements of wake occur per hour. Though it may appear on sleep board questions, SIT is not commonly used in clinical practice to diagnose RLS, as it is not required to fulfill current diagnostic criteria. Restless legs is frequently confused with periodic limb movement disorder ( PLMD). PLMD is not synonymous with RLS nor is it necessary for the diagnosis. PLMD can be seen in 80% to 90% of the polysomnograms in patients with a history of RLS during

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Occasionally EMG/nerve conduction testing for peripheral neuropathy or lumbar radiculopathy is performed especially if the physical exam suggests focal neurologic deficits or if symptoms have a predominantly neuropathic quality. If RLS and PLMD coexist, or if the clinician is specifically concerned about PLMD without RLS, then overnight polysomnography in a sleep lab should be considered. Though B12 or hemoglobin labs are recommended in patients with neuropathic complaints, all patients with RLS should be screened for iron deficiency. Consequently, it is recommended that all patients with RLS have iron saturation and ferritin studies performed. If a patient is iron deficient or if ferritin is <50 ug/L, iron supplementation is recommended. Iron levels should be optimized prior to any other treatment being initiated.10 Q3  | 2014


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CAUS S OF RLS studies have shown abnormalities in the substantia nigra with reduced As mentioned, Ekbom associated iron deficiency with RLS. Common ferritin and iron transporters.11 This helps explain why dopamine causes of secondary RLS include pregnancy, gastric surgery, iron agonist helps RLS symptoms and why dopamine antagonism will deficiency anemia, and end-stage renal disease. RLS has also been worsen RLS symptoms. associated with thyroid disease, peripheral neuropathy, lumbar radiculopathy, ADHD, and fibromyalgia, though these latter cases are A number of gene foci, such as those located on chromosome 12q thought to mimic RLS due to neurologic causes rather than repre- (French families), chromosome 14q (Italian families), and chromosome 9p (American families), have been linked to RLS. Other gene senting true RLS pathology. foci associated with RLS are located on chromosome 20p (French Differential diagnoses of RLS include: Canadian), chromosome 2p (South Tyrol), and also chromosome 16p (also French Canadian).12-18 ● Positional discomfort ● Sleep starts (hypnic jerks) ● PLMD TR ATM NT ● Sleep-related leg cramps Treatment usually begins after the 4th decade of life, but in patients ● Peripheral neuropathy with a strong family history treatment frequently is sought earlier. ● Lumbar radiculopathy Over-the-counter approaches can include quinine (260 mg every ● ADHD night at bedtime) or a glass of tonic water. Magnesium in higher ● Fibromyalgia doses (500 to 1000 mg per day) can also be helpful though GI upset is common with the salt forms of magnesium; magnesium malate The first clues as to the cause of primary RLS came from the treat- or gluconate is usually recommended. Lack of exercise, obesity, and ment of Parkinson’s patients with dopa agonists. Many patients with tobacco use are associated with RLS. Exercise and other lifestyle Parkinson’s disease given dopa agonists, even in very small dosages, changes are typically recommended. reported a significant improvement of their lower extremity akathisias and RLS symptoms. Dopa agonists were then used off label for RLS Iron replacement should always be performed if ferritin or iron satin patients without Parkinson’s disease with similarly low dosages and uration are low. Typically patients will respond to oral iron supsimilar benefit. Shortly thereafter pramipexole and ropinirole were plementation, but in many cases IV iron infusions are necessary to FDA approved for RLS. keep ferritin levels >50 ug/L.19 The most commonly used medications for RLS include benzodiazepines, anticonvulsants, narcotics, We now know that the rate limiting reaction for dopamine synthesis muscle relaxants, and dopa agonists (see Table). Levodopa/carbidopa is tyrosine hydroxylase for which iron is the critical cofactor. It is thus (Sinemet®) may encourage “anticipation,” where patients experience considered that primary RLS may represent a central nervous system their symptoms earlier and earlier during the day, and is therefore form of iron deficiency which is bypassed by the use of dopa agonist. not considered first-line therapy at this time.20 Two newer medicaIt is also thought that iron deficiency may reduce dopamine receptor tions recently FDA approved for RLS, gabapentin enacarbil and the DA 2 type binding sites in the central nervous system. Postmortem rotigotine transdermal system, are particularly effective.

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Gabapentin enacarbil extended release (Horizant®) is available in only 1 dose, 600 mg, and is recommended to be taken at 6pm, a few hours before sleep. It is well tolerated and effective. Most common side effects of gabapentin enacarbil extended release include sedation, dizziness, headache, fatigue, and nausea.21 Rotigotine transdermal system (Neupro®) is a dopa agonist that is available in 1, 2, 4, 8 mg patches, used daily, and is very effective in the treatment of RLS. In my experience, there is lower incidence of side effects using the transdermal system effect compared to the oral dopa agonists. Most common side effects of rotigotine transdermal system include local site reactions, nausea, somnolence, and headache. Gambling and other addictive behaviors which can be seen with the oral dopa agonists have not as yet been described with the rotigotine transdermal system.22 A common cause of referral to a sleep center for treatment of RLS is iatrogenesis, as many prescription as well as OTC medications can exacerbate RLS symptoms. Since we know that dopa agonism helps RLS, it is understandable that dopamine antagonists, commonly used to treat mood and behavior disorders, will induce symptoms. Any medication that significantly increases the activating neurotransmitters (such as serotonin, norepinephrine, and dopamine) and activating neuromodulators (such as histamines) can also exacerbate RLS symptoms. Consequently the use of OTC sleep aids and allergy medicines that contain antihistamines are the most common causes of induced or exacerbated RLS. Most antidepressants, including tricyclics (amitriptyline), serotonin and norepinephrine reuptake inhibitors (venlafaxine, duloxetine), and serotonin specific reuptake inhibitors (sertraline, paroxetine) are all associated with RLS exacerbation.23,24 In May of 2014, the FDA approved the first topical device for the treatment of RLS. The “relaxis” is a noninvasive, and nonpharmaceutical device that the patient lays on in bed which produces vibration that gradually ramps up then down over 30 minutes. It was found to be superior to placebo in 2 controlled trials. Side effects may include worsening of RLS symptoms. It will be available by prescription only.25,26

6. Allen RP, Picchietti D, Hening WA , et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. Sleep Med. 2003;4:101–119. 7. Allen RP, Stillman P, Myers AJ . Physician-diagnosed restless legs syndrome in a large sample of primary medical care patients in western Europe: prevalence and characteristics. Sleep Med. 2010;11(1):31–37. 8. Hening W, Walters AS, Allen RP, et al. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med. 2004;5:237–246. 9. Coleman RM . Periodic movements in sleep (nocturnal myoclonus) and restless legs syndrome. In: Guilleminault C, ed. Sleeping and Waking Disorders: Indications and Techniques. Menlo Park, CA: Addison-Wesley; 1982:265–295. 10. Mizuno S, Mihara T, Miyaoka T, et al. CSF iron, ferritin and transferrin levels in restless legs syndrome. J Sleep Res. 2005;14:43–47. 11. Allen RP, Barker PB, Wehrl F, et al. MRI measurement of brain iron in patients with restless legs syndrome. Neurology. 2001;56:263–265. 12. Winkelmann J, Polo O, Provini F, et al. Genetics of restless legs syndrome (RLS): state-of-the-art and future directions. Mov Disord. 2007;22(suppl 18):S449–458. 13. Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet. 2007;39:1000–1006. 14. Pichler I, Hicks AA , Pramstaller PP. Restless legs syndrome: an update on genetics and future perspectives. Clin Genet. 2008;73:297–305. 15. Winkelmann J, Lichtner P, Schormair B, et al. Variants in the neuronal nitric oxide synthase (nNOS, NOS1) gene are associated with restless legs syndrome. Mov Disord. 2008;23:350–358. 16. Lohmann-Hedrich K, Neumann A, Kleensang A, et al. Evidence for linkage of restless legs syndrome to chromosome 9p: are there two distinct loci? Neurology. 2008;70:686–694. 17. Young JE, Vilarino-Guell C, Lin S-C, et al. Clinical and genetic description of a family with a high prevalence of autosomal dominant restless legs syndrome. Mayo Clin Proc. 2009;84:134–138. 18. Levchenko A, Montplaisir J-Y, Asselin G, et al. Autosomal-dominant locus for restless legs syndrome in French-Canadians on chromosome 16p12.1. Mov Disord. 2009;24:40–50. 19. Wang J, O’Reilly B, Venkataraman R, et al. Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: a randomized, double-blind, placebo-controlled study. Sleep Med. 2009;10(9):973–975. 20. Happe S, Trenkwalder C. Role of dopamine receptor agonists in the treatment of restless legs syndrome. CNS Drugs. 2004;18:27–36.

CONCLUSiON RLS is a clinical diagnosis made by applying the NIH URGE criteria and is a common condition. Overnight polysomnography is not required to make the diagnosis. Iron metabolism is involved with the disease process, and a number of genes have been identified. Dopa agonists and gabanoids are FDA approved for therapy.

21. Kushida CA , Becker PM , Ellenbogen AL , et al, for the XP052 Study Group. Randomized, double-blind, placebo-controlled study of XP13512/GSK 1838262 in patients with RLS . Neurology. 2009;72:439–446. 22. Trenkwalder C, Benes H, Poewe W, et al. Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2008;7:595–604. 23. Ondo WG. Restless legs syndrome. Curr Neurol Neurosci Rep. 2005;5:266–274.

References 1. Willis T. The London Practice of Physick, or the Whole Practical Park of Physick. London, England: Thomas Basset and William Crook; 1685. 2. Ekbom KA . Restless legs. Acta Med Scand. 1945;158:1–123. 3. Ekbom KA . Restless legs syndrome. Neurology. 1960;10:868–873. 4. Ekbom KA . Asthenia crurum paraesthetica (irritable legs). Acta Med Scand. 1944;118:197–209. 5. Ekbom KA . [Restless legs in blood donors]. Sven Läkartidn. 1956;53:3098–3103.

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24. Ondo W. Secondary restless legs syndrome. In: Ray Chaudhuri K, Odin P, Olanow CW, eds. Restless Legs Syndrome. London, England: Taylor & Francis; 2004:57. 25. Burbank F, Buchfuhrer MJ, Kopjar B. Sleep improvement for restless legs syndrome patients. Part 1: pooled analysis of two prospective, double-blind, sham-controlled, multi-center, randomized clinical studies of the effects of vibrating pads on RLS symptoms. J Parkinsonism Restless Legs Syndrome. 2013;3:1–10. 26. Burbank F, Buchfuhrer MJ, Kopjar B. Improving sleep for patients with restless legs syndrome. Part II: meta-analysis of vibration therapy and drugs approved by the FDA for treatment of restless legs syndrome. J Parkinsonism Restless Legs Syndrome. 2013;3:11–22.

Q3  | 2014


“It takes ‘Mu’ to tango.” Opioids play an important role in chronic pain relief by binding to mu-receptors in the brain and blocking pain signals.1 But they also bind to mu-receptors in the bowel. That’s why patients taking opioids for chronic pain can develop opioid-induced constipation (OIC). The incidence of OIC varies and has been reported as high as 81%.* To start the OIC conversation, call 1-800-601-9063 and request an educational poster for your office.

Opioid-Induced Constipation is µ-nique *Published estimates of the incidence of OIC in patients receiving opioids for chronic pain vary due to differences in the studies conducted (eg, study design, definition of constipation, opioids used). Meta-analyses of randomized controlled trials suggest that 15%–41%2-4 of these patients develop OIC, while observational and survey-based studies suggest that 37%–81%5-9 develop OIC. 1. Camilleri M. Am J Gastroenterol. 2011;106(5):835-842. 2. Kalso E et al. Pain. 2004;112(3):372-380. 3. Papaleontiou M et al. J Am Geriatr Soc. 2010; 58(7):1353-1369. 4. Moore RA et al. Arthritis Res Ther. 2005;7(5):R1046-1051. 5. Bell TJ et al. Pain Med. 2009;10(1):35-42. 6. Anastassopoulos KP et al. J Manag Care Pharm. 2012;18(8):615-626. 7. Cook SF et al. Aliment Pharmacol Ther. 2008;27(12):1224-1232. 8. Tuteja AK et al. Neurogastroenterol Motil. 2010;22(4):424-430, e96. 9. Mahowald ML et al. Arthritis Rheum. 2005;52(1):312-321.

©2014 AstraZeneca.

3023201

7/14


by Kevin

L. Zacharoff MD, FACIP, FACPE, FAAP


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P DiATRiC PAIN  MANAG M NT

In today’s healthcare environment, we as healthcare providers have ethical, legal, and moral responsibilities to assess, measure, and consider risk of chronic pain in children and adolescents.

Often when people think of chronic pain patients and the risks associated with prescription pain medications, they think only of adults. In fact, the prevalence of chronic pain in children and adolescents is significant, and thought needs to be given about how this chronic pain population is treated—from assessment, to formulation of a treatment plan, to follow-up. Children and adolescents are often treated as a disparate population when it comes to chronic pain treatment, but they suffer many of the same adverse effects as their adult counterparts, and therefore deserve the same appropriate treatment. Additionally, this patient population may be at significant risk of aberrant drug-related behaviors. This article discusses the different dimensions of risk of children and adolescents with chronic pain and how to make sure they are assessed and treated appropriately. abstract:

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CHRONiC PAiN A PROBL M iN CHiLDR N?

When we think about chronic pain in the United States today, it’s reasonable to say we are referring to adults in chronic pain. When we think about risk and chronic pain, what most likely comes to mind is finding the balance between risk of undertreatment and the unintended serious consequences of prescription pain medication abuse and misuse. e e

Chronic pain is a significant problem in the child and adolescent AR TH Y AT RiSK? patient population. In today’s healthcare environment, we as health- Additional questions need to be asked about chronic pain in children. care providers have ethical, legal, and moral responsibilities to assess, Are they a population at “risk” and, if so, at risk of what? Are they measure, and consider risk of chronic pain in children and adoles- at risk of adverse effects of treatment (or lack of treatment)? Are cents. Arguments can be made that there is a standard of care requir- they at risk of developing aberrant drug-related behaviors (ADRBs) ing assessment of pain in children after surgery or during active similar to those in adult chronic pain patients? Are they at risk for phases of a disease,1 but much more needs to be done to account for undertreatment of their chronic pain? Are they at risk of misuse (or differences in this patient population to ensure nondisparate pain overuse) of opioids if these medications are appropriate components of the treatment plan? treatment in all situations.

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Other questions that should be addressed are whether certain factors exist that may make this patient population different from adult patients with chronic pain. For example, children at any age may deny pain if the questioner is a “stranger,” if they think they “are supposed to be brave,” if they are scared or think that one of the treatments will result in “a shot.”

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CHiLDR N AND CHRONiC PAiN iN TH LiT RATUR Unfortunately, the literature is not replete with studies of chronic pain in children and, according to a 1995 report from the International Association for the Study of Pain ( IASP), they may have often been neglected as a chronic pain population as a result.1 A more recent study by King et al2 in 2011 reported that chronic pain is a significant problem in children and adolescents today, along with evidence from prior comprehensive reviews performed some 22 years ago.3 As to the significance of chronic pain in children and adolescents, the prevalence of headaches alone is estimated to be between 23% and 51%. Abdominal pain occurs in 10% to 27% of this children/adolescent patient population. Other examples of common types of chronic pain in children include cancer-related pain, sickle cell disease, and Crohn’s disease. The lack of scientific information about chronic pain in children is one of many problems. Another is similar to all patient populations suffering from chronic pain and which most of us have not been taught—assessment and management of chronic pain.4 The IASP stated: “To our knowledge, there has not yet been any ethical or legal action for failure to measure pain in children… A clear standard of care has emerged that requires the routine measurement of pain in children who are at risk for pain, for example, following surgery and during active phases of diseases such as cancer, sickle cell disease, or rheumatoid arthritis.”1

Despite this statement, many practitioners still have not been taught about the assessment and management of chronic pain in children.

them. For example, in 2007, Meltzer examined the use of sleep medications in hospitalized children and adolescents, compared to hospitalized adults.5 Findings were that 50% to 75% of hospitalized adults were prescribed sleep medication as needed, compared with only 3% of children and adolescents. The reasons for this disparity could be multifaceted and pose a number of questions. Could it be that dosing for children and adolescents for these medications falls outside of medication labeling? Could it be that the perception is that these patients don’t often require anything to help them sleep when they are hospitalized? Could it be that there is a lack of familiarity and/or comfort with prescribing sleep medications for children and adolescents? Or could it be that other factors exist as well. The answers to these questions are likely often “yes,” but regardless of the reason(s), these patients may be at risk of disparate chronic pain assessment and treatment.

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SOM IMPORTANT DiFF R NC S If we conclude that children and adolescents with chronic pain have many similarities to adult patients with similar pain conditions, we need to recognize some differences as well. For example, parents and caregivers are much more likely to play a role in pain treatment, including monitoring, “protecting,” encouraging, and even instructing the patient.6 Parental influence should not be minimized in children with chronic pain.

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TH “OTH R” RiSK The question also remains as to “the other problem”—risk of ADRBs in this patient population. In 2010, Fortuna et al reported that nonmedical use of prescription pain medications had increased by 162% in the past decade, and had surpassed all illicit substance use in the United States with the exception of marijuana.7 Data also showed that adolescents and young adults were the most likely group to abuse prescription medications. In fact, the National Survey on Drug Use and Health reported that 12.6% of adolescents between the ages of 12 and 17 and 31.4% of young adults reported nonmedical use of prescription medications at some point in their lifetime.

King and colleagues found that chronic and recurrent pain is significantly prevalent in children and adolescents, with girls generally Fortuna also looked at trends in increased prescribing for adolescents experiencing chronic pain more often than boys across all pain types, and young adults and found that in 1994 a controlled substance was and overall prevalence rates increasing in both boys and girls with age.2 prescribed to 15- to 19-year-olds at 2.3 million visits, increasing to Interestingly, musculoskeletal pain occurs in children and adolescents 5.7 million visits in 2007; and that number is even higher today. The at rates similar to adults. While it is thought that poorly treated acute increased rate of prescribing occurs across multiple clinical settings, pain in children and adolescents can have long-term consequences, including ambulatory offices and emergency departments. Overall, there is conflicting evidence as to whether inadequately treated pain these investigators found that a controlled medication was prescribed in childhood increases the likelihood of the development of chronic in 1 out of every 6 young adult visits, and 1 out of every 9 adolescent pain later in life. Scientific evidence is also missing about the impact visits. Breakdown of common primary reasons identified for opioid of other factors, such as socioeconomic and psychosocial, on develop- prescriptions in these patients included back/musculoskeletal pain ment and incidence of chronic pain in children. (19%); acute injury (12%); “general reasons” (11%); ear, nose, and throat and dental-related issues (9%); and gastrointestinal issues (8%). Prescriptions for opioids or controlled medications were prescribed at higher rates in the southern and western portions of the United DO W TR AT CHiLDR N DiFF R NTLY? Another significant possible variable in the way children and ado- States, with the highest rate of abuse and misuse in the same regions lescents are assessed and treated for chronic pain is the way we treat in people age 12 and older.8

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The fundamental need to adequately treat children/adolescents in chronic pain with prescription medications when indicated must be balanced, as with adults, with cognizance of the potential abuse, misuse, and diversion of these medications. In this younger patient population, there is often no routine inquiry about substance abuse history, other prescription medications being taken, or family history of substance abuse. The basic premise then is that, much like in the adult patient population, improved education and enhanced communication are important aspects of chronic pain treatment in children. If we are not doing this in a reproducible fashion in adults, it may be even less likely that it will be done in children, despite the fact that they are a significant population at risk. Prescription medications such as opioids, stimulants, tranquilizers, and sleeping pills are the fastest growing classes of substances abused by adolescents.9 Prescription opioids are abused the most, yet stimulant medication abuse has been studied the most. The risk of nonmedical use of prescription opioids in children and adolescents is real and should be considered whenever opioid therapy is warranted. Johnston looked at the prevalence of nonmedical prescription drug use in 12th graders and found that opiates had overtaken other prescription medications by 2005.10 McCabe et al surveyed over 7000 students to determine the prevalence of medical and nonmedical use of prescription opioids among high school seniors in the US. Disturbingly, 17.6% of this group reported lifetime medical use of prescription opioids, with 12.9% reporting nonmedical use of prescription opioids. Over 37% of students who used opioids for nonmedical reasons reported intranasal use. An estimated 80% of nonmedical users had an earlier history of medical use, with the opioid obtained from a valid prescription. While gender differences were minimal, racial and ethnic differences were significant. In summary, this survey found that nearly 1 in 4 high school seniors surveyed had exposure to an opioid, with 1 in 8 reporting nonmedical use of an opioid at least once in their lifetime. Also of interest was the fact that peers served as the leading source of diversion for opioids among adolescents.11 Boyd et al looked at the motivation for nonmedical use of opioids in students age 12 to 18 (7th to 12th graders) and investigated if these motivations were linked to higher risk of developing long-term substance abuse disorders.12 This web-based survey of more than 1000 children found that 12% of students engaged in nonmedical use of opioids in the 12 months prior to the survey, compared to just 3% for sleep medications, 2% for sedatives, and 2% for stimulants. Motivation for nonmedical use was pain relief and “some other reason” 79% of the time, with pain relief accounting for 69%, and to “get high” 11%.

CONCLUSiON As for risk of undertreatment of chronic pain in children, there are some key things to consider. Certainly in the absence of available correlates, they deserve to be treated as if they were adult patients with chronic pain, using adult-based principles for safe and effective pain management. We need to consider this group of chronic pain patients as a disparate group that is often underrepresented or even unrepresented. This phenomenon may exist because most prescription pain medications are not labeled for use in these patients, that there is a perception that children are “resilient” or their central

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nervous system is not fully developed, that the educational deficits for pain treatment in this population is larger than that for other patients, or that assessment may be difficult. From the perspective of ADRBs, there are many questions that should be answered. Adolescents particularly may be a significant population at risk of ADRBs and are often on the brink of a degree of independence. Existing questions: Should adolescents manage their own prescription pain medications? Is anyone screening the parents or caregivers for risk of substance abuse? Is anyone screening the adolescent or child? Is there a need for tools to do this? What if there are peers who present increased risk of ADRBs? What are we doing to make prescription pain medications safer when they are indicated for chronic pain treatment in children? It is clear that chronic pain is a problem in this patient population much like their adult counterparts and they are at risk of poor treatment. It is also clear that children need to be considered a population at risk as well. We need to treat them in a way that balances benefits and risk in the safest and most efficacious way possible, while making sure that their poorly treated pain doesn’t doom them to a resulting lifelong sentence of chronic pain while making sure abuse and misuse of prescription pain medications doesn’t become a part of their future.  References 1. International Association for the Study of Pain. Pain measurement in children. Pain Clinical Updates. July 1995. 2. King S, Chambers CT, Huquet A, et al. The epidemiology of chronic pain in children and adolescents revisited: a systematic review. Pain. 2011;152:2729–2738. 3. Goodman JE, McGrath PJ . The epidemiology of pain in children and adolescents: a review. Pain. 1991;46:247–64. 4. Kuttner L. A Child in Pain: How to Help, What to Do. Point Roberts, Washington: Hartley & Marks Publishing; 1996. 5. Meltzer LJ, Mindell JA , Owens JA , et al. Use of sleep medications in hospitalized pediatric patients. Pediatrics. 2007;119:1047–1055. 6. Dunford E, Thompson M, Gauntlett-Gilbert J. Parental behaviour in paediatric chronic pain: a qualitative observational study. Clin Child Psychol Psychiatry. 2013 Jun 27. [Epub ahead of print.] 7. Fortuna JR , Robbins BW, Joynt M, et al. Prescribing of controlled medications to adolescents and young adults in the United States. Pediatrics. 2010;126:1108–1116. 8. Colliver JD, Kroutil LA , Dai L, et al. Misuse of prescription drugs: data from the 2002, 2003, and 2004 National Surveys on Drug Use and Health. Rockville, MD: Substance Abuse and Mental Health Services Administration, Office of Applied Studies; 2006. DHHS publication SMA 06–4192, Analytic Series A-28. 9. Rogers PD, Copley L. The nonmedical use of prescription drugs by adolescents. Adolesc Med State Art Rev. 2009;20(1):1–8, vii. 10. Johnston LD, O’Malley PM , Bachman JG, et al. Monitoring the future: national results on adolescent drug use: overview of key findings, 2005. Bethesda, MD: National Institute on Drug Abuse. 11. McCabe SE, West BT, Teter CJ, et al. Medical and nonmedical use of prescription opioids among high school seniors in the United States. Arch Pediatr Adolesc Med. 2012;166(9):797–802. 12. Boyd CJ, McCabe SE, Cranford JA , et al. Adolescents’ motivations to abuse prescription medications. Pediatrics. 2006;118(6):2472-2480.

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WHERE OTHERS SEE COMPLEX PROBLEMS, MALLINCKRODT SEES UNIQUE SOLUTIONS Today’s Mallinckrodt Pharmaceuticals combines more than 146 years of expertise with the determined focus needed to solve the complex specialty pharmaceutical challenges of today. Whether it’s the production of medicines for pain or ADHD, the development of drugs that treat CNS conditions, or providing patients with hospital-based analgesia treatment options, we are working to make complex products simpler, safer and better for patients. Learn more at www.mallinckrodt.com

Mallinckrodt, the “M” brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company. © 2014 Mallinckrodt.


with

Steven D. Passik PhD

Steven D. Passik is Director of Clinical Addiction Research and Education at Millennium Laboratories in San Diego, California.

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“I work with some of my best friends and people I admire, love, and respect every day.”

What inspired you to become a psychologist? I was always intrigued by the paradox of addiction. I was always drawn to trying to understand why behaviors that so often result in suffering are so hard to change. I grew up in the 70s in Brooklyn, New York, and many of my friends did drugs. Some are now doctors and lawyers, some are cops and firemen, and some are dead (of addiction). All did the same drugs. Why were some able to stop and others not? I had great mentors in college who helped me to nurture my curiosity. Why did you focus on pain management? I had finished a partial fellowship in addiction when my first girlfriend died of cancer. I then decided to become a psychologist who worked with people with cancer and did a fellowship in psycho-oncology at Memorial Sloan Kettering Cancer Center. It was 1987, the height of the AIDS epidemic in New York City, and someone was needed to work with people dying of AIDS and who also had addiction issues. I then met Russ Portenoy and Bill Breitbart and the rest is history. I never saw such compassion and expertise so easily and seamlessly interwoven as when watching them work. I wanted to be the psychologist version of them! Who were your mentors? This one is easy: Russ Portenoy, Jimmie Holland, Bill Breitbart, Kathy Foley, Perry Fine, and Ray Houde. (May Ray rest in peace. He understood the interface of pain and addiction better than anyone of his generation.) All taught me everything I know about pain and encouraged and supported me long before I had any idea of what I was talking about. I try to be as generous to my mentees as my mentors were to me. Ken Kirsh was once my mentee. He is such a genius. He turned the tables and mentors me as my main collaborator over 20+ years.

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If you weren’t a healthcare provider, what would you be? I wanted to play for the Knicks but I couldn’t go to my left so I am not really sure. I play bass guitar so I’d like to say I’d be a paunchy middle-aged Hebraic rock star. Or a sushi chef. Or a professional horse racing handicapper. It’s hard to say. I graduated college at 20 and already knew I wanted to go in the direction I went in. I even had to stop playing in bands so I could get out of graduate school and finish my internships. Why did you leave academia for the commercial arena? I felt that the only way to continue to contribute to the research database on risk management in a meaningful way was to leave academia and take the extraordinary opportunity that Millennium offered me. I work with some of my best friends and people I admire, love, and respect every day. I wrote my first paper on urine drug testing 2 decades ago. I have always believed in it and other tools that would make practitioners good enough at recognizing and responding to concerns about addiction that they would treat pain comfortably, safely, and aggressively. I wanted to continue to contribute to the science in this area but in academia found it becoming too difficult to conduct studies. I was so busy working clinically that I no longer had the time to be in the research and education realms. I realize there is a certain irony in that. I often semi-joke that I left academia to get some academic work done. What is your most marked characteristic? When I was in graduate school and training to be a psychologist I had to go for my own psycho­ dynamically oriented psychotherapy. I did the horizontal bop (psychoanalysis) lying on the couch suffering myself, as they say, 3 times per week for

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PUNDIT PROFILE/ STEVEN D. PASSiK

“Despite my inclination towards righteous indignation I am an optimist at heart and believe the best trait a human being can cultivate is gratitude.”

5 years. I learned that my favorite emotion is righteous  indignation. I gravitated to the right fi elds because  I get to feel it every day! I work in areas that feel important, ARE important, and in which there is complexity and it is never justifi ed to feel too comfortable  or complacent. The desire to help people with pain, cancer, and psychological problems related to them,  etc, is something I feel every day. I feel they deserve better than they get and that is where the righteous  indignation comes in. What do you consider your greatest achievement? The publishing of the Pain and Chemical Dependency textbook with Howard Smith. It was a  mountain of work, a great achievement, and I think it sold 450 copies and my mother bought 448 of them.  But that aside, to edit such a book and to do it with  such a wonderful co-editor makes me and my parents very proud. If you had to choose one book, one film, and one piece of music to take into space for an undetermined amount of time, what would they be? Book: Catcher in the Rye. This book resonated  with me as an angry young man and made me realize you could go crazy about the hypocrisy in the  world or you could channel such feelings into doing something for the good of others rather than be consumed by it. I just wish it had come with instructions  on how not to become the crotchety old guy.

72 | PWJ | www.painweek.org

Film: Annie Hall. It helped me understand how to be a  Brooklyn Jewish Boy and live in the world. Music: Anything by Stevie Ray Vaughan. Anything. What would you like your legacy to be?  I would like to be remembered as someone who  thought fi rst about what was good for patients and  didn’t think of simple solutions to their complex problems. Someone who could advocate for AND against opioids as needed, who cared about and tried to  prevent addiction while trying to make sure that people in pain had everything available to them that  might help. I wouldn’t mind being thought of as an  iconoclast and as anti-dogma. Oh, and an addicted horse player. (If the shoe fi ts.) What is your motto?  My motto was something I fi rst read many years  ago when I was tearing through all of James Kirkwood’s books—and I don’t mean P.S. Your Cat is Dead, though that has always resonated with me, ie, when you think a situation has bottomed out, never fear things can get  worse! One of his other works, There Must Be a Pony, mentioned the story of the narcissistic and entitled person who was unsatisfi ed with a roomful of riches.  His “dumber” sibling, meanwhile, is delighted to receive  a roomful of horse manure. When asked why he is so happy, the sibling says, “With all of this manure there  must be a pony.” Despite my inclination towards righteous indignation I am an optimist at heart and believe  the best trait a human being can cultivate is gratitude.

Q3  | 2014


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GRALISE® (gabapentin) tablets BRIEF SUMMARY: For full prescribing information, see package insert. INDICATIONS AND USAGE GRALISE is indicated for the management of Postherpetic Neuralgia (PHN). GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration. DOSAGE AND ADMINISTRATION Postherpetic neuralgia • GRALISE should be titrated to an 1800 mg dose taken orally once daily with the evening meal. GRALISE tablets should be swallowed whole. Do not split, crush, or chew the tablets. • If GRALISE dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of one week or longer (at the discretion of the prescriber). • Renal impairment: Dose should be adjusted in patients with reduced renal function. GRALISE should not be used in patients with CrCl less than 30 or in patients on hemodialysis. • In adults with postherpetic neuralgia, GRALISE therapy should be initiated and titrated as follows: Table 1 GRALISE Recommended Titration Schedule Day 1 Day 2 Days 3-6 Days 7-10 Days 11-14 Day 15 Daily dose 300 mg 600 mg 900 mg 1200 mg 1500 mg 1800 mg CONTRAINDICATIONS GRALISE is contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients. Table 2 GRALISE Dosage Based on Renal Function Once-daily dosing Creatinine clearance (mL/min) GRALISE dose (once daily with evening meal) ≥ 60 1800 mg 30-60 600 mg to 1800 mg < 30 GRALISE should not be administered Patients receiving hemodialysis GRALISE should not be administered WARNINGS AND PRECAUTIONS GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration. The safety and effectiveness of GRALISE in patients with epilepsy has not been studied. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Table 3 Risk by Indication for Antiepileptic Drugs (including gabapentin, the active ingredient in Gralise) in the Pooled Analysis Indication Epilepsy Psychiatric Other Total Placebo patients with events per 1000 patients 1.0 5.7 1.0 2.4 Drug patients with events per 1000 patients 3.4 8.5 1.8 4.3 Relative risk: incidence of events in drug patients/incidence in placebo patients 3.5 1.5 1.9 1.8 Risk difference: additional drug patients with events per 1000 patients 2.4 2.9 0.9 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing GRALISE must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which products containing active components that are AEDs (such as gabapentin, the active component in GRALISE) are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that GRALISE contains gabapentin which is also used to treat epilepsy and that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Withdrawal of Gabapentin Gabapentin should be withdrawn gradually. If GRALISE is discontinued, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber). Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. The clinical significance of this finding is unknown. In clinical trials of gabapentin therapy in epilepsy comprising 2,085 patient-years of exposure in patients over 12 years of age, new tumors were reported in 10 patients, and preexisting tumors worsened in 11 patients, during or within 2 years after discontinuing the drug. However, no similar patient population untreated with gabapentin was available to provide background tumor incidence and recurrence information for comparison. Therefore, the effect of gabapentin therapy on the incidence of new tumors in humans or on the worsening or recurrence of previously diagnosed tumors is unknown. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking antiepileptic drugs, including GRALISE. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. GRALISE should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Laboratory Tests Clinical trial data do not indicate that routine monitoring of clinical laboratory procedures is necessary for the safe use of GRALISE. The value of monitoring gabapentin blood concentrations has not been established. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 359 patients with neuropathic pain associated with postherpetic neuralgia have received GRALISE at doses up to 1800 mg daily during placebo-controlled clinical studies. In clinical trials in patients with postherpetic neuralgia, 9.7% of the 359 patients treated with GRALISE and 6.9% of 364 patients treated with placebo discontinued prematurely due to adverse reactions. In the GRALISE treatment group, the most common reason for discontinuation due to adverse reactions was dizziness. Of GRALISE-treated patients who experienced adverse reactions in clinical studies, the majority of those adverse reactions were either “mild” or “moderate”. Table 4 lists all adverse reactions, regardless of causality, occurring in at least 1% of patients with neuropathic pain associated with postherpetic neuralgia in the GRALISE group for which the incidence was greater than in the placebo group. Table 4 Treatment-Emergent Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Postherpetic Neuralgia (Events in at Least 1% of all GRALISE-Treated Patients and More Frequent Than in the Placebo Group) Body system—preferred term GRALISE N = 359, % Placebo N = 364, % Ear and Labyrinth Disorders Vertigo 1.4 0.5 Gastrointestinal Disorders Diarrhea 3.3 2.7 Dry mouth 2.8 1.4 Constipation 1.4 0.3 Dyspepsia 1.4 0.8 General Disorders Peripheral edema 3.9 0.3 Pain 1.1 0.5

Infections and Infestations Nasopharyngitis 2.5 2.2 Urinary tract infection 1.7 0.5 Investigations Weight increased 1.9 0.5 Musculoskeletal and Connective Tissue Disorders Pain in extremity 1.9 0.5 Back pain 1.7 1.1 Nervous System Disorders Dizziness 10.9 2.2 Somnolence 4.5 2.7 Headache 4.2 4.1 Lethargy 1.1 0.3 In addition to the adverse reactions reported in Table 4 above, the following adverse reactions with an uncertain relationship to GRALISE were reported during the clinical development for the treatment of postherpetic neuralgia. Events in more than 1% of patients but equally or more frequently in the GRALISE-treated patients than in the placebo group included blood pressure increase, confusional state, gastroenteritis viral, herpes zoster, hypertension, joint swelling, memory impairment, nausea, pneumonia, pyrexia, rash, seasonal allergy, and upper respiratory infection. Postmarketing and Other Experience with other Formulations of Gabapentin In addition to the adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been reported in patients receiving other formulations of marketed gabapentin. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose fluctuation, breast hypertrophy, erythema multiforme, elevated liver function tests, fever, hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome. Adverse events following the abrupt discontinuation of gabapentin immediate release have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain and sweating. DRUG INTERACTIONS Coadministration of gabapentin immediate release (125 mg and 500 mg) and hydrocodone (10 mg) reduced hydrocodone Cmax by 3% and 21%, respectively, and AUC by 4% and 22%, respectively. The mechanism of this interaction is unknown. Gabapentin AUC values were increased by 14%; the magnitude of this interaction at other doses is not known. When a single dose (60 mg) of controlled-release morphine capsule was administered 2 hours prior to a single dose (600 mg) of gabapentin immediate release in 12 volunteers, mean gabapentin AUC values increased by 44% compared to gabapentin immediate release administered without morphine. The pharmacokinetics of morphine were not affected by administration of gabapentin immediate release 2 hours after morphine. The magnitude of this interaction at other doses is not known. An antacid containing aluminum hydroxide and magnesium hydroxide reduced the bioavailability of gabapentin immediate release by about approximately 20%, but by only 5% when gabapentin was taken 2 hours after antacids. It is recommended that GRALISE be taken at least 2 hours following antacid administration. There are no pharmacokinetic interactions between gabapentin and the following antiepileptic drugs: phenytoin, carbamazepine, valproic acid, phenobarbital, and naproxen. Cimetidine 300 mg decreased the apparent oral clearance of gabapentin by 14% and creatinine clearance by 10%. The effect of gabapentin immediate release on cimetidine was not evaluated. This decrease is not expected to be clinically significant. Gabapentin immediate release (400 mg three times daily) had no effect on the pharmacokinetics of norethindrone (2.5 mg) or ethinyl estradiol (50 mcg) administered as a single tablet, except that the Cmax of norethindrone was increased by 13%. This interaction is not considered to be clinically significant. Gabapentin immediate release pharmacokinetic parameters were comparable with and without probenecid, indicating that gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Gabapentin has been shown to be fetotoxic in rodents, causing delayed ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To provide information regarding the effects of in utero exposure to GRALISE, physicians are advised to recommend that pregnant patients taking GRALISE enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Nursing Mothers Gabapentin is secreted into human milk following oral administration. A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on the nursing infant is unknown, GRALISE should be used in women who are nursing only if the benefits clearly outweigh the risks. Pediatric Use The safety and effectiveness of GRALISE in the management of postherpetic neuralgia in patients less than 18 years of age has not been studied. Geriatric Use The total number of patients treated with GRALISE in controlled clinical trials in patients with postherpetic neuralgia was 359, of which 63% were 65 years of age or older. The types and incidence of adverse events were similar across age groups except for peripheral edema, which tended to increase in incidence with age. GRALISE is known to be substantially excreted by the kidney. Reductions in GRALISE dose should be made in patients with age-related compromised renal function. [see Dosage and Administration]. Hepatic Impairment Because gabapentin is not metabolized, studies have not been conducted in patients with hepatic impairment. Renal Impairment GRALISE is known to be substantially excreted by the kidney. Dosage adjustment is necessary in patients with impaired renal function. GRALISE should not be administered in patients with CrCL between 15 and 30 or in patients undergoing hemodialysis [see Dosage and Administration]. DRUG ABUSE AND DEPENDENCE The abuse and dependence potential of GRALISE has not been evaluated in human studies. OVERDOSAGE A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation. Acute oral overdoses of gabapentin immediate release in humans up to 49 grams have been reported. In these cases, double vision, slurred speech, drowsiness, lethargy and diarrhea were observed. All patients recovered with supportive care. Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. CLINICAL PHARMACOLOGY Pharmacokinetics Absorption and Bioavailability Gabapentin is absorbed from the proximal small bowel by a saturable L-amino transport system. Gabapentin bioavailability is not dose proportional; as the dose is increased, bioavailability decreases. When GRALISE (1800 mg once daily) and gabapentin immediate release (600 mg three times a day) were administered with high fat meals (50% of calories from fat), GRALISE has a higher Cmax and lower AUC at steady state compared to gabapentin immediate release. Time to reach maximum plasma concentration (Tmax) for GRALISE is 8 hours, which is about 4-6 hours longer compared to gabapentin immediate release. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of pancreatic acinar cell adenoma and carcinomas was found in male rats receiving the high dose; the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma concentrations of gabapentin in rats receiving the high dose of 2000 mg/kg/day were more than 10 times higher than plasma concentrations in humans receiving 1800 mg per day and in rats receiving 1000 mg/kg/day peak plasma concentrations were more than 6.5 times higher than in humans receiving 1800 mg/day. The pancreatic acinar cell carcinomas did not affect survival, did not metastasize and were not locally invasive. The relevance of this finding to carcinogenic risk in humans is unclear. Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known whether gabapentin has the ability to increase cell proliferation in other cell types or in other species, including humans. Gabapentin did not demonstrate mutagenic or genotoxic potential in 3 in vitro and 4 in vivo assays. No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately 11 times the maximum recommended human dose on an mg/m2 basis).

© December 2012, Depomed, Inc. All rights reserved. GRA-410-P.1


GRALISE (gabapentin) tablets are indicated for the management of postherpetic neuralgia (PHN).

PLEASE GRALISE ME! Offer effective 24-hour pain control for PHN1 • Rapid titration to an effective dose*1-3 • Statistically significant reduction in pain scores†1,2 • Once-daily dosing with the evening meal • The most common adverse reaction (≥ 5% and twice placebo) to GRALISE (gabapentin) is dizziness1

* 2-week titration to 1800 mg/day. † In a 10-week clinical trial, approximately one-third of GRALISE (gabapentin) patients achieved a 50% reduction in pain from baseline and approximately one-half achieved a 30% reduction in pain with an 1800 mg once-daily dose (mean baseline pain score was 6.6 for GRALISE-treated patients).1,3

Indication and Usage GRALISE (gabapentin) tablets are indicated for the management of postherpetic neuralgia (PHN). GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration.

Important Safety Information GRALISE is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. Antiepileptic drugs (AEDs) including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Across all GRALISE clinical trials, the other most common adverse reactions (≥ 2%) are somnolence, headache, peripheral edema, diarrhea, dry mouth, and nasopharyngitis. Dosage adjustment of GRALISE is necessary in patients with impaired renal function. GRALISE should not be administered in patients with a creatinine clearance rate < 30 mL/min or in patients undergoing hemodialysis.

Because every moment counts in PHN Please see adjacent page for Brief Summary of Prescribing Information. Full Prescribing Information and Medication Guide are available at GRALISE.com. References: 1. GRALISE [prescribing information]. Newark, CA: Depomed Inc.; December 2012. 2. Sang CN, et al. Gastroretentive gabapentin (G-GR) formulation reduces intensity of pain associated with postherpetic neuralgia (PHN). Clin J Pain. 2013;29:281-288. 3. Data on file, Depomed Inc.

January 2014, Depomed Inc. All rights reserved. GRA-409-P.2