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COMPREHENSIVE MANAGEMENT OF CHRONIC PAIN IN PERSONS WITH NEUROMUSCULAR DISEASE WITH MONOTHERAPY: CANNABISP.12 MUSIC THERAPY: THE IMPACT ON MODULATING EMOTIONAL AND COGNITIVE DOMAINS OF PAIN PERCEPTION IN PATIENTS WITH CANCERP.28 MOOD DISORDERS AND CHRONIC PAIN: BIOPSYCHOSOCIAL IMPLICATIONSP.36 SEX & GENDER DIFFERENCES IN PAIN AND ANALGESIA: DO WE NEED PINK AND BLUE PILLS?P.43


Butrans is a Schedule III extended-release opioid analgesic WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, and ACCIDENTAL EXPOSURE Abuse Potential Butrans contains buprenorphine, an opioid agonist and Schedule III controlled substance with an abuse liability similar to other Schedule III opioids, legal or illicit [see Warnings and Precautions (5.1)]. Assess each patient’s risk for opioid abuse or addiction prior to prescribing Butrans. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depressive disorder). Routinely monitor all patients receiving Butrans for signs of misuse, abuse, and addiction during treatment [see Drug Abuse and Dependence (9)]. Life-Threatening Respiratory Depression Respiratory depression, including fatal cases, may occur with use of Butrans, even when the drug has been used as recommended and not misused or abused [see Warnings and Precautions (5.2)]. Proper dosing and titration are essential and Butrans should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Monitor for respiratory depression, especially during initiation of Butrans or following a dose increase. Accidental Exposure Accidental exposure to Butrans, especially in children, can result in a fatal overdose of buprenorphine [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 moderate to severe chronic pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. Limitations of Use: Butrans is not for use: as an as-needed (prn) analgesic; for pain that is mild or not expected to persist for an extended period of time; for acute pain; for postoperative pain unless the patient is already receiving chronic opioid therapy prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time. 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 ■

Abuse Potential Buprenorphine can be abused in a manner similar to other opioid agonists, legal or illicit. Assess risk for opioid abuse or addiction prior to prescribing. Routinely monitor all patients for signs of misuse, abuse, and addiction. Addiction can occur even under appropriate medical use. Misuse or abuse of Butrans by chewing, swallowing, snorting or injecting buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of the opioid and pose a significant risk that could result in overdose and death Life-Threatening Respiratory Depression Respiratory depression is the primary risk of Butrans and may lead to respiratory arrest and death. 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. 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 Accidental exposure to Butrans, especially in children, can result in a fatal overdose Elderly, Cachectic, and Debilitated Patients Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics. Monitor such patients closely, particularly when initiating and titrating Butrans and when Butrans is given concomitantly with other drugs that depress respiration

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. Even usual therapeutic doses of Butrans may decrease respiratory drive to the point of apnea Interactions with Alcohol, CNS Depressants, and Illicit Drugs Hypotension, profound sedation, coma or respiratory depression may result if Butrans is added to a regimen that includes other CNS depressants, alcohol, or illicit drugs 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 after initiating or titrating Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients who may be susceptible to the intracranial effects of CO retention for signs of sedation and respiratory depression, particularly when initiating therapy with Butrans. Opioids may also obscure the clinical course in a patient with a head injury Application Site Skin Reactions In rare cases, severe application site skin reactions with signs of marked inflammation including “burn,” “discharge,” and “vesicles” have occurred

Application of External Heat Avoid exposing the Butrans application site and surrounding area to direct external heat sources. There is a potential for temperaturedependent 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 Avoidance of Withdrawal When discontinuing Butrans, gradually taper the dose. Do not abruptly discontinue Butrans

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

Anaphylactic/Allergic Reactions Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post-marketing experience

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

©2013 Purdue Pharma L.P. Stamford, CT 06901-3431 G8365-A 12/13


for transdermal administration BRIEF SUMMARY OF PRESCRIBING INFORMATION (For complete details please see the Full Prescribing Information and Medication Guide.) WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, and ACCIDENTAL EXPOSURE Abuse Potential BUTRANS contains buprenorphine, an opioid agonist and Schedule III controlled substance with an abuse liability similar to other Schedule III opioids, legal or illicit [see Warnings and Precautions (5.1)]. Assess each patient’s risk for opioid abuse or addiction prior to prescribing BUTRANS. The risk for opioid abuse is 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 depressive disorder). Routinely monitor all patients receiving BUTRANS for signs of misuse, abuse, and addiction during treatment [see Drug Abuse and Dependence (9)]. Life-Threatening Respiratory Depression Respiratory depression, including fatal cases, may occur with use of BUTRANS, even when the drug has been used as recommended and not misused or abused [see Warnings and Precautions (5.2)]. Proper dosing and titration are essential and BUTRANS should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Monitor for respiratory depression, especially during initiation of BUTRANS or following a dose increase. Accidental Exposure Accidental exposure to BUTRANS, especially in children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE BUTRANS is indicated for the management of moderate to severe chronic pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. Limitations of Use BUTRANS is not for use: • As an as-needed (prn) analgesic • For pain that is mild or not expected to persist for an extended period of time • For acute pain • For postoperative pain unless the patient is already receiving chronic opioid therapy prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time 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 Abuse Potential BUTRANS contains buprenorphine, a partial agonist at the mu opioid receptor and a Schedule III controlled substance. Buprenorphine can be abused in a manner similar to other opioid agonists, legal or illicit. 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 BUTRANS in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain. Assess each patient’s risk for opioid abuse or addiction prior to prescribing BUTRANS. The risk for opioid abuse is 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). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use. Misuse or abuse of BUTRANS by chewing, swallowing, snorting or injecting buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of the opioid and pose a significant risk that could result in overdose and death [see Overdosage (10)]. 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 Respiratory depression is the primary risk of BUTRANS. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. 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)]. 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. Instruct patients against use by individuals other than the patient for whom BUTRANS was prescribed and to keep BUTRANS out of the reach of children, as such inappropriate use may result in fatal respiratory depression. To reduce the risk of respiratory depression, proper dosing and titration of BUTRANS are essential [see Dosage and Administration (2.1, 2.2)]. Overestimating the BUTRANS dose when converting patients from another opioid product can result in fatal overdose with the first dose. Respiratory depression has also been reported with use of modified-release opioids when used as recommended and not misused or abused. To further reduce the risk of respiratory depression, consider the following: • Proper dosing and titration are essential and BUTRANS should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. • BUTRANS is contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression [see Contraindications (4)]. 5.3 Accidental Exposure Accidental exposure to BUTRANS, especially in children, can result in a fatal overdose of buprenorphine. 5.4 Elderly, Cachectic, and Debilitated Patients Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance compared to younger, healthier patients. Therefore, 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)]. 5.5 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. 5.6 Interactions with Alcohol, CNS Depressants, and Illicit Drugs Hypotension, profound sedation, coma or respiratory depression may result if BUTRANS is added to a regimen that includes other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, muscle relaxants, 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, consider the patient’s use, if any, of alcohol or illicit drugs that cause CNS depression. If BUTRANS therapy is to be initiated in a patient taking a CNS depressant, start with a lower BUTRANS dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.3)]. 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 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 (7.3)]. 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 Avoidance of Withdrawal Symptoms of withdrawal include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Significant fluid losses from vomiting and diarrhea can require intravenous fluid administration. When discontinuing BUTRANS, gradually taper the dose [see Dosage and Administration (2.3)]. Do not abruptly discontinue BUTRANS. 5.18 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. 5.19 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 adverse reactions described elsewhere in the labeling include: • Respiratory Depression [see Warnings and Precautions (5.2)] • QTc Prolongation [see Warnings and Precautions (5.7)] • Hypotensive Effects [see Warnings and Precautions (5.8)] • 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 Hepatic Enzyme Inhibitors and Inducers CYP3A4 Inhibitors Co-administration of ketoconazole, a strong CYP3A4 inhibitor, with BUTRANS, did not have any effect on Cmax (maximum concentration) and AUC (area under the curve) of buprenorphine. Based on this observation, the pharmacokinetics of BUTRANS are not expected to be affected by co-administration of CYP3A4 inhibitors. However, certain protease inhibitors (PIs) with CYP3A4 inhibitory activity such as atazanavir and atazanavir/ritonavir resulted in elevated levels of buprenorphine and norbuprenorphine following sublingual administration of buprenorphine and naloxone. Patients in this study reported increased sedation, and symptoms of opiate excess have been found in post-marketing reports of patients receiving sublingual buprenorphine and atazanavir with and without ritonavir concomitantly. Atazanavir is both a CYP3A4 and UGT1A1 inhibitor. As such, the drug-drug interaction potential for buprenorphine with CYP3A4 inhibitors is likely to be dependent on the route of administration as well as the specificity of enzyme inhibition [see Clinical Pharmacology (12.3)]. CYP3A4 Inducers The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied. Monitor patients receiving concurrent therapy with BUTRANS and CYP3A4 inducers (e.g., phenobarbital, carbamazepine, phenytoin, rifampin) closely for reduced efficacy or signs of withdrawal [see Clinical Pharmacology (12.3)]. 7.2 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 selfinjection 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 selfadminister benzodiazepines while taking BUTRANS, and warn patients to use benzodiazepines concurrently with BUTRANS only as directed by their physician. 7.3 CNS Depressants Concurrent use of BUTRANS and other central nervous system (CNS) depressants (e.g., sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, other tranquilizers, and alcohol) can increase the risk of respiratory depression, hypotension, and profound sedation or coma. Monitor patients receiving CNS depressants and BUTRANS for signs of respiratory depression and hypotension. When such combined therapy is contemplated, reduce the initial dose of one or both agents. 7.4 Skeletal Muscle Relaxants BUTRANS, like other opioids, may interact with skeletal muscle relaxants to enhance neuromuscular blocking action and increase respiratory depression. 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 Teratogenic Effects (Pregnancy Category C) There are no adequate and well-controlled studies with BUTRANS in pregnant women. BUTRANS should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and 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. NonTeratogenic 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 BUTRANS is not for use in women immediately prior to and during labor, where use of short-acting analgesics or other analgesic techniques are more

appropriate [see Indications and Usage (1)]. Occasionally, opioid analgesics may 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. Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. An opioid antagonist, such as naloxone, should be available for reversal of opioid-induced respiratory depression in the neonate in such situations. 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)]. 8.7 Neonatal Opioid Withdrawal Syndrome Chronic maternal use of buprenorphine during pregnancy can affect the fetus with subsequent withdrawal signs. Neonatal 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 withdrawal syndrome vary based on the drug used, duration of use, the dose of last maternal use, and rate of elimination drug by the newborn. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance BUTRANS contains buprenorphine, a mu opioid partial agonist and Schedule III controlled substance with an abuse potential similar to other Schedule III opioids. BUTRANS can be abused and is subject to misuse, abuse, addiction and criminal diversion. 9.2 Abuse Abuse of BUTRANS poses a hazard of overdose and death. This risk is increased with compromise of the BUTRANS Transdermal System and with concurrent abuse of alcohol or other substances. BUTRANS has been diverted for nonmedical use. All patients treated with opioids, including BUTRANS, 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. 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 in persons with substance use disorders. Drug-seeking tactics include, but are not limited to, 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 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 may be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state law, is strongly advised. The risks of misuse and abuse should be considered when prescribing or dispensing BUTRANS. Concerns about abuse and addiction, should not prevent the proper management of pain, however. Treatment of pain should be individualized, balancing the potential benefits and risks for each patient. 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 (5.6), and Drug Interactions (7.2)]. Compromising 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 (8.7)]. 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 See FDA-approved patient labeling (Medication Guide) Abuse Potential Inform patients that BUTRANS contains buprenorphine, a Schedule III controlled substance that is subject to abuse. Instruct patients not to share BUTRANS with others and to take steps to protect BUTRANS from theft or misuse. Life-Threatening Respiratory Depression Discuss the risk of respiratory depression with patients, explaining that the risk is greatest when starting BUTRANS or when the dose is increased. Advise patients how to recognize respiratory depression and to seek medical attention if they are experiencing breathing difficulties. Accidental Exposure Instruct patients to take steps to store BUTRANS securely. Accidental exposure, especially in children, may result in serious harm or death. Advise patients to dispose of unused BUTRANS folding in half and flushing down the toilet. Risks from Concomitant Use of Alcohol and other CNS Depressants Inform patients that the concomitant use of alcohol with BUTRANS can increase the risk of life-threatening respiratory depression. Inform patients that potentially serious additive effects may occur if BUTRANS 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 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. 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 Therapie-Systeme AG, Andernach, Germany U.S. Patent Numbers 5681413; 5804215; 6264980; 6315854; 6344211; RE41408; RE41489; RE41571. © 2013, Purdue Pharma L.P. This brief summary is based on Butrans Prescribing Information 303135-0A, Revised 07/2013


GUEST EDITOR  GARY PUBLISHER  Aventine

W. JAY MD, FAAPM, DAAPM

Co.  6 Erie Street, Montclair, NJ 07042

ART DIRECTOR  DARRYL

FOSSA

EDITORIAL DIRECTOR  DEBRA

WEINER

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.


Global Education Group (Global) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education to physicians. Global Education Group designates this live activity for a minimum of 32.0 AMA PRA Category 1 Credit(s) TM. This activity will be approved for continuing pharmacy, psychology, nurse practitioner, nursing and dentistry education. Applications for certification of social work NASW and family physician AAFP hours will be applied for. For more information and complete CME/CE accreditation details, visit our website at www.painweek.org.


/ PWJ / Q1 / 2014 10 | GUEST EDITOR’S LETTER by gary w. Jay

FEATURES

12 | NEUROLOGY

COMPREHENSIVE MANAGEMENT OF CHRONIC PAIN IN PERSONS WITH NEUROMUSCULAR DISEASE WITH MONOTHERAPY: cannabis

36 | BEHAVIORAL

MOOD DISORDERS AND CHRONIC PAIN: biopsychosocial implications by geralyn Datz

44 | SEX&GENDER

DIFFERENCES IN PAIN AND ANALGESIA: do we need pink and blue pills by roger b. Fillingim

by gregory t. Carter

55 | PARTICIPATING ORGANIZATION

28 | MUSIC THERAPY

by barby Ingle

THE IMPACT ON MODULATING EMOTIONAL AND COGNITIVE DOMAINS OF PAIN PERCEPTION IN PATIENTS WITH CANCER

THE POWER OF PAIN FOUNDATION

57 | PUNDIT PROFILE with daniel b. Carr

by andrew Rossetti

6 | PWJ | www.painweek.org

Q1  | 2014


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

A DIFFERENT KIND OF CONSTIPATION NEEDS A DIFFERENT KIND OF TREATMENT. • Opioid-induced constipation (OIC) is unique and often unresponsive to laxative therapy1 • RELISTOR® (methylnaltrexone bromide) targets the underlying cause of OIC without affecting analgesia2 • Most patients experienced a BM within 4 hours of the first dose and ≥3 weekly BMs when dosed every other day in clinical trials2,3 • 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 opioidinduced 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. REL 13/02-2


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


See See what what acute-pain acute-pain patients patients may may not not bebe telling telling you. you. Read Read the the survey survey summary summary atat TurnTheConversation.com TurnTheConversation.com Unintended Unintended consequences consequences such such as as diversion, diversion, abuse, abuse, andand societal societal riskrisk have have cast cast a shadow a shadow over over thethe opioid opioid legacy. legacy. How How dodo wewe address address thethe growing growing concerns concerns of of opioid opioid abuse abuse while while continuing continuing ourour primary primary mission mission of of providing providing care? care? Let’s Let’s start start talking talking about about responsibility. responsibility.

Abuse Abuse

This Thisisiswhat whatwe weall allintend intend……

This Thisisiswhat whatcan canhappen happen…… Relief Relief Physicians Physicians have have long long relied relied onon opioids opioids to to provide provide relief relief to to many many patients patients in in pain; pain; however, however, even even properly properly administered, administered, opioids opioids cancan have have unintended unintended consequences consequences affecting affecting individuals individuals andand society society at at large. large.

See See what what acute-pain acute-pain patients patients may may not not bebe telling telling you. you. Read Read the the survey survey summary summary atat TurnTheConversation.com TurnTheConversation.com Mallinckrodt, Mallinckrodt, the “M” the “M” brand brand markmark and and the Mallinckrodt the Mallinckrodt Pharmaceuticals Pharmaceuticals logologo are trademarks are trademarks of a of Mallinckrodt a Mallinckrodt company. company. © 2013 © 2013 Mallinckrodt. Mallinckrodt.


GARY W.

JAY

MD, FAAPM, DAAPM

W elcome to the third issue of PWJ!

Dr. Roger B. Fillingim discusses the fact that men and women are quite likely to experience pain differently and react differently to various forms of analgesics, for a number of physiological reasons, which certainly affects treatment. He pulls together a great deal of important information that the pain practitioner should know, including μ-opioid intake, as well as the issues sexual dimorphism studies have identified. Dr. Gregory T. Carter looks at the management of chronic pain secondary to neuromuscular disease using cannabis monotherapy. He discusses a number of neuromuscular diseases, including neurodegenerative disorders and associated neuropathies. While noting that these disorders may be associated with significant pain, he also explores the negative impact these disorders may have on quality of life. His discussions of cannabinoids and the endocannabinoid system are illuminating and give readers good information regarding the use of cannabinoids to treat other medical problems as well. Dr. Andrew Rossetti gives a possibly different view of music therapy, noting that it can be an analgesic, used to enable relaxation and help patients take their minds off their pain as they become more “overtaken” by music. While music does modulate emotion (think Pavarotti performing Leoncavallo’s Vesti La Giubba), it may also moderate anxiety and even anxiety-enhanced muscle tension. It can certainly moderate affect and mood. The articles herein may bring up questions or comments, or give you thoughts on other topics you would like to see in the future. You are encouraged to let us know!

As this journal moves forward, it continues to expand its breadth of coverage to new and lesser known topics important for frontline practitioners to understand. These subjects may enable the clinician We want to thank all of the contributing authors for their wonto better perform his/her job—providing optimal pain manage- derful work and insights into the various fields and aspects of pain ment—with a greater armamentarium. After all, the goal of the management that are covered in this issue. We hope that they can PWJ is to provide clinically useful information about new and existing answer some important questions as well as provide a great deal of treatment approaches to various pain conditions. The practitioner’s food for thought. role in an interdisciplinary pain treatment program is the “Captain of the Medical Ship”—ie, to encourage patients to utilize other treat- — GARY W. JAY MD, FAAPM , DAAPM ment modalities that may be needed. Physical therapy, psychotherapy, and biofeedback therapy can help patients improve functionality and ameliorate their pain to the greatest extent possible. This issue provides a wonderful diversity of topics: the importance of the biopsychosocial characteristics of chronic pain and their relationship to mood disorders is examined by Dr. Geralyn Datz. She discusses the too important to overlook psychophysiological aspects associated with concurrent behavioral problems. Interestingly, while interdisciplinary pain treatment programs have been around for decades, about every 10 years or so what is old becomes new again. The importance of treating the “psycho” part of pain as a “biopsychosocial” phenomenon is reiterated, the need for identification and understanding of mood disorders, and the clinical strategies, psychological assessments, and treatment are discussed. The case for the importance of an interdisciplinary (or multidisciplinary) treatment program for the chronic, complex pain patient is made, along with the significance of dealing with depression and anxiety in these patients.

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Gregory T. Carter  MD, MS

P.12

Geralyn Datz PhD

P.36

Roger B. Fillingim PhD

P.43

Andrew Rossetti MMT, MT-BC

Gregory Carter is medical director at St. Luke’s Rehabilitation Institute in Spokane, Washington. He cofounded the Muscular Dystrophy Association (MDA)/Amyotrophic Lateral Sclerosis Center at the University of Washington and the MDA Regional Neuromuscular Disease Center at Providence St. Peter Hospital in Olympia, Washington, where he later received the Excellence in Clinical Care Award from the MDA. In 2012, Dr. Carter received the Distinguished Researcher Award from the American Association of Neuromuscular and Electrodiagnostic Medicine.

Geralyn Datz specializes in behavioral medicine and is the owner and clinical director of Southern Behavioral Medicine Associates in Hattiesburg, Mississippi, which assesses, treats, and seeks independent medical opinions for psychological disorders. She is a consultant to QuantiaMD; an interviewee in newspapers, on television, and the internet; and has been an invited presenter at annual meetings, retreats, and workshops. Her coauthored articles have appeared in many publications. She is the president elect of the Southern Pain Society.

Roger Fillingim is past-president of the American Pain Society, professor at the University of Florida (UF) College of Dentistry, and director of the UF Pain Research and Intervention Center for Excellence. He has received several awards, including a UF Research Foundation Professorship and the Wilbert E. Fordyce Clinical Investigator Award from the American Pain Society. His research program endeavors to identify the mechanisms and clinical implications of individual differences in pain responses. P.28

Andrew Rossetti is the coordinator of a comprehensive music therapy program in radiation oncology at the Louis Armstrong Center for Music and Medicine at Beth Israel Medical Center in New York. He is a distance adjunct for the online master’s program in music therapy at Saint Mary of the Woods College, Indiana. He is currently coordinator/investigator of an IRB-approved research project at Beth Israel’s radiation oncology department: the Effects of Environmental Music Therapy Anxiety Levels and Perception of Waiting Time in the Radiation Oncology Waiting Room.

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ACRONYMS ALS: amyotrophic lateral sclerosis motor neuron disease

CMT: Charcot-Marie-Tooth disease (inclusive of all forms) peripheral neuropathy

FSHD: facioscapulohumeral muscular dystrophy primary myopathy

GBS: Guillain-Barré syndrome LGMD: limb girdle muscular dystrophy primary myopathy

MD: myotonic muscular dystrophy, types 1 and 2 primary myopathy (channelopathy)

PPS: postpolio syndrome SMA: spinal muscular atrophy motor neuron disease

by Gregory

T. Carter MD, MS

Neuromuscular diseases (NMDs) include a variety of conditions that affect components of a motor unit (motor neuron cells, nerve, neuromuscular junction, and muscle fibers), sensory and autonomic nerves, or their supportive structures, such as myopathies (polymyositis, dermatomyositis, inclusion body myositis, muscular dystrophies, and metabolic myopathies), diseases of the neuromuscular junction (myasthenia gravis, Eaton-Lambert syndrome), and neuropathies (Charcot-Marie-Tooth disease [CMT ], Guillain-Barré syndrome [GBS]). The major diseases referenced most often in this paper are listed under Acronyms (above). These are not rare diseases, and most clinicians will encounter some patients with a NMD in their clinical practice.1 abstract:

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dronabinol be a Schedule III “ How canprescription drug, consisting of 100% THC, the most psychoactive ingredient in cannabis,

yet, natural cannabis, containing 5% to 15% THC…be a Schedule I drug (dangerous, without medical uses)?


NEUROLOGY

…very little is known about the nature of pain in most NMDs although it is presumed to be neuropathic, myofascial, and biomechanical. The nature of pain in NMD has been underinvestigated.

esearch conducted over the last decade sug-

gests that chronic pain may be a significant problem in many patients with NMDs.2-23 Bushby and colleagues, for example, reported on the pain problems of 4 adults with facioscapulohumeral muscular dystrophy ( FSHD), who described between 3 and 7 different pain problems each.7 In a sample of 55 persons with GBS, 89% reported pain during the course of their illness.2 Of these individuals with pain, 47% described the pain as distressing, horrible, or excruciating (mean pain rating was 7 on a 0 to 10 Visual Analog Scale). In a large survey (N = 617) specifically targeting pain in persons with CMT, we found that 71% of the respondents to the survey reported having pain.3 Of those reporting pain, the most common sites included the low back (70%), knees (53%), ankles (50%), toes (46%), and feet (44%). Thirty-nine percent reported that their pain was severe enough to interfere with activities of daily living. Moreover, the pain severity reported by the survey respondents was comparable to (that is, not significantly different from) pain in persons with other painful conditions, such as postherpetic neuralgia, complex regional pain syndrome type 1 (also called reflex sympathetic dystrophy), and diabetic neuropathy.

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A nother study examined pain in NMD by analyzing data from a previous quality of life (QOL) survey of persons with a variety of NMDs, including limb girdle muscular dystrophy ( LGMD), FSHD, myotonic muscular dystrophy types 1 and 2 (MD), spinal muscular atrophies (SMA ), and CMT.12 All 1432 participants were administered, by mail, the SF-36 (a short-form health survey of 36 items), which assesses, among other things, pain severity using the 2-item Bodily Pain Scale ( BPS). The proportions of persons reporting at least some amount of pain in the previous 4 weeks were 70%, 96%, and 82%, for participants with SMA , CMT, and MD, respectively. Average BPS scores for these samples were 74.1, 49.8, and 61.4, respectively. With the exception of adult SMA , the frequency and severity of pain reported by patients with slowly progressive NMDs was significantly greater than levels of pain reported by the US population, and was comparable to pain reported by subjects with osteoarthritis and chronic low back pain. Prior studies indicated that nearly 70% and 90% of patients with MD and FSHD, respectively, report pain.5 Q1  | 2014


Pain is known to negatively impact QOL and greatly increase disease burden in NMD,13,24 yet little is known about how the extent and site of pain contribute to overall function in persons with NMD and chronic pain. Furthermore, other than data indicating that pain is a common symptom, very little is known about the nature of pain in most NMDs although it is presumed to be neuropathic, myofascial, and biomechanical. Overall, the nature of pain in NMD has been underinvestigated. Larger, prospective studies are needed to more succinctly characterize pain in these diseases, especially since pain can be treated and nearly eliminated even though curative treatments may still be decades away. Future studies are needed to investigate possible underlying pathophysiologic or biomechanical reasons for pain occurring at specific pain sites. Once these causes are identified, it may be possible to develop more effective, and possibly preemptive, interventions to treat pain in this NMD population. A better understanding of the nature of pain in NMDs would also shed light on whether specific therapies, such as improving the quality of restorative sleep in NMD patients with known concomitant sleep disorders, might improve their experience of pain. Developing more effective strategies for treating pain in this population even as genetic-based therapies become available is still needed because it is not clear whether improving muscle function through gene manipulation will positively affect the experience of pain in patients with NMD. Such strategies might also include psychological modalities. A recent study examined the effect of muscle disease on QOL, including how disease severity, mood, and illness perception may influence individual experiences in this patient population.22 As expected, QOL was reduced in this patient population, particularly for physical domains, including pain. Yet psychological domains are also negatively affected.22 The current literature suggests that disease severity is the best determinant for physical domains of QOL, with mood and illness perception being the main determinants for the psychological domains of QOL. The interplay between the physical and psychological domains of QOL in patients with NMD is complex at best.

0 to 10) pain, on average and at its worst.15 As can be seen, about three-quarters of the sample population reported experiencing pain, with the percentage ranging from 60% (for patients with amyotrophic lateral sclerosis [ALS]) to 100% (for patients with postpolio syndrome [ PPS]). Average pain, for those who reported having pain, was in the low-moderate range (4.00 to 6.28 across diagnostic groups, 5.06 overall), and worst pain was in the high-moderate range (5.59 to 7.33, 6.65 overall), but there was considerable variability of pain intensity within each diagnostic group, as indicated by the relatively large standard deviations associated with the pain intensity ratings. About one-quarter (27%) of the sample reported that the average pain intensity they experienced was severe (range from 9% for other NMD diagnosis to 50% for patients with MD), and a little over one-half (56%) reported that their worst pain went into the severe range.

PAiN QUALiTY iN NMD The results concerning the quality of NMD-related pain reported by the study participants are presented in Table 2.15 There was clear variation in the description of NMD pain as rated by the study participants, with a significant difference (F = 46.07, P < .001) across descriptors as tested by repeated measures analysis of variance (rANOVA). The results of univariate paired t-tests indicate that cold and itchy were rarely used to describe pain in this sample, with these pain qualities rated as significantly lower (P < .05) than all the others. On the other hand, deep, tiring, sharp, and dull were frequently used, and rated as significantly higher (P < .05) than all of the other pain descriptors.

While there was limited power to detect significant differences between the diagnostic groups on the pain descriptors, an examination of the means and standard deviations of the pain descriptor ratings suggests a great deal of variability within each diagnostic group; no clear pattern of pain description appears to differentiate pain associated with any one NMD diagnosis over the others. CHARACT RiSTiCS OF Only one omnibus test for differences between diagnostic groups PAiN MANAG M NT iN NMD was statistically significant; this was for ratings of fearful pain (F = Patients with NMD have previously reported that any number of 2.46, P < .05). Univariate analyses indicate that much of this effect is treatments may be used to reduce their pain or help them better attributable to patients with ALS and MD who reported their pain as manage pain.15 These include physical and occupational therapy, significantly more fearful than did patients with CMT, FSHD, and nerve blocks, biofeedback/relaxation training, acupuncture, mag- other NMD diagnoses.15 nets, massage, hypnosis, counseling/psychotherapy, mexiletine, gabapentin, pregabalin, tricyclic antidepressants, narcotics/opioids, acetaminophen, aspirin/ibuprofen, muscle relaxants (including ben- PAiN INT RF R NC zodiazepines), and cannabis (medical marijuana). Now we can review Table 3 lists the average ratings of pain interference with the 10 activsome of the research data I have collected along with my colleagues ities of the modified Brief Pain Inventory ( BPI ) Pain Interference at the University of Washington to give the reader a flavor of the scale. An omnibus ANOVA of the interference scores across activities nature of pain these patients report having. was significant (F = 12.76, P < .001), suggesting some variability in the impact of NMD-related pain on different activities. Univariate Table 1 lists the percentage of the sample population who reported paired t-tests between the ratings indicated that this effect is because experiencing pain in the previous 3 months, as well as the percent- pain interfered less with relations with other people and self-care age within each diagnostic group who reported pain. The table also (P < .05) than with the other activities. Also, pain interference with lists the average and worst pain intensity rating, and the percentage normal work (including work outside the home and housework) and of respondents who experience moderate (pain rated as 5 or 6 on a recreational activities was significantly higher than pain interference scale of 0 to 10) and severe (pain rated as 7 or greater on a scale of with other activities, except interference with sleep.

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The means reported in Table 3 also suggest some differences between diagnostic groups in the extent to which pain interferes with daily activities, despite the low power available to detect differences because of the low sample sizes within each diagnostic group. rANOVA s yielded significant (P < .05) effects for diagnostic group for 4 of the activities: general activity, relations with other people, self-care, and social activities. Univariate analyses indicated that, for the general activity item, patients with ALS and MD report significantly greater pain interference than patients with LGMD or patients with other NMD diagnoses. Similarly, on the relations with other people item, patients with ALS and MD reported significant greater pain interference than patients with CMT or other NMD diagnoses. For self-care, the significant effects were attributable to patients with CMT and other NMD diagnoses who reported significantly lower levels of pain interference on this activity than did patients with ALS. Finally, for social activities, patients with CMT reported significantly less pain interference than patients with ALS, MD, and PPS. Overall, the pattern of these findings suggest that patients with ALS and MD, in general, report the greatest pain interference, and patients with CMT the least among all NMD diagnoses.

diagnostic group), along with the means and standard deviations of the US norms for these scales. As might be expected, the study participants reported significantly greater dysfunction than subjects in the SF-36 normative sample as measured by the physical functioning (t = 16.84, P < .001), role–physical (t = 6.29, P < .001), bodily pain (t = 13.48, P < .001), general health (t = 7.46, P < .001), vitality (t = 7.13, P < .001), and social functioning (t = 8.20, P < .001) scales. Interestingly, however, there were not significant differences between the study participants and the US norms on the SF-36 role–emotional or mental health scales. The only significant difference to emerge between diagnostic groups was for the SF-36 BPS (t = 2.95, P < .05). The results of the univariate analyses indicate that this effect was related primarily to the significant differences between patients with ALS and MD and patients with CMT and other NMD diagnoses. Consistent with the pattern of results found concerning the pain interference ratings, patients with the former diagnoses had significantly lower scores (indicating greater pain severity on the SF-36 BPS) than patients with the latter diagnoses.

…only about two-thirds of those participants who tried narcotics for pain were still using this treatment at the time of the survey.

PAiN LOCATiON The percent of participants with pain who reported pain at each location are presented in Table 4. The most frequent pain site overall was back (49%), followed by leg(s) (47%), shoulder (43%), neck (40%), buttocks/hips (37%), feet (36%), arms (36%), and hands (35%). Head/face (20%), chest (17%), and abdomen/pelvis (16%) pain were relatively rare. While the rates of pain at different sites were often similar across some NMD diagnoses, there were some interesting exceptions. Patients with CMT, for example, reported rates of pain at different sites that tended to be either very similar to or lower than the rates of other diagnostic groups, on average, except when it came to legs (60%) and feet (66%) pain, which were the most frequent pain problems in persons with CMT. Patients with PPS, on the other hand, reported shoulder pain as their most common pain complaint (85%), followed closely by back (77%), neck, hand, buttocks, and feet pain (69% each). Back (78%), shoulder (67%), and buttocks (61%) pain were most common among participants with FSHD as well. There were no locations of pain in participants with other diagnoses (LGMD, ALS, MD, and other NMD diagnoses) that occurred with a frequency that was greater than 60%.

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QUALiTY OF LiF The means and standard deviations of the SF-36 scores for all of the study participants with pain are listed in Table 5 (overall and by

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PAiN TR ATM NTS /  TR ATM NT-R LAT D PAiN R Li F Table 6 lists the percentage of patients with pain who tried the listed pain treatment at some point, and the percentage of those who tried the treatment and were still using it. The average amount of pain relief produced by the treatment is also listed. Because it is possible that patients with only mild or even moderate pain may not seek out pain treatments, the percentages of patients with severe pain (average pain 7 or greater on a 0 to 10 scale) who have tried and, of these, who continue to use the pain treatments listed, are also presented in Table 6. As can be seen, ibuprofen/ aspirin (61% of all respondents with pain, 47% of those with severe pain) is the treatment most often tried for pain management, followed by acetaminophen (47% of all subjects with pain, 37% of those with severe pain), physical therapy (43%, 50%) and narcotic analgesics (35%, 42%).

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However, the treatments that provided the greatest relief were not necessarily those that were most frequently used. The average relief rating on a 0 to 10 scale for chiropractic manipulation was 7.33 for the very few (4%) patients with pain that tried this treatment. Most of these patients reported that they are still receiving this treatment. No patients with severe pain reported ever having tried chiropractic care. Nerve blocks were reported as providing the next highest degree of relief among all treatments (average relief rating = 6.75), although none of the patients who received these were still receiving nerve blocks. Narcotics were also listed as providing more relief than other pain treatments (average rating = 6.37) and were tried by about one-third of the participants with pain Q1  | 2014


overall. Interestingly, however, only about two-thirds of those par- Additionally, cannabinoid type 2 (CB2) receptors are dramatically ticipants who tried narcotics for pain were still using this treatment upregulated in inflamed neural tissues associated with CNS disorat the time of the survey. Other treatments that provided some ders, including ALS and multiple sclerosis.27 The primary murine pain relief on average (relief rating = 5.00 or more on the 0 to 10 model for human ALS is the G93A-SOD1 (glycine 93 changed to scale) were ibuprofen/aspirin, massage, muscle relaxants, acupunc- alanine–superoxide dismutase 1) mutant mouse, which is genetically ture, and hypnosis. Treatments that appeared to provide relatively engineered to replicate familial ALS.28 There is strong evidence in little relief (relief rating < 4.00) were carbamazepine and magnets, the G93A-SOD1 mouse model of ALS that the endocannabinoid although the former received a relative high-relief rating among system is involved, both directly and indirectly, in the pathophysithose participants with severe pain who tried it (6.33). Across all ology of the disease. Several recent studies have highlighted this.29,30 treatments, there was a fair amount of variability (SD range from 2.50 to 4.76 for all respondents with pain) in the relief provided by In G93A-SOD1 mutant mice, endogenous cannabinoids are elevated the pain treatments. in spinal cords of symptomatic mice.27 Furthermore, treatment with nonselective cannabinoid partial agonists before or on symptom appearance minimally delays disease onset and prolongs survival MANAG M NT APPROACH through undefined mechanisms.29 Shoemaker and coauthors demonImmobility should be considered as a source of pain and may lead strated that mRNA levels, receptor binding, and function of CB2, but to adhesive capsulitis, low back pain, pressure areas on the skin, and not CB1, receptors are dramatically and selectively upregulated in generalized myofascial pain. Neuropathic pain is a significant prob- spinal cords of G93A-SOD1 mice in a temporal pattern paralleling lem for patients with CMT and likely is a direct consequence of the disease progression. Daily injections of the selective CB2 agonist neuropathy. Thus, pharmacologic management of pain in NMD AM-1241, initiated at symptom onset, increased the survival interval needs to be broad.25 after disease onset by 56%.29

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Certainly acetaminophen (1000 mg every 6 hours), used along with Rossi and coauthors30 investigated both excitatory and inhibitory nonsteroidal anti-inflammatory drugs ( NSAIDs), may be helpful if synaptic transmission in the striatum of symptomatic G93A-SOD1 there is evidence of any active inflammatory process such as joint ALS mice, along with the sensitivity of these synapses to CB1 recepeffusion or tenosynovitis.13 Tricyclic antidepressants such as nor- tor stimulation. They reported a reduced frequency of glutamate-metriptyline and antiepileptic drugs like pregabalin or gabapentin are diated spontaneous excitatory postsynaptic currents and increased often helpful, particularly for neuropathic pain. Gabapentin also frequency of GABA-mediated spontaneous inhibitory postsynaptic has the added benefit of reducing spasticity via glutamate and gam- currents in recordings from striatal neurons in ALS mice. This is ma-aminobutyric acid (GABA) pathways. Opioids may be necessary likely due to some presynaptic defects in transmitter release. The for refractory pain. If required, opioids are best administered on a sensitivity of CB1 receptors in controlling both glutamate and regular dosing schedule and titrated to the point of comfort. How- GABA transmission was potentiated in ALS mice. This provides ever, great care needs to be used to avoid complications from respi- good evidence that adaptations of the endocannabinoid system might ratory suppression and decreased bowel motility.13 be involved in the pathophysiology of ALS. This is consistent with current theories on pathophysiologic mechanisms of ALS.31,32 Bilsland and colleagues33 showed that treatment of postsymptomatic, 90-day-old G93A-SOD1 mice with a synthetic cannabinoid, CANNABiS TO WIN55,212–2, significantly delayed disease progression. FurtherTR AT PAiN iN NMD more, genetic ablation of the fatty acid amide hydrolase ( FAAH ) enzyme, which results in raised levels of the endocannabinoid ananit is now known that active neurodegeneration, as occurs damide by preventing its breakdown, prevented the appearance in most NMDs, leads to increased concentration of tumor necro- of signs of disease in 90-day-old G93A-SOD1 mice. Surprisingly, sis factor–alpha (TNF-alpha), which rises well above normal levels elevation of cannabinoid levels with either WIN55,212–2 or FAAH during the inflammatory response. Addition of exogenous TNF-alpha ablation had no effect on lifespan. Ablation of the CB1 receptor, in to neurons, both in vitro and in vivo, has been shown to significantly contrast, had no effect on disease onset in G93A-SOD1 mice but potentiate glutamatergic excitotoxicity. Thus, the discovery of drug significantly extended lifespan. Together these results indicate that targets reducing excess TNF-alpha expression may help protect neu- cannabinoids have significant neuroprotective and disease-modifyrons after injury. Zhao and colleagues investigated the neuroprotec- ing effects in this model of ALS and suggest that these beneficial tive role of the cannabinoid type 1 (CB1) receptors after TNF-alpha effects may be mediated by non- CB1 receptor-based mechanisms. exposure in the presence or absence of CB1 agonists.26 They demonstrated that CB1 activation blocks the TNF-alpha induced increase in inflammation, thus protecting the neurons from damage. Thus, TH ROL OF TH neuroprotective strategies that increase CB1 activity may help to ENDOCANNABiNOiD SYST M reduce damage to motor neurons in ALS that are mediated by central The endocannabinoid anandamide demonstrates dopamine-blocknervous system (CNS) inflammation. ing and anti-inflammatory effects and is also tonically active in

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the periaqueductal gray matter.31 Endocannabinoids also modulate glutamatergic neurotransmission indirectly via N-methyl-D-aspartate receptors, and these pathways can be modulated to produce a clinical effect, such as reduction in motor tone, increase in seizure threshold, protection from neuronal injury, decrease in perception of pain, and elevation in mood state.26,34-40 These clinical, biochemical, and pathophysiologic patterns could reflect an underlying abnormality in the endocannabinoid system in ALS that could be potentially treated with exogenous cannabinoids; that is, via clinical use of cannabis or some derivative thereof. In addition to the neuroprotective effect, patients report that cannabis helps in treating symptoms of the disease, including alleviating pain and muscle spasms, improving appetite, diminishing depression, and helping to manage sialorrhea (excessive drooling) by drying up saliva in the mouth.41-43 Indeed, in a large survey it was noted that ALS patients who were able to obtain cannabis found it preferable to prescription medication in managing their symptoms. However, this study also noted that the biggest reason why ALS patients were not using cannabis was their inability to obtain it, either for legal or financial reasons or lack of safe access.41,44

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may lower the amount of opiates needed, and since cannabinoids do not cause respiratory depression or constipation, their use may be very advantageous. The antiemetic effect of cannabis may help with the nausea sometimes associated with narcotic medications. In addition to pain, spasticity is also a major problem for some NMD patients, particularly those with ALS. Cannabis has an inhibitory effect via augmentation of GABA pathways in the CNS.57,58 One survey study has shown that ALS patients do subjectively report that cannabis helps alleviate symptoms of spasticity.41 As mentioned previously, cannabis is also a potent antisalivatory compound, and ALS patients have reported benefit in controlling saliva when using it. Although this remains to be studied, other potential uses of cannabis in managing NMD symptoms include improving appetite, mood state, and sleep patterns.

…patients report that cannabis helps in treating symptoms of the disease, including alleviating pain and muscle spasms, improving appetite, diminishing depression, and helping to manage sialorrhea…

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HOW WOULD AN NMD PATi NT SAF LY US CANNABiS AS M DiCiN ? Cannabinoids are volatile and vaporize at temperatures in the range of 200°F, much lower than the point of actual combustion.59,60 Heated air can be drawn through cannabis, and the active compounds will vaporize and can be inhaled. This delivers the cannabinoids in a rapid manner that can be easily titrated to desired effect.59 Additionally, cannabis can be ingested orally or through a feeding tube using extracts prepared in lipophilic or alcohol-based media. However, absorption via oral methods is much slower, making dose titration more difficult.

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HOW DO S CANNABiS WORK FOR PAiN iN NMD? Cannabis may reduce pain sensation, likely through a brainstem circuit that also contributes to the pain-suppressing effects of morphine.45-51 Cannabinoids produce analgesia by modulating rostral ventromedial medulla neuronal activity in a manner similar to, but pharmacologically distinct from, that For patients with severe dysphagia, inhalation of morphine.46 This analgesic effect is also offers obvious advantages. Dosing for sympexerted by some endogenous cannabinoids tom management is “titrate to desired effect” (anandamide) and synthetic cannabinoids and an individual, patient-controlled, dosing (methanandamide), and may be prevented by the use of selective model may be used. Dosing paradigms for clinical effects in terms of antagonists.47,48 Thus cannabinoids are centrally and peripherally pain treatment have been previously described in the literature.61,62 acting analgesics with a different mechanism of action than opioids, A patient-determined, self-titrated dosing model is acceptable given although the analgesia produced by cannabinoids and opioids may the low toxicity of cannabis and the multiple variables involved here. involve similar and synergistic pathways at the brainstem level. A However, based on the available studies, a typical pulmonary adminrecent systematic review and meta-analysis of double-blind ran- istration dosing range would likely be 1 to 2 grams per day of candomized controlled trials that compared any cannabis preparation nabis with an average tetrahydrocannabinol ( THC) content of 20% to placebo among subjects with chronic pain found a total of 18 by weight.59,60 This dosing would allow the NMD patient to safely completed trials. The studies indicate that cannabis is moderately use cannabis to treat pain. efficacious for treatment of chronic pain.51 The literature regarding the specific efficacy of cannabinoids to treat chronic pain in patients with NMDs is still largely absent, with the exception of CONCLUSiON neuropathic pain.52-56 In the setting of advanced NMD, the med- Despite obvious changing trends in the acceptance of cannabis as ications should be titrated to the point of comfort. Concomitant valid medicine, there continues to be significant pushback on the use of narcotics may be needed if pain is severe. However, cannabis part of federal regulatory agencies.61-68 Yet, as our population ages,

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including patients with chronic pain and NMD, long-term drug safety becomes an important issue.69,70 For long term, palliative care opioids may produce significant morbidity.63 In this author’s opinion, cannabis is a much safer alternative with broad applicability for palliative care. Yet the federal regulatory laws continue to be inconsistent with available medical science. How can dronabinol be a Schedule III prescription drug, consisting of 100% THC , the most psychoactive ingredient in cannabis, yet, natural cannabis, containing 5% to 15% THC but also many other beneficial, nonpsychoactive cannabinoids, be a Schedule I drug (dangerous, without medical uses)? As the field of pain medicine grows, so does the need to reclassify cannabis and make it broadly available to our chronic pain patients. This should be done under close physician supervision and oversight. The foundation of this argument is made in the context of improving palliative care and reducing opioid-related morbidity in the chronic pain population, particularly those with NMD. 

the role of chronic pain. Phys Med Rehabil Clin N Am. 2012;23(3):719–729. 14. Alschuler KN, Jensen MP, Goetz MC , et al. Effects of pain and fatigue on physical functioning and depression in persons with muscular dystrophy. Disabil Health J. 2012;5(4):277–283. 15. Jensen MP, Abresch RT, Carter GT, et al. Chronic pain in persons with neuromuscular disorders. Arch Phys Med Rehabil. 2005;86(6):1155–1163. 16. Hoffman AJ, Jensen MP, Abresch RT, et al. Chronic pain in persons with neuromuscular disorders. Phys Med Rehabil Clin N Am. 2005;16(4):1099–1112. 17. Stoelb BL , Carter GT, Abresch RT, et al. Pain in persons with postpolio syndrome: frequency, intensity, and impact. Arch Phys Med Rehabil. 2008;89(10):1933–1940. 18. Graham CD, Rose MR , Grunfeld EA , et al. A systematic review of quality of life in adults with muscle disease. J Neurol. 2011;258(9):1581–1592. 19. Guy-Coichard C, Nguyen DT, Delorme T, et al. Pain in hereditary neuromuscular disorders and myasthenia gravis: a national survey of frequency, characteristics, and impact. J Pain Symptom Manage. 2008;35(1):40–50. 20. Kalkman JS, Zwarts MJ, Schillings ML , et al. Different types of fatigue in patients with facioscapulohumeral dystrophy, myotonic dystrophy and HMSN -I. Experienced fatigue and physiological fatigue. Neurol Sci. 2008;29(suppl 2):S238-S240.

Please note: Tables begin on page 21. References

21. Peric S, Rakocevic-Stojanovic V, Stevic Z, et al. Health-related quality of life in patients with myotonic dystrophy type 1 and amyotrophic lateral sclerosis. Acta Neurol Belg. 2010;110(1):71–77.

1. Emery AE . Population frequencies of inherited neuromuscular diseases— a world survey. Neuromuscul Disord. 1991;1(1):19–25.

22. Rose MR , Sadjadi R, Weinman J, et al; for the Muscle Study Group. Role of disease severity, illness perceptions, and mood on quality of life in muscle disease. Muscle Nerve. 2012;46(3):351–359.

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23. Burns TM , Graham CD, Rose MR , et al. Quality of life and measures of quality of life in patients with neuromuscular disorders. Muscle Nerve. 2012;46(1):9–25.

3. Carter GT, Jensen MP, Galer BS, et al. Neuropathic pain in Charcot-Marie-Tooth disease. Arch Phys Med Rehabil. 1998;79(12):1560–1564.

24. Miró J, Gertz KJ, Carter GT, et al. Chronic pain in neuromuscular disease: pain site, and intensity differentially impacts function. Phys Med Rehabil Clin N Am. 2012;23(4):895–902.

4. Abresch RT, Jensen MP, Carter GT, et al. Assessment of pain and health-related quality of life in slowly progressive neuromuscular disease. Am J Hosp Palliat Care. 2002;19(1):39–48. 5. Jensen MP, Hoffman AJ, Stoelb BL , et al. Chronic pain in persons with myotonic and facioscapulohumeral muscular dystrophy. Arch Phys Med Rehabil. 2008;89(2):320–328. 6. Kalkman JS, Schillings ML , van der Werf SP, et al. Experienced fatigue in facioscapulohumeral dystrophy, myotonic dystrophy, and HMSN -I. J Neurol Neurosurg Psychiatry. 2005;76(10):1406–1409. 7. Bushby KMD, Pollitt C, Johnson MA , et al. Muscle pain as a prominent feature of facioscapulohumeral muscular dystrophy (FSHD): four illustrative case reports. Neuromuscul Disord. 1998;8(8):574–579. 8. Nieto R, Raichle KA , Jensen MP, et al. Changes in pain-related beliefs, coping, and catastrophizing predict changes in pain intensity, pain interference, and psychological functioning in individuals with myotonic muscular dystrophy and facioscapulohumeral dystrophy. Clin J Pain. 2012;28(1):47–54. 9. Miró J, Raichle KA , Carter GT, et al. Impact of biopsychosocial factors on chronic pain in persons with myotonic and facioscapulohumeral muscular dystrophy. Am J Hosp Palliat Care. 2009;26(4):308–319. 10. Carter GT, Jensen MP, Hoffman AJ, et al. Pain in persons with myotonic muscular dystrophy, type 1. Arch Phys Med Rehabil. 2008;89(12):2382. 11. Engel JM , Kartin D, Carter GT, et al. Pain in youths with neuromuscular disease. Am J Hosp Palliat Care. 2009;26(5):405–412. 12. Abresch RT, Carter GT, Jensen MP, et al. Assessment of pain and health-related quality of life in slowly progressive neuromuscular disease. Am J Hosp Palliat Care. 2002;19(1):39–48. 13. Carter GT, Miró J, Abresch RT, et al. Disease burden in neuromuscular disease:

Q1  | 2014

25. Carter GT, Joyce NC , Abresch AL , et al. Using palliative care in progressive neuromuscular disease to maximize quality of life. Phys Med Rehabil Clin N Am. 2012;23(4):903–909. 26. Zhao P, Leonoudakis D, Abood ME, et al. Cannabinoid receptor activation reduces TNFalpha-induced surface localization of AMPAR-type glutamate receptors and excitotoxicity. Neuropharmacology. 2010;58(2):551–558. 27. Yiangou Y, Facer P, Durrenberger P, et al. COX- CB 2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol. 2006;6:12. 28. Gurney ME, Pu H, Chiu AY, et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science. 1994;264:1772–1775. 29. Shoemaker JL , Seely KA , Reed RL , et al. The CB 2 cannabinoid agonist AM -1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset. J Neurochem. 2007;101(1):87–98. 30. Rossi S, De Chiara V, Musella A, et al. Abnormal sensitivity of cannabinoid CB1 receptors in the striatum of mice with experimental amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2010;11(1–2):83–90. 31. Maccarrone M, Finazzi-Agro A. The endocannabinoid system, anandamide and the regulation of mammalian cell apoptosis. Cell Death Differ. 2003;10:946–955. 32. Burgess RW, Cox GA , Seburn KL . Neuromuscular disease models and analysis. Methods Mol Biol. 2010;602:347–393. 33. Bilsland LG, Dick JR , Pryce G, et al. Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice. FASEB J. 2006;20(7):1003–1005. 34. Kapur A, Zhao P, Sharir H, et al. Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands. J Biol Chem. 2009;284(43):29817–29827.

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NEUROLOGY

35. Zhang M, Adler MW, Abood ME, et al. CB 2 receptor activation attenuates microcirculatory dysfunction during cerebral ischemic/reperfusion injury. Microvasc Res. 2009;78(1):86–94. 36. Wallace MJ, Martin BR , DeLorenzo RJ . Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity. Eur J Pharmacol. 2002;452:295–301. 37. Wallace MJ, Blair RE, Falenski KW, et al. The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J Pharmacol Exp Ther. 2003;307:129–137. 38. Baker D, Pryce G, Giovannoni G, et al. The therapeutic potential of cannabis. Lancet Neurol. 2003;2:291–298. 39. Mechoulam R, Panikashvili D, Shohami E. Cannabinoids and brain injury: therapeutic implications. Trends Mol Med. 2002;8:58–61. 40. Richardson JD, Kilo S, Hargreaves KM . Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain. 1998;75:111–119. 41. Amtmann D, Weydt P, Johnson KL , et al. Survey of cannabis use in patients with amyotrophic lateral sclerosis. Am J Hosp Palliat Care. 2004;21:95–104. 42. Carter GT, Abood ME, Aggarwal SK , et al. Cannabis and amyotrophic lateral sclerosis: practical and hypothetical applications, and a call for clinical trials. Am J Hosp Palliat Med. 2010;27(5):347–356. 43. Carter GT, Bedlack R, Hardiman O, et al, for the ALSUntangled Group. ALSUntangled No. 16: cannabis. Amyotroph Lateral Scler. 2012;13(4):400–404. 44. Aggarwal SK , Carter GT, Sullivan MD, et al. Characteristics of patients with chronic pain accessing treatment with medicinal cannabis in Washington State. J Opioid Manag. 2009;5(5):257–286. 45. Zeltser R, Seltzer Z, Eisen A, et al. Suppression of neuropathic pain behavior in rats by a non-psychotropic synthetic cannabinoid with NMDA receptor-blocking properties. Pain. 1991;47(1):95–103.

ataxia in multiple sclerosis. J Neurol. 1989;263(2):120–122. 58. Lichtman AH, Martin BR . Spinal and supraspinal components of cannabinoidinduced antinociception. J Pharmacol Exp Ther. 1991;258(2):517–523. 59. Abrams DI, Vizoso HP, Shade SB, et al. Vaporization as a smokeless cannabis delivery system: a pilot study. Clin Pharmacol Ther. 2007;82(5):572–578. 60. Pomahacova B, Van der Kooy F, Verpoorte R. Cannabis smoke condensate III: the cannabinoid content of vaporised Cannabis sativa. Inhal Toxicol. 2009;21(13):1108–1112. 61. Aggarwal SK , Carter GT, Sullivan MD, et al. Medicinal use of cannabis in the United States: historical perspectives, current trends, and future directions. J Opioid Manag. 2009;5(3):153–168. 62. Aggarwal SK , Carter GT, Sullivan MD, et al. Prospectively surveying health-related quality of life and symptom relief in a lot-based sample of medical cannabis-using patients in urban Washington State reveals managed chronic illness and debility. Am J Hospice Palliat Care. 2013. [Epub ahead of print] PMID: 22887696 63. Carter GT, Flanagan A, Earleywine M, et al. Cannabis in palliative medicine: improving care and reducing opioid-related morbidity. Am J Hosp Palliat Med. 2011;28(5):297–303. 64. Carter GT, Mirken B. Medical marijuana: politics trumps science at the FDA . Med Gen Med. 2006;8(2):46. 65. Aggarwal SK , Kyashna-Tocha M, Carter GT. Dosing medical marijuana: rational guidelines on trial in Washington State. Med Gen Med. 2007;9(3):52. 66. Aggarwal SK , Carter GT, Zumbrunnen C, et al. Psychoactive substances and the political ecology of mental distress. Harm Reduct J. 2012;9(1):4. 67. Aggarwal SK , Carter GT, Sullivan MD, et al. Distress, coping, and drug law enforcement in a series of medical cannabis patients. J Nerv Ment Dis. 2013;201(4):292–303.

46. Elikkottil J, Gupta P, Gupta K. The analgesic potential of cannabinoids. J Opioid Manag. 2009;5(6):341–357.

68. Aggarwal SK , Carter GT, Sullivan MD, et al. From ounces to zero: a medical geographic study of dispensing a cultivated batch of “plum” cannabis flowers to medical marijuana patients in Washington State. J Psychoactive Drugs. 2013;45(2):141–155.

47. Karst M, Wippermann S. Cannabinoids against pain. Efficacy and strategies to reduce psychoactivity: a clinical perspective. Expert Opin Investig Drugs. 2009;18(2):125–133.

69. Molton I, Jensen MP, Ehde DM , et al. Coping with chronic pain among younger, middle-aged, and older adults living with neurologic injury and disease: a role for experiential wisdom. J Aging Health. 2008;20:972–996.

48. Meng ID, Manning BH, Martin WJ, et al. An analgesia circuit activated by cannabinoids. Nature. 1998;395(6700):381–383.

70. Carter GT, Weiss MD, Chamberlain JR , et al. Aging muscular dystrophy: pathophysiology and clinical management. Phys Med Rehabil Clin N Am. 2010;21(2):429–450.

49. Agurell S, Halldin M, Lindgren JE, et al. Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev. 1986;38(1):21–43. 50. Richardson JD. Cannabinoids modulate pain by multiple mechanisms of action. J Pain. 2000;1(1):2–14. 51. Martín-Sánchez E, Furukawa TA , Taylor J, et al. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Med. 2009;10(8):1353–1368. 52. Wilsey B, Marcotte T, Deutsch R, et al. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain. 2013;14(2):136–148. 53. Abrams DI, Jay CA , Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68(7):515–521. 54. Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain. 2008;9(6):506–521. 55. Ware MA , Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ. 2010;182(14):E694-E701. 56. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2009;34(3):672–680 57. Meinck HM , Schönle PW, Conrad B. Effect of cannabinoids on spasticity and

20 | PWJ | www.painweek.org

Q1  | 2014


Q1  | 2014 6.65

Worst pain a

18% 56%

Percentage reporting moderate worst pain b

Percentage reporting severe worst pain c

(2.60)

27%

Percentage reporting severe average pain c

(SD)

28%

(2.58)

5.06

73%

All Subjects

Percentage reporting moderate average pain b

(SD)

Average pain

a

Percentage reporting pain

NMD Diagnosis Pain Measure

a

54%

19%

(2.48)

6.69

27%

27%

(2.57)

5.15

75%

CMT

ALS

61%

28%

(2.31)

7.06

28%

33%

(2.61)

5.28

60%

DM

72%

0%

(2.87)

7.33

50%

11%

(3.21)

6.28

69%

SD = standard deviation. Assessed using a 0 (no pain) to 10 (pain as bad as can be) scale for those subjects with pain. b Moderate pain = pain rated as 5 or 6 on a 0 to 10 scale. c Severe pain = pain rated as 7 or greater on a 0 to 10 scale.

61%

18%

(2.63)

6.89

25%

39%

(2.52)

5.25

64%

LGMD

NMD Diagnosis

44%

25%

(2.89)

6.06

19%

19%

(2.24)

4.25

89%

FSHD

Table 1. Pain Frequency and Severity for All Subjects and Across NMD Diagnostic Groups

PPS

69%

8%

(2.43)

7.08

39%

15%

(2.53)

5.31

100%

36%

23%

(2.54)

5.59

9%

36%

(2.00)

4.00

82%

Other

NEUROLOGY

www.painweek.org  | PWJ | 21


22 | PWJ | www.painweek.org 2.96 (3.61) 5.23 (2.80) 1.96 (3.40) 3.67 (3.54) 2.67 (3.59) 5.37 (3.28) 3.18 (3.86) 3.39ab (3.39) 3.43 (3.52) 6.07 (2.67) 6.68 (2.73) 4.76 (2.80)

3.81bc (3.44) 5.65 a (2.84) 1.91d (3.18) 2.92ef (3.36) 1.96 g (2.95) 6.18 ag (3.28) 2.79e (3.39) 3.30 bf (3.42) 4.14 c (3.69) 6.07g (2.48) 6.70 h (2.57) 4.11c (2.85)

Hot (SD)

Dull (SD)

Cold (SD)

Sensitive (SD)

Itchy (SD)

Tiring (SD)

Sickening (SD)

Fearful (SD)

Punishing (SD)

Unpleasant (SD)

Deep (SD)

Surface (SD)

4.3 (2.70)

7.39 (1.73)

6.63 (1.91)

4.08 (3.69)

2.15 a (2.52)

2.24 (2.73)

6.65 (2.99)

1.65 (2.95)

3.08 (3.15)

2.42 (3.53)

6.35 (2.33)

3.85 (3.28)

5.64 (3.88)

CMT

3.81 (2.95)

7.29 (1.61)

6.94 (2.05)

5.06 (3.23)

5.17b (4.12)

3.44 (3.38)

6.78 (3.37)

1.39 (2.59)

3.50 (3.73)

0.89 (2.11)

6.39 (2.12)

4.11 (3.86)

6.00 (3.55)

ALS

4.12 (3.12)

6.35 (3.48)

6.18 (3.64)

5.28 (4.48)

4.83 b (3.73)

3.17 (4.09)

6.94 (3.44)

2.71 (3.65)

3.17 (3.96)

3.00 (3.74)

5.17 (3.76)

4.35 (3.69)

6.47 (3.87)

DM

3.93 (2.60)

5.63 (2.99)

5.19 (2.32)

3.37 (3.42)

2.13 a (2.85)

1.88 (2.90)

6.53 (3.42)

1.38 (2.63)

2.38 (3.38)

1.56 (2.39)

6.00 (3.12)

3.75 (2.70)

4.31 (3.52)

FSHD

4.46 (3.23)

6.77 (2.52)

5.69 (2.32)

5.17 (3.86)

3.62ab (2.63)

2.62 (3.25)

5.46 (3.23)

2.31 (2.46)

3.15 (3.24)

0.92 (1.61)

6.08 (2.47)

4.25 (3.49)

7.45 (2.21)

PPS

*All rated on a 0 (not sharp, hot, dull, etc) to 10 (the most sharp, hot, dull, etc, sensation imaginable). Note: Different superscripts associated with the mean ratings for each pain descriptor (averaged across all diagnostic groups) indicate significant (P < .05) differences between descriptors. Different subscripts associated with the mean ratings for the fearful pain descriptor indicate significant (P < .05) differences between diagnostic groups for that descriptor.

6.07 (2.91)

5.77 (3.46)

LGMD

Sharp (SD)

All Subjects a

Pain Quality Item*

NMD Diagnosis

Table 2. Pain Quality for All Subjects With Pain and Across NMD Diagnostic Groups

3.06 (2.84)

6.53 (2.62)

5.52 (2.11)

3.40 (3.60)

2.26 a (3.49)

1.95 (3.12)

5.60 (3.42)

1.50 (2.09)

1.33 (2.29)

2.05 (3.08)

4.55 (3.00)

4.00 (3.58)

5.00 (3.58)

Other

NEUROLOGY

Q1  | 2014


Q1  | 2014 2.57ab (2.71) 3.25 (3.01) 3.79 (3.33) 3.88 (3.41) 2.19abc (2.53) 3.79 (3.44) 3.46 (3.86) 3.04 abc (3.46) 4.00 (3.53) 3.68 abc (3.32)

3.70 ab (3.10) 3.81ab (2.89) 3.99 b (3.34) 4.46 c (3.39) 2.56 d (2.85) 4.04 abc (3.48) 3.91b (3.07) 2.60 d (3.24) 4.63 c (3.59) 3.41a (3.21)

Mood (SD)

Mobility (ability to get around) (SD)

Normal work (SD)

Relations with other people (SD)

Sleep (SD)

Enjoyment of life (SD)

Self-care (SD)

Recreational activities (SD)

Social activities (SD)

CMT

2.08 a (2.64)

5.17 (3.23)

1.08 d (2.20)

3.68 (3.18)

4.23 (3.51)

1.38 a (2.14)

4.33 (2.57)

3.46 (2.72)

3.32 (2.61)

4.00 bc (2.69)

ALS

4.88 b (4.20)

6.00 (4.34)

4.75 c (3.86)

4.83 (3.76)

3.39 (3.81)

3.72cd (3.48)

6.00 (4.20)

4.65 (3.69)

4.50 (3.29)

5.00 c (3.68)

DM

4.39 b (3.11)

5.06 (3.54)

3.33 abc (3.79)

5.24 (3.33)

4.61 (3.85)

4.33 d (3.73)

6.06 (3.57)

5.50 (4.12)

4.78 (3.02)

5.00 c (3.40)

FSHD

3.00 abc (3.25)

4.63 (4.40)

2.31abd (2.73)

3.63 (3.24)

4.06 (3.34)

2.75 abcd (2.93)

4.13 (3.69)

3.69 (3.68)

4.19 (3.10)

3.63 abc (3.34)

PPS

4.31bc (3.09)

5.23 (3.14)

3.08 abcd (3.48)

3.23 (2.74)

4.08 (2.81)

2.62abcd (2.69)

4.23 (3.47)

4.23 (3.19)

4.15 (2.94)

4.33 abc (3.11)

*All rated on a 0 (does not interfere) to 10 (completely interferes). Note: Different superscripts associated with the mean ratings for each activity (averaged across all study all diagnostic groups) indicate significant (P < .05) differences between activity items. Different subscripts associated with the mean ratings for the relations with other people, self-care, and social activity interference items listed separately by diagnostic group indicate significant (P < .05) differences between diagnostic groups for these activity interference ratings.

LGMD

All Subjects

General activity (SD)

Pain Interference Item*

NMD Diagnosis

Table 3. Pain Interference for All Subjects With Pain and Across NMD Diagnostic Groups

2.33 ab (2.15)

3.00 (2.63)

1.52ad (2.11)

3.57 (2.20)

4.14 (3.76)

1.71ab (1.45)

3.14 (2.54)

3.10 (2.62)

3.19 (2.32)

2.29a (2.17)

Other

NEUROLOGY

www.painweek.org  | PWJ | 23


24 | PWJ | www.painweek.org 20% 40% 43% 49% 17% 36% 35% 37% 16% 47% 36%

Neck

Shoulder(s)

Back

Chest

Arm(s)

Hand(s)

Buttock/hip(s)

Abdomen/pelvis

Legs

Feet

All Subjects

Head/face

Pain Location

23%

39%

11%

36%

30%

32%

16%

48%

46%

39%

16%

LGMD

66%

60%

6%

26%

37%

26%

6%

54%

34%

29%

17%

CMT

23%

30%

13%

20%

27%

33%

10%

33%

37%

27%

7%

ALS

27%

50%

31%

35%

39%

31%

27%

42%

31%

46%

27%

DM

22%

44%

17%

61%

44%

50%

17%

78%

67%

50%

33%

FSHD

Percentage With Pain at Each Site for Each NMD Diagnosis

Table 4. Pain Locations for All Subjects With Pain and Across NMD Diagnostic Groups

69%

62%

23%

69%

69%

54%

31%

77%

85%

69%

39%

PPS

33%

56%

22%

44%

26%

44%

22%

37%

33%

44%

19%

Other

NEUROLOGY

Q1  | 2014


Q1  | 2014 62.28 b (17.77) 51.50 b (15.74) 58.76 b (20.37) 47.95 b (17.10) 67.12b (20.93)

84.15 a (23.28)

80.96 a (34.00)

75.15 a (20.34)

71.95 a (20.34)

60.86 a (20.96)

83.28 a (22.69)

81.26 (33.04)

74.74 (18.05)

Physical functioning (SD)

Role–physical (SD)

Bodily pain (SD)

General health (SD)

Vitality (SD)

Social functioning (SD)

Role–emotional (SD)

Mental health (SD) 73.93 (14.69)

76.28 (22.69)

66.79 (23.74)

50.45 (15.73)

63.70 (22.79)

51.90 ab (15.21)

66.20 (21.32)

48.39 (17.82)

LGMD

CMT

71.83 (17.63)

78.26 (19.74)

74.00 (17.80)

46.00 (15.57)

58.83 (19.60)

52.83 ab (12.35)

60.42 (15.93)

58.43 (16.86)

ALS

68.70 (16.09)

76.04 (22.75)

59.44 (22.09)

45.32 (17.70)

51.62 (20.25)

43.84 b (18.54)

56.77 (14.58)

44.38 (14.64)

69.07 (14.04)

73.53 (22.09)

60.00 (20.29)

41.44 (18.33)

49.73 (16.70)

44.21b (16.78)

61.76 (16.81)

56.67 (15.39)

DM

NMD Diagnosis

74.58 (13.54)

83.33 (21.94)

73.13 (23.30)

45.57 (20.89)

59.90 (19.51)

58.18 a (15.16)

71.09 (21.76)

46.83 (13.53)

FSHD

*All standardized to range from 0 to 100, with 100 indicating highest level of self-reported functioning. † From Ware et al.55 Note: Different superscripts associated with the mean ratings for SF-36 scale score indicate significant (all P < .05) differences between general US norms and the study participants for these scales.

73.23 (14.94)

79.01 (21.44)

50.41b (15.98)

Norms †

SF-36 Scale Score*

All NMD Subjects

Table 5. SF-36 Scale Scores for All Subjects With Pain and Across NMD Diagnostic Groups

PPS

76.67 (13.84)

81.94 (19.41)

66.15 (18.50)

51.28 (17.30)

65.91 (19.51)

51.22ab (17.79)

58.33 (15.39)

48.77 (14.66)

78.25 (12.76)

84.92 (21.67)

68.10 (17.78)

54.50 (15.00)

60.50 (20.49)

57.30 a F = 2.95 (12.07 P = .01)

59.52 (14.20)

50.95 (15.32)

Other

NEUROLOGY

www.painweek.org  | PWJ | 25


26 | PWJ | www.painweek.org 18% / 50% 18% / 60% 15% / 38% 11% / 25% 11% / 25% 8% / 55% 9% / 67% 4% / 85% 4% / 17% 3% / 0% 2% / 3%

Neurontin

Muscle relaxants

Tricyclic antidepressants

Acupuncture

Magnets

Biofeedback/relaxation training

Counseling

Chiropractic manipulation

Carbamazapine

Nerve blocks

Hypnosis

5.00 (4.24)

6.75 (4.76)

3.80 (4.38)

7.33 (3.78)

4.70 (2.50)

4.42 (2.50)

3.13 (3.16)

5.29 (3.22)

4.53 (3.28)

5.78 (2.88)

4.78 (3.02)

5.48 (2.73)

6.37 (2.74)

4.54 (2.66)

4.11 (2.93)

5.22 (2.83)

Average Relief (SD) b

0% / n/a

5% / 0%

8% / 33%

0% / n/a

18% / 71%

11% / 75%

11% / 25%

3% / 100%

18% / 29%

21% / 50%

24% / 56%

34% / 39%

42% / 56%

50% / 37%

37% / 50%

47% / 78%

Percentage Tried/ Percentage Still Use a

10.00 (0.00)

6.33 (3.79)

4.17 (2.64)

4.50 (1.91)

1.75 (2.87)

6.00 (0.00)

5.43 (2.99)

4.25 (1.26)

4.57 (3.05)

4.91 (3.36)

5.75 (2.79)

3.89 (2.25)

3.31 (2.87)

4.25 (3.05)

Average Relief (SD) b

All Subjects With Severe Pain (n = 138)

SD = standard deviation. Percentage still use = percentage of subjects who reported a history of using the pain treatment at one time who are currently using or receiving the treatment. b Subjects who had used the treatment rated the amount of relief provided by each on a 0 (no relief) to 10 (complete relief) scale.

34% / 44%

Massage

a

43% / 42% 35% / 63%

Narcotics

47% / 58%

Acetaminophen

Physical therapy

61% / 65%

Percentage Tried/ Percentage Still Use a

Ibuprophen/aspirin

Pain Treatment

All Subjects With Pain ( N = 141)

Table 6. Percentage of Participants With Pain Who Have Tried Each Treatment/ Percentage of Participants Who Still Use the Treatment, and Average Relief Rating Associated With Each Treatment

NEUROLOGY

Q1  | 2014


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Rossetti MMT, MT-BC

by Andrew 


Music therapy has proven to be an effective way of treating anxiety in cancer patients receiving external beam radiation therapy.

Music therapy’s presence as an analgesic is growing in a myriad of clinical contexts, including many hospital ambulatory and inpatient cancer settings. The efficacy of music in medicine may lie in its capacity to integrate evidence-based constructs and psychological approaches to pain management with music’s inherent physiological, emotional, associative, and cognitive effects to favorably modulate the complex multidimensional somatic experience that is pain. The statistics on frequency and multiple types of pain suffered by cancer patients, and those with difficulties faced with approaches limited to pharmacological pain management, are particularly troublesome. It is compelling to note that the palliative effects of music analgesia are evident in a population— cancer patients—that experiences a wide gamut of pain types. Focus on the complex psychological processes that regulate pain perception as a subjective experience has led to novel approaches in pain management and subsequent research of their efficacy. Music therapy proves to be an elegant and effective tool in addressing the role and interaction of emotion and anxiety in the perception of pain. abstract:

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MUSIC THERAPY

is a subjective experience intricately influenced by culture and one’s prior traumatic experiences. It includes emotional and state elements as well as purely nociceptive or neuropathic features.1 Though considerable controversy still exists as to how emotion may be defined, it is generally accepted that emotions have physiological as well as psychological aspects, and that we experience emotion as a bodily awareness and judge the events that provoke emotions accordingly. Similarly, state refers to one’s subjective evaluation in the moment of one’s entire being— intraception of mind and body. Music therapy has proven to be an effective way of treating anxiety in cancer patients receiving external beam radiation therapy. At the Louis Armstrong Center for Music and Medicine, in alliance with our radiation oncologists, we have developed a working model for pain management within the context of music psychotherapy based on biopsychosocial constructs, Porges’ polyvagal theory, current trauma theory, and the extensive body of literature addressing music’s effects on psyche and soma. Our team of music therapists, doctors, and nurses are actively researching aspects of music therapy’s efficacy in addressing pain and anxiety associated with the cancer patient’s experience of radiation and chemotherapy. The following series of postulates form a working hypothesis and rationale for specific music therapy interventions in pain management with patients in fragile environments:

Emotional mechanisms are an integral part of the pain process Music can be used to generate/modulate emotion

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Prolonged pain can lead to autonomic nervous system (ANS) hyperarousal and increased sympathetic activity Music can modulate ANS response and vagal tone

Anxiety is an exacerbating factor in the pain experience Music can be used modulate state anxiety

Negative affect and mood states can contribute to increased severity of perceived pain Music can be used to modulate affect and mood

Muscle tension can exacerbate pain perception Music can be used in release-oriented strategies to reduce muscle tension

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MUSiC PSYCHOTH RAPY:

is influenced by attentional, emotional, cognitive, and evaluatory mechanisms. It may be most useful to consider the similarities of music and pain as percepts.

When Sigmund met Ludwig

As previously stated,2 music psychotherapy employs principals of Music may be thought to exist initially as transmitted vibrations, psychotherapy and incorporates music and its elements as an integral and only when it is processed on a cognitive level does it “become” part of the dynamic relationship. Music’s role is thus to be an agent distinguished as music in the brain. Likewise, in keeping with the of change as well as providing a context or ‘space’ for that change to gate control and neuromatrix theories, transmitted messages are occur. Transference and countertransference are manifested and not experienced as pain until cognitively processed, evaluated, and worked through using improvisation, songs, and imagery in music. “made sense of.”5 Music psychotherapy may be seen as a process in which change, a goal of all therapeutic interventions, happens within the relationship Gate control theory accommodates psychological perspectives to between patient and therapist. Music serves to create a safe platform explain phenomena ignored by earlier sensory specific models of or context where painful feelings, perhaps too difficult to express in pain, and identifies specialized systems in the cerebrum involved words, may be expressed in and through music. The process itself can with distinct dimensions of pain—sensory discriminative, motivabe viewed as a patient’s acceptance of the ‘therapist as liaison.’ Liaison tional/affective, cognitive/evaluative. As such, identification allows to the inner workings of self, as well as to illness and treatment itself, for exploration on how these dimensions may be manipulated to and/or a liaison to the clinical team and treatment needs identified modulate the pain response itself.5 by the team. Music psychotherapy is provided within a continuum whereby the music therapist does not give answers or advice, but In pain perception, the brain may be seen as a dynamic system that seeks to contextualize and provide avenues for the patient to gain per- filters, selects, and modulates input. This mechanism acts upon pain’s spective—literally ‘seeing from two different points of view to gain psychological components, including attention, past experience, anxdepth of perception’—as the primary step in ‘seeing’ where change iety, affect, and the meaning of the situation.6 One important aspect may occur, and moving towards it.2 Numerous models of music psy- of music psychotherapy is to access the brain mechanisms that open chotherapy are employed in practice. Dr. Joanne Loewy, director of pathways to the modulation of pain itself through reduction of anxBeth Israel Medical Center’s Louis Armstrong Center for Music and iety and associative affectual response. Medicine, developed a model of music psychotherapy that draws from Maslow, Yalom, Anna Freud, Jean Piaget, and Perls’ Gestalt theory.3 It is this model that is the basis for music therapy as practiced on Beth TH POLYVAGAL TH ORY Israel’s oncology units, and it employs elements of psychodynamic theory as well as humanistic philosophy to provide the patient with The phylogenetic and neuroanatomic guidelines provided in Porges’ perspective on their unique patterns of relating to the world. polyvagal theory delineate a justification for the use of music therapy interventions to reduce anxiety. It elucidates the mechanisms within the sympathetic and parasympathetic activity of the ANS, Loewy states: which are regulated by the myelinated section of the vagus, or 10th Music psychotherapy is exploratory in nature, and funccranial nerve.7

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tions through assessment and processing of awareness of self, other, and of the moment; thematic expression: listening, performing; collaboration; therapeutic relationship; concentration, range of affect; investment/motivation; use of structure; integration; self-esteem; risk-taking and independence.3

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PAiN P RC PTiON AND R SPONS : No Simple Matter In the years following Melzack and Wall’s gate control theory of pain published in 1965, a substantial amount of research confirmed the presence of descending neurophysiological pathways through which psychological states can either exacerbate or inhibit nociceptive input and the experience of pain.4 Few would argue against the construct that greater emotional distress and anxiety are associated with an increase in perceived pain intensity, or that the perception of pain Q1  | 2014

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Myelinated enervations of the vagus form a complex neural bidirectional pathway linking the brainstem to many organs. In linking the ties between the polyvagal theory and music in clinical contexts, particular interest lies within our vocal intonation being mediated by vagal connections to the larynx, the orbicularis oculi, which is a muscle in the face that closes the eyelids and contributes to our forming a so-called “Duchenne” or authentic smile, and the stapedius muscle in the middle ear function, which is mediated by vagal connection. These areas are involved in emotional state signaling, singing/vocal prosody, and listening to sound/music. The stapedius muscle along with the tympanic membrane is activated by music. Thus, music can be employed as an effective tool for influencing vagal tone, and in doing so can influence sympathetic and parasympathetic activity, as well as emotion.7 In effect, music may be seen to be a means for vagal stimulation, and thus, a direct path to modulating ANS function.

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MUSIC THERAPY

CLiNiCAL APPLiCATiON: Connecting the Dots Recent studies have provided evidence in the effectiveness of music therapeutic methods for the treatment of distinct types of pain.12-17 It may be more important to point out that while current music-based intervention studies provide feasibility and efficacy, these findings are far from homogenous. This may be partially understood by considering the intervention type and practitioner methodology.

Porges states: Music may be used to calm, enable feelings of safety, and reduce the social distance between people...intertwined with emotion, affect regulation, interpersonal social behavior, and other psychological processes related to personal responses to environmental, interpersonal, and intrapersonal challenges…[music] can elicit a variety of emotional experiences that are paralleled by adaptive psychological states [and] trigger the client’s neuroception of safety.7 Moreover, the neural regulation of the autonomic nervous system is linked to the neural regulation of the muscles of the face and head, which signal our emotional state. These muscles of the face and head are involved both in actively listening to (ie, the modulation of our middle ear muscles) and in producing of music…by singing (ie, the modulation of the laryngeal and pharyngeal muscles) or by playing a wind instrument.7

MUSiC AND EMOTiON Music offers its listeners a broad range of possible emotional experiences that may well be one of the primary reasons why people turn to music for recreation, support, or motivation. Music is capable of communicating basic emotions universally across different cultures,8-10 and provides for a sense of “shared intentionality.”11

When available, feasible, desired by the patient, and consistent with the goals of care, nonpharmacological pain management interventions are routinely delivered by experienced clinicians. Portenoy states that among the most useful are the so-called mind-body approaches, which are classified as both psychological and integrative interventions18 and include music psychotherapy, and music and medicine.

In a recent interview Portenoy stated: It is well known that patients with cancer commonly access complementary and alternative medicine approaches, sometimes known generically as integrative therapies, either in an effort to manage the cancer itself or in an effort to manage symptoms. Patients with pain frequently seek out these strategies. It is important for oncologists to understand this very heterogeneous group of treatments, and to note that some actually have very good evidence of efficacy.19

In following the aformentioned postulates on music’s role in altering pain perception, music analgesia may be effectively provided through a number of strategies. Specific interventions and approaches have been the object of a large number of clinical studies. They rely on a full assessment, as well as diverse physiological and psychological mechanisms that are contingent upon varying elements of the pain process.

The communication of emotions by music has been a topic that has received a great deal of attention for quite some time, and empir- Music-assisted release strategies focus on lowering tension, where ical studies have described the role of individual features (tempo, music can serve as a stimulus and structuring element for the movemode, articulation, timbre) in predicting the emotions suggested or ment and/or vocalization that serve as the basis for this approach. invoked by the music. Emotion is perhaps communicated through This may be an effective vehicle for release of emotional as well as music by its metaphoric content—both literally (such as a low physical tension. Musical crescendo drives the potential for cathartic register melody in 2/4 time consisting of the tonic and a perfect response within this process. fourth below in alternating quarter notes to conjure up the image of a huge lumbering animal) and figuratively (such as Beethoven’s Other interventions may focus on engaging both perceived and Pastoral, which while it cannot be said that its sounds mimic any- experienced emotion in music. These interventions ideally employ thing in particular, it tends to, in most cases, evoke an image of a live music accompanied by simultaneous verbal processing of the bucolic countryside). Musical elements tend to play a strong role patient’s experience to redirect emotional mechanisms of the pain in the cuing related to ‘what’ we should feel. Harmonic tension process to reduce the often perceived intensity. is often felt as tension. Our response to the climactic scenes of Hitchcock’s Psycho, for instance, would be quite different without Diverse music therapy interventions address anxiety’s role in pain the high-pitched minor seconds played on violin to warn us of perception. It has long been accepted that regulation of breathing impending horror. can modulate state anxiety. Entrainment of breathing through

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music—a bi-directional calibration of respiratory rate, pattern, and depth to dynamic live music—can serve as an effective anxiolytic. State anxiety can also be approached with music interventions that seek to modulate affect and mood state, which are highly viable given music’s evidence-based shown effect on mood. State anxiety might also be reduced through music enhanced guided visualization. Imagery-based interventions have gained acceptance in a myriad of clinical contexts. Imagery instructions are usually designed to help patients develop a detailed mental visualization of a safe and comforting place on which to focus their attention during painful procedures or other pain experiences. Though imagery can be provided by the therapist, gentle suggestion to aid patients in developing their own unique imagery is preferable. Imagery is likely to be most effective at eliciting relaxation when it incorporates multiple senses,20 and perhaps the most potent of these in this context is the auditory sense. Live music may be used to provide an entrained dynamic soundtrack to accompany and guide the patient’s imagery rendering it more vivid. Cognitive elements of pain perception such as attention components can be redirected through patient integration in music experiences. Approaches include active listening, as well as directed vocalization and toning, and often contribute to sensory override to disrupt completion of pain signaling patterns. An inverse process might also be employed. With music providing a safe holding environment the patient can be directed to focus on the area where s/he might be experiencing the feeling of pain. S/he is led toward guided identifiers through separating the physical sensations that often accompany pain, and which become confining and then contribute to greater intensity of perceived pain—namely, tension, change in tissues, heat, tingling or numbness, and pressure. Identifying these distinct sensations on a conscious level can contribute to perceiving less intensity of pain by “subtraction” or “ungrouping” and can prevent activation of emotional schema that may increase pain sensation. Various altered state induction techniques may be applied to the management of a wide range of varying experiences within the pain spectrum. Repetitive-patterned hypnotic styled live music can be played to facilitate and speed induction. Music’s metaphoric content may be effectively used to bring a patient to deepened altered states where suggestion may have more defined impact. Aspects of both traditional relaxation procedures and imagery can be incorporated in the offering of these techniques, in combination with hypnotic and posthypnotic suggestion. Suggestions may be intended to induce analgesia or to transform the pain from a place of extreme tension toward a nonpainful sensation, such as heaviness.21

CONCLUSiON Music psychotherapy when combined with pharmacological analgesia offers a tandem approach to pain management for patients with cancer. While there is a need for further clinical research on its efficacy, with Q1  | 2014

greater focus on the development of methodological and technical implications, music psychotherapy as integrative medicine may prove to be a valuable tool towards safe and effective management of pain.  References 1. Turk D, Melzack R. Handbook of Pain Assessment. Second ed. New York, NY: Guildford; 2001. 2. Rossetti A, Canga B. Environmental Music Therapy: Rationale for ‘Multi-Individual’ Music Psychotherapy in Modulation of the Pain Experience in Music and Medicine: Integrative Models in the Treatment of Pain. Mondanaro J, Sara G, eds. New York, NY: Satchmo Press; 2013. 3. Loewy JV. The use of music psychotherapy in the treatment of pediatric pain. In: Dileo C, ed. Music Therapy in Medicine: Theoretical and Clinical Applications. Silver Spring, MD: AMTA ; 1999:185–206. 4. Bruehl S, Chun OK . Psychological interventions for acute pain. In: Hadjistavropoulos T, ed. Pain: Psychological Perspectives. Oxford, UK: Taylor and Francis; 2003:259. 5. Hadjistavropoulos T, Craig KD. An introduction to pain. In: Hadjistavropoulos T, Craig KD, eds. Pain: Psychological Perspectives. Oxford, UK: Taylor & Francis; 2003. 6. Melzack R, Katz J. The gate control theory: research for the brain. In: Hadjistavropoulos T, ed. Pain: Psychological Perspectives. Oxford, UK: Taylor and Francis; 2003. 7. Porges SW. The Polyvagal Theory: Neurophysiological Foundations of Emotions, Attachment, Communication, and Self-Regulation. New York, NY: Norton; 2011. 8. Peretz I. Towards a neurobiology of musical emotions. In: Juslin PN, Soloboda JA , eds. Handbook of Music and Emotion: Theory, Research, Applications. Oxford, UK: University Press; 2010:99–126. 9. Bigand E, Vieillard S, Madurell F, et al. Multidimensional scaling of emotional responses to music: the effect of musical expertise and of the duration of the excerpts. Cogn Emot. 2005;19(8):1113–1139. 10. Peretz I, Gagnon L, Bouchard B. Music and emotion: perceptual determinants, immediacy and isolation after brain damage. Cognition. 1998;68:111–141. 11. Cross I. Musicality and the human capacity for culture. Musicae Scientiae. 2008:12;147–167. 12. Cepeda MS, Carr DB, Lau J, et al. Music for pain relief. Cochrane Database Syst Rev (Online). 2006;(2):CD 004843. 13. Schwoebel J, Coslett HB, Bradt J, et al. Pain and the body schema: effects of pain severity on mental representations of movement. Neurology. 2002;59(5):775–777. 14. Silvestrini N, Piguet V, Cedraschi C, et al. Music and auditory distraction reduce pain: emotional or attentional effects? Music Med. 2011;3:264–270. 15. Voss JA , Good M, Yates B, et al. Sedative music reduces anxiety and pain during chair rest after open-heart surgery. Pain. 2004;112(1–2):197–203. 16. McCaffrey R, Freeman E. Effect of music on chronic osteoarthritis pain in older people. J Adv Nurs. 2003;44(5):517–524. 17. Guétin S, Giniès P, Siou DK , et al. The effects of music intervention in the management of chronic pain. Clin J Pain. 2012;28(4):329–337. 18. Portenoy R. Treatment of cancer pain. Lancet. 2011;377:2236–2247. 19. Portenoy R. Interview March 04, 2011. Russell Portenoy, MD: My Approach to Pain Management for Cancer Patients. http://www.practiceupdate.com/ expertopinion/116. 20. Turk DC , Meichenbaum D, Genest M. Pain and Behavioral Medicine. New York, NY: Guilford Press; 1983. 21. Wright BR , Drummond PD. Rapid induction analgesia for the alleviation of procedural pain during burn care. Burns. 2000;26:275–282.

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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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F ATUR S: ●● One-Minute Clinician ●● PAINWeek eNewsletter “ BRAINFOOD” that you can put to use right away, 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. Don’t miss out on any of the new resources PAINWeek is now providing!


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Datz PhD

by Geralyn 


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TH MAJORiTY OF PAiN PATi NTS HAV COMORBiD MOOD OR ANXi TY DiSORD RS, iTH R PR C DiNG PAiN OR D V LOPiNG AS A CONS QU NC OF PAiN.

abstract: “Why isn’t my patient getting better?!” Lack of progress or delayed recovery in pain treatment can be due to uncontrolled mood or anxiety disorders in patients with pain. These patients may have difficulty managing stress, be in a constant search to be “fixed,” and be emotionally reactive. The majority of pain patients have comorbid mood or anxiety disorders, either preceding pain or developing as a consequence of pain. Biopsychosocial theory offers an effective heuristic for understanding the complex psychological, social, and neurochemical changes involved in depression and anxiety, and why chronic pain is reciprocally influenced by these disorders via central sensitization. Q1  | 2014

Activity levels, mood, medical compliance, sleep, mindset, and fears and avoidance of pain are all exacerbated by mood disorders, and in turn negatively influence pain treatment outcomes. It is vital to understand how to properly identify, treat, and manage psychological comorbidities in pain treatment settings. This article describes clinical strategies, psychological assessments, and treatments for adjunctive techniques to facilitate providers’ management of these patients. Cognitive behavioral therapies are strongly supported, evidence-based treatments for pain, as well as depression and anxiety, and will be shared as an option for offering multidisciplinary care. www.painweek.org  | PWJ | 37


BEHAVIORAL

PARADiGM SHiFT

Modern treatment of chronic pain is biopsychosocial1 and involves treating the patient as a “whole person.” This means addressing physical discomfort, as well as the psychological response to it. This psychological response includes many areas, such as how pain impacts mood, sleep, motivation, eating habits, physical activity, and work status. The biopsychosocial approach also takes into account the patients’ cultural norms and expectations about pain and medical treatment, and the social system surrounding the patient (which may be supportive or not), their spiritual conception of their pain, and their litigation status. The contribution of psychological and social domains have their own unique impact on recovery potential. Thankfully, biopsychosocial approaches are now becoming well known amongst pain practitioners and are a continued topic of research. Several treatment guidelines (such as the American College of Occupational and Environmental Medicine and Official Disability Guidelines, etc) now incorporate the biopsychosocial model into pain treatment, as do many insurers. These requirements have allowed not only attention to be given to the whole person with pain, but for reimbursement of mental health/psychological services as well. A relevant example is the requirement for a psychological evaluation prior to proceeding with a neurostimulation trial. This recommendation exists due to several well-controlled studies which showed that untreated, negatively impacting psychosocial factors significantly interfere with surgical recovery and rehabilitation.2 A growing body of compelling data demonstrates that psychological factors play a significant role in the exacerbation, maintenance, and propagation of pain disability: ›› With respect to surgical outcomes, psychological assessments are predictive of spinal surgery response, predicting 80% of response in both invasive and noninvasive procedures.3

One study quantified the impact of affective disorders (depression and anxiety, specifically) in terms of disability days off of work. Bair and colleagues,9 studied 500 pain patients with differing psychological presentations. Time off from work was significantly impacted by the presence of affective disorders, and the impact was additive. Patients with both anxiety and depression missed the most work overall (see Table 1).

›› Psychopathology (such as depression and anxiety symptoms) negatively influences treatment outcomes from invasive procedures including medial branch nerve blocks, spinal cord stimulation, intrathecal pumps, and spine surgery.3-6

Table 1. Impact of Comorbid Affective Disorders in Patients With Chronic Musculoskeletal Pain by Disability Days9

›› Job dissatisfaction and depression are better predictors than physical injury in return to work.7

Without anxiety or depression

›› Depression and anxiety increase pain intensity and disability, contributing to a negative cycle, where functional limitations are perpetuated.8

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Pain Patient Category

# Disability Days 18

With anxiety only

32.2

With depression only

38.0

With both anxiety and depression

42.6

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Unfortunately for patients with pain, “cures” don’t exist. Of the treatments available, many have also fallen very short of the persistent needs of patients with chronic pain. Research suggests that, while popular, spine surgeries are often associated with only short-term benefits, and modest-to-small benefits when compared to nonoperative modalities long term.10 Medications, particularly opioids, are often prescribed for pain relief. While helpful to some patients in the short term, the long-term efficacy and side-effect-to-benefit ratio has been steadily questioned.11 Opioids have come into the crosshairs of regulatory scrutiny due to overprescribing and high rates of overdose deaths, propensity for addiction, side effects, and medical misuse.12 It is clear that no one treatment for chronic pain will suffice. Assessing and intervening on mental health aspects of chronic pain is part of a well-designed, biopsychosocial approach.

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AFF CTiV DiSORD RS Affective disorders are mood disorders (including major depression and bipolar) and anxiety disorders (including generalized anxiety, posttraumatic stress disorder [ PTSD], and panic disorder) that negatively affect social, emotional, and/or occupational functioning. Symptoms vary and can be mild, moderate, or severe. Other subtypes of affective disorders include cyclothymic disorder and bipolar II disorder, and obsessive compulsive disorder and social anxiety. For the purposes of this discussion, and due to their greater prevalence in chronic pain patients, the diagnoses of major depression, bipolar, PTSD, generalized anxiety, and panic disorder will be the primary referenced diagnoses. Affective disorders occur at much higher rates in chronic pain patients then they do in the general population, generally at a rate of double or greater.13

disorders activate common areas of the brain. Shared activation of the sympathetic nervous system, involvement of the hypothalamic-pituitary axis, and downregulation of benzodiazepine receptors in the frontal cortex has also been shown. Psychological mechanisms are proposed to explain the relationship between pain, depression, and anxiety.9

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D PR SSiV DiSORD RS Prevalence rates of major depressive disorder among chronic pain patients range from 21% to 57% of general chronic pain patients and 30% to 64% among those experiencing chronic musculoskeletal pain in particular.8,14 While some people experience only one episode of depression in their lifetime, most tend to have multiple episodes. Major depression can be extremely debilitating, often interfering with a person’s ability to function in daily activities such as working, sleeping, studying, eating, and can sometimes be of such severity that psychotic features—delusions, hallucinations—become part of its presentation. Chronic pain patients diagnosed with a depressive disorder may present with insomnia, back aches, headaches, fatigue, worthlessness, suicidal ideations, frequent visits to a healthcare provider, and/or a persistent search for medical explanations to their problems. In one study examining pain and depression levels in patients with spinal cord injuries (SCI ),15 of the 20% of the sample that endorsed both depression and pain, this group had higher pain severity, evidenced less improvement over time, and utilized more SCI specialty care. It appears that, when combined, depression and pain are especially debilitating to patients.

There are several strategies that healthcare providers can employ for depressed patients. Patients who are high utilizers of treatment may initially need frequent appointments with the provider.16 AntiGiven the high comorbidity between chronic pain and affective dis- depressants are often considered. Referrals to mental health providorders, it is not surprising that biologic explanations point towards ers (eg, psychologists, counselors) for cognitive behavioral therapy shared neurobiological and neuroanatomical pathways that are (CBT ) are also a first-line recommendation when treating deprescommon to pain, anxiety, and depression. Neurotransmitters rel- sion and pain. CBT reduces negative thoughts about pain, targets evant to all 3 conditions include monoamines (eg, serotonin and depressed emotions and helplessness, reduces arousal, and regulates norepinephrine), gamma-aminobutyric acid, glutamate, adenosine, sleep patterns. CBT is delivered by qualified health professionals, and chemical compounds such as cannabinoids, and other neuropep- but encourages a self-management approach to reduce dependency tides.9 In addition, f MRIs have shown that chronic pain and affective on the healthcare system. CBT is an effective treatment for pain

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UNFORTUNAT LY FOR PATi NTS WiTH PAiN, ‘CUR S’ DON’T XiST.

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BEHAVIORAL

and pain-related depression, and has outperformed psychotropics in meta-analyses.17 A psychiatric consultation may be warranted if a patient continues to be treatment resistant, have severe symptoms, or need specific psychopharmacology. Participation in mindfulness exercises, faith groups, and community involvement may be additional sources of support.

disorder, its signs and symptoms, and not take these occasionally challenging patients personally. There is often a strong negative social stigma to bipolar disorder. It may be helpful to be reminded that many well-known individuals have been diagnosed with bipolar disorder, and while some of their struggles are public knowledge, they have also lead creative and productive lives. Some examples include Kay Redfield Jamison, Jim Carrey, Carrie Fisher, Kurt Cobain, Demi Lovato, Jean Claude Van Damme, and Frank Sinatra. Secondly, psychiatry involvement, or skilled psychopharmacology, with this population is usually critical, particularly in regulating mood and sleep patterns. Establishing firm practice rules and boundary setting is important. Finally, taking suicidal statements or innuendo seriously is paramount in this population.

Bipolar disorder is a type of depressive disorder and is characterized by intense magnification and unpredictability of common emotions. Patients with bipolar disorder can quickly swing from extremes of happiness, energy, and clarity to sadness, fatigue, and confusion. They may demonstrate extreme changes in energy, activity, sleep, and behavior, and must have some form of a manic episode, and may experience both depression-related and manic-related symptoms together. A manic episode is typically characterized by a mood change An evidenced-based psychotherapy treatment for those patients with in which a person demonstrates an overly or excessive joyful or out- a bipolar disorder is CBT, often coupled with mood-stabilizing medgoing mood, is irritable or verbally aggressive, or is in an excited state ications. Common techniques used in CBT for those with a bipolar (feeling “high” without substance use) for disorder include cognitive restructuring a long period of time (such as over several (eg, changing negative or harmful thought days). Mood swings may be less extreme patterns and behaviors into more adaptive among some patients, particularly those alternatives) and behavioral activation (eg, whose mood meets criteria for hypomania; keeping social rhythms regulated, learning however, bipolar disorder can also be of to notice changes in mood). such severity that psychotic features, such as delusions or hallucinations, are present. Between episodes of mania, hypomania, or ANXi TY DiSORD RS depression, patients may be free of symptoms or have lingering symptoms. Anxiety is a normal reaction to stress and can be beneficial, but for some it can Chronic pain patients also diagnosed with become excessive. Each anxiety disorder a bipolar disorder can pose special chalhas different symptoms but they all cluster lenges in their treatment, including irriaround excessive or irrational worry, fear, tability, instability of mood and behavior, and dread. The main clinical symptoms of excessive utilization and consumption of anxiety include feeling keyed up or on edge, time. Other prominent symptoms could fatigue, difficulty concentrating or mind include overdoing in a manic episode, sedgoing blank, irritability, muscle tension, entary behaviors or features of reinjury and sleep disturbance, typically insomnia. during a depressed mood, need for hosTo the pain practitioner, patients with anxpitalization, and resistance to the idea that pain is multifactorial. iety frequently complain “Not enough is being done!” Other cardinal Patients with a dual diagnosis of chronic pain and a bipolar disorder symptoms of the pain patient with anxiety include anger, nightmares, are at an especially high risk for suicide. Bipolar disorders have one social isolation, self-medicating behaviors, a focus on cardiac sympof the highest suicide rates among all psychiatric disorders; about toms, and fears of movement and reinjury. Anxiety sensitive patients 20% of patients have attempted suicide.18 tend to catastrophize and misinterpret sensations of arousal related to pain, which in turn activates the central nervous system, unforRecent data18 suggest that those with bipolar disorder are at increased tunately causing greater perceived pain.19 risk for fibromyalgia, migraine headaches, and completed suicide. About 13% to 25% of patients with fibromyalgia are also diagnosed Pain and anxiety are both associated with physiological arousal. with a bipolar disorder. Individuals with this dual diagnosis may have Bodily changes stemming from arousal (heart rate, breathing “pseudofibromyalgia” in which they have no elevation in substance changes, sweating, hypervigilance) usually serve a protective funcP spinal fluid levels and do not respond to the traditional treatment tion by promoting escape and withdrawal from danger. However, of fibromyalgia. A quarter to nearly 40% of patients diagnosed with prolonged arousal, due to pain and/or anxiety (such as in anxiety bipolar I disorder also have migraines. The presence of migraines in disorders and in chronic pain states) can have detrimental physical depressed people is now conceptualized as a bipolar spectrum trait. effects: degradation of muscle, bone, and neural tissue can occur.15 Individuals with pain conditions may use worry as a strategy for There are several strategies healthcare professionals can use when reducing somatic arousal associated with pain, and as a result may interacting with bipolar patients. It is important to understand the become prone to developing generalized anxiety disorder.20,21

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The most commonly diagnosed anxiety disorders in pain patients are generalized anxiety and panic disorder.21 Almost all (95%) pain patients with anxiety disorder had experienced anxiety disorder before onset of pain.8 It is hypothesized that premorbid diathesis for anxiety is exacerbated by onset of pain, and this is believed to be a result of both genetic predisposition and anxiety sensitivity.8

PTSD PTSD is an anxiety and trauma disorder that deserves special mention due to high prevalence rates among patients with a chronic pain condition, as well as their tendency to exhibit an intense and widespread chronic pain coupled with a unique hyposensitivity to pain. PTSD is characterized by a continued maladaptive reaction to a traumatic event, typically through the following behaviors and symptoms: avoidance, emotional numbing, dissociation, hyperarousal or startle, and re-experiencing. Prevalence rates of chronic pain conditions among those with PTSD are high—studies show that between 22% to 80% of PTSD patients also have chronic pain, which places them at a 5 to 8 times greater likelihood for having chronic pain than the general population.22 Those with musculoskeletal pain are about 4

providers), facilitate the use of nonpharmacological modalities for pain, and use caution with prescribing centrally-acting medications.23 In urban primary care settings, PTSD is very underdiagnosed,26 with patients reporting mostly physical symptoms. In these patients, self-medicating is very common and seen in about 50% of urban primary care patients.26 Evidenced-based CBT is frequently used when treating those with anxiety disorders, including PTSD. Common techniques utilized in CBT for those with an anxiety disorder include cognitive restructuring, such as challenging and changing thinking patterns that support fears or worrying, behavioral activation, or changing the way people react to anxiety-provoking situations, exposure therapy (exposure to fears and/or anxiety-provoking situations in order to desensitize the patient to the triggers), and relaxation training. Healthcare provider strategies for managing anxiety disorders are provided in Table 2. Given the high prevalence of mood and anxiety disorders in chronic pain patients, as well as the poor treatment outcomes in those with this comorbidity, the identification of mental health disorders in chronic pain patients is critical. Psychological assessment is often imperative in these patients for several reasons. Patients often lack

Table 2. Healthcare Provider Strategies: DOs and DON ’Ts for Pain Patients With Anxiety Disorders DO

DON ’T

Be empathic to overwhelming fears

Invalidate

Understand the specific disorder and its symptoms

Pathologize

Address fears of pain and instill hope

Demoralize or minimize

Decrease activity avoidance

Ignore activity level

Closely monitor prescriptions

Assume compliance or underestimate risk of overdose

Refer to mental health provider

Be the patient’s only support

Consider targeted pharmacology

Overload with centrally acting Rx

times more likely to have PTSD than those without.23 Chronic pain conditions are also highly prevalent among patients with PTSD with particular trauma: 30% to 50% of PTSD patients have been involved in a motor vehicle accident; 45% of PTSD patients have had burn injuries; 80% of PTSD patients are Vietnam veterans; and 47% of PTSD patients are Operation Iraqi Freedom veterans.23 In a sample of veterans being treated in an intensive PTSD program, 66% of the patients also had a concurrent chronic pain diagnosis.24 Considering these studies, it is not surprising that PTSD is a risk factor for the development of chronic pain, transitioning from acute to chronic pain, and pain disability.25

objectivity to and understanding of their psychological functioning and may not even have knowledge of psychological disorders. Patients may also minimize or magnify psychological symptoms for a variety of reasons, possibly including desires to avoid the still existing stigma of having a psychological disorder, and/or feeling shame, embarrassment, or guilt. Furthermore, physicians tend to rely on patient report (which may not be accurate or insightful) and/or have their own biases about mental health diagnoses and treatment.

When treating individuals diagnosed with PTSD and a chronic pain condition, encourage a multidisciplinary pain management treatment approach (eg, including mental health, medical, and psychiatric

Using psychological assessment and testing as part of a multidisciplinary and comprehensive pain management approach can greatly assist patients and providers. It is considered good clinical practice,

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CONCLUSiON

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is biopsychosocial, and is reimburseable.27 In addition to providing diagnostic classification, psychological evaluation affords the ability to proactively respond to risky patients, plan patient-specific interventions, and predict likely thoughts, feelings, behaviors, and events (including patient satisfaction with care) that will negatively impact treatment outcome. 

References

1. Gatchel RJ, Peng YB, Peters ML , et al. The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychol Bull. 2007;133(4):581–624. 2. Bruns D, Disorbio JM . Assessment of biopsychosocial risk factors for medical treatment: a collaborative approach. J Clin Psychol Med Settings. 2009;16(2):127–147. 3. Block AR , Ohnmeiss DO, Guyer RD, et al. The use of presurgical psychological screening to predict the outcome of spine surgery Spine J. 2001;1:274–282. 4. Wasan AD, Jamison RN, Tipirneni N, et al. Psychopathology predicts the outcome of medial branch blocks with corticosteroid for chronic axial low back or cervical pain: a prospective cohort study. BMC Musculoskelet Disord. 2009;10:22. 5. Heckler DR , Gatchel RJ, Lou L, et al. Presurgical behavioral medicine evaluation for implantable devices for pain management: 1 year prospective study. Pain Pract. 2007;7(2):110–122.

20. Borkovec T, Alcaine O, Behar E. Avoidance theory of worry and generalized anxiety disorder. In: Heimberg RG, Turk CL , Mennin DS, eds. Generalized Anxiety Disorder: Advances in Research and Practice. New York, NY: Guilford Press; 2004:77–108. 21. McWilliams L, Goodwin R, Cox B. Depression and anxiety associated with three pain conditions: Results from a nationally representative sample. Pain. 2004;111:77–83. 22. Defrin R, Ginzburg K, Schreiber S, et al. Quantitative testing of pain perception in subjects with PTSD —implications for the mechanism of the coexistence between PTSD and chronic pain. Pain. 2008;138:450–459. 23. Gibson C. Review of posttraumatic stress disorder and chronic pain: the path to integrated care. J Rehabil Res Dev. 2012;49:753–776. 24. Shipherd J, Keyes M, Duncan E, et al. Veterans seeking treatment for posttraumatic stress disorder: what about comorbid chronic pain? J Rehabil Res Dev. 2007;44:153–166. 25. Moeller-Bertram T, Keltner J, Strigo I. Pain and post traumatic stress disorder — review of clinical and experimental evidence. Neuropharmacology. 2012;62:586–597. 26. Liebschutz J, Saitz R, Samet J, et al. PTSD in urban primary care: high prevalence and low physician recognition. J Gen Intern Med. 2007;22:719–726. 27. Datz G, Bruns D. Billing for psychological services for patients with chronic pain. In: Deer TR , Leong MS, Buvanendran A, et al, eds. Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches. New York, NY: Springer; 2013:845–857.

6. Williams D, Gehrman C, Ashmore J, et al. Psychological considerations in the surgical treatment of patients with chronic pain. Tech Neurosurg. 2003;8:168–175. 7. Carragee EJ, Alamin TF, Miller JL , et al. Discographic, MRI and psychosocial determinants of low back pain disability and remission: a prospective study in subjects with benign persistent back pain. Spine J. 2005;5:24–35. 8. Dersh J, Polatin P, Gatchel R. Chronic pain and psychopathology: research findings and theoretical considerations. Psychosomatic Med. 2002;64:773–786. 9. Bair M, Wu J, Damush T, et al. Association of depression and anxiety alone and in combination with chronic musculoskeletal pain in primary care patients. Psychosom Med. 2008;70:890–897. 10. Chou R, Baisden J, Carragee EJ, et al. Surgery for low back pain: a review of the evidence for an American Pain Society Clinical Practice Guideline. Spine. 2009;34(10):1094–1109. 11. Ballantyne JC , Fleisher LA . Ethical issues in prescribing for chronic pain. Pain. 2010;148:365–367. 12. Centers for Disease Control and Prevention. Vital Signs: Overdoses of Prescription Opioid Pain Relievers— United States, 1999–2008. MMWR . 2011;60:1–6. 13. Roy-Byrne P, Davidson K, Stein M, et al. Anxiety disorders and comorbid medical illness. Gen Hosp Psychiatry. 2008;30:208–225. 14. Lee G. Contributing factors of depression for individuals with chronic musculoskeletal pain in workers’ compensation settings— an ecological conceptualization in rehabilitation counseling intervention. J Rehabil. 2010;76:3–12. 15. Ullrich P, Lincoln R, Tackett M, et al. Pain, depression, and health care utilization over time after spinal cord injury. Rehabil Psychol. 2013;58:158–165. 16. Hildebrandt D, Westfall J, Nicholas R, et al. Are frequent callers to family physicians high utilizers? Ann Fam Med. 2004;2:546–548. 17. Hoffman BM , Papas RK , Chatkoff DK , et al. Meta-analysis of psychological interventions for chronic low back pain. Health Psychol. 2007;26(1):1–9. 18. Stoney S. Treatment of pain in bipolar patients: clinical challenges. Pract Pain Manage. 2011;11:Issue #6. 19. Sullivan MJ, Thorn B, Haythornthwaite JA , et al. Theoretical perspectives on the relation between catastrophizing and pain. Clin J Pain. 2001;17(1):52–64.

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Roger B. Fillingim PhD

by


Roger B. Fillingim PhD

by


abstract: Sex and gender differences

in pain have been well documented. Women are at greater risk for developing many chronic pain conditions, and some evidence indicates that procedural and postoperative pain may be more severe among women than men. Laboratory studies have consistently demonstrated increased sensitivity to pain among women, suggesting that there may be sex differences in the functioning of pain processing systems. Investigators have also reported sex differences in responses to pain treatment. On the whole, women appear to experience greater opioid analgesia, but these sex differences depend on the specific medication used, as well as the type of pain being treated. A few studies have also suggested sex

differences in placebo responses, with men showing more robust placebo analgesia. Multiple mechanisms contribute to these sex differences in pain and analgesia, including hormonal and genetic factors, as well as psychosocial factors, such as pain catastrophizing and gender roles. While the evidence to date does not support the need for pink and blue pills, the findings do demonstrate important differences in how men and women process and experience pain. Further research to explicate these sex differences is needed to improve treatment for both women and men. The purpose of this article is to briefly summarize what we know now about sex, gender, and pain and to discuss the clinical implications and important areas for future research.

...CONSIDERABLE ANECDOTAL EXPERIENCE SUGGESTS THAT WOMEN MAY BE AT RISK FOR UNDERTREATMENT OF THEIR PAIN.

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SEX&GENDER

magine the waiting room

of a clinic specializing in the treatment of fibromyalgia. What do you notice about the patients waiting to see the doctor? There are no telltale signs of their pain condition; they come in all shapes and sizes; some are meticulously dressed, and others not. But, one thing is obvious—most of them are women. And you would have the same experience at clinics treating headache, irritable bowel syndrome, temporomandibular disorders, and interstitial cystitis. These and many other chronic pain conditions are considerably more common in women than men.1,2 This greater burden of pain in women has prompted a substantial amount of research in recent decades addressing sex and gender differences.

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S X DiFF R NC S iN CLiNiCAL PAiN

pain have been mixed, with some reporting greater pain in women, others finding greater pain in men, and some showing no sex differences.1 Taken together, the clinical findings demonstrate clear sex differences in pain prevalence, and less consistent evidence suggesting that pain is more severe among women.

Epidemiologic studies have routinely reported that chronic pain is more prevalent among women than men. For example, several population-based surveys have ascertained the prevalence of chronic pain by asking questions such as, “Have you experienced pain lasting more than 3 months during the last 12 months?”3 Despite S X DiFF R NC S iN using different definitions of chronic pain, multiple studies from PAiN P RC PTiON different countries have consistently reported higher prevalence of chronic pain among women, though the magnitude of the sex The greater prevalence of clinical pain among women has prompted difference varies across studies (see Figure). A similar pattern of investigators to examine whether there are sex differences in pain sex differences has been reported for specific types of chronic pain, perception to test the hypothesis that increased pain sensitivity in including back pain, migraine, musculoskeletal pain, oral pain, and women may contribute to their greater risk for clinical pain. These widespread pain.1,2 types of studies have used multiple laboratory methods of pain induction, including heat, pressure, cold, electrical, ischemic, and chemical Whether women also experience more severe clinical pain has been stimuli. The findings from these studies are remarkably consistent in investigated. In chronic pain patients seeking health care, findings their direction, in that women almost always exhibit greater sensitivare mixed, with women reporting more severe pain in some studies ity than men to experimentally induced pain, while the magnitude of but not in others.4-9 A recent study, based on data from more than the sex difference varies across studies and across pain modalities.1,2,11 11,000 electronic medical records in which pain ratings were captured In addition to static measures of basal pain perception, several studies routinely in the course of clinical care, found that women consis- have used more dynamic methods to assess sex differences in the functently reported higher pain levels than did men.10 Findings regarding tioning of pain modulatory systems, including both pain facilitation sex differences in the severity of postprocedural or postoperative and pain inhibition. Regarding pain facilitation, temporal summation

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Figure. Prevalence of Chronic Pain for Women and Men

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PR VAL NC OF CHRONiC PAiN FOR WOM N AND M N

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e

% of Population* Bergman3

38% 31%

Blyth32

20% 17%

Bouhassira33

35% 28%

Breivik34

11% 10%

Gerdle35

59% 48%

Rustoen36

28% 23%

Smith37

52% 49%

Tsang38

45% 31%

von Korff 39

20% 18%

Wijnhoven40

49% 41%

Women  ■ Men  ■ The figure shows the prevalence of chronic pain in the general population as reported in 10 different studies from various geographic regions. The definition of chronic pain varies across studies. *The numbers represent the percentage of the population reporting chronic pain according to the definition specified in that study. Bolded numbers reflect findings that show statistically significant sex differences.

of pain refers to an increase in pain that accompanies repeated pain- anecdotal experience suggests that women may be at risk for underful stimulation, and this phenomenon is thought to reflect a form of treatment of their pain. A frequently cited study reported that women transient central sensitization. Several studies have demonstrated were more likely to be prescribed sedatives after cardiac surgery, that women show greater temporal summation than men in response while men were more likely to receive analgesics.16 However, this to both heat and mechanical stimulation.1 Regarding pain inhibition, study was fraught with methodological issues, including small sample conditioned pain modulation (CPM ) is a method that assesses the size, failure to assess pain, failure to consider medication doses, and extent to which pain applied at one body site reduces the perception an unconventional statistical approach designed to overcome the of a second painful stimulus applied to a remote body site. Across absence of mean differences in the frequency of analgesic adminismultiple studies, men show greater CPM than women, suggesting tration. A recent review of the literature on gender bias in pain treatgreater pain inhibitory function among men.12 These findings from ment found little evidence to indicate that women were less likely to laboratory pain studies indicate a consistent pattern of sex differences, receive pain treatment than men; however, providers’ stereotypes such that women report greater basal pain sensitivity, enhanced pain and gender appear to interact with the patient’s gender and clinical facilitation, and reduced pain inhibition relative to men. However, the characteristics to influence treatment decisions.17 extent to which these sex differences in pain perception contribute to sex differences in clinical pain remains to be determined. Another question relates to whether the effectiveness of treatments varies for women vs men. In particular, sex differences in responses to opioid analgesics have received considerable attention in both S X DiFF R NC S iN clinical and laboratory-based research. The clinical studies are prePAiN TR ATM NT dominantly in the acute postoperative pain setting, and the bulk of these studies examine sex differences in analgesic consumption, Whether women and men receive different pain treatments and while a few studies directly assess analgesic efficacy. whether treatments are differentially effective across sex has been another topic of investigation. Despite the more frequent use of Additional studies have examined opioid analgesia tested against analgesics and other forms of health care for pain,13-15 considerable experimental pain measures. Moreover, both clinical and experimental

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SEX&GENDER

approaches have examined responses to a variety of opioids, including morphine and other µ-opioid agonists, as well as mixed action opioids (for example, nalbuphine, butorphanol). A recent meta-analysis based on this literature concluded18:

1 In clinical studies, no sex difference emerges when considering response to all µ-opioids; however, when restricting the analysis to studies of patient-controlled analgesia with morphine, women showed significantly lower morphine consumption than men.

2 In laboratory pain studies, women showed greater morphine analgesia compared to men, though the magnitude of the difference is modest.

3 Clinical studies reveal a large sex difference for analgesic responses to mixed action opioids (that is, µ/k agonist–antagonist drugs), with women showing greater analgesia.

4 Experimental studies show no sex differences in analgesic responses to mixed action opioids.

It is also worth noting that sex differences in side effects of opioids have also been observed, with women exhibiting greater unpleasant effects, including opioid-induced nausea and vomiting, while men have reported more positive side effects, such as drug liking.19-23 Thus, even if opioids are more efficacious among women, the greater incidence of side effects could offset the analgesic advantage. Sex differences in responses to other pharmacologic interventions have received far less empirical attention. One small experimental pain study demonstrated greater analgesic responses to ibuprofen among men24; however, a much larger analysis of ibuprofen analgesia after oral surgery revealed no sex differences.25 More recently, an examination of multiple nonopioid analgesics after oral surgery replicated this absence of sex differences.26 An important consideration in interpreting analgesic studies is the potential placebo response. For example, the anti-inflammatory ketorolac increased cold pressor pain tolerance more for men than for women, but this was also true for the placebo condition.27 Thus, there was no sex difference in ketorolac analgesia after accounting for the placebo condition. Similarly, a recent study demonstrated that men who believed they received ibuprofen showed greater analgesic responses than men who believed they received placebo, regardless of whether they received actual drug or placebo.28 However, women experienced minimal analgesia regardless of drug or expectation condition. More robust placebo responses among men have also been reported by other investigators,29 but not in all studies.30 However, in studies involving a placebo manipulation

Table Categories of Explanations for Sex Differences in Pain and Analgesia2 Category

Description and Examples

Experiential

Sex differences in pain are attributable to sex differences in pain experiences (eg, clinical pain frequency, menstrual pain) or events that could influence pain (eg, abuse, familial pain history)

Psychological

Sex differences in pain are related to sex differences in psychological functioning that can modulate pain experience (eg, anxiety, depression, catastrophizing)

Genetic

Sex differences in pain are due to chromosome effects, such as X chromosome gene imprinting or Y chromosome genes

Neurochemical

Sex differences in pain are attributable to sex differences in the function of neurochemical systems, such as adenosine receptors, endogenous opioids, cytokines, etc

Organizational

Sex differences in pain are due to the developmental effects of sex hormones, such as in-utero hormonal exposure

Activational

Sex differences in pain are related to ongoing effects of sex hormones in adulthood, such as menstrual cycle effects on pain

Systems Level

Sex differences in pain are due to differences in the function of biological systems, such as the cardiovascular system, inflammation, etc

Sociocultural

Sex differences in pain are due to sociocultural influences, such as gender roles, which may encourage different responses to pain in women and men

Note: These categories are not mutually exclusive. Indeed, interactions across categories are likely important determinants of sex differences in pain.

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designed to engage placebo responses, the balance of evidence indicates that men exhibit more robust placebo responses than do women.

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Multiple biopsychosocial mechanisms contribute to sex differences in pain, a full review of which is beyond the scope of this article (see reference citations 1, 2, 11, 31). Mogil2 recently identified several categories of explanations for sex differences in pain and analgesia, as summarized in the Table. Briefly, a variety of experiential and psychosocial influences appear to contribute to sex differences, including sex differences in pain experiences and potential differential contributions of psychosocial factors, such as mood/affect, catastrophizing, and gender roles. Moreover, considerable evidence implicates several genetic, hormonal, and neurochemical mechanisms as potentially important contributors to sex differences in pain and analgesia.

CLiNiCAL IMPLiCATiONS OF S X DiFF R NC S iN PAiN AND ANALG SiA

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While abundant evidence has demonstrated robust sex differences in clinical and experimental pain responses, these findings arguably have had little direct impact on the clinical management of pain. There are several potential explanations for this. First, the experimental findings derive overwhelmingly from studies of healthy young adults, and the relevance of these results to various forms of clinical pain remains unknown. Second, other than largely retrospective studies of opioids for postoperative pain, research investigating sex differences in responses to pain treatment has been limited. More systematic investigation of sex differences in responses to a variety of pain interventions could provide more clinically actionable information. Third, as noted by Mogil,2 the majority of evidence addresses quantitative sex differences; that is, which sex experiences greater pain or greater analgesia. Of more direct clinical relevance would be studies of qualitative sex differences, in which a given factor influences pain or analgesia differently in women compared to men. Qualitative differences can reflect sex-specific pain mechanisms, which may directly translate to sex-specific treatments. Nonetheless, several potential clinical implications can be drawn from the existing literature and may point toward important areas for future research.

CONCLUSiON First and foremost, the increased scientific interest in sex, gender, and pain has raised awareness that men and women are likely to experience pain quite differently and for legitimate reasons. For example, abundant evidence now demonstrates that sex hormones can substantially influence pain processing via multiple pathways. Also, there is greater recognition that sex-related “psychosocial” influences on Q1  | 2014

pain are ultimately mediated by biological mechanisms, ranging from effects on immune and inflammatory processes to central nervous system pain processing. This knowledge should help to reduce potential gender biases in pain diagnosis and treatment. Second, because women are clearly at greater risk for many forms of chronic pain, prevention efforts may need to be designed specifically to target women. Third, given the findings suggesting that women experience both increased analgesia and greater side effects in response to opioids, sex-specific dosing may ultimately be beneficial. However, it is important to note that sex is only one of many factors that can influence chronic pain risk and treatment responses. While sex-specific treatments—pink and blue pills—may be developed in the future, at present pain treatment should be tailored to each individual based on all available information, including but not limited to his or her sex.  References 1. Fillingim RB, King CD, Ribeiro-Dasilva MC , et al. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain. 2009;10(5):447–485. 2. Mogil JS . Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon. Nat Rev Neurosci. 2012;13(12):859–866. 3. Bergman S, Herrström P, Hogstrom K, et al. Chronic musculoskeletal pain, prevalence rates, and sociodemographic associations in a Swedish population study. J Rheumatol. 2001;28(6):1369–1377. 4. Edwards R, Augustson E, Fillingim R. Differential relationships between anxiety and treatment-associated pain reduction among male and female chronic pain patients. Clin J Pain. 2003;19:208–216. 5. Fillingim RB, Doleys DM , Edwards RR , et al. Clinical characteristics of chronic back pain as a function of gender and oral opioid use. Spine. 2003;28(2):143–150. 6. George SZ , Bialosky JE, Wittmer VT, et al. Sex differences in pain drawing area for individuals with chronic musculoskeletal pain. J Orthop Sports Phys Ther. 2007;37(3):115–121. 7. Keefe FJ, Affleck G, France CR , et al. Gender differences in pain, coping, and mood in individuals having osteoarthritic knee pain: a within-day analysis. Pain. 2004;110(3):571–577. 8. Robinson ME, Wise EA , Riley JL 3rd, et al. Sex differences in clinical pain: a multi-sample study. J Clin Psychol Med Settings. 1998;5(4):413–424. 9. Turk DC , Okifuji A. Does sex make a difference in the prescription of treatments and the adaptation to chronic pain by cancer and non-cancer patients? Pain. 1999;82(2):139–148. 10. Ruau D, Liu LY, Clark JD, et al. Sex differences in reported pain across 11,000 patients captured in electronic medical records. J Pain. 2012;13(3):228–234. 11. Racine M, Tousignant-Laflamme Y, Kloda LA , et al. A systematic literature review of 10 years of research on sex/gender and experimental pain perception–part 1: are there really differences between women and men? Pain. 2012;153(3):602–618. 12. Popescu A, LeResche L, Truelove EL , et al. Gender differences in pain modulation by diffuse noxious inhibitory controls: a systematic review. Pain. 2010;150(2):309–318. 13. Eggen AE . The Tromso Study: frequency and predicting factors of analgesic drug use in a free-living population (12–56 years). J Clin Epidemiol. 1993;46:1297–1304. 14. Isacson D, Bingefors K. Epidemiology of analgesic use: a gender perspective. Eur J Anaesthesiol Suppl. 2002;26:5–15. 15. Fernandez-Liz E, Modamio P, Catalan A, et al. Identifying how age and gender influence prescription drug use in a primary health care environment in Catalonia, Spain. Br J Clin Pharmacol. 2008;65(3):407–417.

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16. Calderone KL . The influence of gender on the frequency of pain and sedative medication administered to postoperative patients. Sex Roles. 1990;23(11–12):713–725.

37. Smith BH, Elliott AM , Chambers WA , et al. The impact of chronic pain in the community. Fam Pract. 2001;18(3):292–299.

17. LeResche L. Defining gender disparities in pain management. Clin Orthop Relat Res. 2011;469(7):1871–1877.

38. Tsang A, Korff M, Lee S, et al. Common chronic pain conditions in developed and developing countries: gender and age differences and comorbidity with depression-anxiety disorders. J Pain. 2008;9(1):883–891.

18. Niesters M, Dahan A, Kest B, et al. Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies. Pain. 2010;151(1):61–68. 19. Cepeda MS, Farrar JT, Baumgarten M, et al. Side effects of opioids during short-term administration: effect of age, gender, and race. Clin Pharmacol Ther. 2003;74(2):102–112.

39. Von Korff M, Crane P, Lane M, et al. Chronic spinal pain and physical-mental comorbidity in the United States: results from the national comorbidity survey replication. Pain. 2005;113(3):331–339. 40. Wijnhoven HA , de Vet HC , Picavet HS . Prevalence of musculoskeletal disorders is systematically higher in women than in men. Clin J Pain. 2006;22(8):717–724.

20. Fillingim RB, Ness TJ, Glover TL , et al. Morphine responses and experimental pain: sex differences in side effects and cardiovascular responses but not analgesia. J Pain. 2005;6(2):116–124. 21. Riley JL 3rd, Hastie BA , Glover TL , et al. Cognitive-affective and somatic side effects of morphine and pentazocine: side-effect profiles in healthy adults. Pain Med. 2010;11(2):195–206. 22. Zacny JP. Morphine responses in humans: a retrospective analysis of sex differences. Drug Alcohol Depend. 2001;63(1):23–28. 23. Zun LS, Downey LV, Gossman W, et al. Gender differences in narcotic-induced emesis in the ED. Am J Emerg Med. 2002;20(3):151–154. 24. Walker JS, Carmody JJ . Experimental pain in healthy human subjects: gender differences in nociception and in response to ibuprofen. Anesth Analg. 1998;86(6):1257–1262. 25. Averbuch M, Katzper M. A search for sex differences in response to analgesia. Arch Intern Med. 2000;160(22):3424–3428. 26. Moore RA , Straube S, Paine J, et al. Minimum efficacy criteria for comparisons between treatments using individual patient meta-analysis of acute pain trials: examples of etoricoxib, paracetamol, ibuprofen, and ibuprofen/paracetamol combinations after third molar extraction. Pain. 2011;152(5):982–989. 27. Compton P, Charuvastra V, Ling W. Effect of oral ketorolac and gender on human cold pressor pain tolerance. Clin Exp Pharmacol Physiol. 2003;30(10):759–763. 28. Butcher BE, Carmody JJ . Sex differences in analgesic response to ibuprofen are influenced by expectancy: a randomized, crossover, balanced placebo-designed study. Eur J Pain. 2012;16(7):1005–1013. 29. Aslaksen PM , Bystad M, Vambheim SM , et al. Gender differences in placebo analgesia: event-related potentials and emotional modulation. Psychosom Med. 2011;73(2):193–199. 30. Averbuch M, Katzper M. Gender and the placebo analgesic effect in acute pain. Clin Pharmacol Ther. 2001;70(3):287–291. 31. Racine M, Tousignant-Laflamme Y, Kloda LA , et al. A systematic literature review of 10 years of research on sex/gender and pain perception–part 2: do biopsychosocial factors alter pain sensitivity differently in women and men? Pain. 2012;153(3):619–635. 32. Blyth FM , March LM , Brnabic AJ, et al. Chronic pain in Australia: a prevalence study. Pain. 2001;89(2–3):127–134. 33. Bouhassira D, Lantéri-Minet M, Attal N, et al. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain. 2008;136(3):380–387. 34. Breivik H, Collett B, Ventafridda V, et al. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006;10(4):287–333. 35. Gerdle B, Björk J, Henriksson C, et al. Prevalence of current and chronic pain and their influences upon work and healthcare-seeking: a population study. J Rheumatol. 2004;31(7):1399–1406. 36. Rustoen T, Wahl AK , Hanestad BR , et al. Gender differences in chronic pain— findings from a population-based study of Norwegian adults. Pain Manag Nurs. 2004;5(3):105–117.

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Q1  | 2014


(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.

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


The

POWER of PAiN FOUNDATiON Ingle

by Barby 

Q1  | 2014

The mission of the Power of Pain Foundation (POPF) is to promote public and professional awareness of neuropathy conditions while educating those affected by neuropathic pain, as well as their families, friends, and healthcare providers. Our foundation also teaches patients to be self-advocates, promotes action-oriented awareness, and tries to improve pain care through activities and efforts that eliminate undertreatment.

www.painweek.org  | PWJ | 55


PARTICIPATING ORGANIZATION

Through supporting education for pain patients, family members, caretakers, and medical professionals, we make an important contribution to the overall knowledge and treatment of chronic pain. This allows our foundation to affect millions of lives.

POPF was created by ken taylor and the ingle family, Many patients in pain tend to isolate themselves from attending because of their commitment to helping others, and because I didn’t life’s special occasions, or even going shopping. The POPF hosts a get the proper or timely help I needed in dealing with reflex sympa- variety of events to get the patients back into society at some functhetic dystrophy (RSD). The foundation evolved from a family dis- tioning level. We have online webinars, a Facebook page, a Twitter cussion and morphed into a powerful communications vehicle. Each following, comedy shows, and also provide peer-to-peer mentoring Thanksgiving, our family meets to discuss potential projects that we to patients and caregivers via phone, email, and social media outcan do as a family. In 2006, the discussion turned to how hard it was lets. We help patients do the research needed to be their own best for me and so many others to find a diagnosis and receive proper treat- advocate. Patients can email or call to get names of providers who ment. As with many chronic conditions, the sooner RSD is treated specialize in their specific condition. properly, the better the chances for remission and recovery. POPF gives us the opportunity to share our knowledge for overcoming the You can be your own best advocate by taking steps to lead your life. challenges that pain patients face every day with activities of daily Don’t rely on others to make your decisions, do your research, or living. My family and I had to learn the hard way and now want to pass keep you organized. To become the Chief of Staff of my own medical on our knowledge to give hope and answers to all patients, caregivers, team, I focused on these areas: finding the correct doctor, preparing and health professionals. We have over 100 volunteers around the for and planning the doctor visit, following my care plan, and staycountry who help run POPF. The POPF focuses on education, social ing on top of my medical billing statements. Staying organized and connections, the RSD Quilt Project, and public awareness projects prepared helps me get through the day with less stress, anxiety, and involving all conditions having neuropathy pain involvement. pain. It can do the same for other pain patients.

Our education projects focus on the patient, caregivers, and health- The POPF sponsors the BlogTalk radio show Living with HOPE, care professionals. In the past 7 years we have been a part of 68 hosted by Trudy Thomas, the POPF Nevada Ambassador. Trudy educational events in many states, including California, Washing- interviews patients and caregivers, doctors and therapists, both traton, Nevada, Arizona, Kansas, Missouri, Oklahoma, New York, and ditional and alternative practitioners. Living with HOPE empowers, Virginia. The ultimate goal of the POPF is to give chronic pain informs, and educates the listeners with information that may not be patients the education and ability to perform their regular activities readily available in their local area. Through the power of the interin the community. We also team up with community sponsors to net Trudy has the ability to communicate with and speak to some of help bolster society’s ability to provide full opportunities and appro- the most knowledgeable doctors and researchers in the world. Topics priate support for its pain citizens. Through supporting education have included: meditation, biofeedback, guided imagery, breathing for pain patients, family members, caretakers, and medical profes- exercises, holistic healing, coping strategies, depression, spinal cord sionals, we make an important contribution to the overall knowledge stimulation, chronic pain treatments, ketamine, Calmare (Scrambler and treatment of chronic pain. This allows our foundation to affect Therapy ®), Cortical Integrative Therapy (CIT®), mirror box therapy, millions of lives. low light laser therapy, functional restoration, intravenous immunoglobulin, neuropathies, complex regional pain syndrome (CRPS), To increase public awareness of what pain patients deal with on a daily and neuroinflammatory disease. basis, we host programs to reach crowds that might not normally hear our messages. We do movie nights where first we have a presentation One extremely important project POPF is very excited to be hosting about the POPF or show a PSA . At our pain day at the park/rink, we is the RSD Quilt Project. We are doing all in our power to promote team up with pro sports teams to reach the 20,000+ people in atten- and grow this great cause to bring much deserved and needed awaredance. We have tables on the concourse giving away free resources ness to RSD/CRPS. The RSD Quilt Project is on display at many of for the community, do an on-field presentation, and bring in a POPF our events and also requested by individuals and other charities to celebrity ambassador to perform and draw in the game attendees. display at their own events and fundraisers all over the country. It is a Advertising in national magazines and distributing bracelets to the great way to show the public a display of our emotions and represent public also increases awareness. Another awareness tool: Give Me our physical pain without words. All squares sent in to be dedicated a B.R.E.A.K. cards, to hand out to friends, family, and others with to the RSD Quilt Project will also be added to the slideshow at www. whom a person has interactions. The acronym B.R.E.A.K. includes rsdcrps.org. If you would like to take part you can send a 12" × 12" notices—R = Realize that I look healthy but have limitations—and patch to the Power of Pain, c/o RSD Quilt Project, 38556 N. Dave requests—A = Ask before you touch me. The cards are a quick way Street, San Tan Valley, AZ 85140.  to set expectations; give one to your hairdresser prior to getting your hair done. They can also help remind people, for future interactions. To learn more about POPF; visit www.powerofpain.org.

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Q1  | 2014


with

Daniel B. Carr MD, MA, FABPM

Daniel B. Carr is Professor of Public Health and Community Medicine, and Program Director, Pain, Research Education & Policy at Tufts University School of Medicine. In 2012 he presented the PAINWeek keynote address, “A Public Health View of Pain Education: Have We Been Backwards, Upside Down, or Both?”

Q1  | 2014

www.painweek.org  | PWJ | 57


PUNDIT PROFILE/ DANIEL B. CARR

What inspired you to become a healthcare provider?

What is your most marked characteristic? An “embedded sense of duality.” This phrase was my journalist/critic brother’s distillation of my awkwardly worded agreement with his speculation that we might be cousins of George Carr Shaw (Bernard Shaw’s father), and the nature of the cognitive quirk I felt we all had in common. It’s hard to explain this in a few words. “Stubbornness” also deserves mention.

The illness and ultimately death of my father on Christmas day, 1970, soon after his discharge from the Bronx VA Hospital, which was then very much a Dickensian setting. That ghastly, tragic experience showed me I could function rationally and calmly amidst ghastly, tragic experiences and lessened any reservations I might have felt about my ability to function in medical settings.

What do you consider your greatest achievement?

Why did you focus on pain management? I didn’t, initially. As an endocrinology research fellow at Mass General, I collaborated with Mike Arnold of Joseph Martin’s lab to develop one of the early assays for beta-endorphin. We applied this to study hormonal effects of physical conditioning, and authored the famous “runners’ endorphins” study in the New England Journal of Medicine. Soon we were collaborating with many people including some in anesthesiology. Sensing a long-term opportunity, I went back and did another residency in that field. I imagined I’d divide my time between neuroanesthesia and lab work, but the department chair had other ideas. In the final months of my residency he approached me with an offer to work alongside the lone anesthesiologist who had been doing pain medicine at the MGH since Henry Beecher’s era in the 1940s. Although not my plan, it made sense and I apprenticed myself to that older clinician for about 5 years. Who were your mentors? As a medical student at Columbia: the intensivist Glenda Garvey; the endocrinologist Andrew Frantz; and the neurologist Sid Gilman. At one point I considered going into neurology. As an endocrine fellow at the MGH: John Potts, Michael Rosenblatt, and Joseph Martin—the latter two later were Deans at Tufts and Harvard, respectively. In anesthesiology at the MGH: its long-term chairman Richard Kitz (whose friendship I still cherish) and Donald Todd, to whom I apprenticed in pain and regional anesthesia. Dick Kitz asked Michael Cousins to provide a blueprint for the growth of the MGH Pain Center, and Michael became a friend and collaborator. If you weren’t a healthcare provider, what would you be? Something in physics—I have a master’s degree in that area from Columbia. Or possibly a nautical trade—I used to have a Coast Guard license, ran a sailing school, and delivered sailboats.

58 | PWJ | www.painweek.org

I’m working on it right now. What is your favorite language?

“I imagined I’d divide my time between neuroanesthesia and lab work, but the department chair had other ideas.”

My personal sample is inadequate to support a reply. I do, however, enjoy hearing my son speak Mandarin and my younger daughter speak Gaelic. If you had to choose one book, one film, and one piece of music to take into space for an unde‑ termined amount of time, what would they be? My house is strewn with books. I can’t see myself bringing only one. If pressed, I’d bring Montaigne’s Essays because of his classical learning—that I always associate with calming timeless wisdom—and the book’s ability to provide companionship, owing to the clarity with which it conveys Montaigne’s reasonable personality. Plus, it’s long enough not to be a quick read. Perhaps because my journalist brother has always covered drama, music, and cinema, I’ve never been deeply engaged with movies. If pressed, maybe a toss-up between Chaplin’s Modern Times and Wilder’s One, Two, Three. I find Ravel an antidote to feeling unraveled; so, his string quartet. None of these choices are meant to be a pinnacle; instead, just meant to slow the psychosis that would slowly creep over me if I really did find myself in space for an undetermined amount of time. What would you like your legacy to be? On a public level: students, trainees, and colleagues whose own wishes to make the world a better place were brought a little bit closer to fruition as a result of their interaction with me. On a private level, my wife and I are blessed with wonderful, interesting, and sincere children—our legacy. What is your motto? I don’t have one.

Q1  | 2014


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

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