PAINWeek Journal No. 1 Q4

n0. 1 q 4 2013

FEMALE CHRONIC PELVIC PAINP.6 MIGRAINES PT 2P.14 AUTISM AND PAINP.24 THE COMPLEXITY MODELP.32 UDT: 10 QUESTIONS TO ASK WHEN FACING AN INAPPROPRIATE RESULTP.40

NEW

15 mcg/hour Now Available

ButransÂŽ (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.

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.

Now with 4 Strengths, Butrans Offers Increased Dosing Flexibility Butrans is a Schedule III, single-entity opioid analgesic

Butrans 5 mcg/hour ■

■

Butrans 10 mcg/hour

Butrans 20 mcg/hour

Do not exceed a dose of one 20 mcg/hour Butrans system due to the risk of QTc interval prolongation Butrans doses of 10, 15 and 20 mcg/hour are for opioid-experienced patients only 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

·

Butrans 15 mcg/hour

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 CO2 retention for signs of sedation and respiratory depression, particularly when initiating therapy with Butrans.

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

For more information, please visit Butrans.com ©2013 Purdue Pharma L.P., Stamford, CT 06901-3431 F8365-A1 9/13

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

· Anaphylactic/Allergic Reactions

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

· Application of External Heat

Avoid exposing the Butrans application site and surrounding area to direct external heat sources. There is a potential for 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

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 CHARLES PUBLISHER Aventine

E. ARGOFF MD, CPE

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, DAAPM, FAAPM Chief Medical Officer RAPID Pharmaceuticals Rockville, MD

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 © 2013, 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.

/ PWJ / Q4 / 2013 2 | GUEST EDITOR’S LETTER by charles e. Argoff

FEATURES

6 | REGIONAL PAIN SYNDROMES

FEMALE CHRONIC PELVIC PAIN

by colleen m. Fitzgerald

14 | EXPERT OPINION

MIGRAINES PART 2: variants and treatment by gary w. Jay

24 | BEHAVIORAL

AUTISM AND PAIN: clinical traits, sensory perceptions, and practice recommendations for clinicians

32 | KEY TOPIC

THE COMPLEXITY MODEL: a novel approach to improve chronic pain care by john f. Peppin / martin d. Cheatle

40 | PAIN&CHEMICAL DEPENDENCY

UDT: 10 questions to ask when facing an inappropriate result by ted w. Jones / darren McCoy

49 | PARTICIPATING ORGANIZATION U.S. PAIN FOUNDATION

by paul Gileno

53 | PUNDIT PROFILE with michael r. Clark

by barbara l. Kornblau / susan McNulty / scott m. Robertson

Q4 | 2013

www.painweek.org | PWJ | 1

CHARLES E.

ARGOFF MD, CPE

Dr. Gary Jay concludes a 2-part analysis of migraine, begun in the previous issue of the PWJ. Here, he surveys the characteristics of the important migraine variants, and also details the less-frequently encountered complicated migraine types, to better equip readers to answer the question “If you, the clinician, are called at 2:00 in the morning by a patient who reports these issues, should you meet the patient immediately in the ER?” Dr. Jay also considers the common treatment of migraine, as well as the new evidence-based guidelines for treatment selection.

In our feature on Behavioral, Dr. Barbara Kornblau, Susan McNulty, and Scott Robertson examine the clinical traits and sensory perceptions of adults and children with autism from the perspective of how this patient population experiences and reports chronic pain. The authors observe that despite the prevalence of the condition, few clinicians receive substantive professional training in the healthcare needs of these patients. The authors overview the common cognitive profile of the autistic individual, and offer practice recommendations for both the pain specialist and the frontline clinician in the addressing challenges in communication and social interaction, sensory and motor skills, and assistive tools and instruments that are available.

The disparity between the scope of chronic pain suffering and the available base of pain specialists in the US has been well and frequently documented. By default, primary care clinicians are called upon to manage this burgeoning patient population. But, Drs. John eLCOMe TO THiS eDiTiON of the PAINWeek Journal, hereinafter Peppin and Martin Cheatle observe, it will not be enough to simply referred to by its cover acronym, PWJ. As a longtime member of the offer more nominal training to the already beleaguered PCP. A new faculty of the PAINWeek National Conference, and of the Ameri- approach, termed “The Complexity Model” is needed to effectively can Society of Pain Educators, I am excited about the availability of assess and stratify patients by need, and to engage the appropriate this new resource for frontline clinicians who are concerned with level of clinical expertise, often in an ongoing collaboration of pain managing their patients with chronic pain. As we have said many specialist and PCP. times, the need is great, the subject is complex, and the available specialist resources are few. It is the mission of PWJ to be a part of the And finally, our Pain and Chemical Dependency feature for this educational process; to offer useful, actionable information that can quarter offers important insight to clinicians on how to react to inaphelp primary care practitioners function more effectively as part of propriate urine drug test ( UDT ) results. Dr. Ted Jones and Darren a multidisciplinary team, engaging different therapies and treatment McCoy have created a clinical guide of 10 questions that are designed approaches in the pursuit of better patient outcomes. to prompt thoughtful and rational consideration of a treatment plan in the face of an inappropriate UDT result. The objective is to foster Here’s what you’ll find in this issue of the PWJ. Read, learn, enjoy, case-specific treatment decisions that will ultimately lead to better and above all, let us know what you would like to see in future outcomes for the patient. editions!

We thank all of our contributing authors for their insights and Dr. Colleen Fitzgerald was recently honored with the inaugural expertise, and we hope you find this issue of the PWJ to be a useful Research Excellence Award at the Midwest Pain Society’s annual adjunct to your pursuit of excellence on behalf of your patients and scientific meeting. She has contributed her expertise on women’s your practice. pain conditions in her course presentations at PAINWeek for many years. In this article, Dr. Fitzgerald offers a comprehensive review — CHARLES E. ARGOFF MD, CPE of female chronic pelvic pain, a range of conditions that are at the convergence of complex etiology, multiple and often disconnected stakeholders, inadequate medical training in pain management, and uncertain evidence for treatment effectiveness. The case is made for more intensive clinical research for CPP, in view of its prevalence and associated potential for disability.

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e

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e

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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”

e

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●● One-Minute Clinician F ATUR S: “BRAINFOOD” that you can put to use right away, ●● PAINWeek eNewsletter News in pain management and information on upcoming every day PAINWeek activities. ●● PWJ — PAINWeek Journal Feature Highlight ●● Conference Registration News Excerpts and links to articles from our quarterly pain Alerts on discounts and special deals on PAINWeek and management publication.

PAINWeekEnd conferences. ●● Pundit Profile ●● Expert Opinion What makes our faculty tick—who inspired them, their Video interviews with PAINWeek faculty on key topics greatest achievements, and the legacies they hope to like risk assessment, rational polypharmacy, differential leave behind. Find out in these insightful interviews with diagnosis of migraine headache and more!

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COLLEEN M. FiTZG RALD MD, MS

e

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GARY W. JAY MD, DAAPM, FAAPM

P.14

TED W. JON S PHD, CPE

BARBARA L. KORNBLAU JD, OTR/L, CPE, DASPE

SUSAN MCNULTY OTD, OTR/L, CPE

JOHN F. P PPiN DO, FACP

SCOTT M. ROB RTSON PHD, MHCI

MARTIN D. CH ATL PHD

Martin Cheatle is Clinical Assistant Professor of Psychology in Psychiatry and Director of Behavioral Medicine at the Penn Pain Medicine Center, and Director of Pain and Chemical Dependency Research at the Center for Studies of Addiction at the University of Pennsylvania. Dr. Cheatle has over 28 years of experience in the treatment of patients with chronic pain and concomitant addiction as director of both university and community based integrative pain programs.

Dr. Fitzgerald is the Medical Director for the Chronic Pelvic Pain Program at Loyola University Health System and an associate professor in the Department of Obstetrics & Gynecology, Division of Female Pelvic Medicine and Reconstructive Surgery at Loyola University Chicago Stritch School of Medicine. She recently received the Inaugural Research Excellence Award from the Midwest Pain Society for her outstanding work in the field of pain research.

Gary W. Jay is chief medical officer for Levare Pharma, LLC, and senior strategist and senior medical director for INC Research, LLC. He is also president of the Eastern Pain Association, Raleigh-Durham, NC. Having specialized in pain since 1980, he has written over 100 medical articles in peer-reviewed journals dealing with headache, pain (all types), the autonomic nervous system, and mild traumatic brain injury; he has also authored many third-party medical textbook chapters.

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Ted W. Jones is a clinical psychologist at the Behavioral Medicine Institute, Knoxville, TN. He joined the psychology group Behavioral Medicine Institute, and has been in an on-site office at Pain Consultants of East Tennessee since 2000. Dr. Jones is president of Pain Education Institute, a nonprofit educational organization, and is a certified pain educator (CPE).

P.24

Barbara Kornblau is an attorney and licensed occupational therapist, with both advocacy and academic experience. She was Dean of the School of Health Professions and Studies at the University of Michigan, Flint, and professor of Occupational Therapy and Public Health at Nova Southeastern University. Currently she serves as Executive Director at the Society for Participatory Medicine (SPM), an organization devoted to advancing communication and cooperation among all healthcare stakeholders.

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Susan McNulty received her MA in Occupational Therapy from the University of Southern California (USC) in 2004 and then practiced in community and inpatient mental health settings.

In 2010, she completed her Doctorate of Occupational Therapy (OTD) with a focus on pain management and chronic daily headaches. In 2013 she received her Certified Pain Educator (CPE) credential through the American Society of Pain Educators. She is currently an instructor at the University of St. Augustine in San Marcos, CA, for the Masters of Occupational Therapy Program.

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John F. Peppin is Director of the Center for Bioethics, Pain Management and Medicine. Dr. Peppin has published numerous articles in the fields of pain management, palliative care, and bioethics and is board certified in internal medicine, pain medicine, and hospice and palliative medicine. Dr. Peppin has presented lectures and posters at numerous national conferences.

In 2011, he was named PAINWeek Clinician of the Year, and is currently Medical Director, Global Pharmaceuticals at Mallinckrodt Pharmaceuticals.

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Scott Michael Robertson, an autistic adult, received his PhD in information sciences and technology from Penn State University and his master’s degree in human–computer interaction from Carnegie Mellon University. Scott serves as Vice Chair of Development of the Autistic Self Advocacy Network (ASAN), a national nonprofit organization that he co-founded in 2006. Scott will begin a Public Policy Fellowship funded by the Joseph P. Kennedy, Jr. Foundation in 2014.

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by COLLEEN

e

M. FiTZG RALD MD, MS

abstract: This review article discusses the current evidence regarding pathophysiology, known etiologies, diagnosis, and treatment in female chronic pelvic pain (CPP). A discussion of the various pelvic pain subtypes—interstitial cystitis (painful bladder syndrome), endometriosis, vulvodynia, irritable bowel syndrome, pudendal neuralgia, and pelvic floor myofascial pain and dysfunction—is also explored. Additionally, attention is given to musculoskeletal causes of female pelvic pain and rehabilitation treatments, as are implications for future research.

Q4 | 2013

www.painweek.org | PWJ | 7

iNTRODUCTiON

REGIONAL PAIN SYNDROMES

emale pelvic pain has multifactorial etiologies. There are numerous stakeholders involved in caring for women with these chronic symptoms including those in primary care, gynecology, gastroenterology, urology, neurology, physical medicine and rehabilitation, psychology, and physical therapy. Each specialist brings his or her own background and training to the evaluation of these complex patients. Unfortunately for the suffering patient, an interdisciplinary evaluation of CPP is often not the reality. In addition, the economic pressure for a high volume clinic is compounded by inadequate medical training in pain management. What is also challenging is that there is an overall lack of evidence for effective and durable CPP treatments.

Epidemiology: A Common Problem

The precision of diagnosis is limited by converging neural input. By the time painful stimuli from the periphery reaches the brain, considerable integration of inputs (which may represent both somatic and visceral input) can occur.1 At the sensory cortex, there is even Approximately 25% of women aged 18- to 50-years-old have CPP.6 more integration, which is probably how a patient’s psychological Similarly, the point prevalence of pelvic girdle or musculoskeletal status can further modulate the pain experience. Hormonal status pain is approximately 20%.5,7,8 CPP is identified as the indication appears to influence the extent of visceral innervation2 as well as the for laparoscopy in 40% of women undergoing this procedure.9 It is a patient’s pain perception.3 diagnosis that accounts for 10% to 18% of hysterectomies.10 Although it is a common condition, only 25% of women surveyed actually seek CPP is defined by the American College of Obstetrics and Gynecol- medical evaluation regarding the pain.8 Known risk factors associogy as “noncyclic pain of 6 or more months duration that localizes to ated with noncyclic CPP include a history of drug or alcohol abuse, the anatomic pelvis, anterior abdominal wall at or below the umbili- miscarriage, pelvic inflammatory disease, previous cesarean section, cus, the lumbosacral back or the buttocks. To meet criteria, the pain pelvic pathology, history of abuse, and psychological comorbidity.11 should be severe enough to cause some disability.”4 Unfortunately, most studies failed to even describe the location and/or duration of symptoms. The nomenclature in CPP can also be problematic. For example, CPP in general implies a regional and visceral organ etiology, yet many women have more generalized and nonvisceral pain.

Pelvic girdle pain is a term in the literature that reflects a primary CPP subtypes are comorbid with other CPP and nonpelvic pain conmusculoskeletal etiology in CPP.5 Studies also define CPP by cyclic ditions.12 In gynecology, the differential diagnosis in female CPP or noncyclic status depending on the presentation of symptoms. includes endometriosis, adenomyosis, pelvic adhesions, chronic

Differential Diagnosis/Comorbidities

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pelvic infections, ovarian cysts, residual ovary syndrome, ovarian remnant syndrome, post-hysterectomy pain, pelvic congestion syndrome, fibroids, and vulvodynia. In urology, interstitial cystitis, urethral syndrome, chronic urinary tract infections, and bladder stones are considered. In gastroenterology, common pelvic pain diagnoses include irritable bowel syndrome, chronic appendicitis, constipation, and inflammatory bowel disease. The musculoskeletal differential includes myofascial pain particularly of the pelvic floor, nerve entrapment syndromes, sacroiliac joint pain, lumbar degenerative disc disease, hip pathology, and hernias, all of which can contribute to the presentation of CPP. Although most patients have been thoroughly evaluated for worrisome causes of CPP, the following symptoms are suggestive of consideration for possible reevaluation: bleeding per rectum, new bowel symptoms over age 50, new pain after menopause, pelvic mass, suicidal ideation, excessive weight loss, irregular vaginal bleeding over age 40, and/or postcoital bleeding.

CPP Subtypes: Interstitial cystitis (IC)/ Painful bladder syndrome (PBS) IC/PBS is a urologic diagnosis characterized by suprapubic pain and urinary urgency and frequency. This diagnosis is 9 times more prevalent in women.13 It is commonly diagnosed in women in their 40s14 and appears to be comorbid with fibromyalgia, vulvodynia, and endometriosis.15,16 Female hormone use, history of fewer pregnancies, and total number of nonbladder symptoms are associated with IC/PBS.17 Patients with IC/PBS have been found to have significant quality-of-life impairment, particularly if they have other pain comorbidities.18 Unfortunately, the average time between the development of IC/PBS symptoms to confirmed diagnosis can be several years.19 The current mechanistic understanding of IC/PBS in women remains elusive. Proposed etiologies have included bladder glycosaminoglycan (GAG) layer injury with resultant neurogenic inflammation; autoimmune basis with mast cell infiltration; epithelial dysfunction; and infectious, peripheral, central sensitization.20

Overactive bladder (OAB) and urinary tract infection can present with similar symptoms to IC/PBS and should be considered. OAB is characterized by urinary urgency and frequency with or without incontinence. It is differentiated from IC/PBS by the addition of pelvic pain specifically in the suprapubic region. Chronic urinary tract infections are heralded by urinary urgency, frequency, and dysuria with or without suprapubic pain and should be confirmed by urine culture.

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IBS PATi NTS WiLL TYPiCALLY HAV A NORMAL PHYSiCAL XAMiNATiON.

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On history, patients should be queried for risk factors for bladder visceral sensitivity such as prior instrumentation as a child, recurrent urinary tract infections, and history of sexual abuse. Urinary habits should be determined and patients ruled out for urinary tract infection and nephrolithiasis. Older patients with a history of smoking should prompt further investigation with cystoscopy. On abdominal examination, suprapubic tenderness is the hallmark.

On pelvic examination, anterior vaginal wall, bladder base, and pelvic floor muscle (levator ani and obturator internus) tenderness is often found. Pelvic floor muscle function should be assessed. Patients with CPP commonly have a nonrelaxing pelvic floor with elevated baseline tension or overactivity of the pelvic floor musculature (PFM). Further diagnostic testing may include maximum cystometric capacity with a retrograde filling test with consideration for bladder hydrodistention and visualization of potential glomerulations or Hunner’s ulcers during cystoscopy and an intravesical anesthetic challenge.

Endometriosis Endometriosis is defined as the presence of endometrial glands and stroma outside the endometrial cavity and uterine musculature. The location and morphologic appearance of the endometriotic lesion does not appear to correlate with pain symptoms. Adjacency to nerve fibers and density of those projections may be more predictive of pain.21 Women with endometriosis also appear to have generalized pain sensitivity, not just regional pelvic pain sensitivity.22 Symptoms of endometriosis may include disabling menstrual cramps, chronic pelvic pain or low back pain as well, pain during or after intercourse, painful bowel movements, painful urination during menstrual periods, heavy menstrual periods, premenstrual spotting or bleeding between periods, and/or a history of infertility.

The role of diagnostic laparoscopy is to rule out endometriosis or pelvic adhesions.23 These lesions are readily apparent on surgical evaluation yet unfortunately 30% to 50% of diagnostic laparoscopies are negative. Laparoscopic excision of the implants with histologic confirmation is now considered the standard of care, as the positive predicted value of visual diagnosis is only 45%.

Irritable bowel syndrome (IBS) IBS is defined as at least 3 months of continuous or recurrent symptoms including pain relieved by defecation and/or associated with change in frequency of stool or consistency of stool.24 Patients may have constipation www.painweek.org | PWJ | 9

REGIONAL PAIN SYNDROMES

or diarrhea predominant symptoms. No structural or biochemical anatomic variability, fluoroscopic, CT, or ultrasound guidance is abnormality is present to explain the symptoms. Approximately 15% recommended.35 Pudendal nerve release36 has been recommended of the general population in western countries have this diagnosis. as the treatment although most patients will undergo multimodal Symptoms suggestive of IBS are present in approximately 50% to 80% treatment including pelvic floor physical therapy. of women with CPP. The symptoms of IBS include abdominal pain, bloating, belching, excessive flatus, painful defecation, sensation of incomplete evacuation, and pelvic pain.25 Travel history should be obtained and further evaluation for rectal bleeding, unexplained CPP anemia, or other risk factors for colon cancer should be explored.

Potential mechanisms contributing to IBS include abnormal motility, heightened visceral perception, psychologic distress, and intralumi- Pelvic girdle pain or musculoskeletal pelvic pain is experienced nal factors irritating the bowel such as lactose, other sugars, bile acid, between the posterior iliac crest and gluteal fold, particularly in the short chain fatty acids, or fluid allergens.26 Many IBS patients can region of the sacroiliac joint.5 The pain may radiate into the posterecall an antecedent gastroenteritis. IBS patients will typically have rior thigh and can also occur in conjunction with pain in the pubic a normal physical examination. Masses, evaluation of the presence of symphysis. Patients have a diminished capacity for standing, walking, scars, and the possibility of an acute abdomen deserve further atten- and sitting. The pain can rise in relation to pregnancy trauma and/or tion. Diagnostic studies should include a complete blood count with reactive arthritis. Lumbar and hip causes must be excluded in order differential; electrolytes; stool for occult blood, white blood cells, to make this diagnosis, and pain is reproducible by specific clinical ova, and parasites; C. difficile toxin; screen for celiac sprue; hydrogen physical examination tests. breath test for lactose intolerance; and consideration for colonoscopy if there is bleeding, a suspected mass, or risk factors for colon cancer. The pelvic floor musculature ( PFM ) is an important musculoskeletal structure in the pelvic girdle. It is comprised of slow twitch type 1 endurance fibers and fast twitch type 2 fibers. These muscles are responsible for continence, pelvic organ support, sexual appreciation, and can be a cause of CPP.37-39 They are considered the floor of the core musculature and work in conjunction with other core muscles This CPP diagnosis is defined as focal chronic nonmalignant uro- in lumbopelvic stability.40 genital pain characterized by chronic vulvar discomfort without any visual abnormality.27 Symptoms of itching, burning, stinging, or There is a long differential diagnosis for considering other musstabbing in the area around the opening of the vagina predomi- culoskeletal causes in CPP including myofascial pain of the pelvic nate. The pain may be provoked, with attempts at penetration with floor, iliopsoas, and/or adductors with concomitant PFM dyssynergia. intercourse, or unprovoked. The pain may also be localized or gen- Vaginismus and dyspareunia are thought to be the result of PFM eralized vulvar dysesthesia. Primary vulvodynia is defined as pain myofascial pain and dysfunction. Skeletal or joint causes include since the time of her first attempted sexual intercourse vs secondary pelvic insufficiency or stress fractures, sacroiliac joint dysfunction, (later development). The main physical finding is a positive Q-tip pubic symphysitis, osteitis pubis, pubic symphysis separation, and test suggestive of vulvar allodynia.28 coccydynia. Lumbar degenerative disc disease and spondylosis needs to be ruled out as do hip causes such as osteoarthritis, stress fracture, This subtype appears to have a 16% lifetime prevalence29 and 61% and/or hip acetabular labral tears. Hip dysplasia, femoral acetabular of women present during their reproductive years, whereas 25% of impingement, and avascular necrosis of the femoral head can also women have symptoms postmenopause.30 Oral contraceptives may lead to pelvic girdle pain. In addition bony metastases that could contribute to the development of localized vulvodynia.27 Patients present with pelvic girdle pain also should be considered in patients with vulvar pain appear to have higher systemic pain perception, with cancer diagnoses. Neurologic causes of pelvic pain can lead to autonomic abnormalities such as low diastolic blood pressure and myofascial pain and include lumbosacral radiculopathy plexopathy higher anxiety traits.31 This diagnosis is comorbid with IBS, fibro- and peripheral neuropathy. The overlap of pelvic floor myofascial myalgia, and IC/PBS.32 pain with other CPP diagnoses is well documented.41,42

Pelvic girdle pain/ of musculoskeletal origin

Vulvodynia

Pudendal neuralgia This CPP diagnosis is characterized by perineal pain that is aggravated by sitting, reduced in standing, not present when recumbent, and relieved with sitting on the toilet.33 It is believed that the possible sites of impingement of the pudendal nerve can occur at the sacrospinous or sacrotuberous ligament at Alcock’s canal. The diagnosis is typically made by pudendal nerve block34 and, due to the high

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Pelvic girdle pain provocation tests can be used to make the diagnosis of musculoskeletal pain and include the posterior pelvic pain provocation (P4) test, Patrick’s Faber test, and a modified Trendelenburg test. Pelvic girdle palpation tests that have been validated in pelvic girdle pain include long dorsal ligament testing and pubic symphysis tenderness.5 The active straight leg test43 is a test of functional stability whereby the patient lifts her leg and finds it difficult.

Pelvic compression then relieves the difficulty. This test has been directly correlated with chronic pelvic girdle pain. In addition, a detailed PFM examination should be performed. The muscles should Q4 | 2013

be assessed both vaginally and rectally for tenderness, quality and coordination of contraction, relaxation, voluntary and involuntary reflexes, and strength. CPP patients in general have diffuse myofascial tenderness and poor relaxation of the PFM. Musculoskeletal imaging is often negative in CPP. Plain X-ray can be used to rule out osteoarthritis, symphyseal separation, or sacroiliitis. MRI of the lumbar spine can be considered in patients with bowel, bladder, or neurologic change associated with pain. Pelvic MRI can identify stress fracture, masses, tendinopathy, muscle tears, and hip or other bony pathology.

Rehabilitation Treatments

CPP Treatment A Cochrane review44 recommends that overall treatments for CPP should include hormonal treatments, specifically medroxyprogesterone, counseling after negative ultrasound, multidisciplinary approach to pain management including physical therapy, psychotherapy, diet, and environmental factors. Lysis of deep adhesions

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diazepam suppositories and topical compounded ointments have varied effects52,53 or lack adequate study. Therapeutic injections are widely used clinically but are not well supported in the literature for CPP. This includes pelvic floor trigger point injections, pelvic joint injection under fluoroscopy, nerve blocks, neurolysis, and botulinum toxin.54 Other treatments for CPP including acupuncture, electrical stimulation, Chinese herbal medicine, and psychological therapies have been described.55,56 Sacral nerve stimulation for CPP has gained promise.57

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Rehabilitation addresses behavioral management as well as multiple biomechanical factors. This includes treatment of the pelvic joint, motor control of core musculature including the pelvic floor, along with body awareness and function. Pelvic floor muscle physical therapy includes manual therapy (vaginal and rectal) with soft tissue and joint mobilization. Modalities such as biofeedback, which can be

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…OV RALL TR ATM NTS FOR CPP SHOULD iNCLUD HORMONAL TR ATM NTS…COUNS LiNG…[AND A] MULTiDiSCiPLiNARY APPROACH TO PAiN MANAG M NT iNCLUDiNG PHYSiCAL TH RAPY, PSYCHOTH RAPY, Di T, AND NViRONM NTAL FACTORS.

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should be considered in patients with endometriosis. Selected medi- performed with surface electromyography or real-time ultrasound, cation options are suggested but not well studied and include nonste- can be an excellent adjunct to manual therapy. Electrical stimulation roidal anti-inflammatories for acute or chronic pain, acetaminophen and vaginal dilators are tools that can also be utilized in pain manand tramadol. Neurologic agents for CPP are often considered first agement, particularly as a home exercise program. line. This includes tricyclic antidepressants such as amitriptyline, antiepileptics such as gabapentin and pregabalin, benzodiazepines, anticholinergics for bladder overactivity, antispasmodics, and ovarian cycle inhibitors for patients with hormonally driven pain.45 The American Urologic Association published guidelines in 2011 for the treatment of IC/PBS.46 First-line treatment should be general relax- Female CPP is a common condition composed of various subtypes. ation, stress and pain management, patient education, and self-care. Although there is a large differential diagnosis for CPP, more definSecond-line treatment is manual pelvic floor physical therapy47 along itive diagnoses can help further guide specific individualized treatwith consideration for amitriptyline, cimetidine, hydroxyzine, and ment. Peripheral and central contributing factors likely play a role intravesical treatments such as heparin or lidocaine. Patients with in the mechanisms behind pelvic pain as CPP subtypes tend to be IC/PBS are advised to avoid citrus, chocolate, caffeine, sodas, alcohol, comorbid with other pain diagnoses. Multimodal treatment should and heavily seasoned foods.48 Medical treatment for IBS ranges from be the rule given the poorly understood etiology. This includes conlaxatives and prokinetics to antibiotics, probiotics, and neuropathic sideration of musculoskeletal targets specifically pelvic floor physical pain medications.25 Vulvodynia treatments have included dietary therapy. Clinical research for CPP should be a priority given its modifications, physical therapy, and vulvar care measures.49 Vesti- prevalence and associated disability. Further randomized control bulectomy has been shown to have fair long-term efficacy.50,51 trials are necessary. No longer should “chronic pelvic pain” alone be the global diagnosis in this population. Women deserve more specific Medical pelvic floor treatments including compounded vaginal diagnoses and comprehensive multidisciplinary care.

Conclusion

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www.painweek.org | PWJ | 11

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4. Howard FM. Chronic pelvic pain. Obstet Gynecol.

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6. Zondervan KT, Yudkin PL, Vessey MP, et al. Chronic pelvic pain in the community—symptoms, investigations, and diagnoses. Am J Obstet Gynecol. 2001;184:1149–1155.

7. Tu FF, As-Sanie S, Steege JF. Prevalence of pelvic musculoskeletal disorders in a female chronic pelvic pain clinic. J Repro Med. 2006;51:185–189.

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21. Berkley KJ, Rapkin AJ, Papka RE. The pains of endometriosis. Science. 2005;308:1587–1589.

22. Bajaj P, Bajaj P, Madsen H, et al. Endometriosis is associated with central sensitization: a psychophysical controlled study. J Pain. 2003;4:372–380.

23. Howard FM. An evidence-based medicine approach to the treatment of endometriosis-associated chronic pelvic pain: placebo-controlled studies. J Am Assoc Gynecol Laparosc. 2000;7:477–488.

24. Sperber AD, Drossman DA, Quigley EM. The global perspective on irritable bowel syndrome: a Rome Foundation-World Gastroenterology Organisation symposium. Am J Gastroenterol. 2012;107:1602–1609.

25. Mayer EA. Clinical practice. Irritable bowel syndrome. N Engl J Med. 2008;358:1692–1699.

26. Camilleri M, Lasch K, Zhou W. Irritable bowel syndrome: methods, mechanisms, and pathophysiology.

The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2012;303:G775–G785.

11. Latthe P, Mignini L, Gray R, et al. Factors predisposing women to chronic pelvic pain: systematic review.

BMJ. 2006;332:749-755.

31. Granot M, Friedman M, Yarnitsky D, et al. Primary and secondary vulvar vestibulitis syndrome: systemic pain perception and psychophysical characteristics.

Am J Obstet Gynecol. 2004;191:138–142.

16. Chung MK, Chung RP, Gordon D. Interstitial cystitis and endometriosis in patients with chronic pelvic pain: The “Evil Twins” syndrome. JSLS. 2005;9:25–29.

17. Warren JW, Wesselmann U, Morozov V, et al.

Numbers and types of nonbladder syndromes as risk factors for interstitial cystitis/painful bladder syndrome.

Urology. 2011;77:313–319.

18. Suskind AM, Berry SH, Suttorp MJ, et al. Healthrelated quality of life in patients with interstitial cystitis/ bladder pain syndrome and frequently associated comorbidities. Qual Life Res. 2013;22:1537–1541.

19. Driscoll A, Teichman JM. How do patients with interstitial cystitis present? J Urol. 2001;166:2118–2120.

20. Adams K, Denman MA. Bladder pain syndrome: a review. Female Pelvic Med Reconstr Surg. 2011;17:279–289.

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44. Stones RW, Mountfield J. Interventions for treating chronic pelvic pain in women. Cochrane Database Syst Rev. 2000:CD000387.

45. Vercellini P, Vigano P, Somigliana E, et al. Medical, surgical and alternative treatments for chronic pelvic pain in women: a descriptive review. Gynecol Endocrinol.

2009;25:208–221.

47. FitzGerald MP, Payne CK, Lukacz ES, et al. Randomized multicenter clinical trial of myofascial physical therapy in women with interstitial cystitis/painful bladder syndrome and pelvic floor tenderness. J Urol.

2012;187:2113–2118.

30. Hansen A, Carr K, Jensen JT. Characteristics and initial diagnoses in women presenting to a referral center for vulvovaginal disorders in 1996-2000. J Reprod Med. 2002;47:854–860.

15. Warren JW, van de Merwe JP, Nickel JC. Interstitial cystitis/bladder pain syndrome and nonbladder syndromes: facts and hypotheses. Urology.

2011;78:727–732.

43. Beales DJ, O’Sullivan PB, Briffa NK. Motor control patterns during an active straight leg raise in chronic pelvic girdle pain subjects. Spine. 2009;34:861–870.

28. Nunns D, Murphy R. Assessment and management of vulval pain. BMJ. 2012;344:e1723.

10. Learman LA, Kuppermann M, Gates E, et al.

Predictors of hysterectomy in women with common pelvic problems: a uterine survival analysis. J Am Coll Surg. 2007;204:633-641.

14. Simon LJ, Landis JR, Erickson DR, et al. The Interstitial Cystitis Data Base Study: concepts and preliminary baseline descriptive statistics. Urology. 1997;49:64–75.

42. Bassaly R, Tidwell N, Bertolino S, et al. Myofascial pain and pelvic floor dysfunction in patients with interstitial cystitis. Int Urogynecol J. 2011;22:413–418.

46. Hanno PM, Burks DA, Clemens JQ, et al.

AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J Urol.

2011;185:2162–2170.

29. Harlow BL, Stewart EG. A population-based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia? J Am Med Womens Assoc. 2003;58:82–88.

13. Curhan GC, Speizer FE, Hunter DJ, et al. Epidemiology of interstitial cystitis: a population based study.

J Urol. 1999;161:549-552.

41. Pastore EA, Katzman WB. Recognizing myofascial pelvic pain in the female patient with chronic pelvic pain. J Obstet Gynecol Neonatal Nurs. 2012. [Epub ahead of print.]

27. Bachmann GA, Rosen R, Arnold LD, et al. Chronic vulvar and other gynecologic pain: prevalence and characteristics in a self-reported survey. J Reprod Med. 2006;51:3–9.

9. Howard FM. The role of laparoscopy in chronic pelvic pain: promise and pitfalls. Obst Gynecol Surv.

1993;48:357–387.

12. Jarrell JF, Vilos GA, Allaire C, et al. Consensus guidelines for the management of chronic pelvic pain.

J Obstet Gynaecol Can. 2005;27:781-826.

et al. Co-activation of the abdominal and pelvic floor muscles during voluntary exercises. Neurourol Urodyn.

2001;20:31–42.

32. Gordon AS, Panahian-Jand M, McComb F, et al.

Characteristics of women with vulvar pain disorders: responses to a Web-based survey. J Sex Marital Ther.

2003;29(suppl 1):45–58.

33. Labat JJ, Riant T, Robert R, et al. Diagnostic criteria for pudendal neuralgia by pudendal nerve entrapment (Nantes criteria). Neurourol Urodyn. 2008;27:306–310.

34. Vancaillie T, Eggermont J, Armstrong G, et al.

Response to pudendal nerve block in women with pudendal neuralgia. Pain Med. 2012;13:596–603.

35. Bellingham GA, Bhatia A, Chan CW, et al. Randomized controlled trial comparing pudendal nerve block under ultrasound and fluoroscopic guidance. Reg Anesth Pain Med. 2012;37:262–266.

36. Robert R, Labat JJ, Khalfallah M, et al. [Pudendal nerve surgery in the management of chronic pelvic and perineal pain]. Prog Urol. 2010;20:1084–1088.

37. Tu FF, Holt J, Gonzales J, et al. Physical therapy evaluation of patients with chronic pelvic pain: a controlled study. Am J Obstet Gynecol. 2008;198:272 e1–7.

38. Tu FF, Fitzgerald CM, Kuiken T, et al. Comparative measurement of pelvic floor pain sensitivity in chronic pelvic pain. Obstet Gynecol. 2007;110:1244–1248.

39. Fitzgerald CM, Neville CE, Mallinson T, et al. Pelvic floor muscle examination in female chronic pelvic pain.

J Reprod Med. 2011;56:117–122.

48. Friedlander JI, Shorter B, Moldwin RM. Diet and its role in interstitial cystitis/bladder pain syndrome (IC/BPS) and comorbid conditions. BJU Int. 2012;109:1584–1591.

49. Landry T, Bergeron S, Dupuis MJ, et al. The treatment of provoked vestibulodynia: a critical review. Clin J Pain. 2008;24:155–171.

50. Andrews JC. Vulvodynia interventions—systematic review and evidence grading. Obstet Gynecol Surv.

2011;66:299–315.

51. Tommola P, Unkila-Kallio L, Paavonen J. Long-term well-being after surgical or conservative treatment of severe vulvar vestibulitis. Acta Obstet Gynecol Scand.

2012;91:1086–1093.

52. Crisp CC, Vaccaro CM, Estanol MV, et al.

Intra-vaginal diazepam for high-tone pelvic floor dysfunction: a randomized placebo-controlled trial. Int Urogynecol J. 2013;May 17. [Epub ahead of print.]

53. Carrico DJ, Peters KM. Vaginal diazepam use with urogenital pain/pelvic floor dysfunction: serum diazepam levels and efficacy data. Urol Nurs. 2011;31:279– 284, 299.

54. Abbott J. Gynecological indications for the use of botulinum toxin in women with chronic pelvic pain.

Toxicon. 2009;54:647–653.

55. Champaneria R, Daniels JP, Raza A, et al. Psychological therapies for chronic pelvic pain: systematic review of randomized controlled trials. Acta Obstet Gynecol Scand. 2012;91:281–286.

56. Carinci AJ, Pathak R, Young M, et al. Complementary and alternative treatments for chronic pelvic pain.

Curr Pain Headache Rep. 2013;17:316.

57. Tirlapur SA, Vlismas A, Ball E, et al. Nerve stimulation for chronic pelvic pain and bladder pain syndrome: a systematic review. Acta Obstet Gynecol Scand.

2013;92:881–887.

40. Sapsford RR, Hodges PW, Richardson CA,

Q4 | 2013

See what acute-pain patients may not be telling you.

Read the survey summary at TurnTheConversation.com Unintended consequences such as diversion, abuse, and societal risk have cast a shadow over the opioid legacy. How do we address the growing concerns of opioid abuse while continuing our primary mission of providing care? Let’s start talking about responsibility.

Abuse

This is what we all intend…

This is what can happen…

Relief Physicians have long relied on opioids to provide relief to many patients in pain; however, even properly administered, opioids can have unintended consequences affecting individuals and society at large.

See what acute-pain patients may not be telling you.

Read the survey summary at TurnTheConversation.com Mallinckrodt, the “M” brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company. © 2013 Mallinckrodt.

by GARY

W. JAY MD, DAAPM, FAAPM

abstract: In the second part of this migraine review article we look at the important migraine

variants as well as deal with complicated migraine and its pathophysiology. Finally, we examine the common treatment of migraine headache as well as the new evidence-based medicine migraine treatment guidelines.

EXPERT OPINION

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MiGRAiN VARiANTS Migraine is a complex disorder, especially as it has so many different presentations.

Table Migraine variants

The author lists more than 10 significant migraine variants (Table), the purpose of which is to answer the question, “If you, the clinician, are called at 2:00 in the morning by a patient who reports these issues, should you meet the patient immediately in the emergency department?”

Acephalgic migraine Hemiplegic migraine Basilar migraine (Bickerstaff syndrome)

Childhood periodic syndromes Retinal migraine (ophthalmic, ocular)

Ophthalmoplegic migraine Complicated migraine Migralepsy Acute confusional migraine Vertiginous migraine Migraine with prolonged aura is a migraine in which the aura, which should last 15–60 minutes, lasts longer than 60 minutes. These patients need a full neurologic work-up.

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AC PHALGiC MiGRAiN

The acephalgic migraine is associated with an aura but no headache.

More common in older patients with a history of migraine with aura, it is suspected in patients with a history of recurrent attacks of unilateral transient monocular blindness with otherwise absent risk factors for other causes of carotid disease and a personal or family history of migraine.

Symptoms may include: Scintillating scotomata Formed stereotyped visual hallucinations

CACNA1A and ATP1A2 regions can be detected. Positron emission tomography ( PET ) studies show early glucose hypometabolism in the contralateral perisylvian region during a FHM.15

Sporadic hemiplegic migraine (SHM) is motor weakness in the absence of family history of similar attacks; this migraine is linked to the CACNA1A and ATP1A2 genes.16 Diagnosis is confirmed by repeated stereotyped reversible episodes. An absence of first- and second-degree relatives with a similar disorder raises the suspicion of SHM.17 The differential diagnosis includes focal seizures with postictal paralysis, mitochondrial cytopathies, intracranial hemorrhage, mass, infection, or cerebral infarction.18 While FHM episodes are typically stereotyped (that is, always the same neurologic picture), SHM episodes may change.

(In a single visual field or bilaterally)

Micropsia Tunnel vision Paroxysmal vertigo Hemisensory dysesthesias Auditory hallucinations Interestingly, a number of the aforementioned symptoms are read in Lewis Carroll’s Alice in Wonderland—Mr. Carroll had a history of migraine. Without question, acephalgic migraines must be differentiated from transient ischemic attacks, occipital lobe seizures, or temporal lobe seizures.1 Keep in mind too that this is the only disorder other than schizophrenia that may be associated with auditory hallucinations.

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WHiL MOST MiGRAiN H ADACH iS G N TiC (THAT iS, iT CAN B PASS D DOWN THROUGH G N RATiONS), F W FORMS OF MiGRAiN HAV B N AS W LL iNV STiGAT D AS H MiPL GiC MiGRAiN , WHiCH HAS MOST OFT N B N STUDi D iN FAMiLiAL COHORTS.

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H MiPL GiC MiGRAiN

While most migraine headache is genetic (that is, it can be passed down through generations), few forms of migraine have been as well investigated as hemiplegic migraine, which has most often been studied in familial cohorts.

Alternating hemiplegic of childhood (AHC) migraine occurs in children. This chronic, progressive disorder is associated with a high With hemiplegic migraine, there is a history of recurrent transient prevalence of neurologic deficit.19 AHC is differentiated from FHM hemiplegia or hemiparesis that occurs during a migraine attack. by infantile onset and characteristic associated symptoms.20 Onset Patients may experience disturbances of consciousness and, rarely, occurs before 18 months,21 and AHC is characterized by vomiting, coma.2-4 The neurologic deficit is transient, clearing in minutes to headache, alternating hemiplegia, loss of consciousness, paroxysmal ocular palsies, choreoathetosis, autonomic dysfunction, and mental hours or resolving with the beginning of the headache.5-7 retardation.22 Differential diagnoses include vascular dysfunction, There are 2 main forms, familial and sporadic. Familial hemiplegic channelopathies, and mitochondrial disorders. migraine ( FHM ) is a genetically heterogeneous autosomal dominant disorder and channelopathy. Most of the affected families have Acute treatment of hemiplegic migraine includes antiemetics, nonmutations on the CACNA1A gene (a defect linked to abnormal volt- steroidal anti-inflammatory drugs ( NSAIDs), and nonnarcotic pain age-dependent P/Q-type calcium channel alpha-1A) on 19p13.8-11 In medication. Vasoconstrictors (triptans or ergots) should be avoided.

FHM type 2, a mutation is seen on ATP1A2 on 1q23, encoding the Prophylactically, the use of beta blockers, calcium channel blockalpha-2 subunit of sodium–potassium pumps,12-14 and FHM type 3 ers, topiramate, and other anticonvulsant medications is indicated, has a mutation in sodium channel gene SCN1A7. Mutations on the although none of these is a “curative” treatment.

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www.painweek.org | PWJ | 17

EXPERT OPINION

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BASiLAR MiGRAiN

(Bickerstaff syndrome)

Differentially one must preclude mitochondrial disorders (lactate levels). For treatment, early use of IV fluids and analgesic medications may be helpful. Some children respond to triptans or ergotamine.

Antiemetics are usually not effective. Prophylactic medications may include cyproheptadine and tricyclic antidepressants ( TCA s).29

Bickerstaff syndrome, as basilar migraine is called, presents with symptoms of vertebrobasilar insufficiency, which may precede a headache. These symptoms most commonly include dizziness and vertigo, but also headache with ataxia, tinnitus, decreased hearing, Abdominal migraine typically occurs in children although it can be nausea and vomiting, diplopia, loss of balance, bilateral paresthesias seen in adults.33 The disorder is associated with paroxysmal midabor paresis, altered consciousness, and, pathognomonically, syncope.23 dominal pain lasting from 1 to 72 hours, associated with nausea and This disorder is most commonly found in adolescent girls and young vomiting, flushing, or pallor. It may also be associated with other women.24 Localized vertebrobasilar vasoconstriction leading to tran- migraine prodromes such as fatigue and drowsiness. Aura and headsient posterior circulation ischemia is seen.25 A novel mutation of the ache are minimal or absent. Children with abdominal migraine may ATP1A2 gene has been found in one family. Differential diagnoses show subtle clumsiness, attention deficit, or developmental delay.29 include various causes of syncope, inner ear disease, intoxication, and Children who experience abdominal migraine may develop migraine posterior fossa pathology.26 late in life. A family history of migraine is common. The disorder may be relieved by sleep. Antiemetics may help abort an acute attack, and other preventive treatment includes low doses of TCA s and/or flunarizine (a calcium channel blocker).27,29,34 CHiLDHOOD P RiODiC SYNDROM S

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Multiple cyclic attacks of pain or vomiting with or without migraine headaches are relatively common in children and adolescents and are also common precursors to migraine when the patients get older.

These used to be referred to as migraine equivalents.

One type of childhood periodic syndrome is cyclic vomiting syndrome, which is marked by recurrent attacks of violent or prolonged

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CYCLiC VOMiTiNG SYNDROM iS THOUGHT TO B S CONDARY TO ABNORMAL ACTiViTY iN TH AR A POSTR MA. GASTROPAR SiS, OCCURRiNG DURiNG MiGRAiN , MAY ALSO B AN TiOLOGiC FACTOR FOR CYCLiC VOMiTiNG AND ABDOMiNAL MiGRAiN .

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Retinal migraine is also called ophthalmic or ocular migraine. It is not an uncommon cause of transient monocular blindness in young adults.35 Recurrent attacks of unilateral visual disturbance or blindness lasting minutes to an hour associated with minimal or no headache can be seen. Physicians must rule out amaurosis fugax (ischemia of retinal arteries). The best way to differentiate retinal migraine from amaurosis fugax is to determine the duration of time it took for the blindness to occur. If blindness occurred immediately, amaurosis fugax is the probable cause because retinal migraine may take several minutes for full monocular blindness to occur.29,36-38 Retinal migraine is described as a gradual visual disturbance in a mosaic pattern of scotomata that gradually enlarges, yielding total unilateral visual loss. Postural changes, exercise, and oral contraceptives may precipitate attacks. This type of migraine may also result from transient vasospasm of the choroidal or retinal arteries.

A personal or family history of migraine helps to confirm the diagnosis.

The clinician must rule out carotid artery disease. Avoid vasoconstrictors and use prophylactics, specifically calcium channel blockers.29,37,38

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OPHTHALMOPL GiC MiGRAiN vomiting without headache that may last hours.27,28 This diagnosis should be suspected if the child has a family history of migraine. The attacks may be precipitated by infection, menstruation, or physical or emotional stress. During the attacks, other symptoms of migraine may be seen including nausea, lethargy, yawning, drowsing, subtle clumsiness, attention deficit, or developmental delay.29,30 Cyclic vomiting syndrome is thought to be secondary to abnormal activity in the area postrema. Gastroparesis, occurring during migraine, may also be an etiologic factor for cyclic vomiting and abdominal migraine.31,32

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Ophthalmoplegic migraine is rare. It occurs predominately in children and is characterized by a migraine-like attack followed within days by periorbital pain and diplopia secondary to cranial neuropathies. Headache may or may not be present. The oculomotor nerve is most commonly involved, causing ptosis and affecting the pupils. The abducens nerve and, rarely, the trochlear nerve may be involved. Other symptoms include altered consciousness, acute confusion, recurrent vomiting, or seizures. The attack may last for days to months and then spontaneously resolve. This migraine has also been seen in adults.29,39-41 Q4 | 2013

Ophthalmoplegic migraine is now classified as a neuralgia by the dysfunction in migraine-related stroke.47,48 Migraine headache is second edition of the International Classification of Headache Disor- associated with an inflammatory state that occurs between headaches, ders ( ICHD-II ). It is possibly secondary to recurrent demyelinating but it also appears to be related to headache frequency. Identifying cranial neuropathies. Differential diagnoses include problems involv- high-risk migraineurs with other modifiable stroke risk factors such ing the parasellar, orbital, and posterior fossa leading to a headache as smoking is, therefore, imperative. and ophthalmoplegia.29,42,43 Prednisone has been used with mixed results in treatment, and prophylactic medications are only possibly The author recalls a case when he first began his practice. The patient beneficial. was a young woman who smoked, took estrogenic birth control pills, and had migraine with aura. She developed a visual quadrantanopia.

Treatment or nontreatment of young women with these 2 factors COMPLiCAT D MiGRAiN (smoking and estrogenic birth control pills) was the subject of many journal articles and letters over a number of years.

Although rare (<1% of migraineurs)44 there are a number of types of complicated migraine including: Migraine with aura is a risk factor both for cardiovascular (CV ) mortality and for all-cause mortality.49 Among a study population Chronic migraine of patients with migraine with aura, hazard ratios for CV mortality and all-cause mortality were 1.27 and 1.21, respectively, compared (see part 1 of this article in PAINWeek Journal, Issue No. 1) with a nonheadache group. Hazard ratios for coronary heart disease and stroke for patients with migraine with aura were 1.28 and 1.40, Status migrainosis Migraine headache lasting for more than 72 hours respectively, compared with a nonheadache group. The possible Frequently requiring hospitalization for IV fluids and nutrition mechanisms for the link between migraine and CV disease include a genetic component, ischemic events caused directly by migraine, and the hypothesis that migraine may be “a systemic disorder that Persistent aura without infarction is affecting vasculature.”50 Aura lasting more than 1 hour but not associated with a cerebral infarction

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Aura can last hours or days, but has no radiographic evidence of cerebral vascular accident (CVA)

Migrainous infarction Migraine-triggered seizures Migrainous infarctions are typically associated with migraine with aura and are found in the presence of silent infarctions or white matter changes on magnetic resonance imaging (MRI ).45 When a CVA occurs during a typical migraine with aura attack, the term migrainous infarction is used. It isn’t known if migraine and stroke have the same underlying etiologies or similar ischemic factors or if migraine is associated with other conditions that can cause CVA .29,46 It is wise to remember that migraine with aura is associated with changes secondary to cortical spreading depression (CSD) and, possibly, more focal vascular ischemia. In patients who have migraine with aura who also have other pre-CVA conditions (atrial fibrillation, carotid stenosis, and others), you may want to treat with NSAIDs, not vasoconstrictors. Nonopioid pain medications can be used, if needed, as well as other prophylactic medications (anticonvulsants, beta blockers, calcium channel blockers, etc).

Inflammatory biomarkers link migraine to stroke in young women.

Inflammatory cytokines interleukin-6 ( IL -6), tumor necrosis factor– alpha ( TNF-α), and transforming growth factor–β1 ( TGF-β1) are elevated in young women with migraine, and these levels correlate with headache frequency, body mass index ( BMI ), and high-sensitivity C-reactive protein (CRP). These markers of endothelial activation—inflammation and coagulation biomarkers—have been shown to be elevated in premenopausal migraineurs interictally as compared to a control group, suggesting a role for endothelial Q4 | 2013

Blood vessel microemboli appear to be a potential source not only of ischemia and stroke but also of migraine with aura.49 On this continuum, one may develop a stroke on the severe end, and on the other end, migraine with aura. Transient ischemic attacks ( TIA s) may reside in between. CSD may be triggered by microemboli that become stuck in blood vessels just long enough to depolarize the surrounding tissue. Dalkara et al51 have proposed that a subpopulation of migraine with aura patients exhibits a transient, regional, hypoperfusion syndrome, which appears to cause local hypoxia, disruption of ionic gradients, and local depolarization that then propagates via CSD. Migraine and epilepsy are comorbid conditions, but the nature of the relationship is unclear—is there an irritable CNS?52 Migralepsy, that is, a migraine-triggered seizure, is defined as a seizure that occurs during or within 1 hour of a migraine with aura. There may be supratentorial focal cerebral edema seen on MRI. Electroencephalograms ( EEG s) are typically normal, interictally, but migraineurs may have diffuse slowing.53,54 Anticonvulsants are the treatment of choice.

Acute confusional migraine is rare and typically found in young children. It is associated with disorientation, episodes of confusion, and vomiting, with or without headache.55,56 It can be relieved by sleep.

Interestingly, transient global amnesia, once thought to be secondary to bilateral temporal lobe seizures, is now thought to be related to the migraine aura, specifically acute confusional migraine. Differential diagnoses include various causes of confusion (epilepsy; and ischemic, hemorrhagic, neoplastic, toxic, metabolic, mitochondrial, and infectious encephalopathies). Prophylactic migraine therapies are felt to be most appropriate.29,57 www.painweek.org | PWJ | 19

EXPERT OPINION

Vertiginous migraine occurs as recurrent episodes of vertigo related to migraine.27,58 In one-third of associated migraine headaches, it lasts 5 to 60 minutes. Typically, nausea and vomiting, photophobia, and headache also occur, and there is a personal or family history of migraine. Differential diagnoses include vertebrobasilar insufficiency and paroxysmal vestibular syndrome.59 Patients only minimally or rarely respond to typical migraine prophylactic therapy, so use medications with anticholinergic properties such as TCA s.29,60

“Odds and Ends”

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H MiCRANiA CONTiNUA Hemicrania continua ( HC) is a persistent, strictly unilateral headache responsive essentially only to indomethacin. The diagnosis per the IHS includes65,68: Headache for more than 3 months fulfilling the following criteria, including: All of the following characteristics of pain Unilateral, without side shift Daily and continuous, without pain-free period

Benign coital headache occurs 70% of the time in susceptible migraineurs, with sudden onset just before, during, or immediately after orgasm. Subacute, crescendo headache (25%) starts before orgasm. Least common is postdural headache, secondary to significant intradural pressure, and is more likely to be associated with nausea and vomiting. You must rule out organic causes such as berry aneurism. Treatment is with indomethacin 75 mg, dihydroergotamine ( DHE -45), or a triptan taken 2 hours before intercourse.29,61,62 Exertional headache is very similar to benign coital headache. It can occur during adolescence through age 50 and can happen with lengthy exercise sessions, beginning at the height of exercise and fading when exercise ends. However, it can also last up to 2 days and may be associated with nausea and vomiting, photophobia, and sonophobia. Exertional headache is secondary to increased venous pressure in the CNS. The clinician must rule out a more serious diagnosis. These patients typically have migraine or a family history of migraine. Treatment is the same as that used for benign coital headache.29,63,64

Moderate intensity, but with exacerbations of severe pain

At least one of the following autonomic features during exacerbations ipsilateral to the side of pain Conjunctival injection and/or lacrimation Nasal congestion and/or rhinorrhea Ptosis and/or miosis

Complete response to therapeutic doses of indomethacin Not attributable to another disorder HC only rarely goes into remission. Indomethacin 75 mg dosed every 6 to 8 hours with food, as needed, is a typically appropriate way to deal with the headache.29 HC is thought to be related to the trigeminal autonomic cephalgias.

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TR ATM NT OF MiGRAiN

The treatment of migraine has been largely unchanged for decades.

Use of the triptans, the first of which was released in the late 1980s, was the last true paradigm shift in the treatment of migraine. Today, Menstrual migraine is defined by the IHS65 as attacks in menstruat- calcitonin gene-related peptide (CGRP) antagonists are being invesing women who have a history of migraine without aura associated tigated in the form of humanized antibodies because the small molewith their menses. The attacks occur exclusively on day 1 ± 2—that cules haven’t had good success. Glial modulators (AV411, COL -144, is, 2 days before or 3 days after the start of menstruation in at least 2 and others) are in development at this time. out of 3 menstrual cycles and at no other times of the cycle.

Migraines are treated acutely or prophylactically. Acute methods Menstrual migraine has been determined to be potentially more include the triptans (5-HT1B/D/F) or DHE -45. Cafergot, an oral ergot difficult to treat than migraine not specifically related to hormones. with caffeine, has long been pulled from the market in the United Migraine prevalence increases in women during adolescence in part States. Although it is indicated that ergotamine and caffeine oral because of changing levels of estrogen and progesterone at puberty. combinations do exist, the author hasn’t found them.29 NSAIDs are In one study, menstrual-related headaches were reported in 42.1% of used alone or 1 hour before a triptan in the presence of allodynia secsubjects; pure menstrual headaches were observed in 3.4%.29 ondary to central sensitization associated with migraine, as detailed previously.

It is the treatment of this diathesis that makes it so very different from treatment of “regular migraine.” The therapy is to perform Topiramate is the most widely used prophylactic medication for mini-prophylaxis—that is, treat the patient with medications begin- migraines, given in doses of 100 to 200 mg per day. Common side ning 5 days before the expected onset of the headache (if before the effects are sedation, confusion, and other CNS issues typically seen menses by a day) or the first day of the menses. The 2 drugs that with the use of an antiepileptic drug. Topiramate is best started at appear to be most appropriate include frovatriptan 2.5 mg twice daily very low doses and increased very slowly to prevent patients from for 5 days before menses and throughout the cycle; the other drug is stopping it. Expect typically a 50% reduction in headaches with prophylactic medications. naproxen sodium 550 mg given the same way.29,66,67

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OnabotulinumtoxinA has been approved to treat chronic migraine, acetazolamide, the antithrombotics acenocoumarol, warfarin, and a common multifactorial diagnosis characterized by headaches on picotamide, and the antidepressants fluvoxamine and fluoxetine. more than 14 days a month. The drug was not found to be helpful Gabapentin was the only antiepileptic given a Level U rating. The for less frequent headaches; nonetheless, it received approval by a TCA protriptyline, the beta blocker bisoprolol, and the calcium narrow margin, with a 10% or less delta or differentiation from pla- channel blockers verapamil, nicardipine, nifedipine, and nimodipine, cebo. Questions about how onabotulinumtoxinA helps migraine after as well as the direct vascular smooth muscle relaxant cyclandelate were also listed in this category. peripheral injections remain.

Other drugs used for migraine prophylaxis include TCA s (which Of note, calcium channel blockers have been used as primary have anticholinergic side effects), beta blockers (which have signif- migraine prophylactic medications for many decades. The author icant side effects including depression, insomnia, weakness, con- believes that the reason for their rating in these guidelines is a change stipation, dizziness, impotence, and a host of possibly significant in consideration of studies (those with completion rates less than 80% medically serious reactions), and calcium channel blockers (with side were not included in the analysis). effects including headache, constipation, dizziness, nausea, edema, congestive heart failure, fatigue, and possibly significant medically The final group of medications included in the guidelines were those serious drug reactions). that are established as possibly or probably ineffective. These were the antiepileptic lamotrigine (established as not effective), clomipOther nonpharmacologic treatments include cognitive behavioral ramine (probably not effective), and acebutolol, clonazepam, nabumetone, oxcarbazepine, and telmisartan (possibly not effective). therapy, biofeedback therapy, acupuncture, and yoga.

eViDeNCe-BASeD MeDiCiNe TReATMeNT GUiDeLiNeS69

It is our responsibility as clinicians to evaluate each headache patient completely and use the medication for treatment that is most appropriate for that individual patient. For an optimal treatment regimen, combinations of acute and prophylactic medications may be needed along with medications for mini-prophylaxis for menstrual-related migraine. Effective treatment depends on how well the clinician understands the disease and the treatments that are most appropriate for each individual patient.

Evidence-based medicine ( EBM ) guidelines were published in April 2012. The guideline reviewers found 284 articles dealing with treatment, but only 29 were classified as class I or class II; studies with completion rates below 80% were downgraded, and several studies in the original guidelines have been downgraded. This latter point is important, as you will see.

We can make a difference in the treatment of migraine headache. We can significantly help most migraine headache patients to have fewer, Level A rating—among medications with established efficacy (≥ 2 less-debilitating headaches and a much-improved quality of life. class I trials), divalproex sodium, sodium valproate, and topiramate made the grade. However, relatively recent reports of birth defects References associated with valproic acid make this drug less likely to be used 1. Tomsak RL , Jergens PB . Benign recurrent transient monocular blindness: a possisince female migraineurs of childbearing age are the most common ble variant of acephalgic migraine. Headache. 1987;27(2):66–69. patients with migraine. Beta blockers, including propranolol, metoprFeely MP, O’Hare J, Veale D, et al. Episodes of acute confusion or psychosis in olol, and timolol, received a Level A rating, and the only triptan found 2. familial hemiplegic migraine. Acta Neurol Scand. 1982;65(4):369–375. to be useful to treat menstrual-related migraine was frovatriptan.

Level B rating—medications that are probably effective (1 class I or 2 class II studies) included the antidepressants amitriptyline and venlafaxine, beta blockers atenolol and nadolol, and triptans naratriptan and zolmitriptan, which may be used to treat menstrual-related migraine.

Level C rating—medications that are possibly effective (1 class II study) included the angiotensin-converting enzyme (ACE) inhibitor lisinopril, the angiotensin-receptor blocker candesartan, the alpha-agonists clonidine and guanfacine, and the antiepileptic drug carbamazepine. Beta blockers in this category included nebivolol and pindolol. The antihistamine cyproheptadine, long used as a primary prophylactic drug for children, was also given a Level C rating.

Level U rating—medications with inadequate or conflicting data to support or refute their use included the carbonic anhydrase inhibitor Q4 | 2013

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8. Kraus RL, Sinnegger MJ, Koschak A, et al. Three new familial hemiplegic migraine mutants affect P/Q-type Ca(2+) channel kinetics. J Biol Chem. 2000;275(13):9239–9243.

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EXPERT OPINION 10. Melliti K, Grabner M, Seabrook GR . The familial hemiplegic migraine mutation R192q reduces G-protein-mediated inhibition of P/Q-type (Ca(V)2.1) calcium channels expressed in human embryonic kidney cells.

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By BARBARA

L. KORNBLAU JD, OTR/L, CPE, DASPE SUSAN MCNULTY OTD, OTR/L, CPE

e

SCOTT M. ROB RTSON PHD, MHCI

BEHAVIORAL

ALL AUTi STiC Pe OPLe FiT A COMMON COGNi TiV e PROFiLe…

abstract: Millions of autistic people live in the US and around the world, yet few clinicians receive any professional training to meet their healthcare needs. This article discusses autism in the context of clinicians who work in pain management.

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The authors review the literature on how autistic adults and children feel, express, and experience pain, and share practice recommendations for pain management clinicians to help them better serve autistic youth and adult patients.

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TH e STORY OF JUAN: Juan, a 21-year-old autistic adult, works at a local blood bank. While transporting several boxes of lab equipment, he bends over, hears a pop, and

immediately feels something weird in his right leg. Juan tells his boss about the incident, and his boss asks him if it hurts. Juan replies only that it feels weird. After a few days of Juan’s repeated complaints of weirdness, his boss tells him to go visit his primary care provider (PCP). How will Juan’s PCP assess his pain in this situation?

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AN OV RVi W OF AUTiSM Diagnosed among millions of adults and children worldwide, autism represents a lifelong neurological developmental disability. Autistic people possess diverse strengths and weaknesses and individual differences that varies how they experience the disability. However, all autistic people fit a common cognitive profile. This profile describes the degree and intensity of traits in 4 core areas:

›› Language and Communication ›› Socialization and Social Relationships ›› Sensory Experience and Motor Skills ›› Planning, Self-Regulation, and Self-Reflection1

1 Language and Communication

manage social activities, they may feel perplexed by ambiguous and subjective unwritten social rules. New life situations and situations in which they do not know “what comes next” can present the most trouble. Autistic people can also find it hard to form and maintain friendships and other social relationships because of their socialization challenges. For instance, Juan finds it very hard to socialize at work and form friendships with his coworkers. He often cannot handle the “unwritten rules” of his job at the blood bank.

3 Sensory Experience and Motor Skills Autistic people commonly feel and experience sensations from the 7 senses—5 plus 2—differently from nonautistic people. These 7 senses consist of sight, sound, smell, taste, and touch, as well as balance (vestibular) and body motion (proprioception). Compared with nonautistic peers, autistic people may experience hypersensitivity (oversensitivity) to some sensations and hyposensitivity (undersensitivity) to other sensations. For instance, Juan has highly sensitive hearing that makes clapping feel painful, but he also has a less sensitive sense of motion. Another autistic person might have undersensitive touch but an oversensitive sense of smell.

Autistic people often experience difficulties with both understanding and expressing language. Frequently, a large gap exists between their ability to understand other people and to express themselves. Autistic people might possess relative strengths or weaknesses with either task. Autistic people may seek out some sensations and avoid other sensaAdditionally, their communication challenges with understanding tions. For instance, an autistic person might avoid others’ shoulder and expressing can involve nonverbal cues, such as facial expressions, touches (tactile avoidance), but greatly enjoy riding roller coastgestures, and postures. In some cases, autistic people’s use of intricate ers (vestibular seeking). In contrast, another autistic individual vocabularies and an extensive factual knowledge might hide their dif- might wish to touch everything in a physical environment (tactile ficulties with communication. For example, Juan possesses extensive seeking), while fearing airplane turbulence (vestibular avoidance). knowledge and a deep vocabulary regarding working in a lab. However, These atypical experiences of environmental sensations can affect he cannot accurately describe specific pain symptoms that would help an autistic person’s emotional and mental state, mental health, and others observing his pain behavior diagnose him. Juan also does not quality of life. project his state of pain and his emotions through his facial expressions.

Likewise, differences in how autistic people experience the sensory world also affect their perceptions of pain, temperature, and 2 Socialization and Social Relationships hunger and thirst. An individual’s perception of and response to pain depends intrinsically on how they feel and express sensations Autistic people often find it challenging to socialize with other from the environment. A 2011 study found an important relationship people in everyday activities. Frequently relying on rules of thumb to between how people experience sensations and feel pain, which they Q4 | 2013

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BEHAVIORAL

expressed through pain catastrophizing, defined as “an exaggerated This inadequate training about autism may help explain why autistic negative cognitive response to actual or anticipated pain experience.”2 adults face major challenges to access quality health care. In a survey Pain catastrophizing can predict pain intensity, the state of disabil- of 209 autistic adults and 228 nonautistic adults, autistic participants ity, and physiological distress.3 Differences in how autistic people described a lower satisfaction with patient-provider communication.7 experience and react to sensations from the environment can shape The autistic participants also experienced a greater likelihood of their pain catastrophizing. Thus, they might project decreased pain unmet healthcare needs for physical health, mental health, and precatastrophizing in some circumstances but increased pain catastro- scription medications. phizing under other conditions.

While managing sensory challenges, autistic people must also often handle difficulties with motor skills and coordination. They frequently find it hard to plan and perform complex tasks that rely on fine motor skills, such as handwriting. Autistic people also often face difficulties with complex tasks that rely on gross motor skills, such as catching and throwing a ball. Some autistic people possess unusual postures and gaits, which clinicians should note for physical examinations dependent on gait. For example, Juan may have an unusual gait that might affect the evaluation of his back and leg issues.

4 Planning, Self-Regulation, and Self-Reflection

“ON e ReCeNT SURVeY...

FOUND AN ABSeNCe OF AUTiSMSPe CiFiC TRAiNiNG AMONG PROViDe RS SeRViNG AUTiSTiC ADULTS.”

Autistic people often experience difficulties with some tasks of executive functioning ( EF ), which regulate activities in the way a CEO oversees a company. EF tasks include conceptualization, organization, planning, and self-reflection of intended actions and thoughts. One common EF difficulty experienced by autistic people involves challenges with shifting attention and multitasking.

Compensating for these challenges, many autistic people intensely direct their focus and attention toward subjects and tasks of interest to them. For instance, Juan often focuses his attention heavily toward video gaming, and he frequently talks extensively about specific genres of videogames.

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H ALTHCAR S RViC S AND AUTiSTiC ADULTS AND CHiLDR N

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Prior research suggests that healthcare providers often do not receive specialized professional training and information about autism.4,5 Particularly, providers typically have the least training and resources about the needs of autistic adults. One recent survey of 346 health providers in Connecticut found an absence of autism-specific training among providers serving autistic adults.6 Less than half of the survey’s respondents serving autistic adults (44.6%) stated they received any training. Less than one-third of the survey’s respondents who did not currently serve autistic adults (27.6%) had received any training.

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Pain Management Experience Among Autistic Adults and Children Some research suggests autistic people may feel, experience, and express sensations of pain differently. For instance, one recent study found autistic adults showed an increased sensitivity to hot and cold painful sensations.8 The 8 autistic participants reported cold pain at higher temperatures and hot pain at lower temperatures than a matched comparison group.

Other studies suggest that many autistic children and adults may not express discomfort from physical pain as nonautistic people do. Some autistic people might not cry, moan, or seek physical comfort in the way that nonautistic people commonly do.

Instead, many autistic people might move in unusual ways, act lethargic, or show signs of psychological distress. Misreading these signs, friends and family members may falsely conclude that an autistic person exhibits complete insensitivity to pain.9-11 Prior research suggests that people with intellectual and developmental disabilities who cannot describe their pain often carry undiagnosed medical conditions.12 For example, Juan’s atypical way of showing pain—his atypical pain behaviors—might put him at greater risk for undiagnosed physical injuries and medical problems.

Juan could break a bone or rupture a disc, but only tell others that he feels weird—without mentioning pain. Juan might not recognize a problem with kidney stones until he notices an absence of urination for a few hours. Some autistic people might act unusually aggressive when they experience pain and have difficulty expressing it. One 2011 study found autistic people may act aggressive when a physician performs a venipuncture for blood work.13 Another observational study of 80 autistic youths showed that participants expressed pain-related aggression through self-injury.14 In some cases, autistic people may not carry a clinical diagnosis of autism when they visit clinicians for issues with pain. Despite increased knowledge of autism during the past decade, many autistic Q4 | 2013

adults and adolescents remain undiagnosed. One study15 from 2004 language. Their choice of communication can vary depending on examines 2 cases of autistic adolescents not previously diagnosed energy level and mental and emotional state.16 While embracing an with autism. An accurate diagnosis of autism can help pain clini- autistic patient’s communication style, clinicians should also look cians understand them better and treat their pain conditions. Pain for differences in how they project and understand nonverbal cues. management clinicians may find themselves the first clinician in Autistic people commonly convey nonverbal cues that may unintena person’s life to recognize traits of autism and refer patients for tionally or purposely differ from their words or other messages. This comprehensive diagnostic assessments of autism. This situation rep- may prove significant if clinicians look for nonverbal pain behaviors resents another important reason pain practitioners should familiar- as part of their assessments. Juan may not express typical or expected ize themselves with autism. Pain management clinicians should also pain behaviors that a nonautistic person with his condition would learn strategies, approaches, and rules of thumb to provide quality express. care to autistic people.

Autistic patients can have trouble filling out forms. Clinicians or their staff should go over any required forms with them. Staff members can walk autistic patients through forms to clarify directions PRACTiC R COMM NDATiONS FOR PAiN and explain any confusing questions. Where feasible, allow autistic AND G N RAL PRACTiC CLiNiCiANS patients extra time to complete forms. As needed and desired, autistic patients can complete these forms at home in advance of the Addressing Communication and Social Challenges appointment.

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Many autistic people lack the communication ability to describe aloud symptoms of pain, physical injuries, and illnesses to clinicians.

Other autistic people may have the ability to do so but find it hard to talk about their medical problems. Thus, clinicians will often find they can obtain better information if they ask specific questions about symptoms that make sense to an autistic patient. Clinicians can then reword questions as necessary to clarify information. Commonly, a clinician might ask these types of questions to learn more about an autistic patient’s medical problem:

›› How uncomfortable are you? Can you tell me more about your discomfort? ›› Is something bothering you? Can you tell me about what bothers you? ›› Does something hurt? Do you feel weird? If so, can you tell me about it? ›› Can you point to the area of the problem?

Can you show me?

Can you draw or sketch the problem?

Helping an autistic patient to identify the specific medical problem, clinicians should think cleverly and creativity. Clinicians might, for instance, make use of an autistic patient’s favorite interest or talent.

For instance, Juan, who has vocal talent, might sing a song about his pain issues. Alternatively, an artistically talented patient might paint or draw important aspects of a medical problem.

Addressing Sensory and Motor Challenges Consider carefully how an autistic patient might respond to different kinds of everyday sensations, including others’ touch. Some autistic people find others touching them can make them feel discomfort or pain. For example, Juan might not want a clinician to shake his hands or touch his shoulder or arm during the exam. He may feel very uncomfortable should the clinician touch his back, interpreting mere light touch of the skin of his lower back as painful. Juan might feel irritated by bothersome sensory elements in the examining room, such as blinking, buzzing, and fluorescent lights; bright and shiny colors; pungent and sharp odors; and loud, unexpected, and background noises.17,18 Clinicians can resolve sensory issues by removing unnecessary sensory irritants from the examining room, reducing background noise, or adjusting lighting. Alternatively, they can move the autistic patient to another room. Clinicians will find it easier to examine autistic patients once they feel more comfortable in the absence of sensory irritants.

Clinicians will also want to explain each step of a physical examination to an autistic patient and indicate what needs to happen and why. During a physical exam, explicitly request permission from an autistic patient before performing each task or step. Autistic patients might indicate their approval or disapproval through spoken assent, written agreement, nonverbal cues, or other means.

While performing a physical exam, clinicians will note that autistic patients might experience challenges with motor skills, balance, and Clinicians will find that autistic people often communicate in ways coordination. Clinicians will sometimes find they need to adapt a other than spoken language. Many autistic people use vocalization, physical exam and treatment to ensure autistic patients can perform sign language, and handwritten notes to communicate with other all required tasks. For example, should Juan’s clinician prescribe people. Other autistic people might carry letter boards, picture exercise, she will want to ensure that Juan can perform the prescribed cards, typing devices that speak aloud, and other means to commu- home exercise program. Accordingly, clinicians may need to adjust nicate. Sometimes autistic people switch between multiple forms of home programs by substituting alternative physical activities that communication that they may partially combine with some spoken the patient can do.

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Assistive Tools and Instruments Standardized tools and instruments can help autistic people describe their pain, injuries, and illnesses to clinicians. These tools and instruments include numerical scales, facial scales, cartoon images, and drawings. In a recent study, researchers investigated how autistic youths described pain.19 The researchers compared the autistic youths with a group of nonautistic youths. Both sets of participants completed the Faces Pain Scale-Revised and a Numerical Rating Scale to indicate how they might feel pain in hypothetical situations. Their parents also rated the amount of pain they would expect their children to show. Researchers found no significant differences between ratings for pain among the autistic and nonautistic youths.

Additionally, parental ratings of their children’s responses to feelings of pain aligned with both groups of autistic and nonautistic youths.

While this study shows that some autistic people can use the Faces Pain Scale-Revised, many autistic people can find facial and numerical scales harder to complete than the participants in this study did.

Some autistic people might find it harder to describe real pain than hypothetical pain. Other autistic people who experience significant challenges with language and communication might have difficulties completing pain scales. Thus, the use of these types of instruments to assess pain may work for some autistic patients but not others.

Recognizing these individual differences, clinicians can create profiles that outline the individual differences of their autistic patients to assist pain diagnosis and treatment.20 A personalized pain profile would describe the unique ways in which an autistic patient experiences, feels, and expresses pain. Additionally, the pain profile would also discuss significant considerations in the 4 areas affected by autism, namely: communication, socialization, sensory and motor, and planning and organization. Adopting these pain profiles in their practice, clinicians can improve assessment, treatment, and care of pain for their autistic patients.

General Practice Recommendations Autistic people can often feel “cognitively overloaded” when faced with time-pressured decisions, or complex information to process.

Clinicians can address these issues by allowing time for autistic patients to think and share their responses. Clinicians will find it helpful to break down complex medical information into simpler, concrete chunks that make sense for autistic patients. Rules, guidelines, and rules of thumb can help clinicians to structure and simplify this information. Where feasible and with HIPAA releases, clinicians can contact friends and family members to learn more about autistic patients’ medical condition and health history.

Since many autistic people find auditory processing—translating what they hear into meaningful information—challenging, clinicians might need to present information in writing. Clinicians can provide written instructions that list major “Do” and “Do Not Do” rules by using concrete, concise phrases. Some autistic people think visually or in pictures. For these individuals who think visually,

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written information might carry accompanying visualizations, such as pictures or figures. For follow-up, clinicians can refer autistic patients to websites with supplemental written information and visualizations.

References 1. New Zealand Ministries of Health and Education. New Zealand Autism Spectrum Disorder Guideline. March 2008. Accessed July 30, 2013.

2. Engel-Yeger B, Dunn W. Exploring the relationship between affect and sensory processing patterns in adults. Brit J Occup Ther. 2011;74(10):456–464.

3. Severeijns R, Vlaeyen JWS, van den Hout MA , et al. Pain catastrophizing predicts pain intensity, disability, and psychological distress independent of the level of physical impairment. Clin J Pain. 2001;17(2):165–172.

4. Golnik A, Ireland M, Borowsky IW. Medical homes for children with autism: a physician survey. Pediatrics. 2009;123(3):966–971.

5. Will D, Barnfather J, Lesley M. Self-perceived autism competency of primary care nurse practitioners. J Nurse Pract. 2013;9(6):350–355.

6. Bruder MB, Kerins G, Mazzarella C, et al. Brief report: the medical care of adults with autism spectrum disorders: identifying the needs. J Autism Dev Disord.

2012;42(11):2498-2504.

7. Nicolaidis C, Raymaker D, McDonald K, et al. Comparison of healthcare experiences in autistic and non-autistic adults: a cross-sectional online survey facilitated by an academic-community partnership. J Gen Intern Med. 2013;28(6):761–769.

8. Cascio C, McGlone F, Folger S, et al. Tactile perception in adults with autism: a multidimensional psychophysical study. J Autism Dev Disord. 2008;38:127–137.

9. Alley CS . Pain sensitivity and observer perception of pain in individuals with autistic spectrum disorder. Sci World J. 2013.

10. Nader R, Oberlander TF, Chambers CT, et al. Expression of pain in children with autism. Clin J Pain. 2004;20:88–97.

11. Tordjman S, Anderson GM , Botbol M, et al. Pain reactivity and plasma betaendorphin in children and adolescents with autistic disorder. PLoS One. 2009;4(8):e5289.

12. Bosch J, Van Dyke C, Smith SM , et al. Role of medical conditions in the exacerbation of self-injurious behavior: an exploratory study. Ment Retard. 1997;35(2):124–130.

13. Bronsard G, Botbol M, Tordjman S. Aggression in low functioning children and adolescents with autistic disorder. PLoS One. 2011;5:e14358.

14. Tordjman S, Antoine C, Cohen DJ, et al. [Study of the relationships between self-injurious behavior and pain reactivity in infantile autism]. Encephale.

1999;25(2):122–134.

15. Bursch B, Ingman K, Vitti L, et al. Chronic pain in individuals with previously undiagnosed autistic spectrum disorders. J Pain. 2004;5(5):290–295.

16. Ganz JB, Earles-Vollrath TL , Heath AK , et al. A meta-analysis of single case research studies on aided augmentative and alternative communication systems with individuals with autism spectrum disorders. J Autism Dev Disord. 2012;42(1):60–74.

17. Chang MC , Parham LD, Blanche EI, et al. Autonomic and behavioral responses of children with autism to auditory stimuli. Am J Occup Ther. 2012;66(5):567–576.

18. Leekam SR , Nieto C, Libby SJ, et al. Describing the sensory abnormalities of children and adults with autism. J Autism Dev Disord. 2007;37(5):894–910.

19. Bandstra NF, Johnson SA , Filliter JH, et al. Self-reported and parent-reported pain for common painful events in high-functioning children and adolescents with autism spectrum disorder. Clin J Pain. 2012;28:715–721.

20. Inglese MD. Pain expression in children with autism spectrum disorder ( ASD): a foundation for instrument development [dissertation]. Gainsville, FL: University of Florida; 2008.

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— Oliver Wendell Holmes

ATLANTAGA 4.26 HOUSTONTX 5.10 COLUMBUSOH 5.17 SAN FRANCiSCOCA 6.7 TARRYTOWNNY 6.14 CHiCAGOIL 6.28

…The Mayday Fund

by JOHN

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e e PHD

F. P PPiN DO, FACP/MARTIN D. CH ATL

More than 25% of the US population experiences chronic pain; yet few physicians specialize in the pain medicine field. The undertreatment of pain was recently brought to national attention to encourage both clinicians and patients to advocate for improved pain care. Chronic pain is complex, and effective assessment and treatment requires an interdisciplinary, multimodal approach. This approach is supported by research that demonstrates the lack of efficacy of many of the unimodal interventions, both pharmacologic and nonpharmacologic. From the perspective of the busy clinician, the treatment of chronic pain can be overwhelming. Given the scarcity of trained pain practitioners and the burgeoning number of patients with chronic pain, a new approach is needed that values the complex nature of chronic pain. A model of care that stratifies treatment and patients by level and type of complexity and promotes communication between specialist and primary care providers will be reviewed. abstract:

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KEY TOPIC

he specialty of pain medicine represents a relatively new field. At the inception of this specialty, the need to effectively treat those patients with chronic pain was great and remains imperative. Prior to pain medicine becoming a neoteric field, pain management was not considered an appropriate treatment goal; rather, chronic pain was considered something the patient had to “learn to live with.” The early “pain community” was concerned with educating physicians and other healthcare professionals (HCPs) about the importance of treating pain, both acute and chronic and at end-of-life. Initially, notions of treatment were simplistic.1 Pharmacotherapy, and especially opioids, became a focus for multiple reasons including the potential broad use for a variety of chronic pain conditions and the influx of research funding from the pharmaceutical industry. Just one illustration of this point is seen in Table 1. A search of PubMed reveals a distinct bias towards the search term “opioid” rather than other treatment modalities. Unfortunately, this unidimensional approach has failed to sufficiently demonstrate long-term efficacy.2,3 There is a clear mandate to provide care to this growing patient This article will partially review the current approach to the treatpopulation of more than 100 million persons suffering from ment of patients with chronic pain and outline a novel model, termed chronic or recurrent pain in the United States. In reality there are “The Complexity Model,” which emphasizes patient stratification not enough trained physicians with the knowledge base to manage and facilitation of an ongoing collaboration between pain specialist this burgeoning patient population.4-6 Because of this shortage, and the PCP. The proposed stratification tool is designed to guide primary care physicians ( PCPs) have, by default, filled a “surrogate” patient selection, triage, and treatment. The methods utilized in role as pain physicians.7 Increasing the involvement of PCPs in developing this tool were similar to that employed in the developthe treatment of chronic pain was born out of necessity and has ment of the Opioid Risk Tool (ORT ).13 The goal of this model is to focused on the appropriate and safe use of opioids.8 Programs for promote a more thorough evaluation of these complex chronic pain PCPs were developed to provide additional training in the principles patients, leading to better treatment regimens and outcomes while of pain management.9,10 However, chronic pain is a dynamic, not burdening the PCP with having to sort out all the complexities multidimensional phenomenon that requires physicians, and other involved in treating chronic pain patients. Further research will be healthcare professionals, to develop an arsenal of interventions, not required to validate this model. just one approach (pharmacotherapy, injections, etc) to promote and maintain improvement.

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Providing the already beleaguered PCP with nominal training in pain medicine will not in itself improve care to the countless numbers Medicine, in its current paradigm, approaches a problem linearly. of undertreated complex pain patients. A new approach is needed to Ockham of Orange14 developed a theory of how data and observations effectively and efficiently assess and stratify patients by need: com- could be taken into account with a single overriding theory, labeled plicated cases require the expertise of a pain medicine specialist; “Ockham’s Razor.” The traditional approach is to examine each indiless complex cases can be managed by the PCP with pain specialist vidual problem by itself and apply the linear approach by rendering a support; and other cases may be easily managed by PCPs.11,12 diagnosis followed by a specific treatment plan, thus adhering to the

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principles of Ockham’s Razor. Most medical professionals may be The complexity model for evaluation and treatment decision-making unfamiliar or uncomfortable in attempting to incorporate a number takes into account the multitude of factors that must be considered to of different symptoms, disease states, medications, and more into a maximize the potential for a positive outcome. This model employs single, complex, multimodal approach. The linear approach may be an intricate stratification process that reflects the complicated nature suitable in treating an acute process such as an inflamed appendix, of chronic pain. Patients with chronic pain should be evaluated and but the medical community has been less than effective when man- stratified based on the criteria listed in the Box. aging complex, chronic diseases, especially chronic pain. According to the Mayday Fund, “Historically, the healthcare system has failed to recognize chronic pain as a legitimate condition. However, it is Box Criteria Used in Evaluation and Stratification of Chronic Pain clear that persistent pain is a complex illness that has many causes and affects every part of life, and in the process, exacts enormous social costs.”15 Unfortunately, changing paradigms in science and academic thinking is not an easy task.16 Medical comorbidities Complexity can be defined as “a system in which large networks of components with no central control and simple rules of operation give rise to complex collective behavior, sophisticated information processing, and adaptation via learning or evolution.”17 It is that “behavior” that we are treating in the chronic pain patient. Further complexity clearly relates to chronic disease, as Johnson states, “…the most lethal diseases have managed to tap into the heart of what makes a complex system so difficult to predict, manage and control—thereby outsmarting the body’s sophisticated, but ultimately limited, defense mechanisms.”18

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TH OPiOiD-FOCUS D MOD L Opioids have, for millennia, provided relief from suffering for patients with pain of cancer and noncancer origin.a Opioids have increasingly become the focus both in the media and in published articles on the treatment of pain. This emphasis on opioid therapy has resulted in a number of issues, including the unidimensional, linear approach to chronic pain; influence from the pharmaceutical industry; and the use of the cancer/end-of-life opioid model in those with pain of noncancer origin. With all the other potential pharmacologic and nonpharmacologic interventions available to treat pain, the overemphasis on opioids has led to an increase in opioid prescribing and presents distinct medical, societal, and psychosocial problems.

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A N W MOD L OF CHRONiC PAiN TR ATM NT STRATiFiCATiON A comprehensive biopsychosocial approach to evaluation and treatment decision-making seems intuitive in dealing with a complex pain patient, but such an approach is often not used. The focused approach is one of physician convenience and training and not necessarily one of proper treatment and evaluation. Barriers to the biopsychosocial approach will continue; for example, reimbursement for the increased time involved, training physicians in the traditional biomedical philosophy, patients’ resistance to a more expansive evaluation that includes psychosocial assessments. Regardless, this approach has been demonstrated to be clinically and economically efficacious for a variety of pain conditions.19-22 Q4 | 2013

Other concomitant symptoms (other than insomnia)

Psychiatric and psychological comorbidities Risk for medication abuse and diversion Number of chronic pain problems Number of past surgeries Tobacco usage Head trauma history Weight/body mass index Sleep disorders Goal setting Educational level and employment status Current pharmacotherapy regimen Coping skills and social support Physical conditioning Current pain level

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KEY TOPIC

The criteria are not listed in order of importance since all need to be evaluated for each specific chronic pain patient. In this model, each of these criteria have been arbitrarily and intuitively given numerical weight. They will then be applied to an individual patient and a score obtained. The total scores have been divided into 4 categories—minimal, low, moderate, and high complexity.

Table 2 consolidates the above information into a scoring form that allows quick summation of the complexity score and a ranking that will help with further treatment and follow-up schedules.

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This new model must of necessity start with a complete patient history and physical. This is critical because it is the baseline evaluation that determines treatment selection and level of monitoring. Patients and their environment are dynamic, and the complexity of their situation will change over time, but the initial evaluation gives the PCP or pain medicine specialist a starting point for successful treatments.

Good documentation is critical with the goal to:

Once the pain specialist and PCP have completed the initial evaluation, determined diagnoses, and outlined a treatment plan, the PCP can monitor the patient, especially if the patient is in the minimal or low complexity stratification groups. Those in the high complexity and some moderate groups may require more frequent follow-up visits with a pain specialist; however, even in these groups, once the comorbidities are diagnosed and treated and the pain is controlled, the PCP may be able to monitor and manage the treatment regimen.

Table 1. Brief Keyword Search of PubMed Looking for Numbers of Articles on Pain* Keywords

No. of Articles

opioids

88,692

opioids + pain

26,728

narcotics + pain

19,735

NSAIDs + pain

15,163

anti-inflammatory + pain

13,209

steroids + pain

11,336

antidepressants + pain

4,392

›› Outline the patient’s pain problems, comorbidities, support system

benzodiazepines + pain

2,355

›› Clearly communicate with the patient’s PCP

muscle relaxants + pain

815

TCA s + pain

94

›› Establish working diagnoses ›› Outline a clear treatment approach ›› Establish the patient’s goals

›› Provide appropriate documentation for reimbursement

Since pain patients oftentimes experience co-occurring mood disor* Search performed November 2012 by KK . ders and can engage in poor pain coping skills such as catastrophizNSAIDs = nonsteroidal anti-inflammatory drugs; TCAs = tricyclic antidepressants ing, a clinical psychologist with expertise in chronic pain can be an essential and invaluable resource. Physical therapy assessment and cotreatment can be helpful in restoring a patient’s mobility, endur- Treatment could be a combination of pharmacologic therapies, ance, and self-efficacy—all leading to improved pain, mood, and interventions (eg, injections, radiofrequency ablation, spinal cord functionality. This interdisciplinary approach is the optimal way to stimulation), physical therapy, cognitive behavioral therapy, and/or treat chronic pain patients. integrative/complimentary therapies. The pharmacologic therapies should be broad and include adjuvants such as antiepileptics, muscle The pain medicine specialist should be a true consultant. Each relaxants, serotonin–norepinephrine reuptake inhibitors, selective patient would be referred, and each should have a PCP. The com- serotonin reuptake inhibitors, tricyclic antidepressants, and other plexity model can only work for managing the most involved cases medications. Opioids are one option and should be used within when there is close cooperation and communication with the PCP. the confines of the risks and complexity stratifications described.

The patient needs to be stratified into the various complexity cat- “Cookie-cutter” approaches are inappropriate for chronic pain egories, have comorbidities assessed, and have an initial treatment patients; rather, an attempt should be made to use all the potential regimen defined. These steps can be performed by the PCP or pain modalities and therapies available in a logical approach that is based medicine specialist depending on the confidence levels of all involved on consensus-based guidelines, when available. clinicians. The PCP can then implement and monitor the treatment regimen, with continued input from the pain medicine specialist as This model is also designed to be a tool for collaboration and improved needed and defined by the complexity category. communication between the pain specialist and the PCP. Although

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OV RSiGHT iNCLUD S FOLLOW-UP TO NSUR T STiNG AND R F RRALS AR MAD AND COMPL T D, PAST R CORDS AR OBTAiN D FOR R Vi W, PHARMACOTH RAPY R GiM NS AR ADH R D TO, AND TR ATM NT GOALS AR ACHi V D OR R ViS D.

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low and some moderately complex patients may be treated with less effort, it is the moderate and high complexity groups that present the greatest challenges. These patients may need to be followed by the pain specialist regularly until comorbidities are diagnosed and treated and their pain and comorbidities are better controlled.

Since there are so many facets involved in managing and coordinating the care of these patients, a “case manager” should be involved to oversee each individual patient’s treatment plan and ensure that consultations, referrals, past records, and testing were obtained or completed. In addition, oversight of the process is needed and can be accomplished by collaboration with a psychologist, pharmacist, or other HCP.

intervention and not necessarily evidence-based. It does not reward or encourage the intellectual effort required for performing an evaluation that may take 90 minutes. If the objective is to improve pain management outcomes and reduce the personal suffering and economic burden of poorly managed pain, the current reimbursement system for cognitive medicine needs to change.4 In addition, interdisciplinary pain programs have been disappearing; only a few such programs continue to function.22 One reason for this reduction is not the paucity of evidence supporting efficacy but the lack of financial support from third-party payers. Data suggest that these programs can offer healthcare dollar savings.23

CONCLUSiON

It is interesting to note that our model does not change the linear approach to medicine. That change needs to come from the bottom The proposed model should be used to stratify patients and to ensure up, and medical schools need to be held accountable for a better that treatment is personalized to the needs of an individual patient— approach to chronic disease management. However, our model coor- including their specific medical and psychological problems. The dinates the linear and individual modalities into a more “holistic” pain medicine specialist needs to work collaboratively with the PCP to stratify the patient and send back recommendations based on that treatment pattern. stratification. For this model to function appropriately, oversight is Necessary Systemic Changes required. That oversight includes follow-up to ensure testing and referrals are made and completed, past records are obtained for Multiple barriers to the implementation of this model include: review, pharmacotherapy regimens are adhered to, and treatment goals are achieved or revised. The patient must begin to accept more ›› Receiving appropriate reimbursement for these types responsibility for his or her treatment and improvement. The pasof evaluations sive approach that a vast majority of patients take—that is, “fix me doctor”—must be resisted. A “pain school” should be developed in a ›› Recognition and institutional support for interdisciplinary group setting.b Psychology is best equipped to lead and develop such approaches a school. The patient would be required to attend on a continuous basis. The school would include information on pain, diet, weight ›› Acceptance of pain medicine specialists in the complexity model loss, exercise, improving pain coping skills, and smoking cessation.

The accountability would function similar to that seen in Alcoholics ›› Design and implementation of research to validate this approach Anonymous and Weight Watchers. and determine which components are effective or ineffective Although a complicated approach to pain management, it is no less The time required for these types of evaluations can be lengthy than these patients deserve. The best model currently extant is the depending on the complexity of the presenting patient and expertise interdisciplinary clinic. A recent analysis has shown that this model of the clinician involved. This time must be reimbursed appropriately. “offers the most efficacious and cost-effective treatment for persons Our current reimbursement system is focused on procedure and with chronic pain.”24 Q4 | 2013

www.painweek.org | PWJ | 37

38 | PWJ | www.painweek.org

No comorbidities

None

None

None

None

None

Normal

None

Low risk (ORT score, 0–3)

None

Single pain complaint

Clear and achievable goals

College or higher

Working, retired, or full-time student

None

Supportive family, close relationships; involved in work or school and no social isolation

Scheduled and regular exercise

None

Medical Comorbidity

Comorbid Symptoms (other than insomnia)

Number of Surgeries

Tobacco Use

Psychiatric Comorbidities

Head Trauma/ Traumatic Brain Injury/ Loss of Consciousness

Weight (body mass index)

Sleep

Opioid Risk Tool (ORT)

Risk for Addiction, Substance Dependency

Number of Chronic Pain Problems

Goals

Education Level

Employment

Current Medications

Social Support

Physical Conditioning

Pain Level

Total Score:

0

Category Moderate disease: heart disease, chronic, mild to moderate COPD

2

1–2

Intermittent exercise or low level

Reduction in some relationships and life roles

<5

Not working

Completed high school only

Clear but unachievable goals

Main pain complaint (MPC ) plus 1 other pain complaint (other than headaches or myofascial pains)

Catastrophizing, chemical coping

Medium risk (ORT score, 4–7)

Mild insomnia

10% above normal

1 incidences

Adjustment disorder

< 1 pack per day

1 surgery

3–5

Walks occasionally outside of house; gardens

Chaotic, little family support and few close relationships; loss of most normal life roles

5–10

Disabled

Did not enter or finish high school

Unrealistic goals

MPC plus > 1 other pain complaint (other than headaches or myofascial pains)

Past history of addiction, not active

High risk (ORT score, ≥ 8)

Moderate insomnia > 1 year

> 30 above normal

≥ 2 incidences

Major depression without anxiety features

> 1 pack per day

2–4 surgeries

Single concomitant symptom: Two concomitant symptoms eg, nausea or diarrhea

Mild chronic disease: hypertension

1

6–8

Chair bound, little activity

> 10

MPC plus transformed and chronic migraines, chronic headaches

Active drug addiction

Severe insomnia > 2 years

Major depression with anxiety features or comorbidity

≥ 5 surgeries

Multiple symptoms or symptom clusters

Moderate to severe disease: chronic disease, such as diabetes, rheumatoid arthritis, chronic kidney disease

3

Table 2. Complexity Model Screening Tool

8–10

Bed bound, inactive

MPC plus fibromyalgia or multiple chronic myofascial pain syndromes, and headaches or other pain complaint

Sleep apnea, obstructive or central, treated

Severe psychiatric disease: eg, schizophrenia, bipolar disorder

Severe disease: postbypass surgery, poorly controlled diabetes, more severe COPD, cancer, malnutrition

4

8–10

MPC plus fibromyalgia, migraines, multiple other pain complaints

Untreated or treatmentintolerant sleep apnea

Very severe disease: end-stage renal/ liver disease, severe or end-stage cancer, end-stage COPD or heart disease

5

Score

KEY TOPIC

Q4 | 2013

Concerns that this approach is too time consuming, is poorly reimbursed, or that pain medicine specialists haven’t been trained in this type of evaluation may be valid in the current system. However, if we are to meet the challenges set forth in the recent Institute of Medicine report, Relieving Pain in America, we must advocate for changing the current approach to training pain specialists, reimbursement, and evaluation and treatment of chronic pain patients.4 From a practical perspective, a thorough evaluation at the first visit would save time at subsequent visits. Medication interactions would be reduced, interfering treatments or redundant treatments would be decreased, and the patient’s comorbidities would be addressed—all of which could save healthcare resources.

In the current atmosphere of “healthcare reform,” greater concern should be felt by pain medicine physicians since there is some speculation that reimbursement will be dependent on outcomes and patient satisfaction. The interdisciplinary approach to chronic pain is the most efficient and efficacious, and we must work to protect this critical asset for our patients. A piecemeal approach will be ineffective and costly to patients, society, and eventually to practitioners.

References 1. Pappagallo M. Aggressive pharmacologic treatment of pain. Rheum Dis Clin North Am. 1999;25(1):193–213.

2. Noble M, Treadwell JR , Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD 006605.

3. Staal JB, de Bie R, de Vet HC , et al. Injection therapy for subacute and chronic low-back pain. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD 001824.

4. Gureje O, Von Korff M, Simon GE, et al. Persistent pain and well-being: a World Health Organization study in primary care. JAMA. 1998;280(2):147–151.

5. Breuer B, Pappagallo M, Tai JY, et al. US board-certified pain physicians practices: uniformity and census data of their locations. J Pain. 2007;8(3):244–250.

6. Parris W. Challenges and issues in pain management and anesthesiology.

Executive Healthcare Magazine. Issue 5. http://www.executivehm.com/article/ Issue-5/Patient-Care-AND -Orthopedics/Challenges-and-Issues-in-Pain-Management-and-Anesthesiology/. Accessed November 21, 2012.

14. Ockham W. Philosophical Writings: A Selection. Rev ed. Indianapolis, IN: Hackett Publishing; 1990.

15. The Mayday Fund. A Call to Revolutionize Chronic Pain Care in America: An Opportunity in Health Care Reform. http://www.painmed.org/files/mayday-report. pdf. Published November 4, 2009. Accessed December 4, 2012.

16. Kuhn T. Structures of Scientific Revolution. Chicago, IL: University of Chicago Press; 1970.

17. Mitchell M. Complexity: A Guided Tour. New York, NY: Oxford University Press; 2009.

18. Johnson NF. Simple Complexity: A Clear Guide to Complexity Theory. Oxford: Oneworld Publications; 2009.

19. Lamb SE, Hansen Z, Lall R, et al; for the Back Skills Training Trial Investigators. Group cognitive behavioural treatment for low-back pain in primary care: a randomised controlled trial and cost-effectiveness analysis. Lancet.

2010;375(9718):916–923.

20. Linton SJ, Nordin E. A 5-year follow-up evaluation of the health and economic consequences of an early cognitive behavioral intervention for back pain: a randomized, controlled trial. Spine (Phila Pa 1976). 2006;31(8):853–858.

21. Thieme K, Flor H, Turk D. Psychological pain treatment in fibromyalgia syndrome: efficacy of operant behavioral and cognitive behavioral treatments. Arthritis Res Ther.

2006;8(4):R121.

22. Turner JA , Manci L, Aaron LA . Short- and long-term efficacy of brief cognitive-behavioral therapy for patients with chronic temporomandibular disorder pain: a randomized, controlled trial. Pain. 2006;121(3):181–194.

23. Noe C, Williams CF. The benefits of interdisciplinary pain management. J Fam Pract. 2012;61(4 suppl):S12–S16.

24. Turk DC . Clinical effectiveness and cost-effectiveness of treatments for patients with chronic pain. Clin J Pain. 2002;18(6):355–365.

Endnotes a. The physiology of pain, whether neuropathic or inflammatory, is consistent regardless of the disease setting. Therefore, the terms “pain of cancer origin” or “pain of noncancer origin” reflect the chronic though similar nature of pain regardless of cause. They are, in these authors’ opinions, a better choice of words than “cancer pain” or “noncancer pain.” b. The concept of “pain school” was originally proposed to the authors by Steven D. Passik, PhD.

7. Cole BE . Resources for education on pain and its management: a practitioner’s compendium. Curr Pain Headache Rep. 2009;13(2):110–119.

8. Wiedemer NL , Harden PS, Arndt IO, et al. The opioid renewal clinic: a primary care, managed approach to opioid therapy in chronic pain patients at risk for substance abuse. Pain Med. 2007;8(7):573–584.

9. Harris JM Jr, Elliott TE, Davis BE, et al. Educating generalist physicians about chronic pain: live experts and online education can provide durable benefits. Pain Med. 2008;9(5):555–563.

10. Bope ET, Douglass AB, Gibovsky A, et al. Pain management by the family physician: the family practice pain education project. J Am Board Fam Pract.

2004;17(suppl):S1–S12.

11. Upshur CC , Luckmann RS, Savageau JA . Primary care provider concerns about management of chronic pain in community clinic populations. J Gen Intern Med. 2006;21(6):652–655.

12. O’Rorke JE, Chen I, Genao I, et al. Physicians’ comfort in caring for patients with chronic nonmalignant pain. Am J Med Sci. 2007;333(2):93–100.

13. Webster LR , Webster RM . Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool. Pain Med. 2005;6(6):432–442.

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by TED

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JON S PHD, CPE/DARREN McCOY FNP- BC

abstract: Clinicians who treat patients for pain receive a good deal of information about urine drug screens, including when to obtain them, how to obtain them, and the chemistry of expected metabolites. However, we believe there is a dearth of information on how to react clinically to inappropriate urine drug test (UDT) results.

Clinicians are faced with important decisions about patient treatment when inappropriate results are obtained. In this article, we present a clinical guide consisting of 10 questions that clinicians should ask themselves when presented with an inappropriate UDT result. These questions encourage clinicians to thoughtfully and rationally consider various aspects of patient care, including the decision of whether to discontinue opioids for a given patient. The answers to these questions will lead clinicians towards making treatment decisions for and with their patients that will result in improved care.

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MAGiN

room, looking at a urine drug test (UDT) report clipped to the front of a chart. The test specimen was submitted the previous month from a patient who is now sitting in a room, waiting to be seen, and expecting to receive another prescription for an opioid medication. The patient claimed to have taken nothing prior to the test other than the hydrocodone the clinician had prescribed for him. However, the test report indicates not only was there hydrocodone in the urine, but also a low concentration of THC. What should the clinician do?

Many clinicians who prescribe opioid medications have already experienced this scenario. Several states (including the authors’ state of Tennessee) mandate that clinicians who prescribe opioids perform drug testing on patients at some minimum fixed interval, with the option available for clinicians to test more frequently. UDTs are the most common method of drug testing, for multiple reasons: UDTs are simple and safe to collect, process, and dispose; UDTs Q4 | 2013

are commonly covered by insurance plans; and UDTs can provide information on exposure to licit or illicit substances during time frames from within a few hours to a few weeks prior to collection.

Companies that market UDTs have provided funds for research, placed advertisements in professional journals, and otherwise represent their products and services in a highly competitive industry. www.painweek.org | PWJ | 41

PAIN&CHEMICAL DEPENDENCY

These companies also produce publications and posters to help clinicians better understand the metabolism of drugs in order to make UDTs easier to understand. The overwhelming focus of these publications has been on administration and interpretation, in terms of why clinicians should be able to trust the accuracy of UDTs. That is, UDT companies want clinicians to believe the data. They make the point that millions of specimens have been processed, and the chemicals and machinery have been repeatedly calibrated and “certified,” so the data are trustworthy.

for opioids will reveal a positive result if enough of certain opioid molecules have been excreted into the urine for the concentration to reach a certain threshold, such as 300 ng/mL. The cutoff levels on IA tests have been set high enough to minimize the likelihood of false-positive results from events like poppy seed consumption (in the case of opioid detection), the use of over-the-counter decongestants (in the case of amphetamine detection), or from passive exposure to marijuana smoke or the use of pantoprazole (in the case of THC detection).

By comparison, there has been a dearth of practical and sound advice for clinicians on how to clinically deal with a UDT once it has been deemed to be inappropriate. Is a “3-strikes-and-you’re-out” policy reasonable? How about 2 strikes? How about 1? Is it reasonable for a clinician to stop prescribing opioids, but continue to offer other modes of treatment to a patient? Should a UDT that tests positive for cocaine be treated differently from a UDT that tests positive for THC? What if a clinician is practicing in a state that has legalized recreational or medicinal use of marijuana? These are critical clinical questions, and the recent literature on UDTs fails to address such questions in a productive manner.

Depending on the reagents used in a given test, IA tests may fail to clarify the presence of the more highly synthetic opioids such as tramadol, tapentadol, fentanyl, or methadone. IA tests also fail to reveal various metabolites that may help give better clues as to the use pattern of a certain chemical. GCMS/ LCMS is able to overcome some of the limitations of IA , but it does so at the expense of additional time and money. Many clinicians use IA for initial testing before sending specimens out for GCMS/ LCMS testing to confirm a finding (either positive or negative) because IA cannot reveal which opioid has been consumed. For example, a positive opiate test result by IA cannot differentiate between a patient’s prescribed morphine, consumption of a codeine-containing cough syrup, or consumption of heroin.

This article presents guidelines to help clinicians make decisions about how to address and deal with inappropriate UDT findings when treating chronic pain patients. These guidelines are based on strategies implemented in a large multidisciplinary pain clinic located in a geographic area notorious for prescription medication misuse and abuse. The authors’ goal is to help reduce medication misuse and abuse while ensuring that opioid medications remain available for those patients who benefit from these medications.

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IS TH UDT FiNDiNG CORR CT AND TRULY iNCONSiST NT WiTH WHAT HAS B N PR SCRiB D? The two most common forms of UDT used in medical practices for purposes of adherence monitoring are immunoassay ( IA) and gas or liquid chromatography and mass spectroscopy (GCMS/ LCMS).

Each has substantial benefits. IA can be performed as a point-of-care test, allowing a prescriber to get an overview of the clinical situation within just a few minutes after urine collection. All IA can provide is a qualitative result on a given class of chemicals. For example, a test

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GCMS/ LCMS is a far more sensitive and specific testing method than IA , which can pose an issue for the prescriber in terms of what to do with results. The routine use of oral morphine frequently produces a concurrent finding on a GCMS/ LCMS test of a relatively low concentration of hydromorphone (eg, a concentration of >2000 ng/mL of morphine, and 150 ng/mL of hydromorphone). Does this mean the patient took hydromorphone? Not necessarily. Rather, it may be the result of the sensitivity of the test, as well as the fact that a certain percentage of patients partially metabolize morphine to hydromorphone.

Clinicians should be aware that some opioid consumption may produce unusual metabolites, particularly at high doses. For example, high doses of morphine can result in positive findings for hydromorphone as well as codeine. Also, high doses of oxymorphone can result in positive findings for oxycodone due to impurities in the manufacturing process. A UDT may reveal ethanol following recent consumption but may also be the result of fermentation of a diabetic patient’s early morning, glucose laden specimen.

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…TH R HAS B N A D ARTH OF PRACTiCAL AND SOUND ADViC FOR CLiNiCiANS ON HOW TO CLiNiCALLY D AL WiTH A UDT ONC iT HAS B N D M D TO B iNAPPROPRiAT .

42 | PWJ | www.painweek.org

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The key to accurately interpreting a UDT finding is having a good relationship with the confirmation lab’s clinical toxicology staff. It is common for a given UDT company to market itself in terms of the ready availability of that laboratory’s clinical toxicology staff to answer questions for clinicians. A clinical toxicologist at a UDT laboratory should be able to give the clinician a good idea of whether a concentration is consistent with what is known in the toxicology literature, as well as whether or not a given finding is truly abnormal.

2

been positive for THC . While individuals vary, the usual toxic dose of cocaine is lower than it is for THC . It is more lethal and medically dangerous than THC . While this does not mean THC is okay (see below for other considerations), the relative danger of use of various illicit substances should be considered. The more medically dangerous or risky the behavior, the more quickly the clinician should discontinue opioid treatment.

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DO S TH UDT FiNDiNG R FL CT A M DiCALLY DANG ROUS B HAViOR? Not everything that is legal should be considered a good idea. Combining alcohol with opioids increases the risk of an adverse event such as overdose, and the risk is even higher when opioids and alcohol are combined with benzodiazepines. Imagine a clinician has prescribed hydrocodone 10 mg up to twice daily on an as-needed basis for a woman with an arthritic knee. She comes to the office, does not seem at all impaired, but appears rather uncomfortable. She tells the clinician that she danced at her son’s wedding the previous night. She admits she had a couple of glasses of champagne with the wedding dinner and was not hurting enough at bedtime to take any hydrocodone, but awoke with agonizing pain in the early morning hours at which time she took a dose of her prescribed medication.

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DO S TH UDT FiNDiNG R FL CT iLL GAL B HAViOR? Medical danger aside, there is an issue of whether or not a behavior is illegal. Consider a UDT finding that is positive for an opioid for which the patient has not received a prescription. The authors think there is a difference between a patient obtaining an opioid illegally from the street or a family member vs obtaining it from another practitioner, prescribed in the usual course of medical practice, for a separate and different pain condition. An example is the difference between a patient buying hydrocodone from a relative as compared to obtaining hydrocodone from the emergency department after a fall and severe sprain or fracture. The latter behavior is not a matter of a patient going to multiple providers to obtain opioids for the same pain disorder (doctor shopping) but a patient who violates the medication agreement by obtaining another opioid for a separate, temporary condition without notifying the original prescriber. The difference can often be checked through the use of state prescription monitoring databases (available in most states, and required to be checked in some states). Checking the database and finding that the patient filled an opioid prescription from another clinician (say, obtaining codeine from a dentist after a tooth extraction) can, in our opinion, be treated differently than when the patient did not obtain the opioid legally.

The clinician counsels the woman to rest the knee, use conservative measures such as a cold pack, and continue her medication unchanged. When her UDT results come back from the lab confirming the presence of hydrocodone, hydromorphone, and ethyl glucuronide (a metabolite of ethanol), the clinician need not waste time worrying that the patient has done anything substantially wrong.

She still needs education, though, on the relative risks of combining prescribed and nonprescribed CNS depressants. Likely, her opioids There is also a continuum of illegal behavior—while obtaining can be continued. an opioid from a family member is still illegal, obtaining an opioid from a purchase on the street from a nonfamily member shows a Though the example above represents something of an ideal situation higher level of disregard for social norms, not to mention the opioid in terms of explanation of an otherwise troubling UDT, clinicians treatment agreement. A patient buying medication on the street is will eventually be confronted with UDTs indicative of more med- engaging in clearly illegal behavior and shows more risk of future ically dangerous behavior. A specimen may contain an opioid that nonadherence to the treatment agreement. While it is not always has been prescribed, and expected to be found, but also may contain clear how the patient truly did obtain an opioid, these factors might an unexpected tranquilizing medication like carisoprodol or a ben- be reported by the patient and should be taken into consideration. zodiazepine. In other cases, questions about an unexpected test may The more clearly illegal the behavior, the more quickly the clinician result in the patient claiming to have “forgotten” to tell the clinician should discontinue opioid treatment. about a prescription for an opioid from a dentist the week before the The authors have heard many practitioners ask how to handle UDTs clinician ordered a UDT. positive for THC, indicative of marijuana consumption. As of this Imagine a patient’s IA test indicates the presence of cocaine. The writing, the President and the United States Attorney General have clinician sends the result out for GCMS/ LCMS and it reveals ben- made it clear that arresting and prosecuting individuals for marijuana zoylecgonine (confirming the actual intake of cocaine, not a false use is not a priority for the Department of Justice. Some states have positive). The patient has not had any recent exposure to cocaine gone so far as to pass legislation allowing recreational use of marijuana. by way of nasopharyngeal surgery, so this genuinely represents an However, also as of this writing, marijuana remains a Schedule I conillicit use of cocaine. Should the clinician give the patient a second trolled substance in the United States. The federal Drug Enforcement chance, or stop prescribing opioids for that patient? Even though Agency is the regulatory entity that gives prescribers the legal authorillicit substance use by a patient is never a desirable behavior, illicit ity to prescribe certain controlled substances. Thus, if a clinician is cocaine use indicates more serious risk-taking than if the test had prescribing legal controlled substances for a patient, and knows that Q4 | 2013

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PAIN&CHEMICAL DEPENDENCY

patient is actively using illegal controlled substances, that clinician is putting his or her ability to prescribe at risk, no matter how innocuous or socially accepted the marijuana use might be in a given part of the country. A positive finding for THC should never be ignored with the thinking “it’s okay” or “it’s legal here.” Practitioners should also not try to circumvent this issue by deferring testing for THC in their UDTs. Legal and regulatory bodies see this as abdicating one’s responsibility and sanctioning THC use among one’s patients. To not test for THC is at least as bad as ignoring a positive finding for THC.

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Good clinical education will, in the authors’ experience, reduce the rate of aberrant behavior in a clinical practice. Good education of patients about their treatment agreement is preferred to simply discharging a large number of patients from care after medication aberrant behavior. Good education on the front end helps staff know how to handle future aberrant behavior. The more a clinician is convinced the patient knew better—was truly educated—the more strongly the clinician is justified in making substantial changes to the treatment plan. If the patient was educated about the treatment agreement and chose to disregard it anyway, a referral for a substance abuse evaluation may be in order. Other possible changes to the treatment plan are discussed more fully under Question #8.

DiD (OR SHOULD) TH PATi NT KNOW B TT R, BAS D ON TH DUCATiON PROViD D? With regard to written treatment agreements, the decision about This question is one that can keep a clinician awake at night, strug- whether or not to continue treatment may actually be out of the pregling with whether or not to discontinue treatment of a patient the scriber’s control, depending on legislation on a state-by-state basis. In clinician may have grown to appreciate over months, years, or decades the authors’ state of Tennessee, workman’s compensation insurance of treatment. Before making a decision to discontinue opioid therapy may arrange for an injured worker to attend a pain management spebased on a UDT result, a clinician must be realistic about how good cialty clinic. If the injured worker receives opioid medication under the initial patient education process was for that individual patient. a written treatment agreement with a pain clinic and violates that written agreement on two occasions (whether an inappropriate UDT For example, was the treatment agreement to prescribe opioids or inappropriate pill count, or failure to follow the recommended simply a handshake and a verbal commitment “in good faith,” or was treatment plan, etc), pain management services are terminated even if there some sort of standardized written agreement between clinician the clinician is willing to continue to treat that patient. This situation and patient? Whether written or verbal, how does the clinician know means good patient education is even more important. the patient really understood the details of the agreement? Does the patient have a learning disability or handicap that could make it more difficult to grasp the details of the agreement, or does the clinician 5 simply assume or hope the patient knew better? Did the clinician DO S TH UDT FiNDiNG R FL CT A PATi NT TAKiNG A tell the patient how to handle ER visits, dental emergencies, getting SUBSTANC FOR PAiN, OR FOR SOM OTH R R ASON? stranded with a flat tire on the way to an appointment, or other A man who has routinely used a 100 mcg/hour fentanyl patch for such urgent/emergent situations, or was that information buried in chronic back pain will likely feel compelled to self-adjust and run out a multi-page treatment agreement? Did the clinician actually advise early if he is given only a 5 mg hydrocodone tablet to take twice daily the patient where to store medication? If the patient exhibited some for postoperative pain following a knee replacement. Some clinicians aberrant behavior previously (eg, discharged from a prior practice would be quick to label such a man as “pill seeking” or “addicted” if for smoking marijuana), did the clinician counsel the patient about he called for an early refill or had a UDT devoid of the prescribed how that behavior, in particular, was unacceptable? medication. The term “pseudo-addiction” has been used in the pain management community for over a decade in an attempt to justify The authors have observed the following method of education about behavior when patients self-adjust. While pseudo-addiction is a nona treatment agreement in multiple pain treatment practices. In many empirical term, the fact remains that some patients have pain that is cases, when the initial prescription for an opioid is written, a secre- inadequately treated. In such cases, there is no prima facie evidence tary or other nonprescribing staff member hands a multi-page treat- that the patient is exhibiting evidence of a substance abuse disorder. ment agreement to the patient with the instructions “Read this, and Rather, it may simply mean the prescriber did not take that patient’s initial the places I’ve highlighted.” Such instruction may or may not individual opioid tolerance into account in prescribing appropriate be followed with “Ask me if you have any questions.” This may actu- postoperative pain medication. ally be the norm for the pain treatment community. Unfortunately, this is not patient education—this is really only obtaining a patient’s While behavior may be simple to assess with UDT, the intent behind signature on a treatment agreement. If clinicians want to decrease that behavior is typically more difficult to glean. Sometimes, the cliadverse events and discontinuation of opioids for violations of treat- nician will be asked to believe the believable. For instance, consider ment agreements, then clinicians need to do a better job of patient a situation in which an elderly woman receives a prescription for education on the front end. Individual or group education sessions time-release morphine 30 mg every 12 hours. Her UDT reveals no in which the treatment agreement is reviewed should become the morphine. She tells the clinician that she took her last dose 4 days norm in the pain treatment community. While this may be expen- prior to the UDT (ie, is 8 tablets “short,” based on the prescribed sive in terms of staff time, clinicians must nonetheless develop and quantity). On questioning, she admits taking an extra dose “on really implement more effective methods of educating patients so there are bad days.” While the clinician cannot really know anything other than that the UDT was devoid of morphine, the rapport with the fewer inappropriate UDTs and adverse events.

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patient may lead the clinician to conclude that the woman is telling the truth and did self-adjust her medication. It does not excuse the behavior, but it at least explains the UDT finding within the scope of reason.

A continuum of relative risk is a useful consideration in this instance.

It is one thing if the woman said she took an extra dose at midday (ie, a 50% increase in her prescribed daily dose) on 8 separate days, compared to if she admitted to doubling the dose of her medication for a few days. Other health issues such as renal insufficiency or sleep apnea might make the double dose potentially lethal, whereas the occasional extra dose would be less likely to be fatal. The clinician should keep these things in mind while deciding whether to trust such a patient with a different oral medication, a transdermal medication, or opioid medication at all.

Other times, the clinician will be asked to believe the unbelievable.

A man may tell his clinician that he has smoked marijuana routinely not to “get high,” but to relieve chronic nausea caused by his antiretroviral medications for HIV. The clinician might believe that claim if

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have substituted oxycodone for the morphine in my bottle.” Whatever the clinician’s personal opinion is with regard to a patient’s explanation, the clinician must consider what others would think as well. It may be that the clinician is called to testify on the case before a state medical board or nursing board, or jury, and it is important to consider how other people will assess the patient’s explanation.

Even if an individual clinician can be persuaded to believe a patient’s account, it may be hard for 9 out of 10 jurors to believe. The authors consider patient dishonesty to be the most critical variable in safely prescribing opioids, and a patient who has proven to be patently dishonest should rarely (if ever) be given a prescription for opioids.

Overall, what the patient says or what the clinician may surmise about why the patient has produced an inappropriate UDT is a factor to consider in determining the next step in treatment. If the clinician thinks the patient’s medication aberrant behavior—a negative UDT—can reasonably be attributed to undertreatment of pain, then adjusting the dose of opioid or changing the opioid prescribed may be the best course, as opposed to discontinuation of the opioid.

Similarly, if the clinician thinks the findings of an inappropriate UDT may reflect the impact of an anxiety disorder, then referral to a mental health specialist may be the best course of action. On the other hand, if the provider believes the patient is not being honest about what happened, discontinuation of opioids should probably follow unless there can be an immediate and substantial change in the clinician–patient relationship. While this question may be difficult to answer, and is not the only one to consider in determining the next step in treatment, it is nonetheless an important question to consider.

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AT WHAT RiSK L V L HAS TH PATi NT B N ASS SS D? If a patient is assessed as being low risk for medication aberrant behavior, then an inappropriate UDT is seen as unexpected and perhaps more likely a one-time event. (Note: This assumes the clinician is performing appropriate and validated risk assessment. How to best conduct risk assessment is beyond the scope of this paper. Overall, a clinician needs as accurate a method of risk assessment as possible, as only in this way can one make appropriate decisions later in treatment.) If a patient is assessed as medium or high risk for medication aberrant behavior, and an inappropriate UDT is obtained, then the result may be disappointing, but not altogether unexpected.

the man were slender, but if the man were obese the clinician would have every reason to doubt the veracity of his claim—and, thus, question his trustworthiness in other matters pertaining to pain management. On the other hand, if that man admitted to having smoked marijuana to calm his anxiety about living with a chronic disease, about being ostracized by his family, etc, the clinician might take that as an opportunity to agree to work with him to find more specific, more acceptable, treatment for his psychological issues (eg, referral for psychotherapy or psychiatry). He might be given another chance with regard to THC use, though the clinician would want to be careful with what is prescribed in light of what had been revealed about the patient’s behavior (ie, contact with the illegal substance distribution chain).

It is easy for a high-risk patient to say “I’ll do better,” but an inappropriate UDT may reveal that no true change of behavior has taken place. In an ideal world, high-risk patients might be given latitude for medication aberrant behavior while the clinician works to remediate the issues prompting such behavior. Unfortunately, this is not the case in the current medico-legal environments in which we practice.

Thus, if all other considerations are equal, the higher the risk (ie, more expected to violate the treatment agreement), the less latitude should be allowed in terms of subsequent aberrant behavior.

Other explanations can test the credibility of a patient. These include “Someone must have spiked my drink,” “I was in a living room where others were smoking marijuana,” and “Someone must

All else being equal, to whom would a clinician be more likely to continue prescribing opioids after an inappropriate UDT: (A) a patient with no history of a mental health disorder, no criminal history, no

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personal or family history of substance abuse, and who has always shown to be responsible with medications in the past, or (B) a patient with a history of a substance abuse disorder, a significant mental health disorder, and who has misused opioid medications in the past?

Risk assessment and current risk rating should have an impact on patient treatment plans and the decision of whether or not to continue opioids.

(eg, a defense attorney) would be if the clinician were to formulate a plan to increase the level of monitoring ( UDTs, pill counts, checking prescription monitoring programs, and/or visit frequency) and document a concrete plan as to how this will be done (“Based on this finding I will increase the frequency of UDTs from twice a year to bi-monthly for at least the next year”).

There are many possible options for clinicians to address inappropriate UDTs in lieu of discontinuing opioids altogether. These include educating, re-educating, adding other treatments, beginning adjuvant medications, referring for an additional treatment, referring for a substance abuse evaluation and/or treatment, and/or consulting with other specialists if, for example, the inappropriate UDT is deemed to be the result of overtaking medication due to undertreated pain, such as in the case of a new disc herniation and radicular symptoms. Other opioid-related options include changing the opioid, adding an opioid, removing an opioid, changing the dosing schedule, and/or changing from a short-acting to a long-acting or time-release opioid. Increasing the opioid dose may be appropriate in some cases. If overtaking of opioid medications is the problem, a IS TH PATi NT B iNG HON ST ABOUT WHAT HAPP N D? referral for a substance abuse disorder evaluation might be considTrust is a major issue when prescribing opioids to a patient. Patients ered. Such evaluations can be very useful to the clinician in helping whom the clinician finds being dishonest present a major risk. Mis- to determine the role opioid treatment might best play in a patient’s takes in judgment about overtaking medication are one thing, but treatment. Whatever the change in a pain treatment plan, it should outright dishonesty constitutes an even more significant problem. A be logically related in some way to the medication aberrant behavior patient who admits up front that she overtook medication presents a shown and be clearly framed as a remediation to the problem such different set of concerns than a patient who does not tell the provider that it will not occur again. that up front, produces a UDT negative for prescribed opioids, and only discusses her behavior after being confronted about the finding. If a patient’s UDT indicates the presence of a substance abuse disorder (eg, the patient tests positive for cocaine), a referral for Being honest does not excuse all medication aberrant behavior (just a substance abuse evaluation and/or treatment is indicated. Some as admitting to a police officer that one has been speeding does not clinicians wonder if continuing to prescribe any opioid is appropriabsolve one of the offense). However, it does offer information to put ate while the patient is in the process of accessing substance abuse into the equation when deciding what course to take. Patients who treatment. In our view prescribing opioids in this situation is likely are working with their clinicians to solve problems are better opioid being done primarily to mitigate patient withdrawal symptoms while candidates than those who hide information. Did the patient report awaiting substance abuse treatment rather than primarily to treat what happened at the visit? Was it reported before the UDT results pain. Clinicians with experience and training in addictionology may came back? Or, was the abnormality only discovered once the UDT feel comfortable doing this, while many pain specialists will not feel results came back? The more the clinician has to deal with denial, comfortable doing this. Prescribing opioids to a person with an active minimization, blaming others, or other such obfuscation, the more substance abuse disorder has risks for the patient and the clinician likely it is that the clinician should discontinue that patient’s opioid and should only be undertaken by persons with experience and traintreatment. ing. To prescribe in this situation is stepping over the boundary of pain treatment into the management of a substance abuse disorder, and we think clinicians should be very conscious of this distinction and tread with great caution.

BAS D ON TH ABOV , HOW SHOULD TH TR ATM NT Another issue that practitioners face is whether to continue to offer PLAN CHANG ?

If a patient has produced an inappropriate UDT that the laboratory other treatments if opioids are discontinued. The pain community has assured is a true finding (and not an unusual expected metabo- seems divided on this issue. Some practitioners state “I discharge lite), then it is incumbent on the clinician to respond in some way the opioid, not the patient,” while others opine that such behavior is and make a change in the patient’s treatment. We cannot emphasize simply an attempt to end the treatment relationship without being strongly enough that ignoring an inappropriate UDT finding is dan- straightforward about it (ie, frustrating the patient into leaving). gerous to the patient, as well as to the clinician’s licensure status. The There is also a legitimate concern about offering interventional treatclinician may document something simple in the clinical record such ments to someone who may be angry after opioids have been disconas “Based on this finding, I will monitor this patient closely for future tinued, since it offers the patient an opportunity to claim an adverse medication aberrant behavior.” More impressive to a case reviewer event from an interventional treatment as a form of retribution, either It is also true that the type of medication aberrant behavior observed is important. A high-risk patient (based on family and personal history of substance abuse) who has metastatic cancer who occasionally smokes marijuana for symptom relief presents a different situation than the low-risk patient (with no personal or family history of substance abuse and no psychiatric comorbidities) who tests positive for a cocaine metabolite. Our point here is that, in a similar set of circumstances, a high-risk patient should be treated with tighter controls and more significant treatment plan changes than a low-risk patient.

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consciously or unconsciously. Whatever the clinician decides on this topic, the fact remains that the clinician should be clear about what treatments will and will not be offered subsequent to discontinuation of opioids, and should give the patient information about other clinicians that may offer the treatments the patient desires.

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Once a recommendation has been made to the patient and a timeline/ deadline established, then the clinician has more information when the time comes in deciding whether to continue opioids or not. If a patient does what is asked and makes the changes requested, a clinician has more rationale and sanction to continue opioid therapy.

If a patient does not do what is asked of him or her within the time frame established, then discontinuation of opioid therapy should be considered.

HAS TH PATi NT MAD CHANG S AS R QU ST D TO D CR AS TH CHANC S OF A GiV N B HAViOR HAPP NiNG AGAiN? 10 The clinician who is prescribing opioid medication reserves the right HAS TH R B N DOCUM NTATiON OF TH UDT to continue medical management after an aberrant behavior, but also FiNDiNGS, TH CLiNiCiAN’S THOUGHT PROC SS, AND has the right to insist on specific changes to help reduce the chances COMMUNiCATiON TO TH PATi NT? that medication aberrant behavior will happen in the future. The UDT results typically come into the office for review between patient types of changes one might recommend were noted earlier, and are appointments. In our experience, since there is not a session/contact both numerous and situation specific. The point of this question is note in which to put the information, the result and the clinician’s to assess if the patient has actually followed through with the change decision about what changes will be made in treatment are not docuin treatment that was recommended. If a patient suffered a theft of mented in the medical record. As there may be an important change medication, the clinician could recommend the purchase of a lockbox in the patient’s treatment as a result, it is important to document or safe and ask for proof that this has been done, such as a photo of the this process. These notes can become critical if a clinician becomes lockbox or receipt of purchase. If the patient showed abuse of alcohol, involved in a licensing board hearing or civil or criminal litigation. the clinician might recommend that the patient attend Alcoholics Anonymous for a certain number of sessions, or the patient might There are several aspects to this documentation. First, the clinician be referred to a substance abuse counselor in the area. In that case, should document that the inappropriate UDT finding has been seen the patient could be asked to bring in an appointment card from that and noted as inappropriate. If others later look at a medical record clinician or have the other clinician send a letter confirming that an appointment was kept. If the patient’s behavior indicated a mental health disorder of some sort, then the patient might be referred to a local psychiatrist or for psychotherapy, documented by a letter or communication from the other clinician so that treatment can be NOT ONLY SHOULD TH R B A coordinated. If an elderly or cognitively challenged patient showed problems taking or storing medications, then it might be recomCHANG iN TH TR ATM NT PLAN, mended that a family member help or take over the medications to TH R N DS TO B prevent future problems. The family member should come in to the DOCUM NTATiON OF CONCR T office with the patient and confirm that he or she has taken control of the medication administration.

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In summary, not only should there be a change in the treatment plan, there needs to be documentation of concrete action and change.

Many patients may promise to do something but then never get around to it. If a patient at our practice says “I’ll try,” we often quote the sage Yoda: “Try not! Do, or do not. There is no try.” Or, as they say in Alcoholics Anonymous: “Try to is lie to.” A patient needs to actually perform the behavior that is being asked of him or her, not just express agreement or intent to do it in the future.

In these instances, a mutually agreed upon deadline must be established and stated when a clinician recommends a change for the patient. Be clear that the patient is expected to have made or attended an appointment by a certain date, brought proof of obtaining a lockbox or safe by a certain date, and the like. To leave such an expectation with an unclear deadline is not fair to the clinician or the patient. The clinician would even be justified in choosing to taper the patient off opioids until a certain behavior is accomplished, helping to increase a patient’s motivation to engage in change.

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and there is important information in the record that appears to have been ignored or overlooked, this can be bad for the clinician from a medico-legal standpoint. A clinician should at least initial the UDT result with a quick note, such as “inappropriate for nonprescribed hydrocodone.” Then, there should be a note about what the clinician thought about the result and what changes will be implemented as a result. This could be in a separate note or in the note for the patient at the next visit. Documentation of an inappropriate UDT finding is important, but even more important is documenting the thought process. Failure to document a thought process about inappropriate UDT results and/or failure to implement a change in treatment portrays a clinician as thoughtless, possibly even reckless. www.painweek.org | PWJ | 47

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The clinician who decides to discharge a patient from care should altogether for violations of the treatment agreement. If a number of craft a letter to the patient explaining the discharge and what ser- patients are making the same mistake, the clinician also needs to vices will and will not be provided to the patient, both short term improve the patient education process. and long term. Such a letter may be sent by certified mail to provide documentation that the patient received it. Clinicians should read 5— Does the UDT finding reflect a patient taking a substance for their state laws and regulations on patient abandonment, to know pain, or for some other reason? To the extent possible, the cliniwhat is expected within that state’s medical community in situations cian should determine why the patient did what he or she did and like this. Clinicians may, or may not, decide to write a tapering dose attempt to find a solution for the underlying problem. of opioid medication, depending on the circumstances. For example, if a patient with a prescription for time-release morphine produces a 6—At what risk level has the patient been assessed? Assuming the UDT that is negative for all opioids (and confirmed negative for all risk assessment process is a good one, higher-risk patients are more morphine), then a tapering dose is not indicated since there is clear expected to engage in aberrant behavior, so their cases should be documentation that the patient had not taken the medication at all. subjected to fewer chances for remediation than lower-risk patients when the circumstances are the same.

Whatever the decision about a tapering dose, it should be documented in a letter to the patient. We recommend a written note that 7— Is the patient being honest about what happened? Patients who states the UDT finding, the clinician’s assessment of the situation, are not forthcoming about their medication aberrant behavior offer and the changes to the treatment plan that will be implemented. Cli- more risk for continued treatment. nicians may find it helpful to create a “Medication Aberrant Behavior Form” or a “Treatment Agreement Violation Form” with sections to 8— Based on the above, how should the treatment plan change? complete on what happened and what action is being taken. By using Some change in treatment is called for when facing an inappropriate such a form consistently, clinicians will have documentation about UDT. Never ignore such a finding. each event and be prompted to include all the necessary information.

This documentation is a valuable defense against accusations that the 9— Has the patient made changes as requested to decrease the clinician ignored or overlooked important information, and shows chances of a given behavior happening again? Always document how the clinician responded to the medication aberrant behavior. whether or not the patient is following through on recommended Documentation should never be overlooked when dealing an inap- changes in treatment. If a recommended change is not implemented by a patient in a reasonable amount of time, then it is more likely that propriate UDT. opioid treatment should be discontinued.

IN SUMMARY To review, here are the 10 questions to ask when facing an inappropriate UDT and how they impact decisions about treatment.

1— Is the UDT finding correct and truly inconsistent with what has been prescribed? Be sure the finding is truly an unexpected one by being educated about UDT results and checking with the confirmation laboratory’s clinical toxicologist.

2— Does the UDT finding reflect a medically dangerous behavior?

The more medically dangerous the behavior, the more likely it is that opioids should be discontinued.

3— Does the UDT finding reflect illegal behavior? A patient who is engaging in outright illegal behavior— obtaining opioid medication without a prescription—is more concerning than a patient not engaging in illegal behavior—being prescribed opioids by another clinician after an outpatient surgery. Checking the PMP or calling the other clinician may provide a rational explanation regarding what really happened.

10— Has there been documentation of the UDT findings, the clinician’s thought process, and communication to the patient? Documentation of awareness of the UDT result, that it is indeed inappropriate, and the manner in which a change in treatment is planned is of the utmost importance. It is particularly important to document how an inappropriate UDT result is handled, as it demonstrates the clinician’s responsible and thoughtful manner of opioid prescribing.

We offer these 10 questions as a guide to helping prescribers deal with inappropriate UDTs. We think that a “3-strikes-and-you’re-out” policy or a “1-and-done” policy or any other simplistic approach to discontinuing opioids is less fair or proper than a reasoned approach based on the facts of the specific behavior and the patient’s behavior overall. Sometimes a single inappropriate UDT calls for immediate discontinuation of opioids, while other times a patient may be continued on opioids despite several medication aberrant behaviors. We have tried here to specify under what circumstances each of these decisions might be made on a rational basis. We hope that these guidelines can help clinicians be more confident and empowered when faced with an inappropriate UDT result.

4— Did (or should) the patient know better, based on the education provided? Consider how well the patient has been educated about the treatment agreement. The better the process for educating each patient, the more the clinician may need to discontinue opioids

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PARTICIPATING ORGANIZATION

U.S. Pain Foundation prides itself on helping those afflicted with pain and medical conditions find answers, obtain relief, and reclaim a purpose in life.

Established 6 years ago, the organization has become a leading source of support and hope.

Its mission is simple: to educate, connect, …warriors do not allow pain inform, and empower to define them; they understand those living with pain they have a choice to either live while also advocating on behalf of the entire in pain or with pain. Warriors pain community. are inspirational.

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BY P OPL WiTH PAiN FOR P OPL WiTH PAiN

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Paul Gileno founded U.S. Pain Foundation 3 years after a work injury caused him to develop degenerative disc disease, failed back syndrome, and complex regional pain syndrome. After multiple failed back surgeries, grueling physical therapy, and various pain management treatments, he had to accept Q4 | 2013

that his pain was chronic. He began exploring new ways to cope, which uncovered personal answers that enabled him to grow and live once more with meaning and purpose.

Paul recognized the need for an organization created by people with pain for people with pain, and thus, the birth of U.S. Pain Foundation.

It is our responsibility to recognize and validate the 100 million Americans who courageously battle pain every day. That is why we offer free positive programs that inform and inspire. Like many organizations, we work on projects that will benefit the community we serve.

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ViSiBL PROJ CT One such effort is the INvisible Project—a photojournalistic showcase of the day-to-day experiences of real people with chronic pain.

The goal is to make visible the experiences and challenges associated with chronic pain that are often hidden behind the walls of hospitals, bedrooms, and the confines of our minds.

Launched in 2010, the INvisible Project has been viewed hundreds of times in over 15 states at various medical conferences, state capitals, and U.S. Pain Foundation-sponsored events. It is estimated that more than 5000 individuals have viewed the project through a live event. However, hundreds of thousands have visited uspainfoundation.org to read the stories, see the photographs, and gather more information.

The INvisible Project has made others living with pain realize that they are not alone and helped to shift perceptions regarding pain disorders and those afflicted by them. In addition, it has been used as an educational www.painweek.org | PWJ | 49

PARTICIPATING ORGANIZATION

tool by legislatures to change laws, by doctors to better treat patients, by patients to connect with others and gain validation, and by the public to increase awareness.

these groups work through difficult emotions to become proactive and empowered. The goal is to obtain healthier coping strategies, discover how to focus on the positive, connect with others, see that one is not alone, find one’s voice and become empowered, claim meaning in life, and feel emotional safety to share feelings. Over the years, U.S. Pain Foundation support groups have worked with more than 325 people, and 21 of them have graduated to become support group leaders.

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PAiN WARRiOR BRAC L T To unite, strengthen, and encourage the pain community to keep fighting for proper care, we created the pain warrior bracelet. Composed of various bright colors to symbolize all the diseases pain affects, the bold words “Pain Warrior” are etched into the band. This is to emphasize and remind those with pain that each person is a warrior.

In our opinion, warriors do not allow pain to define them; they understand they have a choice to either live in pain or with pain. Warriors are inspirational. Because U.S. Pain Foundation wants to recognize and honor the pain warriors of the world, the bracelets are solely for caregivers and people with pain. To date, U.S. Pain Foundation has distributed more than 7500 bracelets.

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TRiUMPH OV R PAiN WALKS U.S. Pain Foundation sponsors the Triumph Over Pain walks to raise awareness while celebrating the courage and strength of those with pain. Initiating a new dialogue between people with pain and the public, these walks validate suffering while informing the public about chronic pain conditions.

In the last 2 years, Triumph Over Pain walks have had more than 1000 participants. It has been incredible to watch how a walk can lead to public awareness regarding the undertreatment of pain, as well as make those with pain realize it is possible to overcome challenges and limitations.

U.S. Pain Foundation understands the true importance of connecting with others, which is why we host patient education events throughout the nation every year. The “Learn About Your Pain” seminar allows attendees to hear engaging speakers and meet organizations dedicated to helping the pain community. It is designed to educate and empower patients and caregivers alike to unite to form a stronger support system in the local community.

SUPPORT GROUPS We believe, from our personal pain journeys, that those who seek support begin to view pain differently. This is why we offer free U.S. Pain Foundation-sponsored support groups in as many locations nationwide as possible. With separate sessions for the patient and caregiver,

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In addition to our support groups, we have created a nonjudgmental, forum-based website for caregivers and those with pain to come together to share personal stories of struggle, perseverance, and triumph. The goal of the site, called Heroes of Healing, is to provide inspiration and encouragement. Designed for participant interaction, membership is free as the focus is on forming a supportive community where it is acceptable to talk about the hardships of pain and the happier times of life. Recently, Heroes of Healing made the Denver 9-News evening broadcast in a story that discussed how the program is the conduit for a remarkable stories and friendship.

IT iS BY COMiNG TOG TH R THAT CHANG OCCURS AND VOLUNTeeR OPPORTUNiTieS AND ADVOCACY MiSP RC PTiONS U.S. Pain Foundation offers different volunteer opporABOUT tunities for those who want to make a difference in the pain community. After all, it is by coming together that PAiN change occurs and misperceptions about pain diminish.

DiMiNiSH. We encourage individuals to share individual pain sto-

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ries, distribute materials and brochures in the community, volunteer at a future U.S. Pain Foundation event, become involved in advocacy measures that would ensure better care and proper access to therapies for all people with pain, or join our ambassador program.

The Ambassador Program is composed of individuals committed to creating pain awareness and generating change within the medical field. In essence, the U.S. Pain Foundation ambassadors make up who we are as an organization. U.S. Pain Foundation relies on these dedicated individuals to connect with others and become the voice of hope, empowerment, awareness, and support in their communities. Since beginning the program 2 years ago, there are more than 150 ambassadors in 24 states.

Our newest program focusing on helping chronic pain patients learn how to tame the pain—while changing the way pain is treated in the United States through positive engagement—is called P.E.A.R., an acronym for Patient Engagement, Awareness, and Reinvention. It emphasizes that each of us must learn about pain before we can truly change the pain.

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Part of our mission is to share information that may help others find answers and relief. U.S. Pain Foundation does not endorse one type of treatment; however, as an organization, we do support all therapies that improve the lives of those with pain. We also team and collaborate with any organization or group that strives to help those suffering.

To stay connected, share resources, and provide inspiration, U.S. Pain Foundation puts out an eNewsletter that reaches 36,000 people.

In addition, U.S. Pain Foundation has distributed over 40,000 pieces of educational and informational materials including INvisible Project magazine, U.S. Pain Foundation and Pain Warrior bracelet brochures, books (such as No, It Is NOT In My Head: The Journey of a Chronic Pain Survivor from Wheelchair to Marathon and Defeat Chronic Pain Now!: Groundbreaking Strategies for Eliminating the Pain of Arthritis, Back and Neck Conditions, Migraines, Diabetic Neuropathy, and Chronic Illness), prescription savings card, and pamphlets from other groups that benefit the pain community. People with pain have used this information to obtain necessary resources, make connections, receive appropriate help, and hold onto hope.

Finally, U.S. Pain Foundation encourages everyone to become involved in advocacy. Advocacy efforts, to us, can be anything from spearheading a campaign that creates more awareness regarding pain-related issues to taking a stand on a national or state-level platform for access to proper care.

U.S. Pain Foundation has found that sharing personal stories of struggle, plight, triumph, and hope is one of the most effective advocacy tools. We focus on making sure everyone understands that one voice can make a difference. Each of us is part of the solution.

U.S. Pain Foundation played a significant role in the passage of legislation that has a direct benefit on the medical care those with pain receive. A total of 850 letters of advocacy have been submitted on behalf of U.S. Pain Foundation members regarding pain issues on both a national and state level, 75 individuals with pain testified on policy issues in various states, and 510 phone calls were made to local legislatures on pain policy issues. In the state of Connecticut, U.S. Pain Foundation was instrumental in working with legislatures to pass S.B. 1083, which reduced the amount of times a patient would be forced to follow fail-first practices with therapies.

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U.S. Pain Foundation strongly believes in the positive impact our programs have had and continue to have on those debilitated by pain.

Those who once felt defeated now feel strong. Those who felt misunderstood and unheard are feeling recognized and validated. This is important as it leads to empowerment. Becoming empowered carries over into all aspects of an individual’s life. U.S. Pain Foundation is here to offer hope, present information, share stories, and honor those whose lives have been affected by pain.

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with

Michael R. Clark MD, MPH, MBA

Michael R. Clark is the Vice Chair for Clinical Affairs in the Department of Psychiatry & Behavioral Sciences, Associate Professor and Director of the Adolf Meyer Chronic Pain Treatment Programs, Johns Hopkins University School of Medicine.

He sits on the Board of Directors of the American Society of Pain Educators and is a course director for the PAINWeek National Conference. In 2013, Dr. Clark presented Chronic Pain Assessment, When Acute Pain Becomes Chronic, and Madwoman in the Attic: Pain and Personality Disorders.

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PUNDIT PROFILE/MICHAEL R. CLARK

What inspired you to become a healthcare provider?

What do you consider your greatest achievement?

When I was a child, I decided to become a doctor. The physicians I knew at that time were intelligent, compassionate, and respected. I wanted to help people and cure the sick. I couldn’t imagine doing anything else.

My two sons. In addition to wanting to be a doctor, my other aspiration was to become a father. I love my boys with all my heart and soul. I see them as the future and I’m proud to call them my legacy. I cannot wait to see how their stories unfold.

Why did you focus on pain management?

As a psychiatrist, I was fascinated with the mind and the disorders of mental life and behavior. I loved thinking about the whole person and their world.

Working with patients with chronic pain offered me the opportunity to care for patients with complex disorders and remain connected to the other disciplines of medicine that I did not want to give up as a psychiatrist.

Who were your mentors?

My first true mentor beyond my parents was Sam Guze, the chair of psychiatry at Washington University when I was a medical student. He was also the Vice Chancellor of the medical school and such an impressive leader. He inspired me to pursue psychiatry, taught me that psychiatry was truly a branch of medicine, and that psychiatrists could be leaders of great institutions.

My next mentor was Paul McHugh, the chair of psychiatry at Johns Hopkins University who I met during my residency. To this day, he continues to teach me, challenge me to think rigorously and coherently, and demonstrate how a psychiatrist can guide society through situations that result from the medical errors of oversimplification and misplaced emphasis.

If you weren’t a healthcare provider, what would you be?

I would be an elementary school teacher. I love children and their innocence, curiosity, and enthusiasm. Guiding them through a tougher and tougher world, protecting them from the intrusions of those who would corrupt them, and seeing them master the skills required for success is fantastically rewarding.

What is your most marked characteristic?

I’m a collaborator. I like working in teams, listening and learning from others, and then synthesizing that expertise into applied solutions for patients and healthcare systems. I try to keep an open mind, be flexible and practical. I really enjoy seeing a problem solved and others benefiting as a result.

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What is your favorite language?

“As a psychiatrist, I was fascinated with the mind and the disorders of mental life and behavior.

I loved thinking about the whole person and their world.”

Well, I only know English and I have absolutely no proclivity for foreign languages or even accents.

I’m always grateful when others help me overseas because I am truly dependent on the kindness of others for survival.

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?

I’m never very good with these types of questions. There are so many wonderful literary and musical compositions. I would want a book that could continue to teach and guide me, whether I was alone or meeting an alien race. Therefore, I would take something I didn’t fully understand and that would demonstrate the principles that I try to live by. One of Aristotle’s books would be high on the list. The film I would pick purely for enjoyment. I would want to be able to distract myself, forget that I was alone, and laugh out loud. I would probably pick some outrageous action movie, maybe one based on a comic book character like Batman or Ironman. They would pick me up and keep me going through the low points.

The piece of music would serve as the emotional anchor. Music is very moving for me. I would pick a religious piece like Amazing Grace to remind me of the grandeur of the universe, evoke a good cry, and remind me of all of those who got me to where I am at the moment.

What would you like your legacy to be?

I’ve often wondered what people would say about me after I’m gone. Paul McHugh likes to remind me that it is a short step from Who’s Who to “Who’s he?” I hope people will remember me as a good person who helped people and cared more about relationships than trophies.

What is your motto?

Taught to me by my mother: “Make yourself a better person, make the world a better place.”

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“I absolutely think every practitioner should pursue the Certified Pain Educator credential, and I think we are certainly seeing job opportunities where we see the CPE is preferred from an applicant.”

—Mary Lynn McPherson, PharmD, BCPS, CPE, FASPE

The Certified Pain Educator examination is administered year-round and open to all qualified candidates.

Take advantage of the special offer for PAINWeek registrants that includes an ASPE membership and the CPE examination fee for only $279 (a savings of $246). Please go to www.paineducators.org to submit your membership and CPE examination applications.* *Please note that the verification process for completed applications (containing all required documentation) may take up to 2 weeks to complete.

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GRALISE® (gabapentin) tablets BRIEF SUMMARY: For full prescribing information, see package insert.

INDICATIONS AND USAGE GRALISE is indicated for the management of Postherpetic Neuralgia (PHN). GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration.

DOSAGE AND ADMINISTRATION Postherpetic neuralgia • GRALISE should be titrated to an 1800 mg dose taken orally once daily with the evening meal. GRALISE tablets should be swallowed whole. Do not split, crush, or chew the tablets.

• If GRALISE dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of one week or longer (at the discretion of the prescriber).

• Renal impairment: Dose should be adjusted in patients with reduced renal function. GRALISE should not be used in patients with CrCl less than 30 or in patients on hemodialysis.

• In adults with postherpetic neuralgia, GRALISE therapy should be initiated and titrated as follows: Table 1 GRALISE Recommended Titration Schedule Day 1 Day 2 Days 3-6 Days 7-10 Days 11-14 Day 15 Daily dose 300 mg 600 mg 900 mg 1200 mg 1500 mg 1800 mg CONTRAINDICATIONS GRALISE is contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients.

Table 2 GRALISE Dosage Based on Renal Function Once-daily dosing Creatinine clearance (mL/min) GRALISE dose (once daily with evening meal) ≥ 60 1800 mg 30-60 600 mg to 1800 mg < 30 GRALISE should not be administered Patients receiving hemodialysis GRALISE should not be administered WARNINGS AND PRECAUTIONS GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration. The safety and effectiveness of GRALISE in patients with epilepsy has not been studied. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Table 3 Risk by Indication for Antiepileptic Drugs (including gabapentin, the active ingredient in Gralise) in the Pooled Analysis Indication Epilepsy Psychiatric Other Total Placebo patients with events per 1000 patients 1.0 5.7 1.0 2.4 Drug patients with events per 1000 patients 3.4 8.5 1.8 4.3 Relative risk: incidence of events in drug patients/incidence in placebo patients 3.5 1.5 1.9 1.8 Risk difference: additional drug patients with events per 1000 patients 2.4 2.9 0.9 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing GRALISE must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which products containing active components that are AEDs (such as gabapentin, the active component in GRALISE) are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that GRALISE contains gabapentin which is also used to treat epilepsy and that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Withdrawal of Gabapentin Gabapentin should be withdrawn gradually. If GRALISE is discontinued, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber). Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. The clinical significance of this finding is unknown. In clinical trials of gabapentin therapy in epilepsy comprising 2,085 patient-years of exposure in patients over 12 years of age, new tumors were reported in 10 patients, and preexisting tumors worsened in 11 patients, during or within 2 years after discontinuing the drug. However, no similar patient population untreated with gabapentin was available to provide background tumor incidence and recurrence information for comparison. Therefore, the effect of gabapentin therapy on the incidence of new tumors in humans or on the worsening or recurrence of previously diagnosed tumors is unknown. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking antiepileptic drugs, including GRALISE. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present.

Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. GRALISE should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Laboratory Tests Clinical trial data do not indicate that routine monitoring of clinical laboratory procedures is necessary for the safe use of GRALISE. The value of monitoring gabapentin blood concentrations has not been established.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 359 patients with neuropathic pain associated with postherpetic neuralgia have received GRALISE at doses up to 1800 mg daily during placebo-controlled clinical studies. In clinical trials in patients with postherpetic neuralgia, 9.7% of the 359 patients treated with GRALISE and 6.9% of 364 patients treated with placebo discontinued prematurely due to adverse reactions. In the GRALISE treatment group, the most common reason for discontinuation due to adverse reactions was dizziness. Of GRALISE-treated patients who experienced adverse reactions in clinical studies, the majority of those adverse reactions were either “mild” or “moderate”. Table 4 lists all adverse reactions, regardless of causality, occurring in at least 1% of patients with neuropathic pain associated with postherpetic neuralgia in the GRALISE group for which the incidence was greater than in the placebo group.

Table 4 Treatment-Emergent Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Postherpetic Neuralgia (Events in at Least 1% of all GRALISE-Treated Patients and More Frequent Than in the Placebo Group) Body system—preferred term GRALISE N = 359, % Placebo N = 364, % Ear and Labyrinth Disorders Vertigo 1.4 0.5 Gastrointestinal Disorders Diarrhea 3.3 2.7 Dry mouth 2.8 1.4 Constipation 1.4 0.3 Dyspepsia 1.4 0.8 General Disorders Peripheral edema 3.9 0.3 Pain 1.1 0.5

Infections and Infestations Nasopharyngitis 2.5 2.2 Urinary tract infection 1.7 0.5 Investigations Weight increased 1.9 0.5 Musculoskeletal and Connective Tissue Disorders Pain in extremity 1.9 0.5 Back pain 1.7 1.1 Nervous System Disorders Dizziness 10.9 2.2 Somnolence 4.5 2.7 Headache 4.2 4.1 Lethargy 1.1 0.3 In addition to the adverse reactions reported in Table 4 above, the following adverse reactions with an uncertain relationship to GRALISE were reported during the clinical development for the treatment of postherpetic neuralgia.

Events in more than 1% of patients but equally or more frequently in the GRALISE-treated patients than in the placebo group included blood pressure increase, confusional state, gastroenteritis viral, herpes zoster, hypertension, joint swelling, memory impairment, nausea, pneumonia, pyrexia, rash, seasonal allergy, and upper respiratory infection. Postmarketing and Other Experience with other Formulations of Gabapentin In addition to the adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been reported in patients receiving other formulations of marketed gabapentin. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose fluctuation, breast hypertrophy, erythema multiforme, elevated liver function tests, fever, hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome. Adverse events following the abrupt discontinuation of gabapentin immediate release have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain and sweating.

DRUG INTERACTIONS Coadministration of gabapentin immediate release (125 mg and 500 mg) and hydrocodone (10 mg) reduced hydrocodone Cmax by 3% and 21%, respectively, and AUC by 4% and 22%, respectively. The mechanism of this interaction is unknown. Gabapentin AUC values were increased by 14%; the magnitude of this interaction at other doses is not known. When a single dose (60 mg) of controlled-release morphine capsule was administered 2 hours prior to a single dose (600 mg) of gabapentin immediate release in 12 volunteers, mean gabapentin AUC values increased by 44% compared to gabapentin immediate release administered without morphine. The pharmacokinetics of morphine were not affected by administration of gabapentin immediate release 2 hours after morphine. The magnitude of this interaction at other doses is not known. An antacid containing aluminum hydroxide and magnesium hydroxide reduced the bioavailability of gabapentin immediate release by about approximately 20%, but by only 5% when gabapentin was taken 2 hours after antacids. It is recommended that GRALISE be taken at least 2 hours following antacid administration. There are no pharmacokinetic interactions between gabapentin and the following antiepileptic drugs: phenytoin, carbamazepine, valproic acid, phenobarbital, and naproxen. Cimetidine 300 mg decreased the apparent oral clearance of gabapentin by 14% and creatinine clearance by 10%. The effect of gabapentin immediate release on cimetidine was not evaluated. This decrease is not expected to be clinically significant. Gabapentin immediate release (400 mg three times daily) had no effect on the pharmacokinetics of norethindrone (2.5 mg) or ethinyl estradiol (50 mcg) administered as a single tablet, except that the Cmax of norethindrone was increased by 13%. This interaction is not considered to be clinically significant. Gabapentin immediate release pharmacokinetic parameters were comparable with and without probenecid, indicating that gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Gabapentin has been shown to be fetotoxic in rodents, causing delayed ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To provide information regarding the effects of in utero exposure to GRALISE, physicians are advised to recommend that pregnant patients taking GRALISE enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Nursing Mothers Gabapentin is secreted into human milk following oral administration. A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on the nursing infant is unknown, GRALISE should be used in women who are nursing only if the benefits clearly outweigh the risks. Pediatric Use The safety and effectiveness of GRALISE in the management of postherpetic neuralgia in patients less than 18 years of age has not been studied. Geriatric Use The total number of patients treated with GRALISE in controlled clinical trials in patients with postherpetic neuralgia was 359, of which 63% were 65 years of age or older. The types and incidence of adverse events were similar across age groups except for peripheral edema, which tended to increase in incidence with age. GRALISE is known to be substantially excreted by the kidney. Reductions in GRALISE dose should be made in patients with age-related compromised renal function. [see Dosage and Administration]. Hepatic Impairment Because gabapentin is not metabolized, studies have not been conducted in patients with hepatic impairment. Renal Impairment GRALISE is known to be substantially excreted by the kidney. Dosage adjustment is necessary in patients with impaired renal function. GRALISE should not be administered in patients with CrCL between 15 and 30 or in patients undergoing hemodialysis [see Dosage and Administration].

DRUG ABUSE AND DEPENDENCE The abuse and dependence potential of GRALISE has not been evaluated in human studies.

OVERDOSAGE A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as high as 8000 mg/kg.

Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation. Acute oral overdoses of gabapentin immediate release in humans up to 49 grams have been reported. In these cases, double vision, slurred speech, drowsiness, lethargy and diarrhea were observed. All patients recovered with supportive care.

Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

CLINICAL PHARMACOLOGY Pharmacokinetics Absorption and Bioavailability Gabapentin is absorbed from the proximal small bowel by a saturable L-amino transport system. Gabapentin bioavailability is not dose proportional; as the dose is increased, bioavailability decreases. When GRALISE (1800 mg once daily) and gabapentin immediate release (600 mg three times a day) were administered with high fat meals (50% of calories from fat), GRALISE has a higher Cmax and lower AUC at steady state compared to gabapentin immediate release. Time to reach maximum plasma concentration (Tmax) for GRALISE is 8 hours, which is about 4-6 hours longer compared to gabapentin immediate release.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of pancreatic acinar cell adenoma and carcinomas was found in male rats receiving the high dose; the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma concentrations of gabapentin in rats receiving the high dose of 2000 mg/kg/day were more than 10 times higher than plasma concentrations in humans receiving 1800 mg per day and in rats receiving 1000 mg/kg/day peak plasma concentrations were more than 6.5 times higher than in humans receiving 1800 mg/day. The pancreatic acinar cell carcinomas did not affect survival, did not metastasize and were not locally invasive. The relevance of this finding to carcinogenic risk in humans is unclear. Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known whether gabapentin has the ability to increase cell proliferation in other cell types or in other species, including humans.

Gabapentin did not demonstrate mutagenic or genotoxic potential in 3 in vitro and 4 in vivo assays. No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately 11 times the maximum recommended human dose on an mg/m2 basis).

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

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

PLEASE GRALISE ME! Help control the agony of PHN

*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 (â&#x2030;Ľ 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.

May 2013, Depomed Inc. All rights reserved. GRA-409-P.1