PAINWeek Journal, Vol 2, Q4 by PAINWeek

vol. 2 q 4 2014

DEALING WITH “DREAD TO TREAT” PATIENTS: RECOGNITION, DIAGNOSIS, AND MANAGEMENT OF ADDICTION IN THE OFFICE BASED PAIN MEDICINE SETTING P.14 NEUROGENIC THORACIC OUTLET SYNDROME (NTOS) P.24 CALLING IN THE MARINES: METHADONE, KETAMINE, AND LIDOCAINEP.32 THE SCORPION, THE FROG, AND THE VIABILITY OF BALANCED POLICIESP.40

NEW

7.5 mcg/hour Now Available

Butrans â&#x20AC;&#x201D; 7 Days of Buprenorphine Delivery

Butrans is a Schedule III extended-release opioid analgesic WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; and NEONATAL OPIOID WITHDRAWAL SYNDROME Addiction, Abuse, and Misuse Butrans exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patientâ&#x20AC;&#x2122;s risk prior to prescribing Butrans, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1) and Overdosage (10)]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Butrans. Monitor for respiratory depression, especially during initiation of Butrans or following a dose increase. Misuse or abuse of Butrans by chewing, swallowing, snorting or injecting buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death [see Warnings and Precautions (5.2)]. Accidental Exposure Accidental exposure to even one dose of Butrans, especially by children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions (5.2)]. Neonatal Opioid Withdrawal Syndrome Prolonged use of Butrans during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)]. Parentheses refer to sections in the Full Prescribing Information.

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

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

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

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

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

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

ADVERSE REACTIONS ■

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

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The first transdermal system to deliver 7 days of buprenorphine

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

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

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

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

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

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

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

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

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

GUEST EDITOR TED PUBLISHER Aventine

W. JONES PhD, CPE

Co. 6 Erie Street, Montclair, NJ 07042

ART DIRECTOR DARRYL

FOSSA

EDITORIAL DIRECTOR DEBRA EDITOR HOLLY

WEINER

CASTER

EDITORIAL BOARD

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

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

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

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

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

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

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

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

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

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

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

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

Global Education Group (Global) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education to physicians. Global Education Group designates this live activity for a minimum of 39.0 AMA PRA Category 1 Credit(s) TM. This activity will be approved for continuing pharmacy, psychology, nurse practitioner, nursing, and dentistry education. Applications for certification of social work NASW and family physician AAFP hours will be applied for. For more information and complete CME/CE accreditation details, visit our website at www.painweek.org.

/ PWJ / Q4 / 2014 12 | GUEST EDITOR’S LETTER by ted w. Jones

FEATURES

CALLING IN THE MARINES: methadone, ketamine, and lidocaine by tanya j. Uritsky / james b.

14 | PAIN&CHEMICAL DEPENDENCY

DEALING WITH “DREAD TO TREAT ”PATIENTS: recognition, diagnosis, and management of addiction in the office based pain medicine setting by heidi h. Allespach / bernd

32 | PHARMACOTHERAPY

Wollschlaeger

Ray / Mary Lynn McPherson

40 | PUBLIC POLICY

THE SCORPION, THE FROG, AND THE VIABILITY OF BALANCED POLICIES by stephen j. Ziegler

49 | PUNDIT PROFILE with jeffrey d. Fudin

24 | EXPERT OPINION

NEUROGENIC THORACIC OUTLET SYNDROME (NTOS) by allen john Togut

8 | PWJ | www.painweek.org

Q4 | 2014

NOW APPROVED FOR THE TREATMENT OF OPIOID-INDUCED CONSTIPATION IN ADULT PATIENTS WITH CHRONIC NON-CANCER PAIN. In a clinical study of patients with chronic non-cancer pain who suffered from opioid-induced constipation: 6 out of 10 RELISTOR® (methylnaltrexone bromide) patients had at least 3 SBMs* per week1

33% of patients taking RELISTOR experienced an SBM* within 4 hours of their first dose1

• RELISTOR targets the underlying cause of opioid-induced constipation without affecting analgesia2 • RELISTOR is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction2 • In the clinical study in adult patients with opioid-induced constipation and chronic non-cancer pain, the most common adverse reactions (≥ 1%) were abdominal pain (21%), nausea (9%), diarrhea (6%), hyperhidrosis (6%), hot flush (3%), tremor (1%), and chills (1%). * Spontaneous Bowel Movement occurring without the use of rescue laxatives.

Indication RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain. Important Safety Information about RELISTOR RELISTOR® (methylnaltrexone bromide) Subcutaneous Injection is contraindicated in patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation. Cases of gastrointestinal perforation have been reported in adult patients with opioid-induced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom.

If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician.

common adverse reactions (≥ 1%) were abdominal pain, nausea, diarrhea, hyperhidrosis, hot flush, tremor, and chills.

Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia and should be monitored for adequacy of analgesia and symptoms of opioid withdrawal.

In clinical studies in adult patients with opioid-induced constipation and advanced illness, the most common adverse reactions (≥ 5%) were abdominal pain, flatulence, nausea, dizziness, and diarrhea.

Avoid concomitant use of RELISTOR with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal. RELISTOR may precipitate opioid withdrawal in a fetus and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In nursing mothers, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. In the clinical study in adult patients with opioid-induced constipation and chronic non-cancer pain, the most

Please see Brief Summary of complete Prescribing Information for RELISTOR on the adjacent page. References 1. Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with chronic nonmalignant pain: a randomized controlled study. J Pain. 2011;12(5):554-562. 2. RELISTOR® (methylnaltrexone bromide) Prescribing Information, Salix Pharmaceuticals, Inc. www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 For additional information, call: 1-866-669-SLXP (7597) To report adverse events, call: 1-800-508-0024 ©2014 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. REL78-0914

The following is a brief summary only; see full Prescribing Information for complete product information. INDICATIONS AND USAGE Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain. Opioid-Induced Constipation in Adult Patients with Advanced Illness RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Limitation of use: Use of RELISTOR beyond four months has not been studied in the advanced illness population. CONTRAINDICATIONS RELISTOR is contraindicated in patients with known or suspected gastrointestinal obstruction and patients at risk of recurrent obstruction, due to the potential for gastrointestinal perforation. WARNINGS AND PRECAUTIONS Gastrointestinal Perforation Cases of gastrointestinal perforation have been reported in adult patients with opioid-induced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom. Severe or Persistent Diarrhea If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their healthcare provider. Opioid Withdrawal Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia. Take into account the overall risk-benefit profile when using RELISTOR in such patients. Monitor for adequacy of analgesia and symptoms of opioid withdrawal in such patients. ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain The safety of RELISTOR was evaluated in a double-blind, placebo-controlled trial in adult patients with opioid-induced constipation and chronic non-cancer pain receiving opioid analgesia. This study (Study 1) included a 4-week, double-blind, placebo controlled period in which adult patients were randomized to receive RELISTOR 12 mg once daily (150 patients) or placebo (162 patients). After 4 weeks of double-blind treatment, patients began an 8-week open-label treatment period during which RELISTOR 12 mg was administered less frequently than the recommended dosage regimen of 12 mg once daily. Adverse reactions in adult patients with opioid-induced constipation and chronic non-cancer pain receiving RELISTOR are shown in the following table. The adverse reactions in the table below may reflect symptoms of opioid withdrawal. Adverse Reactions* in 4-Week Double-Blind, PlaceboControlled Period of Clinical Study of RELISTOR in Adult Patients with Opioid-Induced Constipation and Chronic Non-Cancer Pain RELISTOR Placebo 12 mg once daily n = 162 n = 150 Abdominal Pain 21% 6% Nausea 9% 6% Diarrhea 6% 4% Hyperhidrosis 6% 1% Hot Flush 3% 2% Tremor 1% < 1% Chills 1% 0% * Adverse reactions occurring in ≥ 1 % of patients receiving RELISTOR 12 mg once daily and at an incidence greater than placebo. During the 4-week double-blind period, in patients with opioid-induced constipation and chronic non-cancer pain that received RELISTOR 12 mg every other day, there was a higher incidence of adverse reactions, including nausea (12%), diarrhea (12%), vomiting (7%), tremor (3%), feeling of body temperature Adverse Reaction

change (3%), piloerection (3%), and chills (2%) as compared to daily RELISTOR dosing. Use of RELISTOR 12 mg every other day is not recommended in patients with OIC and chronic non-cancer pain. The rates of discontinuation due to adverse reactions during the double-blind period (Study 1) were higher in the RELISTOR once daily (7%) than the placebo group (3%). Abdominal pain was the most common adverse reaction resulting in discontinuation from the double-blind period in the RELISTOR once daily group (2%). The safety of RELISTOR was also evaluated in a 48-week, open-label, uncontrolled trial in 1034 adult patients with opioid-induced constipation and chronic non-cancer pain (Study 2). Patients were allowed to administer RELISTOR 12 mg less frequently than the recommended dosage regimen of 12 mg once daily, and took a median of 6 doses per week. A total of 624 patients (60%) completed at least 24 weeks of treatment and 477 (46%) completed the 48-week study. The adverse reactions seen in this study were similar to those observed during the 4-week double-blind period of Study 1. Additionally, in Study 2, investigators reported 4 myocardial infarctions (1 fatal), 1 stroke (fatal), 1 fatal cardiac arrest and 1 sudden death. It is not possible to establish a relationship between these events and RELISTOR. Opioid-Induced Constipation in Adult Patients with Advanced Illness The safety of RELISTOR was evaluated in two, double-blind, placebo-controlled trials in adult patients with opioid-induced constipation and advanced illness receiving palliative care: Study 3 included a single dose, double blind, placebo-controlled period, whereas Study 4 included a 14-day multiple dose, double-blind, placebo-controlled period. The most common (≥5%) adverse reactions in adult patients with opioid-induced constipation and advanced illness receiving RELISTOR are shown in the following table. Adverse Reactions from all Doses in Double-Blind, PlaceboControlled Clinical Studies of RELISTOR in Adult Patients with Opioid-Induced Constipation and Advanced Illness* Adverse RELISTOR Placebo Reaction n = 165 n = 123 Abdominal Pain 29% 10% Flatulence 13% 6% Nausea 12% 5% Dizziness 7% 2% Diarrhea 6% 2% * Adverse reactions occurring in ≥ 5 % of patients receiving all doses of RELISTOR (0.075, 0.15, and 0.30 mg/kg/dose) and at an incidence greater than placebo. The rates of discontinuation due to adverse events during the double-blind placebo controlled clinical trials (Study 3 and Study 4) were comparable between RELISTOR (1%) and placebo (2%). Postmarketing Experience The following adverse reactions have been identified during post-approval use of RELISTOR. Because they are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Perforation, cramping, vomiting General Disorders and Administrative Site Disorders Diaphoresis, flushing, malaise, pain. Cases of opioid withdrawal have been reported. DRUG INTERACTIONS Other Opioid Antagonists Avoid concomitant use of RELISTOR with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal. Drugs Metabolized by Cytochrome P450 Isozymes In healthy subjects, a subcutaneous dose of 0.30 mg/kg of methylnaltrexone did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies with RELISTOR in pregnant women. The use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of intravenous methylnaltrexone during organogenesis in rats and rabbits at doses up to 20 times and 26 times, respectively, the maximum recommended human dose (MRHD) of 0.2 mg/kg/day. RELISTOR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether RELISTOR is present in human milk. However, methylnaltrexone bromide is present in rat milk. Because of the potential for serious adverse reactions, including opioid withdrawal, in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of RELISTOR have not been established in pediatric patients. In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs such as convulsions,

tremors and labored breathing were observed, and the juvenile rats were found to be more sensitive to the adverse effects of methylnaltrexone bromide when compared to adult animals. Juvenile dogs administered intravenous methylnaltrexone bromide for 13 weeks had a toxicity profile similar to adult dogs. Geriatric Use In the double-blind studies, a total of 118 (14%) patients aged 65-74 years (79 methylnaltrexone bromide, 39 placebo) and a total of 108 (13%) patients aged 75 years or older (64 methylnaltrexone bromide, 44 placebo) were enrolled. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on pharmacokinetic data, and safety and efficacy data from controlled clinical trials, no dose adjustment based on age is recommended. Renal Impairment No dose adjustment is required in patients with mild or moderate renal impairment. Dose reduction by one-half is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault). Hepatic Impairment No dose adjustment is required for patients with mild or moderate hepatic impairment. OVERDOSAGE A study of healthy volunteers noted orthostatic hypotension associated with a dose of 0.64 mg/kg administered as an intravenous bolus. Monitor for signs or symptoms of orthostatic hypotension and initiate treatment as appropriate. If a patient on opioid therapy receives an overdose of RELISTOR, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms such as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect. Base treatment on the degree of opioid withdrawal symptoms, including changes in blood pressure and heart rate, and on the need for analgesia. PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Administration Advise all patients to: • Inject RELISTOR subcutaneously in the upper arm, abdomen or thigh. Do not inject at the same spot each time (rotate injection sites). • Safely dispose of needles by following the sharps disposal recommendations described in the RELISTOR Instructions for Use. • Be within close proximity to toilet facilities once RELISTOR is administered. • Discontinue RELISTOR if treatment with the opioid pain medication is also discontinued. Advise chronic non-cancer pain patients receiving RELISTOR for opioid-induced constipation to: • Discontinue all maintenance laxative therapy prior to initiation of RELISTOR. Laxative(s) can be used as needed if there is a suboptimal response to RELISTOR after three days. • Inject one dose every day. • Inform their healthcare provider if their opioid regimen is changed, to avoid adverse reactions, such as diarrhea. Advise patients with advanced illness receiving RELISTOR for opioid-induced constipation to: • Inject one dose every other day, as needed, but no more frequently than one dose in a 24-hour period. Gastrointestinal Perforation Advise patients to discontinue RELISTOR and to promptly seek medical attention if they develop unusually severe, persistent, or worsening abdominal pain. Severe or Persistent Diarrhea Advise patients to discontinue RELISTOR if they experience severe or persistent diarrhea. Opioid Withdrawal Advise patients that symptoms consistent with opioid withdrawal may occur while taking RELISTOR, including sweating, chills, diarrhea, abdominal pain, anxiety, and yawning. Pregnancy Advise females of reproductive potential, who become pregnant or are planning to become pregnant that the use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood brain barrier. Nursing Advise females who are nursing against breastfeeding during treatment with RELISTOR due to the potential for opioid withdrawal in nursing infants. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. To report adverse events, a product complaint, or for additional information, call: 1-800-508-0024. Manufactured for: Under License from:

Salix Pharmaceuticals, Inc. Raleigh, NC 27615

Progenics Pharmaceuticals, Inc. Tarrytown, NY 10591

REL-RALAB56-102014

Travel and change of place impart new vigor to the mind. —Seneca

Athens Rhodes Mykonos Santorini Ephesus Istanbul

TED W.

JON S PhD, CPE

W elcome! I am quite pleased to introduce this issue of PWJ to you. It is full of relevant and timely information for frontline practitioners in pain management. As a Certified Pain Educator and former Pain Educator of the Year, as well as current President of the Tennessee Pain Society, I can assure you that PWJ bridges the gaps between research and theory and practice. In my view no other journal does this bridging better. It is critical that the practice of pain treatment be grounded in science and what we see is actually working, not guided by untested philosophical ideas about what we hope is the right way to treat pain. The articles that follow are written by professionals with a deep commitment to pain patients, professionals who have practical hands-on experience to disseminate to their colleagues. Knowledge is our most useful tool, and I hope you find these articles as informative and stimulating as I have. Drs. Heidi H. Allespach and Bernd Wollschlaeger offer help with one of our most challenging situations—treating the addicted patient— and pointedly remind us to differentiate the illness from the person with the illness. They review the signs and symptoms of addicted behavior and give us practical examples on how to set compassionate limits with patients who are showing a lack of control with their opioid medications. They even offer a role play of what to say so that we can join our addicted patients in addressing their issues, rather than taking an adversarial stance (which is so easy to do in the heat of a busy day at a pain practice).

gives us his wisdom from years of experience in assessing and treating this syndrome. Of particular note is how he addresses treatment as well as ways to adapt and deal with this pain disorder rather than hoping for a cure that is so rare in coming. This theme is true for so many of our pain patients: helping them adapt to having a chronic condition and educating them that while a cure is unlikely, improvement is possible. Drs. Tanya J. Uritsky, James B. Ray, and Mary Lynn McPherson spotlight 3 novel pharmaceutical agents—methadone, ketamine, and lidocaine—for when the usual methods of treatment are not getting the job done. Although prescribing of methadone in particular has been criticized of late, these authors remind us that there is a role for it, and that, when used judiciously, it can have a dramatically positive impact. Ketamine and lidocaine, as well, are often underutilized and can be valuable resources. The authors give detailed instruction about when and how to implement these medications, giving clinicians new resources for immediate use in their daily practice. Dr. Stephen J. Ziegler analyzes the impact of federal policy changes to pain treatment and the prescribing of opioids, helping us see both the law enforcement side and the provider side of the prescription drug abuse problem. He supplements this with interview and survey data from personnel who were the direct targets for the policies to be implemented. He concludes that perhaps there are positive results even when policies fail to get fully implemented, as open communication between various parties may be a key to effectively moving forward in a nonadversarial environment. From dealing with the addicted patient to diagnosing a sometimes baffling pain disorder to using novel agents when standard treatments have failed to seeing the big picture of regulating opioid prescribing, PWJ gives you practical information from its network of clinical and policy experts. I hope you will enjoy this, as well as future, issues as PWJ keeps you up-to-date on the critical concerns facing us in the pain treatment world. If you like what you’ve read here, consider joining us in September at PAINWeek 2015, where you can find content like this and so much more. Whether we see you in Las Vegas not, thank you for being interested in appropriate and compassionate pain treatment. Enjoy the issue! —TED W. JONES PhD, CPE

Dr. Allen John Togut explains exactly how neurogenic thoracic outlet syndrome, or NTOS —an often misdiagnosed pain condition—can be assessed through a clinical examination and diagnostic tests. He

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Heidi H. Allespach PhD

P.14

Allen John Togut MD

P.24

Tanya J. Uritsky PharmD, BCPS

P.32

Stephen J. Ziegler PhD, JD

Heidi Allespach is Clinical Assistant Professor and Director of Behavioral Medicine at the University of Miami Miller School of Medicine, Department of Family Medicine & Community Health in Florida. Dr. Allespach coauthored her article with Bernd Wollschlaeger, MD, FAAP, FASAM, MRO, Clinical Assistant Professor at the University of Miami Miller School of Medicine, Department of Family Medicine & Community Health and Medical Director of the Aventura Family Health Center in North Miami Beach, Florida.

Allen Togut is a nationally recognized expert in the field of neurogenic thoracic outlet syndrome. After serving as a general and thoracic surgeon at Geisinger Medical Center in Pennsylvania and the Corning, Brockton, Cardinal Cushing, Goddard, St. Luke’s, and Milton Hospitals in Massachusetts, he went into private practice in Pennsylvania. Now retired, Dr. Togut has presented at numerous PAINWeek National Conferences over the last 8 years.

Tanya Uritsky is a Clinical Pharmacy Specialist in Pain and Palliative Care at the Hospital of the University of Pennsylvania in Philadelphia. Dr. Uritsky coauthored her article with James B. Ray, PharmD, CPE, Clinical Assistant Professor, Virginia Commonwealth University in Richmond and Pharmacy Clinical Coordinator, Pain and Palliative Care, University of Virginia Health System in Charlotteville; and Mary Lynn McPherson, PharmD, BCPS, CPE (see Editorial Board page).

P.40

Stephen Ziegler is an Associate Professor of Public Policy at Indiana University-Purdue University in Fort Wayne, Indiana. Trained as both a social scientist and an attorney, Dr. Ziegler conducts research and consults on the topics of opioid risk management and the impact of drug regulation and enforcement on the treatment plan. He was a Mayday Pain Scholar in 2002 is currently a Mayday Pain and Society Fellow.

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www.painweek.org | PWJ | 13

It’s 4pm on a Friday afternoon and you are wrapping up your clinic, looking forward to a relaxing weekend which, given your incredibly busy week, seemed as if it would never arrive. Just then, your nurse pops her head in the door, says the following sentence, and your stomach clenches and your heart rate increases: “One of your patients is here without an appointment and says he’s run out of his pain medications early and he isn’t leaving until he gets a new prescription.” Just like that, you are filled with dread and the weekend seems even further away.

by Heidi

H. Allespach, PhD/Bernd Wollschlaeger MD, FAAFP, FASAM, MRO

Recognition, Diagnosis, and Management of Addiction in the Office Based Pain Medicine Setting by Heidi

H. Allespach, PhD/Bernd Wollschlaeger MD, FAAFP, FASAM, MRO

PAiN&CHEMICAL DEPENDENCY

dread

verb \❙ dred\ : to fear something that will or might happen transitive verb 1a: to fear greatly 2a: to feel extreme reluctance to meet or face

abstract: In addition to “dread to treat,” other labels that have been used to describe this specific population include “junkie,” ”loser,” “hateful,”1 and “crocks and gomers.”2 Physicians and other healthcare providers may use derogatory labels to cover up their own feelings of inadequacy when working with patients with substance use disorders (SUD). Indeed, patients with SUD are inarguably some of the most difficult to treat, and the vast majority of pain providers will see patients such as these in their clinics on a daily basis. Yet few doctors receive any formal training, in either medical school or residency, in how to diagnose or treat them.3 Physician reactions towards these patients include anger, frustration, disgust, helplessness, and apathy. Unfortunately, when doctors react with such negative emotional states, they become less effective, and more frustrated, when dealing with these extremely complicated patients. Moreover, these feelings of distress, combined with resultant decreased job satisfaction, can serve to put the physician at a higher risk of burnout.4 Taken together, the need for education about these often demanding, and almost always challenging, patients is critical in helping to reduce the overwhelming feelings of dread associated with seeing patients with SUD.

Note: The authors will use the terms “addiction” and “SUD” interchangeably throughout this article.

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One of the most important points to recognize is that the addicted patient is not his or her disease.

TH PROBL M In 2014, the National Institutes of Health reported that illicit drug use in America has been increasing. For example, in 2012, an estimated 23.9 million Americans aged 12 or older—or 9.2% of the population—had used an illicit drug or abused a psychotherapeutic medication (such as a pain reliever, stimulant, or tranquilizer) in the past month. This is up from 8.3% in 2002. The increase mostly reflects a recent rise in the use of marijuana, the most commonly used illicit drug.5 Indeed, prescription and other drug abuse is a major problem in the United States.6 In the past decade alone, there has been more than a 5-fold increase in treatment admissions for prescription painkillers7 and the number of drug overdoses have more than tripled since 1990.8

D FiNiTiONS Addiction is a complex disease. The American Society of Addiction Medicine9 defines addiction as a “…primary, chronic disease of brain reward, motivation, memory, and related circuitry. Dysfunction in these circuits leads to characteristic biological, psychological, social, and spiritual manifestations. This is reflected in an individual pathologically pursuing reward and/or relief by substance use and other behaviors. Addiction is characterized by inability to consistently abstain, impairment in behavioral control, craving, diminished recognition of significant problems with one’s behaviors and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, addiction often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, addiction is progressive and can result in disability or premature death.”

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One of the most important points to recognize is that the addicted patient is not his or her disease.3 In other words, anyone in active addiction will exhibit typical behavioral hallmarks associated with this illness; they may lie, manipulate, and, generally, act in a manner which is quite unpleasant! However, those behavioral and attitudinal manifestations are related to the active addictive process and not necessarily attributable to the person “underneath” the illness. It is common knowledge that most individuals with SUD who are in recovery and are, therefore, abstinent from all substances, are actually bright, sensitive, affable people. This differentiation between the patient and the illness is extremely important in helping the treatment team feel less angry and frustrated with these patients which, in turn, reduces provider distress and improves the overall quality of care they provide. Tolerance occurs when the individual no longer responds to the drug the way they initially responded. Basically, one needs more of the drug in order to receive the same effects. Dependence develops when the neurons adapt to the repeated drug exposure and only function normally in the presence of the drug. Dependence and tolerance can occur when anyone, not just those with addiction, take certain substances for given lengths of time. Pseudoaddiction is often an iatrogenic response due to undertreatment, and the “pseudoaddict” will look (ie, behave) just like someone who actually has the disease of addiction because medication intervals are greater than the duration of action. This can be distinguished from true addiction in that the behaviors resolve when the pain (or anxiety) is effectively treated.

N UROBiOLOGY OF ADDiCTiON In the last 40 years, scientists have achieved major breakthroughs in the understanding of the neurobiology of addiction. Rapid technological advances in brain imaging, mapping of neurocircuitry, and www.painweek.org | PWJ | 17

PAIN&CHEMICAL DEPENDENCY

…addicted individuals suffer from a progressive structural and functional disruption in brain regions… …drug addiction is a disease of the brain and the associated abnormal behaviors are the result of dysfunctional brain tissue.

molecular biology provided the understanding that addicted individ- be assessed prior to initiating opioid therapy.12 There are a wide uals suffer from a progressive structural and functional disruption variety of validated instruments aimed at detecting possible abuse in brain regions that underlie the normal processes of motivation, and misuse behaviors among patients on opioid therapy, including: reward, and inhibitory control. This helped us to comprehend that the Screener and Opioid Assessment for Patients in Pain (SOAPP),13 drug addiction is a disease of the brain and the associated abnormal the Drug Abuse Screening Test ( DAST ),14 the Opioid Risk Tool behaviors are the result of dysfunctional brain tissue.10 The concept (ORT ),15 and the Current Opioid Misuse Measure (COMM ).16 The that addiction is a chronic brain disease, with a similar course as other authors of this article favor using the verbally administered “4 Cs” chronic illnesses, such as diabetes, hypertension, or heart disease, (original author unknown) as a first-line screen. The 4 Cs are quesrepresents a paradigm shift in the treatment of addicted patients. The tions frequently asked in drug treatment centers and that touch on neurobiological substrates for the reinforcing effects of drugs of abuse aspects of DSM-517 SUD criteria: have been largely identified both at the initial site of action (receptor, reuptake site, etc) as well as the circuitry involved (mesocorticolimbic 1. Loss of control—“Have you ever experienced a loss of control in your life because of taking a drug or because of being ‘hung dopamine system and endogenous opioid systems).11 For example, over,’ such as making plans but then having to change them, brain imaging studies have provided evidence that decreases in dopabeing late to work or not showing up to work at all, missing an minergic function represent a key common element of addiction. important event?” This led to the application of medications to modulate the dopamine response in patients suffering from addiction. Equipped with the understanding of neurobiology and neurocircuitry of addiction, we 2. Compulsivity—“Do you find you take more pills/drug than you now have a growing number of pharmacological interventions availoriginally planned?” able to assist us in the treatment of patients suffering from SUD. 3. Continued use despite adverse consequences—“Have you continued to take a drug even though it caused significant negative problems in your life? Do people around you worry about your MANAG M NT OF PATi NTS AT RiSK drug use but you do it anyway? Have you ever had legal or other FOR OPiOiD ABUS problems because of your substance use?” Assessment—As with most SUD, the most important predictors of opioid abuse and addiction are family history and previous 4. Craving—“Do you find yourself thinking a great deal about when your next dose is due? Do you ever feel very irritable or substance abuse history. Of course, by the nature of the disease, anxious until you get your next dose and, once you take your patients with SUD are often reluctant in sharing this type of history medication, do you feel great emotional relief?” with their pain medicine providers! Therefore, all patients should

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The questions above are suggestions only. Should the patient answer All of these described tools should be utilized with all patients to any of them affirmatively, or respond positively to questions on the set boundaries to protect the treatment team as well as to ascertain scales listed above per each instrument’s individual scoring guide- patient safety. However, this boundary setting is especially important lines, we recommend proceeding from the screening process to diag- with patients with pain who are also suspected of having an undernosis using the DSM-5 criteria.17 Of note, the DSM-5, as compared lying SUD. to the DSM-IV-TR ,18 has eliminated the “abuse” and “dependence” categories and now specifies substance use disorders by severity as In addition, both the World Health Organization and the Federal well as other key criterion.17 State Medical Boards have guidelines which are also helpful in appropriate prescribing of drugs to manage chronic pain. Other helpful resources are the Substance Abuse and Mental Health Services B HAViORAL “R D FLAGS” Administration (SAMHSA), Center for Substance Abuse (CSAT ), Providers’ Clinical Support System for Opioid Therapies (PCSS -O), As pain providers well know, patients who are abusing narcotics tend and the Providers’ Clinical Support System for Medication Assisted to exhibit certain undesirable behaviors. Some of these behaviors Treatment ( PCSS -MAT ). include a pattern of requesting early refills, “losing” prescriptions or medications, requesting short- vs long-acting opioid medications, refusal to try combination agonist-antagonist products, asking for PHARMACOLOGiC TR ATM NT OF PAiN iN medications by name because “nothing else works,” and demonstrat- PATi NTS WiTH ADDiCTiON (SUD) ing negative urine drug screen results for the prescribed medication (possibility of diversion).19 New patients may present with vague Tolerance of and physical dependence on opioids can occur after a history and without previous medical records. For an excellent dis- few weeks of daily use. Affected individuals who are physically depencussion on red flag behaviors, as well as prescription drug abuse, dent often experience withdrawal symptoms on sudden cessation of please see Alford et al and the Boston University School of Medicine the opioid medication. The symptoms range from chills and runny (Massachusetts Consortium) curriculum resources on drug abuse nose to abdominal pain, vomiting, and diarrhea, and the withdrawal and addiction.20 severity can be measured by using a Clinical Opioid Withdrawal Scale (COWS).24 It is important to understand that the presence of withdrawal symptoms only indicates physical dependence and not MONiTORiNG PATi NT ADH R NC TO TR ATM NT necessarily abuse or addiction. Although opioid withdrawal is not usually life threatening, physicians should minimize the appearance Setting ground rules prior to the initiation of opioid medication is of withdrawal symptoms by gradually tapering the opioid dosage, critical. Discussing the patient’s expectations, obtaining informed often over a period of weeks. For patients who cannot tolerate opioid consent and a treatment agreement (formerly referred to as a “con- tapering due to intolerable pain or intense and prolonged withdrawal tract”), identifying clearly the clinic’s policy regarding refills and symptoms, long-acting opioid agonists can be used during inpatient office visits, and emphasizing the practice of random urine drug or outpatient withdrawal management. These medications include testing—for both the patient’s and the treatment team’s bene- methadone and buprenorphine. Maintenance treatment of opioid fit—are all common rules to establish at the beginning of office dependency is defined as long-term administration of an opioid agobased opioid dependence treatment.21,22 When utilizing any of these nist or opioid antagonist to achieve abstinence from mostly injected tools, the physician must be aware of their indications and limita- heroin or prescription narcotics. Methadone treatment must follow tions. For example, urine drug testing can measure the adherence strict federal regulations, and all outpatient treatment programs must to the prescribed opioid medication regimen. The absence of the be certified by the federal SAMHSA and registered by the Drug prescribed drug on testing may indicate diversion of the drug, but Enforcement Administration (DEA) in order to prescribe methadone some drug tests do not detect synthetic opioids, such as OxyContin®, for opioid detoxification. or the concentration falls below the cut-off value of the measured drug. It’s therefore recommended to consult with a Medical Review In 2002, the FDA approved buprenorphine for office based opioid Officer—a licensed physician certified to verify the validity of treatment. Buprenorphine is a partial mu-opioid receptor agonist the drug test results submitted to a laboratory. Furthermore, it is with high binding affinity and its ceiling effect prevents accidental important to access the statewide electronic database, or Prescription overdose. Most physicians need to undergo a training and certifiDrug Monitoring Program ( PDMP), which collects designated data cation program to prescribe buprenorphine products for the treaton controlled substances dispensed in the state. The benefits of a ment of opioid dependence, including withdrawal management.25 PDMP: to access legitimate medical use of controlled substances; to Methadone and buprenorphine permit for once-daily dosing that identify and deter or prevent drug abuse and diversion; to facilitate reduces cravings and withdrawal sensations without reinforcing and encourage the identification, intervention with and treatment addictive behaviors. They are also effective medications for treatof persons addicted to prescription drugs; to inform public health ing pain. It’s important to emphasize that both products represent initiatives through outlining of use and abuse trends; and to educate medication assisted approaches in the treatment of opioid depenindividuals about PDMPs and the use, abuse, and diversion of and dence that includes cognitive behavioral therapy (CBT ), substance addiction to prescription drugs.23 abuse counseling, and psychological or psychiatric therapy. Other

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PAIN&CHEMICAL DEPENDENCY

The easiest part of stopping drug use is stopping. The hardest part is staying stopped.

products used in the management of opioid withdrawal, although those in professional occupations who struggle with addiction (ie, not FDA approved, include alpha2-adrenergic agonists, such as clon- attorneys, pilots, and physicians). International Doctors in Alcoholics idine and lofexidine,26 which decrease the autonomic hyperactivity Anonymous ( IDAA) refers to the latter group (www.idaa.org). associated with withdrawal during opioid taper. Other medications, such as baclofen, have shown promise in the reduction of both the One of the authors ( HA) has developed a 3-visit model28 for physiphysical and mental distress of opiate withdrawal.27 After successful cians to administer to help patients better manage overall stress and withdrawal treatment, long-acting monthly depot injections of nal- has adapted this model for use with patients with chronic pain. The trexone can suppress cravings in a selected subpopulation of opioid 4 strategies used in this model are evidence based and were selected from the literature as being highly effective in the reduction of overdependent individuals. all distress, regardless of the source. These strategies are cognitive restructuring, mindfulness, diaphragmatic breathing, and a brief 12 ST P PROGRAM relaxation/imagery exercise. We will focus on one of these strategies, cognitive restructuring, in this article. For more information, and Whether the patient with an SUD is on a narcotic medication or illustrations like the following, please see Management of the Addicted not, or following weaning or more formal drug rehabilitation, it is Patient in Primary Care.3 imperative these patients be referred to the community “fellowships” of Narcotics Anonymous ( NA) or Alcoholics Anonymous (AA). Due to what AA calls the “cunning, baffling, and powerful” nature of COGNiTiV R STRUCTURiNG addiction, patients are at high risk of relapse, or increased use of medication, if they are not actively engaged in attending these 12 Step Cognitive restructuring is a core component of CBT. CBT has been programs. Unlike traditional therapy, these programs have no leaders shown to be highly effective in the reduction of pain as well as in or designated counselors. Meetings are usually 1-hour in duration, are addictive cognitions and behaviors. Best yet, one does not have to free of charge, and are widely available in every city around the world. be a mental health provider to teach patients about this core techFor more information see: www.aa.org or www.na.org. Literature to nique; indeed, educating patients about cognitive restructuring can print and give patients is available on these sites. These authors rec- be accomplished by the physician in a short period of time—even ommend How It Works (AA) and/or the White Booklet ( NA) as great in a busy practice. starting points. It is also helpful for the provider to ask patients who are attending these meetings if they are “working the steps,” if they Put simply, the idea behind cognitive restructuring is essentially that have a “sponsor,” and how the meetings are going in general for them. our thoughts create our feelings which, in turn, influence behaviors It is well-known that patients tend to view as important what their and physical sensations, such as pain. By changing negative cognitions physician views as important, so regular inquiry into their experience (or “negative self-talk”) into more balanced cognitions, we will feel is essential. There are also subgroups in AA that target specifically less distressed and, consequently, perceive less pain.

e e

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e e

COGNiTiV R STRUCTURiNG EXAMPL

The following is an illustration of how a physician might introduce these concepts to his patient with pain and SUD: Doctor: Hello, Joe. The nurse just told me you ran out of your medication again and were not going to leave until you got a new prescription. Is that how you feel? Joe (agitated): Yes, that’s how I feel! I’m not going to be able to get through the weekend without my medication, Doc. You know that. Doctor: Sounds like you are really worried, Joe. I’ve known you for a while, and I am really concerned because this is the second time you have run out of your meds early. And we’ve also discussed the fact that you realize you suffer from the disease of addiction. Joe: I know…I’m really sorry. I know I’m not following our agreement as well as I should and I’m really glad you haven’t kicked me out of the practice yet. I’m 3 days short on my medication. I guess when I’m stressed I take an extra dose and I know that’s wrong. Doctor: What are the kinds of things that stress you out, Joe? Doctor is using communication skills aimed at decreasing patient’s defensiveness Joe: I’m worried my wife is going to get tired of all this and just leave me. I’m stressed because I think my pain is never going to get any better and what will I do then? Doctor: I can see how those thoughts create feelings of anxiety. Can we take a few minutes so I can teach you something? Doctor is setting up introduction to cognitive restructuring techniques Joe: Sure…OK . Doctor: Great! Before we begin, would you please rate your pain for me right now? Joe: It’s about an 8. Doctor: That is pretty severe pain and I know you must feel terrible. Pain affects all areas of our lives. (Joe nods,

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head down). So, Joe, I think what I’m going to teach you will help you feel better. You know how you just told me about your fear that your wife will leave and your pain will never get better? Thoughts create feelings and you can see how those thoughts caused you to feel really anxious and worried, correct? (Joe nods, bringing his head up to meet Doctor’s gaze). Doctor is using an empathic approach to briefly teach patient core elements of cognitive behavioral therapy Doctor continues: And those feelings of anxiety can cause a person to start to become really agitated and panicky— like you were when you spoke to the nurse earlier—and can cause your pain to get worse. Does this make sense? (Joe nods) And in people who have the disease of addiction, it’s even worse: the more anxious you become, the more likely you are to… Joe: …want to take more drugs. Doctor: Yes! You’re getting this, Joe—good work. So, thoughts create feelings. In particular, thoughts about the future create anxiety and thoughts about the past tend to create feelings of depression, guilt, resentment, and so on. All distressing feelings cause pain to increase. So to stop this cycle, we need to ask ourselves, “What can I tell myself about the situation to make me feel less anxious or angry or sad.” What can you tell yourself about your fear that your wife will leave or that your pain will never get better? Doctor uses positive reinforcement—“good work”—and teaches patient about cognitive restructuring and the relationship between thoughts, feelings, and perceptions of pain Joe (long pause): Well…I do have a part of me that knows I’m going to be OK , no matter what. So, I guess I could tell myself, “I just have to stay in the moment and trust that everything will work out.” Did I do that right? Doctor: Perfectly. Joe—without thinking about it, really quickly, rate your pain right now? Joe: Um…it’s…it’s about a 5.

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Eventually we will find (mostly in retrospect, of course) that we can be very grateful to those people who have made life most difficult for us. —Ayya Khema

Doctor: That’s wonderful! Do you see you went down 3 points on the scale just by changing your negative thoughts to more hopeful, rational ones? Having patients rate their pain before and after learning cognitive restructuring can provide them with wonderful feedback and gives control over pain back to the patient Joe (smiling): Seems so simple…but it sure is hard to do, isn’t it? When I’m feeling really anxious, all I hear is the negative stuff. Doctor: And that’s normal. You’re doing great, Joe. Now what would that hopeful, rational part of you tell you about taking extra doses—especially when you have the disease of addiction? (Note: Author HA has often used a patient’s spiritual beliefs, such as God or Higher Power or The Universe, to help him/ her come up with a way to refute negative, reactive cognitions, with excellent results)

Doctor: I completely agree. So here’s what we’re going to do, Joe. I would like you to practice changing negative, reactive self-talk to hopeful, rational thoughts every day. I am going to ask you about how you’re doing with this at your next visit, OK? (Joe agrees) Secondly, as I mentioned when you first started treatment with me, the medication agreement is like a binding contract between us, and you’ve broken it twice. Since I know you, and you’ve been so open and cooperative today and I really do think you want to do what’s right, I’ll give you 3 days of medication. I’d like you to come back on Monday to see me so I can give you your next prescription. However, if this happens again, or the agreement is broken in any other way, I’ll need to do what I think best at that time. And at our next visit we are going to look into other medications to help control your pain that will also help you to achieve your goal of never going back to that active place of addiction, OK?

Doctor now moves to help patient cognitively restructure addictive cognitions

Doctor gives cognitive restructuring “homework” to patient while also setting firm boundaries based on Doctor’s best judgment and relationship with this patient. Doctor also sets up next conversation about changing current opioid medication to either methadone or buprenorphine

Joe (replies quickly): It would definitely tell me not to do it! I know where that will lead and I don’t want to go back there again.

Joe: I’m not crazy about that idea, I gotta be honest, Doc—but I trust you and know that the hopeful, rational part of me would say that you’re right.

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The preceding was only an illustration of one way that cognitive restructuring could be implemented with patients like “Joe” in your own practice. Of course, the above should be adapted to each reader’s own comfort level and relationship with each individual patient, especially in terms of how to handle a second medication agreement violation.

CONCLUSiON By conducting a thorough risk assessment, making an accurate diagnosis, formulating a clear management plan, setting firm boundaries while also being empathic, and by providing the patient with SUD resources and support, many of our “dread to treat” patients may actually become some of the patients we most look forward to seeing. References 1.

Groves JE . Taking care of the hateful patient. N Engl J Med. 1978;298(16):883–887.

2. Shahady EJ . Uncovering the real problems of crocks and gomers. Consultant. 1984;24(4):33–43. 3. Pomm (Allespach) HA , Pomm RM . Management of the Addicted Patient in Primary Care. Springer: New York; 2007. 4. Shanafelt TD, Boone S, Tan L, et al. Burnout and satisfaction with work-life balance among US physicians relative to the general US population. Arch Intern Med. 2012;172(18):1377–1385. 5. National Institute on Drug Abuse. DrugFacts: Nationwide Trends. Revised January 2014. Available at: www.drugabuse.gov/publications/drugfacts/nationwide-trends. 6. Substance Abuse and Mental Health Services Administration. Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings. NSDUH Series H-46, HHS Publication No. (SMA ) 13–4795. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2013. 7. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. Treatment Episode Data Set ( TEDS): 2000–2010. National Admissions to Substance Abuse Treatment Services. DASIS Series S-61, HHS Publication No. (SMA ) 12–4701. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2012.

15. 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. 16. Butler SF, Budman SH, Fernandez KC , et al. Development and validation of the Current Opioid Misuse Measure. Pain. 2007;130(1–2):144–156. 17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition. Arlington, VA: American Psychiatric Association; 2013. 18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. DSM - IV-TR . Washington, DC: American Psychiatric Association; 2000. 19. Pretorius RW, Zurick GM . A systematic approach to identifying drug-seeking patients. Fam Pract Manag. 2008;15(4):A3-A5. 20. Alford D, Jackson A, Liebschutz J, et al. Prescription Drug Abuse: An Introduction. Boston University School of Medicine (Massachusetts Consortium). November 8, 2009. Available at: www.drugabuse.gov/sites/default/files/prescription-drug-abuse_ an-introduction.pdf 21. Chou R. 2009 Clinical Guidelines from the American Pain Society and the American Academy of Pain Medicine on the use of chronic opioid therapy in chronic noncancer pain: what are the key messages for clinical practice? Pol Arch Med Wewn. 2009;119(7–8):469–477. 22. Colson J, Helm S, Silverman SM . Office-based opioid dependence treatment. Pain Physician. 2012;15(3 suppl): ES 231- ES 236. 23. U.S. Department of Justice/Drug Enforcement Agency. Office of Diversion Control. State Prescription Drug Monitoring Programs. Questions & Answers. Available at: www.deadiversion.usdoj.gov/faq/rx_monitor.htm. 24. Wesson DR , Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 2003;35(2):253–259. 25. Substance Abuse and Mental Health Services Administration. Buprenorphine. Physician Waiver Qualifications. Available at: buprenorphine.samhsa.gov/waiver_ qualifications.html. 26. Gerra G, Zaimovic A, Guisti F, et al. Lofexidine versus clonidine in rapid opiate detoxification. J Subst Abuse Treat. 2001;21(1):11–17. 27. Ahmadi-Abhari SA . Baclofen versus clonidine in the treatment of opiates withdrawal, side-effects aspect: a double-blind randomized controlled trial. J Clin Pharm Ther. 2001;26(1):67-71. 28. Family medicine’s stress management program targets healthy mind and body. University of Miami Health System. Miller School of Medicine. Available at: med.miami.edu/news/family-medicines-stress-management-program-targets-healthymind-and-body.

8. Centers for Disease Control and Prevention (CDC ). Vital signs: overdoses of prescription opioid pain relievers— United States, 1999–2008. MMWR Morb Mortal Wkly Rep. 2011;60(43):1487–1492. 9. American Society of Addiction Medicine ( ASAM). For the public: definition of addiction. Public policy statement. Available at: www.asam.org/for-the-public/ definition-of-addiction. 10. Volkow ND, Warren KR . Drug addiction: the neurobiology of behavior gone awry. In: Ries RK , Flellin DA , Miller SC , et al, eds. The ASAM Principles of Addiction Medicine. Fifth Edition. Alphen aan den Rijn; the Netherlands: Wolters Kluwer; 2014:3–18. 11. Nielsen DA , Ji F, Yuferov V, et al. Genome-wide association study identifies genes that may contribute to risk for developing heroin addiction. Psychiatr Genet. 2010;20(5):207–214. 12. Argoff CE, Viscusi ER . The use of opioid analgesics for chronic pain: minimizing the risk for harm. Am J Gastroenterol. 2014;2(1):3–8. 13. Butler SF, Fernandez K, Benoit C, et al. Validation of the Revised Screener and Opioid Assessment for Patients in Pain (SOAPP-R). J Pain. 2008;9:360–372. 14. Staley D, El-Guebaly N. Psychometric properties of the Drug Abuse Screening Test in a psychiatric patient population. Addict Behav. 1990;15:257–264.

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by Allen

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John Togut MD

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eXPeRT OPiNiON

“A biopsychosocial approach, including the patient’s own narrative, offers the best understanding of how the disease affects the individual.”

abstract: In the past, many in medicine had been

skeptical of the diagnostic validity of neurogenic thoracic outlet syndrome (NTOS). Now it is recognized as a valid medical entity. I have had 25 years of experience with NTOS, first as a surgeon and most recently in an office-based practice. I would like to share with you my understanding of its pathogenesis, diagnosis, and treatment. A biopsychosocial approach, including the patient’s own narrative, offers the best understanding of how the disease affects the individual. This understanding drives the best individualized treatment approach.

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EXPERT OPINION

is an entrapment neuropathy of the brachial plexus C5-T1 nerves. It develops from trauma(s) primarily to the sensory portion of the plexus, although there are cases of injury to the motor nerves as well. Because a-delta sensory fibers are hardwired to the motor neurons, sensory injury impacts motor functioning. This trauma occurs in the context of anatomical variations in the interscalene, costoclavicular, and coracopectoral muscle regions. Clinically, the syndrome manifests as pain across the shoulder and chest wall and down the arm, with tingling and numbness of the arm, hand, and fingers. Progressive muscle weakness and disability of the upper extremity are made worse by repeated use of the extremity. e e

PATHOG N SiS A single trauma such as a motor vehicle accident, or recurrent traumas such as repetitive strain injury from working on an assembly line, causes muscle spasm and foreshortening as well as myofascial dysfunction with trigger points. The shoulder commonly falls downward and forward with the head tilting to the same side. This causes a pull on the peripheral nerve which restricts plexus movement. Spasm and shortening of the scalene muscles results in elevation of the first rib. Anterior scalene muscle fibers are frequently attached to C5 and C6 nerves as they travel through this muscle. These attachments will restrict nerve movement.

the patient abduct the ipsilateral arm to as high as possible up to 90 degrees, then dorsiflex that wrist. All these maneuvers create a pull on the plexus. Pain and paresthesia of that extremity define a positive test, because the plexus cannot glide normally. 3. Thumb pressure on the plexus above and below the clavicle and its peripheral branches—ulnar, median, and radial nerves—may elicit pain and paresthesia. If it does, this is a positive Tinel sign and indicates irritability of the plexus and peripheral nerves. Frequently, there is involvement of these peripheral nerves, since they are the same nerve fibers that are in the plexus.

Trauma also creates hemorrhage about and into the nerves with edema and subsequent scarring. This further restricts the movement of the plexus. The trauma occurs in the setting of anatomical 4. In the elevated arm test, or Roos test, the patient places her arms in the surrender position and opens and closes her variations in the structure and insertions of the anterior and middle hands slowly. It is a timed 3-minute test. Pain and paresthescalene muscles. These scalenes form the 2 sides of a triangle with the sia occurring early in the test usually defines a positive test. base formed by the first rib. The brachial plexus and the subclavian artery pass through this triangle. Additionally, connective tissue bands and occasionally a cervical rib impinge upon the plexus and 5. The symptomatic arm is abducted and the patient may develop pain, paresthesia, and loss of the radial pulse. This artery in this triangle. Thus, a restrictive entrapment results from may implicate the pectoralis minor tendon as the culprit. trauma superimposed upon these anatomical variations. Attempts to move the arm and shoulder create the symptoms of pain and 6. For sensory assessment: use brush and pin over the derparesthesia. matomes of the plexus C5-T1 to determine sensory loss (hypothesia), gain (hypesthesia), allodynia, or allopathia. Also, check the 2-point discrimination of the fingers of the DiAGNOSiS BY PHYSiCAL EXAMiNATiON hands (normally 2 to 3 mm). Careful physical examination provides the opportunity to reproduce the patient’s symptoms. This yields a definitive diagnosis. The following is a basic examination: R L VANT LABORATORY T STS US D TO 1. Note the position of the shoulders, head, and neck. CONFiRM TH DiAGNOSiS

2. A nerve tension test may yield reproduction of the patient’s symptoms by tilting the head to the opposite side. Then have

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→ Anterior posterior cervical spine X-ray may show an elongated transverse process of the C7 vertebra or a cervical rib. Q4 | 2014

“A restrictive entrapment results from trauma superimposed upon these anatomical variations. Attempts to move the arm and shoulder create the symptoms of pain and paresthesia.”

→ Somatosensory evoked potential may confirm the sensory nerve injury. → A pain nerve fiber (a-delta or c-fiber) conduction study will define the specific nerve dysfunction.1 → As compared to regular MRI of the brachial plexus, MR neurography of the brachial plexus better demonstrates the involved nerves and the compressive bands, muscles, and bone which impact upon these nerves.2 → Electromyography/nerve conduction studies have only 30% sensitivity. Without visible muscle loss these studies are unlikely to be positive. → Finally, anterior scalene muscle paralysis using lidocaine releases the spasm of this muscle allowing the first rib to descend and transiently improves symptoms and may confirm the diagnosis of NTOS.

TH RAPY With the diagnosis made and the impact on the patient (and the family) understood, attention can be turned to treatment. This is challenging. The patient is generally angry, miserable, in pain, and depressed. He has seen many practitioners, been given many different diagnoses, tried many treatments including surgery with only worsening of the pain and increased limited functioning of the extremity. His coping Q4 | 2014

ability has been severely strained. Often the patient is made to feel that he is at fault, or that the problem is not real. He is beaten and fragile and hurting. So what can the clinician do? Approach this person with sensitivity. The most important step is to educate the patient and family about the diagnosis, and how it developed, using clear language. Engage him and his family in understanding that the success of the treatment depends on him and that you will be his guide. The following are the steps I give the patient: 1. ADAPT: Change what you are doing and how you are doing it. Identify which activities using arms makes symptoms worse. Commit to limit, but not avoid, these activities completely. Keep a diary; it is a useful tool. 2. PACE: Increase the time frame allowed for an activity, and decrease its frequency, always listening to your body’s response. 3. DELEGATE: Give to others tasks which accentuate the symptoms. 4. Employ pharmacy to modify pain, facilitate sleep, and treat depression. These problems need early attention, or treatment failure is likely. 5. Cognitive behavior therapy helps to clarify misunderstandings and helps shift negative thoughts towards positive thoughts and actions. www.painweek.org | PWJ | 27

EXPERT OPINION

6. Controlled myofascial therapy may help release and lengthen muscles and modify trigger points. This may lead to improved posture and reduced symptoms. It is critical to perform this therapy without increasing nerve tension and symptoms. 7. Biofeedback, desensitization, visualization, meditation, mindfulness, and controlled exercise programs might be of benefit. 8. Paralysis of the scalene muscles with onabotulinumtoxin A may give 2 to 3 months of improved symptoms.3 If these therapies do not reduce symptoms then consider a surgical approach. But a careful benefit/burden discussion needs to be had with patient and family. Surgery can help many patients with NTOS but cure is unusual. Urgent surgery is indicated, however, if there is muscle wasting in the hand, as in the case of compression of the lower trunk of the brachial plexus by a cervical rib. Also, if it is shown on examination that compression of the plexus or the subclavian artery by the pectoralis minor muscle creates the symptoms, a tenotomy of that tendon is indicated.

1 |

“Pain clinicians are also pain educators, and it’s critically important for them to understand the basic principles of instructional systems development or instructional design. One approach that I like is the ADDIE model, which stands for analysis, design, development, implementation, and evaluation. One of the most important and most overlooked steps is analyzing the audience. The clinician/educator needs to think through who they’re talking to, what’s their educational background, why do they need to know this, how is the best way to explain and convey.”

In short, make sure the patient goes to surgery with only realistic expectations.

CONCLUSiON Engage the patient with sensitivity. Listen carefully to their narrative. Do a good neurological examination. Communicate with the patient about their role in helping themselves, as well as about available therapies. With you as their guide you can significantly help the patient take charge and cope with this chronic disabling condition.

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1. Hedgecock J, Kelly J, Taub L. Textbook of Pain Electrodiagnosis. Pain Fiber Nerve Conduction Study. Laguna Beach, CA: AASEM Journal Publications; 2010.

3. Jordan SE, Ahn SS, Freischlag JA , et al. Selective botulinum chemodenervation of the scalene muscles for the treatment of neurogenic thoracic outlet syndrome. Ann Vasc Surg. 2000;14(4):365–369.

Psychological Contributors to Pain Jennifer A. Haythornthwaite, PhD

“We have found that even subclinical levels of anxiety and depression can be important in terms of the experience of pain. Another factor that we spend a lot of time investigating in the pain research world is pain related catastrophizing. It has a pervasive effect on people’s ability to manage pain. It is an emotional response to pain but it’s also a cognitive attentional response to pain, in which people become very focused on pain. They have a hard time distracting themselves and breaking their attention away. They also feel very helpless, as though there’s not much they can do to manage their pain.”

References

2. Filler AG, Johnson JP, Villablanca P, et al. MR neurographic findings in diagnosis of thoracic outlet syndrome. Paper presented at the Congress of Neurological Surgeons Annual Meeting; September 27-October 2, New Orleans, LA . Neurosurgery. 1997;41:724.

Instructional Design and Pain Education Mary Lynn McPherson, PharmD, BCPS, CPE, FASPE

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Arm and Hand Pain Sri Nalamachu, MD

“With increased use of technology, like computers and mobile phones, we see a significant increase in carpal tunnel syndrome and tendon problems like tendonitis of the wrist and elbow. The primary care physician should understand what they are dealing with when somebody presents with elbow or hand pain, and what they can do or where they can get the help of a specialist, such as a physiatrist or a neurologist.”

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Reference: 1. Prescribing Information for MOVANTIK. AstraZeneca Pharmaceuticals LP, Wilmington, DE.

mple ials. o .c sam ater p c cess d m h it kto ac relate n rst cta u ovthe ďŹ prod m ng /or t i s amon and i V e b io to mat r fo n i

MOVANTIK is a trademark of the AstraZeneca group of companies. ÂŠ2014 AstraZeneca.

3035622

10/14

by Tanya

J. Uritsky PharmD, BCPS

James Mary

B. Ray PharmD, CPE

Lynn McPherson PharmD, BCPS, CPE, FASPE

PHARMACOTH RAPY

“ THeY ARe NOT GeNeRALLY CHOSeN AS FiRST-LiNe AGeNTS BeCAUSe OF THe PHARMACOKiNeTiC AND PHARMACODYNAMiC iNTRiCACieS THAT MUST Be ACCOUNTeD FOR PRiOR TO AGeNT SeLeCTiON AS WeLL AS DURiNG TReATMeNT.“ There are many patients whose pain will be manageable with standard medication modalities. Unfortunately, there occasionally will come a patient whose pain is refractory to standard therapies. In these situations, it is imperative that the clinician is aware of other medication modalities that may be available to provide some relief of severe pain. Methadone, ketamine, and lidocaine are agents that are often reserved for refractory pain syndromes. They are not generally chosen as first-line agents because of the pharmacokinetic and pharmacodynamic intricacies that must be accounted for prior to agent selection as well as during treatment. Additionally, practitioners may not be comfortable using drugs with which they do not have experience or if they are unfamiliar with the evidence supporting their use. Education about the pharmacology and clinical application of these drugs is essential to appropriate and safe utilization. abstract:

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PHARMACOTHERAPY

patients with very limited prognoses (eg, actively dying) may die before getting the full benefit from methadone. Methadone also has many drug-drug interactions and thus should be avoided or extremely closely monitored in patients that are concomitantly receiving agents that interact with methadone metabolism. As methadone has the propensity to prolong the QTc interval, patients with a history of syncope or arrhythmia would not be good candidates for therapy. Finally, patients who are nonadherent or unreliable should not be treated with methadone.

Opioid-Naïve Considerations Often providers reserve methadone for the refractory pain patient. Methadone can, however, also be an excellent choice in opioid-naïve patients. It is important to be mindful of dosing and start low. Methadone has been available for over 6 decades. It is a racemic Recently, the American Pain Society released recommendations for mixture of R- and S-methadone and it separates itself from the opioid the management of methadone in chronic pain.1 The recommended medications as it is a mu-receptor agonist as well as a N-methyl-D- opioid-naïve dosing for methadone is 2.5 mg by mouth every 8 to aspartate ( NMDA) receptor antagonist. NMDA receptor antago- 12 hours. Once-daily dosing may be appropriate in frail older adults nism is thought to enhance methadone’s role in the treatment of or in those who are taking cytochrome P450 enzyme inhibitors. neuropathic pain as well as in managing patients with suspected Titration of dosing should not be more frequent than every 5 to opioid induced hyperalgesia. Methadone is an attractive choice for 7 days and initially no more than by 5 mg per day. Once patients patients with refractory or uncontrolled pain because it displays these reach 30 to 40 mg per day, titration by 10 mg daily can be considered. alternative mechanisms of action. Careful thought should be given to increasing doses to greater than 40 mg per day as the risk of overdose is increased at higher doses. All patients should receive education and counseling on therapeutic goals, monitoring, and methods for risk reduction.

Mechanism of Action

Agent and Patient Selection

Methadone is most often recognized for its role in maintenance of opioid dependent patients. For this reason, when presented to pain patients as a therapeutic option, it is not always received with open arms. What is most interesting is that many of the reasons that make it a good agent for maintenance therapy are the same reasons that it is an excellent selection for the treatment of chronic pain. Methadone is a very potent agent, so a little goes a long way, and doses are generally less than 30 mg per day, making it an excellent choice for patients experiencing opioid induced adverse effects. It comes in an oral solution formulation, which makes it an option for patients with swallowing difficulties or who require administration through gastrostomy or jejunostomy tubes. It also has a long duration of action, allowing for dosing sometimes as infrequently as once daily, but more often 2 to 3 times daily. Finally, in addition to its demonstrated efficacy, methadone is inexpensive, making it an ideal analgesic for patients on limited incomes, hospice providers, and just about anyone. Patient selection is critical to attain efficacy and safety when initiating and maintaining patients on methadone for pain. Patients with a true morphine allergy should be considered for methadone as it is fully synthetic and does not display cross-reactivity of allergic response. Methadone does not have any significant metabolites and is eliminated through the feces, making it a reasonable option in patients with significant renal impairment. It is important to note which patients may not be good candidates for methadone therapy. As methadone does take 5 to 7 days to reach steady-state concentrations,

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QTc Monitoring Baseline ECG should be obtained in all patients with risk factors for QTc prolongation (see Table). Risk factors for QTc prolongation include electrolyte abnormalities (hypokalemia, hypomagnesemia), impaired liver function, structural heart disease, genetic predisposition, or use of other drugs with QTc prolongation potential.1 It is recommended to not use methadone in patients with a QTc of greater than 500 ms. For a QTc interval between 450 ms and 500 ms, clinicians should evaluate reversible causes and consider an alternative opioid if unable to reverse any causes.

Methadone Conversions Conversion to methadone from other opioids is not linear. The higher the opioid dose that a patient is receiving, the more potent methadone will become. This increased potency is due to differences in chemical structure and binding affinity leading to a lower level of cross-tolerance between methadone and other opioids. There are multiple conversion methods available—all of which can potentially be used safely.2-4 No matter what method one uses to convert to methadone, it is most important to remember to use caution and not to start a patient on more than 30 mg a day of methadone regardless of what conversion calculation you perform. You can keep your conversion as a possible target dose and titrate to that dose if needed, Q4 | 2014

keeping in mind the 5 to 7 day time frame. Methadone should be withheld if there is evidence of sedation.

Table. Methadone: ECG Monitoring Recommendations1 Obtain baseline ECG in patients with »» Risk factors for QTC prolongation »» Any prior ECG with a QTc >450 ms »» A history suggestive of prior ventricular arrhythmia Note: An ECG within the past 3 months with a QTc <450 ms and no new risk factors for QTc prolongation can be used as baseline Consider baseline ECG in patients »» With no known risk for QTc prolongation Note: An ECG within the past year with QTc <450 ms and no new risk factors for QTc prolongation can be used as baseline Follow-up ECG monitoring »» In patients with risk factors for QTc prolongation or a history of syncope, ECG in 2 to 4 weeks after methadone initiation and with significant dose increases »» When methadone dose reaches 30 to 40 mg/day and again at 100 mg/day »» If there are new risk factors for QTc prolongation or signs suggesting arrhythmia

Efficacy The safety concerns having now been well established, there is also plenty of evidence supporting the efficacy of methadone for pain management. In one study of hospice patients receiving 5 mg of morphine every 4 hours, low-dose methadone was added on to their regimen and they reported excellent pain control without dose escalation or opioid induced hyperalgesia.5 In a Cochrane Review of cancer pain, methadone was shown to have similar efficacy to morphine in 9 randomized clinical trials.6 Methadone also held its own in noncancer pain, reported as only slightly less effective than other long-acting opioids and significantly superior to placebo.7,8 In a study of 19 palliative care patients, by 7 days after rotation to methadone, pain scores decreased by 4 points and patients reported moderate to greater than moderate pain relief with methadone therapy.9 In another study, methadone was also shown to provide analgesia when used as an adjuvant to an established opioid regimen—providing a decrease in pain scores of at least 2 points in 75% of patients.10 Finally, when methadone cannot be given orally, it has been shown to be effective and well tolerated when given buccally.11

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Ketamine has been shown to reduce pain in postherpetic

neuralgia, cancer pain, procedural pain, complex regional pain syndrome (CRPS), orofacial pain, and phantom limb pain. The literature for chronic ketamine use will not be reviewed here, but it is most important to weigh the risks vs the benefits as the effects of long-term ketamine use are not well understood. Ketamine should be considered when the patient has neuropathic pain (including phantom limb pain), hyperalgesia or allodynia; responded poorly to opioids; or has a history of high opioid consumption preceding injury or surgery.

Mechanism of Action Ketamine has a few different mechanisms of action. It functions as an NMDA receptor antagonist in the dorsal horn as well as has activity at opioid receptors, inhibits excitatory neurotransmitters, and inhibits the reuptake of dopamine and serotonin. The NMDA receptor becomes active when the axon depolarizes and magnesium is displaced from the NMDA receptor site. This activity contributes to central sensitization and, thus, ketamine is used largely for its antitolerance, antihyperalgesic effects.

Pharmacokinetics Ketamine is highly lipid soluble and has rapid onset within a minute after intravenous administration. The duration of action is 60 minutes and is dose-related. The half-life is 2 to 3 hours. When administered orally, ketamine goes through extensive first pass metabolism and has a bioavailability of about 17%. The oral metabolite, norketamine, is a potent analgesic.

Dosing Dosing for analgesia is significantly lower than that used for anesthesia. The analgesic dosing range for intravenous ketamine is between 0.1 to 0.5 mg/kg/hour. It is generally given up to 600 to 700 mg over 24 hours as a maximum dose for analgesia. To put this in perspective, the dosing for anesthesia or sedation is in the 1.5 to 4.5 mg/kg/ hour range. www.painweek.org | PWJ | 35

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“ TWeNTY-FOUR HOUR PATieNT-CONTROLLeD ANALGeSiA CONSUMPTiON DeCReASeD 30% TO 50% WiTH KeTAMiNe USe AND WAS ASSOCiATeD WiTH A ReDUCeD iNCiDeNCe OF POSTOPeRATiVe NAUSeA AND VOMiTiNG. ADVeRSe eFFeCTS iN THiS POPULATiON WeRe MiLD OR ABSeNT.” While there is no oral preparation, the intravenous preparation can also be administered orally, when mixed with orange juice. The dosing is 10 to 25 mg by mouth 3 to 4 times daily. When converting from IV to oral, the dose ratio can be 1:1 due to the potent analgesic activity of the metabolite, norketamine.12

Pharmacodynamics Ketamine use has been associated with arrhythmias, elevation in intracranial pressure, increased salivation, nausea and vomiting, increased intraocular pressure, central nervous system depression, and spontaneous involuntary movements. Approximately 12% of patients will experience emergence reactions, for which pretreatment with a benzodiazepine will decrease incidence by 50%. Risk factors for the emergence reactions include age greater than 15 years, female gender, dose of greater than 2 mg/kg, and a history of a personality disorder.12

Efficacy e

CANC R PAiN —There

have been several trials done supporting the benefit of ketamine in cancer pain. Much of the data is through uncontrolled trials and case reports, but there are a few randomized

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controlled trials to date, the results of which are inconsistent. In a study by Mercadente et al ketamine bolus dosing reduced pain scores and provided pain relief for up to 12 hours.13 In studies by Yang et al and Lauretti et al in a systemic review by Bredlau et al, an opioid-sparing effect was demonstrated but there was no decrease in pain scores.14 A more recent randomized controlled trial by Hardy et al failed to show any difference in pain control but did show a worsening of toxicity in those patients receiving ketamine infusions.15 This particular study is limited in generalizability. The patients were on a maximum of 480 mg of oral morphine equivalents daily—generally lower than the amount at which we might consider the need to reach for ketamine. First, we might consider an opioid rotation or the utilization of methadone. There was no opioid titration in the 48 hours

Box. Case Study: Ketamine MC is a 58-year-old man with metastatic melanoma, extensive bone metastases, and inguinal/retroperitoneal lymphadenopathy. He has a history of heroin and cocaine use, and has been on a methadone maintenance program since 2005. He is admitted to inpatient hospice unit with severe, refractory pain and increasing weakness. His regimen on admission is methadone 35 mg by mouth every 6 hours, hydromorphone 16 mg by mouth every 2 hours as needed, and dexamethasone 4 mg by mouth daily.

Over the course of 10 days, the following changes were made to his regimen: »» Methadone titrated to 80 mg by mouth every 6 hours »» Dexamethasone 4 mg by mouth twice daily »» Intravenous (IV) hydromorphone, using 10 to 14 mg/hour »» Fentanyl 300 mcg/hour transdermal patch every 72 hours »» Clonazepam 2 mg by mouth every 12 hours »» Gabapentin 600 mg by mouth every night at bedtime Result: No change in pain (7 to 8/10), and no increase in function Treatment plan: »» Initiate ketamine 10 mg IV bolus, 0.2 mg/kg/hour (60 kg, 12 mg/hour) »» Lorazepam 0.5 mg IV at 1 hour prior, then by mouth twice daily Result: The patient is more relaxed, but not sure if pain has improved. He is slightly drowsier, with no hallucinations »» 30% decrease in IV hydromorphone »» Methadone 60 mg by mouth every 6 hours Result: He is able to move in bed, get to commode; pain 5/10 »» Decreased fentanyl to 200 mcg/hour »» Becomes increasingly lethargic, lives 10 more days

prior to initiation of ketamine, and the median breakthrough medication dosing was 1 to 4 doses per day, again a point at which rotation or even uptitration might be warranted before considering ketamine. Finally, the authors found a statistically significant change in the pain Q4 | 2014

at worst levels, although it was not deemed clinically significant. Since pain scores do not always correlate with functional improvement, it is important that in patients with chronic, severe pain that we consider quality of life as well. POSTOPeRATiVe PAiN —The literature supports the use of ketamine in managing postoperative pain. Specific study indications include total knee arthroplasty, abdominal surgery, musculoskeletal trauma, and nephrectomy.16 The incidence of chronic postsurgical pain was also reduced following laparotomy, thoracotomy, breast surgery, and possibly limb amputation.16 A Cochrane Review analyzed 37 trials of 2240 patients.17 It showed that analgesic doses of ketamine reduced rescue analgesic requirements, pain intensity, or both. Twenty-four hour patient-controlled analgesia consumption decreased 30% to 50% with ketamine use and was associated with a reduced incidence of postoperative nausea and vomiting. Adverse effects in this population were mild or absent. PHANTOM LiMB PAIN/NeUROPATHiC PAiN —Phantom limb pain has neuropathic pathology and when ketamine was studied for use in these patients, 2 small studies found decreased stump and phantom pain.18,19 There was no change in thermal sensitivity. These were patients with chronic phantom pain and they were treated with single doses of ketamine over 40 minutes to 1 hour.

Topical ketamine preparations may also help in neuropathic pain.20,21 When 1% ketamine was compared to 2% amitriptyline, placebo, or combined with 2% amitriptyline, it was found over 4 weeks to decrease pain scores by 1 to 1.5 points on the 11 point scale. Pain relief was sustained over 6 months and 90% of the patients reported satisfaction of use in the open-label study.

Mechanism of Action Lidocaine is a sodium channel inhibitor by convention, but it does much more than simply block sodium channels. It exhibits analgesic, anti-inflammatory, and antihyperalgesic effects. Its analgesic effects depend on the sodium channel inhibition as well as inhibition of potassium channels at low concentrations.22 It has activity at the NMDA receptor and the G protein-coupled receptors and its metabolites inhibit glycine transporter 1.23 Its anti-inflammatory properties are due to the inhibition of granulocyte migration and the decrease in release of proinflammatory cytokines.24 As an antihyperalgesic, it suppresses peripheral and central sensitization.

Practical Considerations for Use

It would be prudent to screen patients prior to initiation of lidocaine for analgesia. It is recommended to screen for allergies, check PROCeDURAL PAiN —Ketamine has been shown to have the most a baseline ECG, and perform liver function tests. Careful thought benefit in procedural pain in the pediatric population. Higher doses should be given to cardiac monitoring during infusion as well. Subprovide safe and effective analgesia compared to opioid based treat- jective reporting of adverse effects can also help the practitioner ment, without the concern for respiratory depression. When ket- gauge the need for lidocaine levels. Commonly at levels of 3 to amine was combined with midazolam it was more effective than an 5 mcg/mL, patients may report a metallic taste, peri-oral tingling, opioid based regimen for pediatric fracture reduction. Additionally, numbness or tingling of the tongue, muscular twitching, tremors, ketamine and midazolam delivered by patient-controlled analgesia is lightheadedness, dizziness, headache, or tinnitus.25 This is importsafe and effective for burn dressing changes in adults.16 There is also ant because at levels greater than 5 mcg/mL, severe adverse effects some more recent data that supports the use of ketamine for painful can occur, including tonic-clonic seizures and cardiac arrhythmias. procedures in the emergency department. Lipid emulsion rescue should be available in the case of lidocaine toxicity.26

Surgical Utilization of Lidocaine Lidocaine was first reported for surgical use in 1962. In randomized controlled trials, it has been shown to lower postoperative pain scores and decrease opioid use.27 It may also result in quicker resumption of bowel motility, although the data is not conclusive.28 A systematic review of IV lidocaine use in postoperative pain management demonstrates the greatest benefit in patients undergoing abdominal surgery.27 A recent trial has also shown positive results in complex spine surgery.29 Some unanswered questions remain about the utility of IV lidocaine in postoperative pain management regarding the optimal Q4 | 2014

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dose and duration of therapy. To date, there is limited evidence comparing the utilization of lidocaine against epidural analgesia.30

Nonsurgical Utilization of Lidocaine COMPLeX ReGiONAL PAiN SYNDROMe—There are data supporting the use of IV lidocaine for the treatment of pain due to CRPS. In a double blind, placebo-controlled trial of 32 patients with CRPS, there was a significant difference in the median pain intensity between those patients receiving a dose of 5 mg/kg of IV lidocaine vs placebo. The difference lasted until the conclusion of the study at 10 hours.31 In a retrospective study of 49 patients with refractory CRPS, lidocaine was given in a gradual upward titration to a blood level of 5 mcg/ mL over 5 days. At 3 months, 76% of patients reported at least a 25% reduction in pain, and, of these responders, 31% had a greater than 50% reduction in pain. There was improvement in dynamic and static mechano-allodynia, deep muscle pain, joint pain, and thermal allodynia.32

a small double blind, placebo controlled study of 15 patients with diabetic peripheral neuropathy, patients received 5 mg/kg and 7.5 mg/kg over 4 hours every 4 weeks.33 There was a significant improvement in pain measured by the McGill Pain Questionnaire, a response which was sustained up to 28 days postinfusion. Another study also showed benefit from lidocaine in this population, supporting an improvement in function out to 14 days and in pain at 3 days.34 In postherpetic neuralgia, a crossover trial showed a decrease in pain scores with 5 mg/kg over 60 minutes.35

mixed data for radical retropubic prostatectomy and an open label study that supports efficacy in laparoscopic ventral hernia repair.44,45 It should be noted that in practice, topical lidocaine is often placed around the site of a wound, which is not effective as it is a local therapy that must be applied at the site of injury or pain. It should never be placed on an open wound.

Future Developments Current studies are looking at a modified form of lidocaine, lidocaine N-ethyl bromide (QX-314). This molecule activates TRPV1/ TRPA1 and opens a pore that allows QX-314 to enter into the cells. Its intent as a cream formulation is to be useful for nonhistamine mediated itch.46 It has also been demonstrated that when QX-314 is combined with bupivacaine, a greatly extended duration of peripheral nerve block can be produced.47

Conclusion

P RiPH RAL N UROPATHiC PAiN —In

Other Potential Uses of Lidocaine e

R NAL COLiC—There is a case report supporting the use of lidocaine

in treating renal colic in patients whose pain is refractory to nonsteroidal anti-inflammatory drugs and opioids.36 In a comparative study vs morphine, lidocaine 1.5 mg/kg resulted in 90% improvement in pain compared to a 70% improvement with morphine 0.1 mg/kg.37 POSTAMPUTATiON —There is a randomized, double blind, placebo control crossover study of 32 patients in which a lidocaine 1 mg/kg bolus followed by a 4 mg/kg infusion significantly reduced stump pain, but not phantom pain.38 FiBROMYALGiA—Lidocaine was generally effective and well-tolerated in a study of patients with fibromyalgia.39 Patients received serial infusions for 6 consecutive days with a mean duration of pain relief of 11.5 +/- 6.5 weeks. Most psychosocial measures improved as well.

A Cochrane Review analyzed 12 studies in neuropathic pain, looking at 4 different topical lidocaine formulations.40 It found no evidence from good quality studies to support the use of topical lidocaine to treat neuropathic pain. There is mixed efficacy data for the use of topical lidocaine in postoperative pain. Data does not support the use of topical lidocaine for traumatic rib fractures, persistent inguinal postherniorrhaphy pain, or total knee arthroplasty.41-43 There is

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There may be cases where our standard therapies do not provide adequate relief for our patients. It is important to think outside the box and use more nonconventional therapies to get these patients the relief they need. Generally, we target central sensitization and neuromodulation in these instances. Methadone, ketamine, and lidocaine are all agents that have anecdotal and literature support of their efficacy. With safety being of concern, these agents are best left in the hands of specialists and providers who have experience with their use. References 1. Chou R, Cruciani RA , Fiellin DA , et al. Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain. 2014;15(4):321–337. 2. Ripamonti C, Groff L, Brunelli C, et al. Switching from morphine to oral methadone in treating cancer pain: what is the equianalgesic dose ratio? J Clin Oncol. 1998;16(10):3216–3221. 3. Mercadente S, Casuccio A, Fulfaro F, et al. Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study. J Clin Oncol. 2001;19(11):2898–2904. 4. Ayonrinde OT, Bridge DT. The rediscovery of methadone for cancer pain management. Med J Aust. 2000;173(10):536–540. 5. Salpeter SR , Buckley JS, Bruera E. The use of very low-dose methadone for palliative pain control and the prevention of opioid hyperalgesia. J Palliat Med. 2013;16(6):616–622. 6. Bell RF, Eccleston C, Kalso EA . Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev. 2012;11:CD 003351. 7. Haroutijunian S, McNicol ED, Lipman AG. Methadone for chronic non-cancer pain in adults. Cochrane Database Syst Rev. 2012;11:CD 008025. 8. Nicholson AB . Methadone for cancer pain. Cochrane Database Syst Rev. 2007;4:CD 003971. 9. Rhondali W, Tremellat F, Ledoux M, et al. Methadone rotation for cancer patients with refractory pain in a palliative care unit: an observational study. J Palliat Med. 2013;16(11):1382–1387.

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10. Wallace E, Ridley J, Bryson J, et al. Addition of methadone to another opioid in the management of moderate to severe cancer pain: a case series. J Palliat Med. 2013;16(3):305–309.

32. Schwartzman RJ, Patel M, Grothusen JR , et al. Efficacy of 5-day continuous lidocaine infusion for the treatment of refractory complex regional pain syndrome. Pain Med. 2009;10:401–412.

11. Spaner D. Effectiveness of the buccal mucosa route for methadone administration at the end of life. J Palliat Med. 2014;17(11):1262–1265.

33. Viola V, Newnham HH, Simpson RW. Treatment of intractable painful diabetic neuropathy with intravenous lignocaine. J Diab Comp. 2006:20:34–39.

12. Blonk MI, Koder BG, van den Bemt PM , et al. Use of oral ketamine in chronic pain management: a review. Eur J Pain. 2010;14:466–472.

34. Kastrup J, Petersen P, Dejgård A, et al. Intravenous lidocaine infusion—a new treatment of chronic painful diabetic neuropathy? Pain. 1987;28:69–75.

13. Mercadente S, Arcuri E, Tirelli W, et al. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: A randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage. 2000;20(4):246–252.

35. Rowbotham MC , Reisner-Keller LA , Fields HL . Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia. Neurology. 1991;41:1024–1028

14. Bredlau AL , Thakur R, Korones DN, et al. Ketamine for pain in adults and children with cancer: A systematic review and synthesis of the literature. Pain Med. 2013;14:1505–1517. 15. Hardy J, Quinn S, Fazekas B, et al. Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. J Clin Oncol. 2012;30:3611–3617. 16. Visser E, Schug SA . The role of ketamine in pain management. Biomed Pharmacother. 2006;60:341–348. 17. Bell RF, Dahl JB, Moore RA , et al. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2006;1:CD 004603. 18. Eichenberger U, Neff F, Sveticic G, et al. Chronic phantom limb pain: the effects of calcitonin, ketamine, and their combination on pain and sensory thresholds. Anesth Analg. 2008;106:1265–1273.

36. Soleimanpour H, Hassanzadeh K, Mohammadi DA , et al. Parenteral lidocaine for treatment of intractable renal colic: a case series. J Med Case Rep. 2011;5:256. 37. Soleimanpour H, Hassanzadeh K, Vaezi H, et al. Effectiveness of intravenous lidocaine versus intravenous morphine for patients with renal colic in the emergency department. BMC Urol. 2012;12:13. 38. Wu CL , Tella P, Staats PS, et al. Analgesic effects of intravenous lidocaine and morphine on post-amputation pain: A randomized double-blind, active placebo-controlled, crossover trial. Anesthesiology. 2002;96:841–848 39. Raphael JH, Southall JL , Treharne GJ, et al. Efficacy and adverse effects of intravenous lignocaine therapy in fibromyalgia syndrome. BMC Musculoskelet Disord. 2002:3:21 40. Derry S, Wiffen PJ, Moore RA , et al. Topical lidocaine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014;7:CD 010958.

19. Collins S, Sigtermans MJ, Dahan A, et al. NMDA receptor antagonists for the treatment of neuropathic pain. Pain Med. 2010;11:1726–1742.

41. Ingalls NK , Horton ZA , Bettendorf M, et al. Randomized, double-blind, placebo-controlled trial using lidocaine patch 5% in traumatic rib fractures. J Am Coll Surg. 2010;210(2):205–209.

20. Sawynok J. Topical and peripheral ketamine as an analgesic. Anesth Analg. 2014;119:170–178.

42. Bischoff JM , Petersen M, Uçeyler N, et al. Lidocaine patch (5%) in treatment of persistent inguinal postherniorrhaphy pain. Anesthesiology. 2013;119(6):1444–1452.

21. Prommer EE . Ketamine for pain: an update of uses in palliative care. J Palliat Med. 2012;15(4):474–483.

43. Khanna M, Peters C, Singh JR . Treating pain with lidocaine patch 5% after total knee arthroplasty. PM&R. 2012;4(9):642–646.

22. Wolff M, Schnöbel-Ehehalt R, Mühling J, et al. Mechanisms of lidocaine’s action on subtypes of spinal dorsal neurons subject to the diverse roles of Na+ and K+ channels in action potential generation. Anesth Analg. 2014;119:463–470.

44. Habib S, Polascik TJ, Weizer AZ , et al. Lidocaine patch for postoperative analgesia after radical retropubic prostatectomy. Anesth Analg. 2009;108(6):1950–1953.

23. Werdehausen R, Kremer D, Brandenburger T, et al. Lidocaine metabolites inhibit glycine transporter 1. A novel mechanism for the analgesic action of systemic lidocaine? Anesthesiology. 2012;116:147–158. 24. Brinkrolf P, Hahnenkamp K. Systemic lidocaine in surgical procedures: effects beyond sodium channel blockade. Curr Opin Anesthesiol. 2014;27:420–425. 25. Tremont-Lukats IW, Challapalli V, McNichol ED, et al. Systemic administration of local anesthetics to relieve neuropathic pain: a systematic review and meta-analysis. Anesth Analg. 2005;101:1738–1749.

45. Saber AA , Elgamai MH, Rao AJ, et al. Early experience with lidocaine patch for postoperative pain control after laparoscopic ventral hernia repair. Int J Surg. 2009;7(1):36–38. 46. Roberson DP, Gudes S, Sprague JM , et al. Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons. Nat Neurosci. 2013;16:910–918. 47. Brenneis C, Kistner K, Puopolo M, et al. Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block. Br J Pharm. 2014;171:438–451.

26. Neal JM , Bernards CM , Butterworth JF 4th, et al. ASRA practice advisory on local anesthetic systemic toxicity. Reg Anesth Pain Med. 2010;35:152–161. 27. McCarthy GC , Megalia SA , Habib AS . Impact of intravenous lidocaine infusion on postoperative analgesia and recovery from surgery. Drugs. 2010;70(9):1149–1163. 28. Swenson BR , Gottschalk A, Wells LT, et al. Intravenous lidocaine is as effective as epidural bupivacaine in reducing ileus duration, hospital stay, and pain after open colon resection. Reg Anesth Pain Med. 2010;35:370–376. 29. Farag E, Ghobrial M, Sessler DI, et al. Effect of perioperative intravenous lidocaine administration on pain, opioid consumption, and quality of life after complex spine surgery. Anesthesiology. 2013;119(4):932–940. 30. Wongyingsinn M, Baldini G, Charlebois P, et al. Intravenous lidocaine versus thoracic epidural analgesia. Reg Anesth Pain Med. 2011;36;241–248 31. Tremont-Lukats IW, Hutson PR , Bakonja MM . A randomized, double-masked, placebo-controlled pilot trial of extended IV lidocaine infusion for relief of ongoing neuropathic pain. Clin J Pain. 2006;22:266–271.

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by Stephen

J. Ziegler PhD, JD

PUBLiC POLICY

“Regulatory and law enforcement efforts have the potential, much like any treatment, to result in unintended outcomes by negatively impacting prescribing and the treatment of pain.”

abstract: Undertreated pain and the prevention of prescription drug abuse are significant public health challenges facing the pain and regulatory communities. Although opioids are often effective in treating chronic pain, these same products have also been associated with an alarming increase in morbidity, mortality, and pharmaceutical diversion. State and federal law enforcement efforts to reduce the harms associated with diversion have achieved some success, but some of these well-intentioned investigative efforts have also negatively impacted the treatment of pain by having a chilling effect on prescribers. Subsequent joint efforts between the medical and regulatory communities to reduce the fear of investigation have been short-lived. Consequently, the question becomes whether such policy efforts are viable in the long run, especially when we consider the unique nature of law enforcement and its investigative function. In an effort to answer this question, the following examines the 2004 Frequently Asked Questions consensus document in general and the Balanced Pain Policy Initiative’s 2009 Policy Brief and Procedural Template in particular, discussing their history, impact, and the viability of future reforms. The article concludes that, while balanced policies remain possible between the enforcement and medical communities, they will require open dialogue and on-going collaboration.

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PUBLIC POLICY

e ee

R GULATiON AND TH N C SSiTY OF BALANC D POLiCi S

Federal and state governments have a long history of intervention in the regulation of drugs and the practice of medicine. The labeling of pharmaceutical products and the licensing of health professionals had a positive impact on public health by reducing the wide availability of morphine, heroin, and the proliferation of unlicensed healthcare providers (snake-oil salesman) in the early 1900s.1 Regulatory and law enforcement efforts have the potential, much like any treatment, to result in unintended outcomes by negatively impacting prescribing and the treatment of pain.2 A classic example of such a phenomenon was demonstrated by the Sigler et al study in 1984 when researchers found significant reductions in Schedule II and III prescribing immediately following the implementation of a triplicate prescription monitoring program.3 In an effort to counteract these unintended side effects of governmental intervention (medico-legal iatrogenesis),1 leaders in the pain community advocated for the creation of balanced policies—policies which ensure appropriate access to prescription drugs while at the same time prevent abuse.4 The 2004 Frequently Asked Questions5 and the 2009 Policy Brief and Procedural Template (PBPT)6 represent such attempts and are examined here, with particular emphasis on the more recent 2009 PBPT. e

AN FFORT AT BALANC : The 2004 FAQ

to elaborate on what those misstatements were. (Coincidentally, immediately prior to the DEA’s withdrawal from the FAQ, a physician had used the FAQ in his defense of federal charges stemming from his prescribing practices).8 Eventually, the DEA articulated its concerns with the FAQ by publishing a statement in the Federal Register10 that, among other things, reasserted their authority to conduct investigations of prescribers on the basis of mere suspicion:

In recognition of the chilling effect that law enforcement investigations and prosecutions can have on legitimate pain treatment, a joint effort between 21 healthcare organizations and the federal Drug Enforcement Administration (DEA) resulted in the publication of a consensus document: Prescription Pain Medications: Frequently Asked Questions and Answers for Health Care Professionals, and Law …it is a longstanding legal principle that the Government Enforcement Personnel (hereinafter, FAQ).7 The document, published ‘‘can investigate merely on suspicion that the law is being in August of 2004, “addressed risk assessment, how opioid treatment violated, or even just because it wants assurances that it works, patient behavior, abuse, addiction, rules and laws, and clear is not.’’ United States v. Morton Salt Co., 338 U.S. 632, 642–643 descriptions of how and why the DEA may prosecute a clinician.”5 (1950). It would be incorrect to suggest that DEA must meet The title page indicated that the consensus document was “Supported some arbitrary standard or threshold evidentiary requireby Drug Enforcement Administration, Last Acts Partnership, Pain ment to commence an investigation of a possible violation & Policy Studies Group [of the] University of Wisconsin” and, when of the Controlled Substances Act (CSA). the guidelines were made public, was “embraced” by the head of the DEA .8 Unfortunately, less than 2 months following its release, the DEA withdrew support for the FAQ, claiming it “contained misstate- The University of Wisconsin’s Pain & Policy Studies Group objected ments.”9 Although the DEA could have arguably worked with the 21 to the DEA’s actions but removed the consensus document at the healthcare organizations to correct any misstatements, they declined DEA’s request.11

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“…several [Roundtable] members complained that, while the policy brief and template were good ideas, there was no mechanism for updating, and more information should have been included… sources of diversion, alternatives to opioids, the proper role of prescription monitoring programs in medical practice and data mining by law enforcement or regulatory personnel.”

ANOTHER FFORT AT BALANC : The balanced pain policy initiative’s 2009 policy brief and procedural template

can be located on the websites of the FSMB13 or the Center for Lawful Access and Abuse Deterrence (CLAAD).14 (Note: A Google search also revealed links to the publication at NAAG and CPB; however, neither of the links was found to be working at the time of the search.)

In 2006, two years after the DEA’s withdrawal from the FAQ, the Balanced Pain Policy Initiative (BPPI ) was formed in an effort to restart the national dialogue between the enforcement and medical com- DiD TH PBPT SUFF R THE SAM FAT AS TH FAQ? munities.6 In 2008, the BPPI published a study which examined the An examination of its history and impact frequency of physician prosecutions,12 and in 2009, the same group released the PBPT. The policy brief and procedural template were Following receipt of research funding, a study of the 2009 PBPT was contained within one document and were intended to raise awareness initiated to examine its impact and explore the viability of such joint about the potential impact that investigations have on legitimate pre- efforts in the future. This case study received approval from Purdue scribers and their patients and serve as a guide for law enforcement. University’s institutional review board for research involving human The publication, Balance, Uniformity, and Fairness: Effective Strategies subjects (#1209012696). The study was in 2 phases: the first phase for Law Enforcement for Investigating and Prosecuting the Diversion of would involve interviews with the members of the Law Enforcement Prescription Pain Medications While Protecting Appropriate Medical Prac- Roundtable; the second phase would use a survey of attendees at a tice, was informed by a 27-member Law Enforcement Roundtable that regional training conference hosted by the National Association of met in 2008, made up of national figures from the medical, regula- Drug Diversion Investigators ( NADDI ) in an effort to measure the tory, and legal communities. The title page of the publication listed impact of the PBPT 4 years after its publication. 3 organizations associated with the publication: the Center for Practical Bioethics (CPB), the Federation of State Medical Boards (FSMB), and the National Association of Attorneys General ( NAAG). The PHAS 1: document contained information about the history of the BPPI, the Roundtable interviews Law Enforcement Roundtable’s membership, a list of effective strategies for law enforcement (eg, the need to distinguish between criminal The intention was to interview all members of the Law Enforcement behavior and medical negligence, balancing publicity, having access Roundtable (particularly the 27 from the 2008 meeting, the group to experts, using technological aids, collaborating with agencies, and that informed the creation of the PBPT and whose members are using educational resources), and a procedural template to assist law listed on page 15 of that document). A review of those members enforcement in assessing whether the conduct was criminal, civil, from the 2008 meeting indicated the following profile: federal DEA administrative, or perhaps not even actionable.6 Copies of the PBPT (2 members); CPB (2); nonprofit, private organizations (medicine or

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law) (4); law firms (2); Attorney General Offices (including NAAG) (6); state medical boards (including the FSMB) (3); law schools and universities (3); private health insurance organizations or addiction treatment facilities (3); NADDI (1); and US Attorney (1).6 Potential respondents were first contacted by email, a communication medium that enabled the introduction of the research focus, the source of funding, the voluntariness of their participation, the ability to remain anonymous, and the intended interview questions. While some of the questions evolved over time (consistent with qualitative research designs), the main focus was on the following: → How did they become involved in the project? → Were there significant disagreements? → How did the template come about? → Was the PBPT circulated prior to publication, and how was it distributed after publication? → Did any law enforcement agencies adopt it? → What did they think of the PBPT today, and is there anything they would change? → Are balanced policies with law enforcement viable in the long run? → How should law enforcement access experts in pain management? → Was there a process for updating the PBPT? → How were the members of the Roundtable chosen? → In light of the absence of actual investigators on the panel, was the actual purpose of the project an effort to restart the dialogue at the national level?

For instance, several indicated that while the BPPI project was worthwhile, it probably could have done more with additional funding (one person described the project as having “one-half of a shoe string budget”). Moreover, several members complained that, while the policy brief and template were good ideas, there was no mechanism for updating, and more information should have been included— such as the sources of diversion, alternatives to opioids, the proper role of prescription monitoring programs in medical practice and data mining by law enforcement or regulatory personnel. Some also criticized the membership of the committee and suggested that more stakeholders should have been brought to the table, although one remarked that at least there was a wide range of ideology among panelists. Remarkably, some on the law enforcement/regulatory side thought the panel was heavily weighted in favor of the pain community. When asked about the impact of the PBPT, one member said that they did not think the outcomes were tracked, and none of them could identify any law enforcement agency or association that adopted the PBPT in whole or in part. Moreover, when asked, none of the interviewees knew who law enforcement should contact if they had questions concerning pain treatment (Strategy 3 in the PBPT: Access to Experts), and at least one member added that some regulatory/law enforcement agencies have trouble communicating with each other in the state, let alone the nation (Strategy 5 in the PBPT: Interagency Collaboration). A few emphasized that an updated, userfriendly template should be established, but more along the lines of a voluntary checklist that could serve as a resource, but not one that a legislature should require law enforcement to follow. Although not all agreed that balanced policies created in conjunction with law enforcement are viable in the long run, all seemed to agree that creating such policies can be challenging, especially in the current opioid climate. While the members from the 2008 Roundtable were credited with the production of the PBPT, not all actively participated in the editing process. However, when the document was completed, all members were notified and were asked to assist in its dissemination.

PHAS 2: Pen and paper survey at NADDI conference

During this initial stage involving contacts and interviews, it soon In addition to successfully interviewing about one-third of the 2008 became apparent that most had moved on to other things, and many Roundtable, an assessment of the PBPT’s impact/influence on law were no longer associated with the same institutions from 2008. Some enforcement was made by conducting a survey of investigators attendof the members did not remember the project enough to comment ing a pharmaceutical diversion investigation conference. In April on it; some agreed to an interview and were quite candid in their 2013, an invited talk was presented at the Western Regional NADDI assessments; some agreed at first but later changed their minds; some Training Conference in Las Vegas, Nevada, on the need for balance never returned emails or voice messages; and some outright refused. in pharmaceutical diversion investigations. Prior to the talk a written Moreover, some members who were affiliated with the government, survey was distributed to all 53 attendees along with a copy of the past or present, gave the impression that they would like to speak but PBPT (all but one attendee completed the survey). Although nonranit was a topic that they could not discuss. While saturation was not dom sampling has limited generalizability, and research funds were reached, continued efforts to ascertain the whereabouts and interview limited, the survey was administered to the very group that the PBPT the remaining members of the Roundtable were resulting in dimin- was intended to reach: diversion investigators. The survey found that ishing returns. In the end, contact was made with about one-third of the majority of the attendees, 85% (44/52), had never seen the policy the 2008 panel, and, while their responses may not be representative brief and template before; 6 out of 52 had seen it or portions of it of the panel as a whole, their comments were insightful. before the presentation; and 2 were not sure. Of the 52 that completed

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“…mistakes by investigators or prosecutors will be made, and any investigation or prosecution involving a prescriber will receive a great deal of media coverage—especially when considering the current hysteria associated with opioids, the pressure on public officials to do something quickly about a complex societal problem, and the variation among the states concerning investigations and the releasing of information”.”

the survey, their self-identified positions were mixed and consisted of the following: narcotic investigators (15 attendees); retail pharmacy investigators (6); loss prevention personnel and insurance investigators (5 each); analysts and pharmacy auditors (4 each); pharmacy investigators and pharmacists (2 each); and investigator, registered nurse, physician, pharmacy board investigator, fraud investigator, state compliance auditor, and federal prosecutor (1 each). Two of the respondents did not describe their current positions and were recorded as unknown/missing. Of the 6 that had answered YES and were sure that they had seen the PBPT or portions of it before the presentation, only 3 described themselves as investigators. Those same individuals were then asked if they used it during an investigation and none of them indicated that they had.

DiSCUSSiON When considering the outcomes of the 2004 FAQ and the 2009 PBPT, one wonders whether such future collaborations with law enforcement are possible. Could the relationship between the law enforcement and the medical community be likened to Aesop’s The Scorpion and the Frog, a fable where despite a pre-existing agreement, the scorpion will end up stinging the frog because it is just part of its nature? Yes and no. Any commitment from law enforcement to create balanced policies must be understood in the context of their nature—the need to investigate—even if it means that they too may suffer the same fate as the frog. Q4 | 2014

First, if the primary task of prosecutors remains the prosecution of offenders, then the primary responsibility of law enforcement is to investigate suspected offenders to determine if an offense has occurred and whether that offense should be presented to the prosecutor’s office. Although investigations are known to have a chilling effect on even legitimate prescribing, it would be difficult for the police to determine whether a crime has been committed and whether it should be prosecuted without investigating the matter first. Unlike prosecutors, who can decide whether to pursue charges following an investigation by law enforcement, the temporal nature of the investigative function does not permit the police to have the same luxury. True, the DEA should have worked with the 21 healthcare organizations to correct any misstatements in the FAQ instead of picking up their marbles and going home, but their subsequent statement in the Federal Register (see quote at beginning of article) illustrates the nature of the law enforcement function and the difficulty in forging lasting agreements. But having said that, it is also foreseeable that mistakes by investigators or prosecutors will be made, and any investigation or prosecution involving a prescriber will receive a great deal of media coverage— especially when considering the current hysteria associated with opioids, the pressure on public officials to do something quickly about a complex societal problem, and the variation among the states concerning investigations and the releasing of information.15 Even if the prescriber is ultimately not charged with a crime after being investigated, or is found not guilty or not responsible, the entire www.painweek.org | PWJ | 45

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process will often be devastating to the pain community in general and the accused in particular.

variations in pain treatment and the unintended consequences their actions can have on prescribing. As the landscape changes, on-going collaboration would not only enable continued access to experts, it would also permit updating of the new checklist.

That does not mean, however, that the law enforcement community is not answerable for any of their actions, nor does it mean that they would not benefit from an increased awareness of the unintended While the foregoing seems reasonable, challenges to making that impact that investigations can have on legitimate prescribing and pain dialogue and collaboration happen still remain. For example, not all treatment (a goal of the 2004 FAQ and 2009 PBPT). Law enforcement regulatory agencies will engage in dialogue with the medical comwants to get the bad guys, and the medical community wants to pro- munity (some do not even get along with each other). In fact, it was tect the good guys—and their patients in the process. So perhaps the difficult to even get some government officials to talk about their approach should be one of mutual on-going collaboration where law earlier efforts to restart the dialogue (which is certainly their right, enforcement learns from the medical community about the complexi- but is alarming in a free society and demonstrates the difficulty of ties of pain treatment to reduce the likelihood of targeting a legitimate achieving open dialogue and on-going collaboration). But what if, prescriber, and uses that same information to rebut the claims of a for example, the pain community wants to engage in dialogue but prescriber who is engaging in criminal conduct. the DEA does not and would rather take their marbles home with them? Surprisingly, regulatory and law enforcement agencies are a In light of the relatively short lives of the 2004 FAQ and 2009 PBPT, lot like children: they all must rely on a parent and do not always get could the value of both projects have been more about opening the their way. See, for example, the spread of marijuana legalization laws dialogue rather than developing long-standing policies? Although across the United States despite the DEA’s historic opposition. So, if copies of both documents can still be found on the internet, they some agency or regulator does not want to have a discussion about were ultimately not embraced by the law enforcement community. balance and implement needed reforms, then people need to call the But as at least one member of the Roundtable pointed out, what may agency’s parents—elected officials—and have them replaced with have accounted for their minimal impact was a lack of organizational someone who does. With over 100 million Americans affected by buy-in. True, the DEA appeared to have signed on for the entire FAQ chronic pain, it is a dialogue worth having. voyage by virtue of 1) working with the 21 healthcare organizations over the course of a year, 2) permitting their organization’s name to appear as a supporter on the first page of the consensus document STUDY LiMiTATiONS and, 3) having the leader of their organization voice support for the document after its release. However, it is entirely possible that the This case study was merely one approach to assessing the impact DEA personnel involved in the project from the start may not have of the FAQ in general and the BPPI in particular. As noted earlier, possessed the requisite authority to write checks on behalf of the there was significant nonresponse by members of the Law Enforceorganization. This may also explain why the DEA opted to withdraw ment Roundtable due to passage of time, reassignment, reluctance from the entire project rather than seek the correction of any mis- to discuss, and so on. Nonresponse becomes a problem if the views statements within the consensus document itself. Moreover, the use of those who did not respond differed significantly from those that of the 2004 FAQ as a defense in a federal criminal prosecution proba- did.17 Because potential respondents have a right to refuse to parbly reduced the likelihood that the DEA would reconsider their deci- ticipate in any study, determining the views of those who did not sion to withdraw. The lack of organizational buy-in could also explain participate remains problematic. Secondly, funding for pilot studies the short life of the PBPT and its limited impact on law enforcement. are often limited and the relatively small sample size stemming Although prominent figures from across the United States attended from a purposive sampling method used in the survey of conferthe meetings, there was almost a total absence of actual investigators ence attendees limited generalizability of the results. Nevertheless, on the Law Enforcement Roundtable. In fact, most of the govern- the data that was acquired provided some valuable insight into the ment personnel who were on the Roundtable were not investigators impact of the FAQ and PBPT, as well as the viability of such projat all—they were heads of agencies, not individuals who conduct ects in the future. investigations on a day-to-day basis (the intended audience of the PBPT ). Consequently, a more charitable assessment could be that the PBPT, like the FAQ, was more about restarting the dialogue than CONCLUSiON providing a definitive, long-standing guide to law enforcement. Since open dialogue and on-going collaboration is the solution to creating If the primary goal of the 2009 Balanced Pain Policy Initiative was and maintaining balanced policies,16 future efforts could pick up to restart the national dialogue, they were successful as evidenced where the PBPT left off but also involve other stakeholders such as by their ability to 1) facilitate meetings between several national actual prescribers and diversion investigators. This new group could organizations and their representatives from the legal, medical, use the 2009 PBPT as a starting point and develop a checklist for and regulatory communities and, 2) produce 2 publications (a peer law enforcement to consider in their efforts to detect criminal pre- reviewed article in Pain Medicine and the PBPT ). However, if they scribers. Such an approach would balance the needs of law enforce- also intended for the PBPT to be embraced by law enforcement, the ment to conduct investigations of suspected criminals, which is in intended audience of the project, it appears that they were less suctheir nature, while at the same time increase their awareness of the cessful. A lack of organizational buy-in could have been a substantial

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factor in that outcome and may have also been the case with the 2004 FAQ. Nevertheless, the 2004 FAQ and the 2009 PBPT were worthwhile efforts to create balanced policies. Such policies are possible, even in today’s opioid climate, but will require open dialogue18 and on-going collaboration to remain viable. The issues involved in this article were presented and discussed at 2 professional conferences (PAINWeek 2014 and the Academy of Criminal Justice Sciences in 2013). Funding in support of this study was provided by Purdue Pharma, LP, who had no control or influence in the study’s design, implementation, analysis, or reporting of the results.

Center. Pain & Policy Studies Group. Achieving balance in state pain policy: a progress report card. 2013. Available at: www.painpolicy.wisc.edu/sites/www.painpolicy. wisc.edu/files/prc2013.pdf. 17. Neuman WL . Social Science Research Methods: Qualitative and Quantitative Approaches (6th ed). Boston, MA: Pearson Education; 2006. 18. Shurman JR , Shurman G, Groza A, et al. DEA and doctors working together. Practical Pain Manage. 2014;14(5). Available at: http://www.practicalpainmanagement. com/resources/ethics/dea-doctors-working-together.

References

1. Ziegler SJ . Governmental intervention in prescribing. PWJ. 2013; 1:40–44. 2. Ziegler SJ, Lovrich NP. Pain relief, prescription drugs, and prosecution: a fourstate survey of chief prosecutors. J Law Med Ethics. 2003;31(1):75–100. 3. Sigler KA , Guernsey BG, Ingrim NB, et al. Effect of a triplicate prescription law on prescribing of Schedule II drugs. Am J Hosp Pharm. 1984;41(1):108–111. 4. Pain & Policy Studies Group. Achieving Balance in Federal and State Policy: A Guide to Evaluation. 4th ed. Madison, WI: University of Wisconsin, Paul P. Carbone Comprehensive Cancer Center; 2007. 5. Special Reports. Prescription pain medications: frequently asked questions and answers for health care professionals and law enforcement personnel. J Pain Palliat Care Pharmacother. 2005;19(1):71–104. 6. Center for Practical Bioethics. Balance, Uniformity and Fairness: Effective Strategies for Law Enforcement for Investigating and Prosecuting the Diversion of Prescription Pain Medications While Protecting Appropriate Medical Practice. 2009. [Link no longer available, as noted in this article.] 7. Drug Enforcement Administration Last Acts Partnership. Prescription pain medications: frequently asked questions and answers for health professionals, and law enforcement personnel. Available at: www.aapsonline.org/painman/deafaq.pdf. 8. Kaufman M. DEA withdraws its support of guidelines on painkillers. Washington Post. October 21, 2004:A03. 9. U.S. Department of Justice. Rules 2004. Available at: www.deadiversion.usdoj. gov/fed_regs/rules/2004/fr1116.htm. 10. Drug Enforcement Administration. Federal Register. Dispensing of controlled substances for the treatment of pain. Available at: www.federalregister.gov/articles/ 2004/11/16/04–25469/dispensing-of-controlled-substances-for-the-treatment-of-pain. 11. University of Wisconsin-Madison. Pain & Policy Studies Group. A policy statement and proposed rule re: “prescription series.” Available at: www.painpolicy.wisc. edu/dea-policy-statement-and-proposed-rule-re-prescription-series. 12. Goldenbaum DM , Christopher M, Gallagher RM , et al. Physicians charged with opioid analgesic-prescribing offenses. Pain Med. 2008;9(6):737–747. 13. Center for Practical Bioethics. Federation of State Medical Boards. Policy brief. Balance, uniformity and fairness: Effective strategies for law enforcement for investigating and prosecuting the diversion of prescription pain medications while protecting appropriate medical practice. Available at: www.fsmb.org/Media/Default/PDF/ Publications/pub_bbpi_policy_brief.pdf. 14. Center for Lawful Access and Abuse Deterrence (CLAAD). Policy discussion: protecting consumers from black market prescription drugs. Available at: claad.org/ balance-uniformity-and-fairness-effective-strategies-for-investigating-and-prosecuting-the-diversion-of-prescription-pain-medications-while-protecting-appropriate-medical-practice/. 15. Ziegler SJ . Why don’t we know more about best practices in physician investigations? J Med Regulation, 2011;97(2):7–9. 16. University of Wisconsin School of Medicine and Public Health Carbone Cancer

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PAINWeek 2014 Attendee Interviews

David Smith—Pediatric emergency medicine PAINWeek Pulse In general, I think it’s great. I love the way everything looks, the technology. Everything is really easy. It’s very colorful. It’s very easy to find your way. Favorite Courses I think that The Brain in Pain I found most interesting, about the physiological changes and the neurologic changes that occur in the brain as it’s subjected to chronic pain inputs. I thought that was a very interesting lecture. I got some very good tips from the Headache Evaluation, Examination, and Treatment lecture as well. Planning to Attend PAINWeek 2015? Absolutely! Melissa Geraghty—Health psychologist specializing in chronic pain, cancer, and physical disability PAINWeek Pulse This is a phenomenal conference and I’m so honored to be here. I can’t even begin to tell you what an amazing experience it is. The exhibits are absolutely remarkable. I was talking to 2 of the exhibitors for almost 3 hours last night about a lot of information on pain and advocacy. Scientific Poster Sessions I’m very impressed, and I’m happy that I’m also doing a poster session later today. I was in there earlier and the quality, the professionalism, and also just the flare of being comfortable. Everyone’s so willing to share their information, give a piece of themselves. It’s not, for lack of a better word, stuffy. It’s a very open forum. Planning to Attend PAINWeek 2015? Yes, definitely, without a doubt!

with

Jeffrey D. Fudin PharmD, FCCP

Jeffrey Fudin is Clinical Pharmacy Specialist and Director, PGY-2 Pharmacy Pain Residency Programs, at the Stratton Veterans Affairs Medical Center in Albany, New York, and is Adjunct Professor of Pharmacy Practice at several universities.

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PUNDIT PROFILE/JEFFREY D. FUDiN

“I figured it would be tougher to ‘make it’ as a musician and I could continue playing sax as a pharmacist, but I couldn’t go to music school and practice pharmacy on the side without a license.”

What inspired you to become a healthcare provider? I was most inspired by my father and great uncle, both of whom were pharmacists and attended my alma mater. I can remember my father coming home from the “drug store” smelling like camphor, menthol, and vitamin supplements, probably thiamine. Everyone in town knew him. My great uncle used to tell me stories of how he was called “Doc” and stayed up all night during cough and cold season compounding syrups and elixirs, rolling pills, pressing tablets and capsules, and making powder papers. As a young child it fascinated me. As the years went on, I maintained that captivation, but I knew in my heart that I was meant to be a clinician, which at the time was nontraditional pharmacy and the exception rather than the rule. Why did you focus on pain management? When I began learning about pharmacognosy (medicinals derived from plants), I was particularly amazed that animals could have an exact receptor to uptake certain drugs from plants (such as opium from poppies). I remember being in lab and receiving a prescription written in Latin (hard to believe) for lactam rubrum (red milk) powder to be placed in capsules for pain. Using placebo back then wasn’t all PROPaganda; there was a chemically-based scientific explanation that PROMPTed release of endorphins and subsequent

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opiate receptor stimulation even from sterile water injections. Even back then PROMPT embraced scientific evidence—who knew what I was in for?* *Dr. Fudin is referring to Physicians for Responsible Opioid Prescribing (PROP) and Professionals for Rational Opioid Monitoring and Pharmacotherapy (PROMPT). Who were your mentors? The first was my high school music teacher, Mr. Lou Aulogia. In college the standout was Dr. Robert Marois (professor of pharmacology), followed by Dr. Matthew Verderame (professor of medicinal chemistry), and Dr. John Calvert (clinical professor of pharmacy—a new thing back in the day). If you weren’t a healthcare provider, what would you be? Definitely a musician, especially if I were born during the big band era! In fact, I was very close to entering college as a saxophonist, but I figured it would be tougher to “make it” as a musician and I could continue playing sax as a pharmacist, but I couldn’t go to music school and practice pharmacy on the side without a license. Although, from the likes of some of my patients, it seems that some folks have in fact chosen that route—playing music and selling drugs.

Q4 | 2014

“I saw corruption within the federal government that harmed veterans, and I suffered unyielding retaliation for telling the truth in an effort to protect patients.”

What is your most marked characteristic?

What would you like your legacy to be?

Compulsivity, especially if I think someone or something has wronged innocent people, I find it difficult to ignore. This “quality” is in large part attributable to my professional triumphs.

I saw corruption within the federal government that harmed veterans, and I suffered unyielding retaliation for telling the truth in an effort to protect patients. My legacy is that if you “tell the truth and act with conviction of conscience” as required by the pharmacist oath, it is possible to prevail even in the most daunting of circumstances.

What do you consider your greatest achievement? The greatest achievement for anyone these days is remaining happily married for over 30 years and having 4 honest, caring, successful children. What is your favorite language? Español. If you had to choose one book, one film, and one piece of music to take into space for an undetermined amount of time, what would they be? Book: The Other Side of Midnight by Sidney Sheldon. Film: All of the Die Hard movies rolled into one.

What is your motto? A few years back, I’d say it was Reinhold Niebuhr’s Serenity Prayer: God grant me serenity to accept the things I cannot change Courage to change the things I can, and Wisdom to know the difference. But now that I’m older and wiser, I embrace the Senility Prayer: God grant me the senility to forget The people I never liked anyway Good fortune to run into the ones I do, and Eyesight to tell the difference.

Music: In the Mood, by Glen Miller.

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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”

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

Don’t miss out on any of the new resources PAINWeek is now providing!

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).

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

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

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

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

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

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