PAINWeek Journal - Premier Issue No. 1

n0. 1 q 3 2013

RISK ASSESSMENT 2.0/P.5 CENTRALIZED PAIN/P.10 STICK IT TO ME/P.19 MIGRAINES PART 1/P.30 GOVERNMENTAL INTERVENTION IN PRESCRIBING/P.39

Butrans® (buprenorphine) Transdermal System is indicated for the management of moderate to severe chronic pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

Limitations of Use: Butrans is not for use: as an as-needed (prn) analgesic; for pain that is mild or not expected to persist for an extended period of time; for acute pain; for postoperative pain unless the patient is already receiving chronic opioid therapy prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time.

One Butrans—7 Days of Buprenorphine Delivery Butrans is a Schedule III, single-entity opioid analgesic Initiate treatment with Butrans 5 mcg/hour when Butrans is the patient’s first opioid analgesic Individually titrate Butrans to a dose that provides adequate analgesia and minimizes adverse reactions The minimum Butrans titration interval is 72 hours, based on the pharmacokinetic profile and time to reach steady state levels

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ADMINISTRATION OF BUTRANS Butrans is for transdermal use (on intact skin) only. Each Butrans is intended to be worn for 7 days

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Instruct patients not to use Butrans if the pouch seal is broken or the patch is cut, damaged, or changed in any way and not to cut Butrans Instruct patients to apply immediately after removal from the individually sealed pouch Apply Butrans to the upper outer arm, upper chest, upper back or the side of the chest. These 4 sites (each present on both sides of the body) provide 8 possible application sites. Rotate Butrans among the 8 described skin sites. After Butrans

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removal, wait a minimum of 21 days before reapplying to the same skin site Apply Butrans to a hairless or nearly hairless skin site. If none are available, the hair at the site should be clipped, not shaven. Do not apply Butrans to irritated skin. If the application site must be cleaned, clean the site with water only. Do not use soaps, alcohol, oils, lotions, or abrasive devices. Allow the skin to dry before applying Butrans If problems with adhesion of Butrans occur, the edges may be taped with first aid tape.

If Butrans falls off during the 7 days dosing interval, dispose of the transdermal system properly and place a new Butrans on at a different skin site

WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, and ACCIDENTAL EXPOSURE Abuse Potential Butrans contains buprenorphine, an opioid agonist and Schedule III controlled substance with an abuse liability similar to other Schedule III opioids, legal or illicit [see Warnings and Precautions (5.1)]. Assess each patient’s risk for opioid abuse or addiction prior to prescribing Butrans. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depressive disorder). Routinely monitor all patients receiving Butrans for signs of misuse, abuse, and addiction during treatment [see Drug Abuse and Dependence (9)].

Life-Threatening Respiratory Depression Respiratory depression, including fatal cases, may occur with use of Butrans, even when the drug has been used as recommended and not misused or abused [see Warnings and Precautions (5.2)]. Proper dosing and titration are essential and Butrans should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Monitor for respiratory depression, especially during initiation of Butrans or following a dose increase.

Accidental Exposure Accidental exposure to Butrans, especially in children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions (5.3)].

Parentheses refer to sections in the Full Prescribing Information.

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CONTRAINDICATIONS Butrans is contraindicated in patients with: significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; known or suspected paralytic ileus; hypersensitivity (eg, anaphylaxis) to buprenorphine WARNINGS AND PRECAUTIONS Abuse Potential Buprenorphine can be abused in a manner similar to other opioid agonists, legal or illicit.

Assess risk for opioid abuse or addiction prior to prescribing. Routinely monitor all patients for signs of misuse, abuse, and addiction.

Addiction can occur even under appropriate medical use. Misuse or abuse of Butrans by chewing, swallowing, snorting or injecting buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of the opioid and pose a significant risk that could result in overdose and death Life-Threatening Respiratory Depression Respiratory depression is the primary risk of Butrans and may lead to respiratory arrest and death. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Butrans, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression. Proper dosing and titration of Butrans are essential.

Overestimating the Butrans dose when converting patients from another opioid product can result in fatal overdose with the first dose Accidental Exposure Accidental exposure to Butrans, especially in children, can result in a fatal overdose

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Elderly, Cachectic, and Debilitated Patients Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics.

Monitor such patients closely, particularly when initiating and titrating Butrans and when Butrans is given concomitantly with other drugs that depress respiration Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with Butrans. Even usual therapeutic doses of Butrans may decrease respiratory drive to the point of apnea Interactions with Alcohol, CNS Depressants, and Illicit Drugs Hypotension, profound sedation, coma or respiratory depression may result if Butrans is added to a regimen that includes other CNS depressants, alcohol, or illicit drugs QTc Prolongation Avoid in patients with Long QT Syndrome, family history of Long QT Syndrome, or those taking Class IA or Class III antiarrhythmic medications Hypotensive Effects Butrans may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. Monitor patients after initiating or titrating Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients who may be susceptible to the intracranial effects of CO2 retention for

signs of sedation and respiratory depression, particularly when initiating therapy with Butrans. Opioids may also obscure the clinical course in a patient with a head injury

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Application Site Skin Reactions In rare cases, severe application site skin reactions with signs of marked inflammation including “burn,” “discharge,” and “vesicles” have occurred

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

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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

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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

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Avoidance of Withdrawal When discontinuing Butrans, gradually taper the dose. Do not abruptly discontinue Butrans

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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

The first transdermal system to deliver 7 days of buprenorphine in 1 application For more information, or to print the Butrans Trial Offer and Butrans Savings Cards, please visit Butrans.com

One Butrans, Once Weekly Please read Brief Summary of Full Prescribing Information on the following pages.

Purdue is firmly committed to maintaining the highest standards of sales and marketing practices in the industry while continuing to advance the proper treatment of patients. If Purdue’s sales and marketing practices fail to meet this standard, we urge you to contact us at 1-888-726-7535.

For more information, please visit Butrans.com

©2012 Purdue Pharma L.P. Stamford, CT 06901-3431 E8365-A1 9/12

for transdermal administration BRIEF SUMMARY OF PRESCRIBING INFORMATION (For complete details please see the full prescribing information and Medication Guide.)

WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, and ACCIDENTAL EXPOSURE Abuse Potential BUTRANS contains buprenorphine, an opioid agonist and Schedule III controlled substance with an abuse liability similar to other Schedule III opioids, legal or illicit [see Warnings and Precautions (5.1)]. Assess each patient’s risk for opioid abuse or addiction prior to prescribing BUTRANS. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depressive disorder). Routinely monitor all patients receiving BUTRANS for signs of misuse, abuse, and addiction during treatment [see Drug Abuse and Dependence (9)].

Life-Threatening Respiratory Depression Respiratory depression, including fatal cases, may occur with use of BUTRANS, even when the drug has been used as recommended and not misused or abused [see Warnings and Precautions (5.2)].

Proper dosing and titration are essential and BUTRANS should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Monitor for respiratory depression, especially during initiation of BUTRANS or following a dose increase.

Accidental Exposure Accidental exposure to BUTRANS, especially in children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions (5.3)].

1 INDICATIONS AND USAGE BUTRANS is indicated for the management of moderate to severe chronic pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. Limitations of Use BUTRANS is not for use: • As an as-needed (prn) analgesic • For pain that is mild or not expected to persist for an extended period of time • For acute pain • For postoperative pain unless the patient is already receiving chronic opioid therapy prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time 4 CONTRAINDICATIONS BUTRANS is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected paralytic ileus • Hypersensitivity (e.g., anaphylaxis) to buprenorphine [see Warnings and Precautions (5.12), and Adverse Reactions (6)] 5 WARNINGS AND PRECAUTIONS 5.1 Abuse Potential BUTRANS contains buprenorphine, a partial agonist at the mu opioid receptor and a Schedule III controlled substance.

Buprenorphine can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing BUTRANS in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain. Assess each patient’s risk for opioid abuse or addiction prior to prescribing BUTRANS. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use. Misuse or abuse of BUTRANS by chewing, swallowing, snorting or injecting buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of the opioid and pose a significant risk that could result in overdose and death [see Overdosage (10)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Respiratory depression is the primary risk of BUTRANS. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of BUTRANS, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with BUTRANS and following dose increases. Instruct patients against use by individuals other than the patient for whom BUTRANS was prescribed and to keep BUTRANS out of the reach of children, as such inappropriate use may result in fatal respiratory depression. To reduce the risk of respiratory depression, proper dosing and titration of BUTRANS are essential [see Dosage and Administration (2.1, 2.2)]. Overestimating the BUTRANS dose when converting patients from another opioid product can result in fatal overdose with the first dose.

Respiratory depression has also been reported with use of modified-release opioids when used as recommended and not misused or abused. To further reduce the risk of respiratory depression, consider the following: • Proper dosing and titration are essential and BUTRANS should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. • BUTRANS is contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression [see Contraindications (4)].

5.3 Accidental Exposure Accidental exposure to BUTRANS, especially in children, can result in a fatal overdose of buprenorphine. 5.4 Elderly, Cachectic, and Debilitated Patients Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance compared to younger, healthier patients. Therefore, monitor such patients

closely, particularly when initiating and titrating BUTRANS and when BUTRANS is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)]. 5.5 Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with BUTRANS, as in these patients, even usual therapeutic doses of BUTRANS may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in these patients if possible. 5.6 Interactions with Alcohol, CNS Depressants, and Illicit Drugs Hypotension, profound sedation, coma or respiratory depression may result if BUTRANS is added to a regimen that includes other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, muscle relaxants, other opioids). When considering the use of BUTRANS in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient’s use, if any, of alcohol or illicit drugs that cause CNS depression. If BUTRANS therapy is to be initiated in a patient taking a CNS depressant, start with a lower BUTRANS dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.3)]. 5.7 QTc Prolongation A positive-controlled study of the effects of BUTRANS on the QTc interval in healthy subjects demonstrated no clinically meaningful effect at a BUTRANS dose of 10 mcg/hour; however, a BUTRANS dose of 40 mcg/hour (given as two BUTRANS 20 mcg/hour Transdermal Systems) was observed to prolong the QTc interval [see Clinical Pharmacology (12.2)]. Consider these observations in clinical decisions when prescribing BUTRANS to patients with hypokalemia or clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia. Avoid the use of BUTRANS in patients with a history of Long QT Syndrome or an immediate family member with this condition, or those taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide). 5.8 Hypotensive Effects BUTRANS may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7.3)]. Monitor these patients for signs of hypotension after initiating or titrating the dose of BUTRANS. 5.9 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking BUTRANS who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with BUTRANS. BUTRANS may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of BUTRANS in patients with impaired consciousness or coma. 5.10 Hepatotoxicity Although not observed in BUTRANS chronic pain clinical trials, cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual buprenorphine for the treatment of opioid dependence, both in clinical trials and in post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injection drug abuse may have played a causative or contributory role. For patients at increased risk of hepatotoxicity (e.g., patients with a history of excessive alcohol intake, intravenous drug abuse or liver disease), obtain baseline liver enzyme levels and monitor periodically and during treatment with BUTRANS. 5.11 Application Site Skin Reactions In rare cases, severe application site skin reactions with signs of marked inflammation including “burn,” “discharge,” and “vesicles” have occurred. Time of onset varies, ranging from days to months following the initiation of BUTRANS treatment. Instruct patients to promptly report the development of severe application site reactions and discontinue therapy. 5.12 Anaphylactic/Allergic Reactions Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post-marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine is a contraindication to the use of BUTRANS. 5.13 Application of External Heat Advise patients and their caregivers to avoid exposing the BUTRANS application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds while wearing the system because an increase in absorption of buprenorphine may occur [see Clinical Pharmacology (12.3)]. Advise patients against exposure of the BUTRANS application site and surrounding area to hot water or prolonged exposure to direct sunlight. There is a potential for temperature-dependent increases in buprenorphine released from the system resulting in possible overdose and death. 5.14 Patients with Fever Monitor patients wearing BUTRANS systems who develop fever or increased core body temperature due to strenuous exertion for opioid side effects and adjust the BUTRANS dose if signs of respiratory or central nervous system depression occur.

5.15 Use in Patients with Gastrointestinal Conditions BUTRANS is contraindicated in patients with paralytic ileus. Avoid the use of BUTRANS in patients with other GI obstruction. The buprenorphine in BUTRANS may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase. 5.16 Use in Patients with Convulsive or Seizure Disorders The buprenorphine in BUTRANS may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during BUTRANS therapy.

5.17 Avoidance of Withdrawal Symptoms of withdrawal include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Significant fluid losses from vomiting and diarrhea can require intravenous fluid administration. When discontinuing BUTRANS, gradually taper the dose [see Dosage and Administration (2.3)]. Do not abruptly discontinue BUTRANS. 5.18 Driving and Operating Machinery BUTRANS may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of BUTRANS and know how they will react to the medication. 5.19 Use in Addiction Treatment BUTRANS has not been

studied and is not approved for use in the management of addictive disorders. 6 ADVERSE REACTIONS The following adverse reactions described elsewhere in the labeling include: • Respiratory Depression [see Warnings and Precautions (5.2)] • QTc Prolongation [see Warnings and Precautions (5.7)] • Hypotensive Effects [see Warnings and Precautions (5.8)] • Application Site Skin Reactions [see Warnings and Precautions (5.11)] • Anaphylactic/Allergic Reactions [see Warnings and Precautions (5.12)] • Gastrointestinal Effects [see Warnings and Precautions (5.15)] • Seizures [see Warnings and Precautions (5.16)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 5,415 patients were treated with BUTRANS in controlled and open-label chronic pain clinical trials. Nine hundred twenty-four subjects were treated for approximately six months and 183 subjects were treated for approximately one year. The clinical trial population consisted of patients with persistent moderate to severe pain. The most common serious adverse drug reactions (all <0.1%) occurring during clinical trials with BUTRANS were: chest pain, abdominal pain, vomiting, dehydration, and hypertension/blood pressure increased. The most common adverse events (≥ 2%) leading to discontinuation were: nausea, dizziness, vomiting, headache, and somnolence.

The most common adverse reactions (≥ 5%) reported by patients in clinical trials comparing BUTRANS 10 or 20 mcg/hour to placebo are shown in Table 2, and comparing BUTRANS 20 mcg/hour to BUTRANS 5 mcg/hour are shown in Table 3 below: Table 2: Adverse Reactions Reported in ≥ 5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Naïve Patients Open-Label Double-Blind Titration Period Treatment Period BUTRANS BUTRANS Placebo MedDRA (N = 1024) (N = 256) (N = 283) Preferred Term Nausea 23% 13% 10% Dizziness 10% 4% 1% Headache 9% 5% 5% Application site 8% 4% 7% pruritus Somnolence 8% 2% 2% Vomiting 7% 4% 1% Constipation 6% 4% 1% Table 3: Adverse Reactions Reported in ≥ 5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Experienced Patients Open-Label Double-Blind Titration Period Treatment Period BUTRANS BUTRANS 20 BUTRANS 5 MedDRA (N = 1160) (N = 219) (N = 221) Preferred Term Nausea 14% 11% 6% Application site 9% 13% 5% pruritus Headache 9% 8% 3% Somnolence 6% 4% 2% Dizziness 5% 4% 2% Constipation 4% 6% 3% Application site 3% 10% 5% erythema Application 3% 8% 6% site rash Application 2% 6% 2% site irritation The following table lists adverse reactions that were reported in at least 2.0% of patients in four placebo/active-controlled titration-to-effect trials.

Table 4: Adverse Reactions Reported in Titration-to-Effect Placebo/ Active-Controlled Clinical Trials with Incidence ≥ 2% MedDRA Preferred Term BUTRANS (N = 392) Placebo (N = 261) Nausea Application site pruritus Dizziness Headache Somnolence Constipation Vomiting Application site erythema Application site rash Dry mouth Fatigue Hyperhidrosis Peripheral edema Pruritus Stomach discomfort

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

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

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

urinary tract infection, upper respiratory tract infection, nasopharyngitis, influenza, sinusitis, and bronchitis Injury, poisoning and procedural complications: fall Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: back pain, arthralgia, pain in extremity, muscle spasms, musculoskeletal pain, joint swelling, neck pain, and myalgia Nervous system disorders: hypoesthesia, tremor, migraine, and paresthesia Psychiatric disorders: insomnia, anxiety, and depression Respiratory, thoracic and mediastinal disorders: dyspnea, pharyngolaryngeal pain, and cough Skin and subcutaneous tissue disorders: pruritus, hyperhidrosis, rash, and generalized pruritus Vascular disorders: hypertension Other less common adverse reactions, including those known to occur with opioid treatment, that were seen in < 1% of the patients in the BUTRANS trials include the following in alphabetical order: Abdominal distention, abdominal pain, accidental injury, affect lability, agitation, alanine aminotransferase increased, angina pectoris, angioedema, apathy, application site dermatitis, asthma aggravated, bradycardia, chills, confusional state, contact dermatitis, coordination abnormal, dehydration, depersonalization, depressed level of consciousness, depressed mood, disorientation, disturbance in attention, diverticulitis, drug hypersensitivity, drug withdrawal syndrome, dry eye, dry skin, dysarthria, dysgeusia, dysphagia, euphoric mood, face edema, flatulence, flushing, gait disturbance, hallucination, hiccups, hot flush, hyperventilation, hypotension, hypoventilation, ileus, insomnia, libido decreased, loss of consciousness, malaise, memory impairment, mental impairment, mental status changes, miosis, muscle weakness, nervousness, nightmare, orthostatic hypotension, palpitations, psychotic disorder, respiration abnormal, respiratory depression, respiratory distress, respiratory failure, restlessness, rhinitis, sedation, sexual dysfunction, syncope, tachycardia, tinnitus, urinary hesitation, urinary incontinence, urinary retention, urticaria, vasodilatation, vertigo, vision blurred, visual disturbance, weight decreased, and wheezing. 7 DRUG INTERACTIONS 7.1 Hepatic Enzyme Inhibitors and Inducers CYP3A4 Inhibitors Co-administration of ketoconazole, a strong CYP3A4 inhibitor, with BUTRANS, did not have any effect on Cmax (maximum concentration) and AUC (area under the curve) of buprenorphine. Based on this observation, the pharmacokinetics of BUTRANS are not expected to be affected by co-administration of CYP3A4 inhibitors.

However, certain protease inhibitors (PIs) with CYP3A4 inhibitory activity such as atazanavir and atazanavir/ritonavir resulted in elevated levels of buprenorphine and norbuprenorphine following sublingual administration of buprenorphine and naloxone. Patients in this study reported increased sedation, and symptoms of opiate excess have been found in post-marketing reports of patients receiving sublingual buprenorphine and atazanavir with and without ritonavir concomitantly. Atazanavir is both a CYP3A4 and UGT1A1 inhibitor. As such, the drug-drug interaction potential for buprenorphine with CYP3A4 inhibitors is likely to be dependent on the route of administration as well as the specificity of enzyme inhibition [see Clinical Pharmacology (12.3)].

CYP3A4 Inducers The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied. Monitor patients receiving concurrent therapy with BUTRANS and CYP3A4 inducers (e.g., phenobarbital, carbamazepine, phenytoin, rifampin) closely for reduced efficacy or signs of withdrawal [see Clinical Pharmacology (12.3)]. 7.2 Benzodiazepines There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines.

In many, but not all of these cases, buprenorphine was misused by selfinjection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists. Closely monitor patients with concurrent use of BUTRANS and benzodiazepines. Warn patients that it is extremely dangerous to selfadminister benzodiazepines while taking BUTRANS, and warn patients to use benzodiazepines concurrently with BUTRANS only as directed by their physician. 7.3 CNS Depressants Concurrent use of BUTRANS and other central nervous system (CNS) depressants (e.g., sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, other tranquilizers, and alcohol) can increase the risk of respiratory depression, hypotension, and profound sedation or coma. Monitor patients receiving CNS depressants and BUTRANS for signs of respiratory depression and hypotension. When such combined therapy is contemplated, reduce the initial dose of one or both agents. 7.4 Skeletal Muscle Relaxants BUTRANS, like other opioids, may interact with skeletal muscle relaxants to enhance neuromuscular blocking action and increase respiratory depression. 7.5 Anticholinergics Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when BUTRANS is used concurrently with anticholinergic drugs. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects (Pregnancy Category C) There are no adequate and well-controlled studies with BUTRANS in pregnant women. BUTRANS should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and the fetus. In animal studies, buprenorphine caused an increase in the number of stillborn offspring, reduced litter size, and reduced offspring growth in rats at maternal exposure levels that were approximately 10 times that of human subjects who received one BUTRANS 20 mcg/hour, the maximum recommended human dose (MRHD). Studies in rats and rabbits demonstrated no evidence of teratogenicity following BUTRANS or subcutaneous (SC) administration of buprenorphine during the period of major organogenesis. Rats were administered up to one BUTRANS 20 mcg/hour every 3 days (gestation days 6, 9, 12, & 15) or received daily SC buprenorphine up to 5 mg/kg (gestation days 6-17). Rabbits were administered four BUTRANS 20 mcg/hour every 3 days (gestation days 6, 9, 12, 15, 18, & 19) or received daily SC buprenorphine up to 5 mg/kg (gestation days 6-19). No teratogenicity was observed at any dose. AUC values for buprenorphine with BUTRANS application and SC injection were approximately 110 and 140 times, respectively, that of human subjects who received the MRHD of one BUTRANS 20 mcg/hour. NonTeratogenic Effects In a peri- and post-natal study conducted in pregnant and lactating rats, administration of buprenorphine either as BUTRANS or SC buprenorphine was associated with toxicity to offspring. Buprenorphine was present in maternal milk. Pregnant rats were administered 1/4 of one BUTRANS 5 mcg/hour every 3 days or received daily SC buprenorphine at doses of 0.05, 0.5, or 5 mg/kg from gestation day 6 to lactation day 21 (weaning).

Administration of BUTRANS or SC buprenorphine at 0.5 or 5 mg/kg caused maternal toxicity and an increase in the number of stillborns, reduced litter size, and reduced offspring growth at maternal exposure levels that were approximately 10 times that of human subjects who received the MRHD of one BUTRANS 20 mcg/hour. Maternal toxicity was also observed at the no observed adverse effect level (NOAEL) for offspring. 8.2 Labor and Delivery BUTRANS is not for use in women immediately prior to and during labor, where use of short-acting analgesics or other analgesic techniques are more

appropriate [see Indications and Usage (1)]. Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. An opioid antagonist, such as naloxone, should be available for reversal of opioid-induced respiratory depression in the neonate in such situations. 8.3 Nursing Mothers Buprenorphine is excreted in breast milk. The amount of buprenorphine received by the infant varies depending on the maternal plasma concentration, the amount of milk ingested by the infant, and the extent of first pass metabolism. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of buprenorphine is stopped. Because of the potential for adverse reactions in nursing infants from BUTRANS, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efficacy of BUTRANS in patients under 18 years of age has not been established. 8.5 Geriatric Use Of the total number of subjects in the clinical trials (5,415), BUTRANS was administered to 1,377 patients aged 65 years and older. Of those, 457 patients were 75 years of age and older. In the clinical program, the incidences of selected BUTRANS-related AEs were higher in older subjects. The incidences of application site AEs were slightly higher among subjects < 65 years of age than those ≥ 65 years of age for both BUTRANS and placebo treatment groups.

In a single-dose study of healthy elderly and healthy young subjects treated with BUTRANS 10 mcg/hour, the pharmacokinetics were similar. In a separate dose-escalation safety study, the pharmacokinetics in the healthy elderly and hypertensive elderly subjects taking thiazide diuretics were similar to those in the healthy young adults. In the elderly groups evaluated, adverse event rates were similar to or lower than rates in healthy young adult subjects, except for constipation and urinary retention, which were more common in the elderly. Although specific dose adjustments on the basis of advanced age are not required for pharmacokinetic reasons, use caution in the elderly population to ensure safe use [see Clinical Pharmacology (12.3)]. 8.6 Hepatic Impairment In a study utilizing intravenous buprenorphine, peak plasma levels (Cmax) and exposure (AUC) of buprenorphine in patients with mild and moderate hepatic impairment did not increase as compared to those observed in subjects with normal hepatic function. BUTRANS has not been evaluated in patients with severe hepatic impairment. As BUTRANS is intended for 7-day dosing, consider the use of alternate analgesic therapy in patients with severe hepatic impairment [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3)]. 8.7 Neonatal Opioid Withdrawal Syndrome Chronic maternal use of buprenorphine during pregnancy can affect the fetus with subsequent withdrawal signs. Neonatal withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration and severity of neonatal withdrawal syndrome vary based on the drug used, duration of use, the dose of last maternal use, and rate of elimination drug by the newborn. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance BUTRANS contains buprenorphine, a mu opioid partial agonist and Schedule III controlled substance with an abuse potential similar to other Schedule III opioids. BUTRANS can be abused and is subject to misuse, abuse, addiction and criminal diversion. 9.2 Abuse Abuse of BUTRANS poses a hazard of overdose and death. This risk is increased with compromise of the BUTRANS Transdermal System and with concurrent abuse of alcohol or other substances. BUTRANS has been diverted for nonmedical use. All patients treated with opioids, including BUTRANS, require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get “high”, or the use of steroids for performance enhancement and muscle build up. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include, but are not limited to, emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.

Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. BUTRANS may be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state law, is strongly advised. The risks of misuse and abuse should be considered when prescribing or dispensing BUTRANS. Concerns about abuse and addiction, should not prevent the proper management of pain, however. Treatment of pain should be individualized, balancing the potential benefits and risks for each patient. Risks Specific to the Abuse of BUTRANS BUTRANS is intended for transdermal use only. Abuse of BUTRANS poses a risk of overdose and death. This risk is increased with concurrent abuse of BUTRANS with alcohol and other substances including other opioids and benzodiazepines [see Warnings and Precautions (5.6), and Drug Interactions (7.2)]. Compromising the transdermal delivery system will result in the uncontrolled delivery of buprenorphine and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions (5.1)]. Abuse may occur by applying the transdermal system in the absence of legitimate purpose, or by swallowing, snorting or injecting buprenorphine extracted from the transdermal system. 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or

other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. BUTRANS should not be abruptly discontinued [see Dosage and Administration (2.3)]. If BUTRANS is abruptly discontinued in a physicallydependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.7)]. 10 OVERDOSAGE Clinical Presentation Acute overdosage with BUTRANS is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations.

Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. Naloxone may not be effective in reversing any respiratory depression produced by buprenorphine. High doses of naloxone, 10-35 mg/70 kg, may be of limited value in the management of buprenorphine overdose.

The onset of naloxone effect may be delayed by 30 minutes or more. Doxapram hydrochloride (a respiratory stimulant) has also been used. Remove BUTRANS immediately. Because the duration of reversal would be expected to be less than the duration of action of buprenorphine from BUTRANS, carefully monitor the patient until spontaneous respiration is reliably re-established.

Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects as buprenorphine continues to be absorbed from the skin. After removal of BUTRANS, the mean buprenorphine concentrations decrease approximately 50% in 12 hours (range 10-24 hours) with an apparent terminal half-life of approximately 26 hours. Due to this long apparent terminal half-life, patients may require monitoring and treatment for at least 24 hours. In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal. The severity of the withdrawal produced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient with an opioid antagonist, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) Abuse Potential Inform patients that BUTRANS contains buprenorphine, a Schedule III controlled substance that is subject to abuse. Instruct patients not to share BUTRANS with others and to take steps to protect BUTRANS from theft or misuse. Life-Threatening Respiratory Depression Discuss the risk of respiratory depression with patients, explaining that the risk is greatest when starting BUTRANS or when the dose is increased. Advise patients how to recognize respiratory depression and to seek medical attention if they are experiencing breathing difficulties.

Accidental Exposure Instruct patients to take steps to store BUTRANS securely.

Accidental exposure, especially in children, may results in serious harm or death. Advise patients to dispose of unused BUTRANS folding in half and flushing down the toilet. Risks from Concomitant Use of Alcohol and other CNS Depressants Inform patients that the concomitant use of alcohol with BUTRANS can increase the risk of life-threatening respiratory depression.

Inform patients that potentially serious additive effects may occur if BUTRANS is used with other CNS depressants, and not to use such drugs unless supervised by a health care provider. Important Administration Instructions Instruct patients how to properly use BUTRANS, including the following: 1. To carefully follow instructions for the application, removal, and disposal of BUTRANS. Each week, apply BUTRANS to a different site based on the 8 described skin sites, with a minimum of 3 weeks between applications to a previously used site.

2. To apply BUTRANS to a hairless or nearly hairless skin site. If none are available, instruct patients to clip the hair at the site and not to shave the area. Instruct patients not to apply to irritated skin. If the application site must be cleaned, use clear water only. Soaps, alcohol, oils, lotions, or abrasive devices should not be used. Allow the skin to dry before applying BUTRANS. Hypotension Inform patients that BUTRANS may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).

Driving or Operating Heavy Machinery Inform patients that BUTRANS may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in BUTRANS. Advise patients how to recognize such a reaction and when to seek medical attention. Pregnancy Advise female patients that BUTRANS can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant.

Healthcare professionals can telephone Purdue Pharma’s Medical Services Department (1-888-726-7535) for information on this product.

Distributed by: Purdue Pharma L.P., Stamford, CT 06901-3431 Manufactured by: LTS Lohmann Therapie-Systeme AG, Andernach, Germany U.S. Patent Numbers 5681413; 5804215; 6264980; 6315854; 6344211; RE41408; RE41489; RE41571. © 2012, Purdue Pharma L.P. This brief summary is based on Butrans Prescribing Information 302546-0C, Revised 07/2012

GUEST EDITOR KEVIN PUBLISHER Aventine

L. ZACHAROFF MD, FACPE, FACIP, FAAP

Co. 6 Erie Street, Montclair, NJ 07042

ADVERTISING & CUSTOM COMMUNICATIONS MICHAEL ART DIRECTOR DARRYL

SHAFFER

FOSSA

EDITORIAL DIRECTOR DEBRA

WEINER

EDITORIAL BOARD

Charles E. Argoff MD, CPE Professor of Neurology Albany Medical College Department of Neurology Director Comprehensive Pain Center Albany Medical Center Department of Neurology Albany, NY Paul Arnstein RN, PhD, ACNS-BC, FNP-C, FAAN Clinical Nurse Specialist for Pain Relief Massachusetts General Hospital Boston, MA 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

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

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

Gary W. Jay MD, DAAPM, FAAPM Consultant/Senior Strategist and Senior Medical Director CNS for INC Research, LLC Business Development Raleigh-Durham, NC

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

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 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

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

PWJ is published by Aventine Co. Copyright © 2013, Aventine Co. The opinions stated in the enclosed printed materials are those of the authors and do not necessarily represent the opinions of Aventine or its publication staff.

Aventine Co. does not give guarantees or any other representation that the printed material contained herein is valid, reliable, or accurate. Aventine Co. does not assume any responsibility for injury arising from any use or misuse of the printed materials contained herein. The printed materials contained herein are assumed to be from reliable sources, and there is no implication that they represent the only, or best, methodologies or procedures for the pain condition discussed. It is incumbent upon the reader to verify the accuracy of any diagnosis and drug dosage information contained herein, and to make modifications as new information arises.

All rights are reserved by Aventine Co. to accept, reject, or modify any advertisement submitted for publication. It is the policy of Aventine Co. to not endorse products.

Any advertising herein may not be construed as an endorsement, either expressed or implied, of a product or service.

Send correspondence to info@painweek.org.

/ PWJ / Q3 / 2013 2 | GUEST EDITOR’S LETTER by kevin L.

Zacharoff

FEATURES

5 | BEHAVIORAL

RISK ASSESSMENT 2.0 by steven d.

Passik / ted w. Jones

10 | NEUROLOGY

CENTRALIZED PAIN: our new clinical challenge by forest

Tennant

19 | PHARMACOTHERAPY

STICK IT TO ME: topical and transdermal pain relievers by kathryn a.

Q3 | 2013

Walker / mary lynn McPherson

28 | PARTICIPATING ORGANIZATIONS NATIONAL FIBROMYALGIA & CHRONIC PAIN ASSOCIATION by jan

Chambers

30 | EXPERT OPINION

MIGRAINES part 1: epidemiology, definitions, and pathophysiology by gary w.

Jay

39 | PUBLIC POLICY & REGULATION

GOVERNMENTAL INTERVENTION IN PRESCRIBING: preventing harm and medicolegal iatrogenesis by stephen j.

Ziegler

46 | PUNDIT PROFILE with barbara l.

Kornblau

www.painweek.org | PWJ | 1

e

K VIN L.

ZACHAROFF MD, FACPE, FACIP, FAAP

the Guest Editor, I am honored and take great pleasure in welcoming you to the inaugural edition of the PAINWeek Journal. It seems to me that it is both a natural progression and a necessary step for PAINWeek to develop a literary bridge to deliver knowledge to frontline practitioners that complements the successful meetings that take place throughout the year.

Many of the existing pain-related publications often target pain specialists, which may devalue some of the cutting-edge information delivered to frontline practitioners. Reasons for this diminished value are because the information delivered sometimes lacks the necessary translation into practical, clinically meaningful points that can make a difference in the lives and practices of frontline practitioners. In my opinion, the information needs to resonate with this group of clinicians (presumably you) in order to make it most relevant and valuable.

My background is first and foremost as a member of the Board of Directors of the American Society of Pain Educators. Additionally, I am the Vice President of Medical Affairs at Inflexxion, Inc., a Board Certified Anesthesiologist with over 20 years of clinical practice experience in Anesthesiology and Pain Medicine, and an active faculty member and clinical instructor at the State University of New York Stony Brook School of Medicine. In addition to speaking and presenting at many pain meetings throughout the year, I have also authored a number of articles and books on the subject of pain management, including The PainEDU.org Manual: A Pocket Guide to Pain Management, 3rd and 4th editions; Managing Chronic Pain With Opioids in Primary Care, 2nd edition; Your Guide to Pain Management: A Road Map for painACTION.com, 1st and 2nd editions; and Cross-Cultural Pain Management: Effective Treatment of Pain in the Hispanic Population.

Lastly, I manage the web-based resource, PainEDU.org, which is the single largest nonpromotional educational resource for clinicians just like you, with almost 60,000 registrants to date. Specifically focusing on physicians, nurses, pharmacists, and psychologists, PainEDU’s mission aligns with PAINWeek and is entirely devoted towards educating nonspecialist clinicians about the management of pain. The program contains information about all aspects of pain management, from assessment to treatment planning and follow-up. The curriculum also includes detailed strategies for safe and appropriate use of opioids in pain management and continuing medical education programs for all of the above-mentioned disciplines on these topics.

There are a number of relevant, thoughtful articles for the frontline practitioner managing pain in this inaugural issue.

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n the first of a two-article series on headache pain, Dr. Gary Jay comprehensively covers the basic aspects of epidemiology, pathophysiology, and terminology. His insight and clinical experience are quite valuable, giving the sense to the reader that they are getting a real-world perspective—something quite valuable to the frontline practitioner. Very often we know that access to experts can be a difficult issue for practitioners in primary care. This article is like having Dr. Jay at your disposal to give you guidance with this very prevalent pain condition.

Dr. Stephen Ziegler makes an interesting case in his article for the possible downsides of governmental intervention and impact on patient access to prescription pain medications—a phenomenon we definitely see increasing, especially in the area of chronic opioid therapy. Coining the term “medico-legal iatrogenesis,” he explores and comments on the past history of governmental influence on prescribing practices in the United States. Dr. Ziegler also warns the reader to keep the patient in mind and consider issues of access when digesting regulatory shifts in policy.

Drs. Kathryn Walker and Mary Lynn McPherson give a very thoughtful review on the differences between topical and transdermal analgesic therapy, as well as clinical application of a variety of different molecules available for treating pain. Their article is filled with a number of clinical “pearls” that should be very useful for any clinician treating pain, but especially important for those treating patient populations who are not appropriate candidates for other routes of administration. Reading this article is just like being in front of Dr. McPherson, who is one of the best speakers this author has ever seen.

Drs. Steven Passik and Ted Jones basically give the reader a “presentation in an article,” revisiting a very timely topic—the issue of assessing opioid risk. The authors adeptly present a detailed historical perspective of tools and practices developed to assess risk of abuse, misuse, and other illicit behaviors, in the context of chronic opioid therapy. Passik and Jones fully succeed with the intention of giving clinicians a sense of what role tools play in the management of chronic pain, along with clinical judgment and other important ingredients for safe prescribing in today’s controversial opioid climate.

Lastly, Dr. Forest Tennant, one of the true pioneers in pain management, gives us a wonderful review of centralized pain. Replete with case presentations and commentaries on pain management, this piece provides valuable information to all readers. Throughout this article, the hands-on experience of one of the true leaders of the field comes through clearly, and is sure to be well-appreciated by the reader, who will have a sense that they have just sat down and had a conversation with the author when they are done reading this well-written, meaningful article.

So welcome to the PAINWeek Journal, and start reading! I hope you enjoy this issue as much as I think you will.

—KEVIN L. ZACHAROFF, MD, FACIP, FACPE, FAAP Q3 | 2013

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

Gary W. JAY MD, DAAPM, FAAPM

P.30

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

TED W. JONES PHD, CPE P.5 Ted W. Jones is a clinical psychologist at the Behavioral Medicine Institute, Knoxville, TN. He joined the psychology group Behavioral Medicine Institute, and has been in an on-site office at Pain Consultants of East Tennessee since 2000. Dr. Jones is president of Pain Education Institute, a nonprofit educational organization, and is a certified pain educator (CPE).

MARY LYNN MCPHERSON PHARMD, BCPS, FASPE, CPE

STEVEN D. PASSIK PHD

FOREST TENNANT MD, DRPH

P.10

KATHRYN A. WALKER PHARMD, BCPS, CPE

P.19

STEPHEN J. ZIEGLER PHD, JD

P.39

P.19

Mary Lynn McPherson is a professor and vice chair in the Department of Pharmacy Practice and Science at the University of Maryland (UMD) School of Pharmacy in Baltimore.

Dr. McPherson serves on the Board of the Hospice Network of Maryland and is a fellow and president of the Board of Directors for the American Society of Pain Educators. She has written 4 books, including Demystifying Opioid Conversion Calculations, as well as many book chapters and peer-reviewed articles on pain management, palliative care, and other topics.

P.5

After a 25-year academic and clinical career at Memorial Sloan-Kettering Cancer Center, University of Kentucky, and Vanderbilt University, Dr. Passik has recently joined Millennium Laboratories and Millennium Research Institute as director of Clinical Addiction Research and Education and principal investigator. He has authored over 120 scholarly articles and has nearly 200 publications overall.

Forest Tennant, is an internist and addictionologist who specializes in the research and treatment of intractable pain at the Veract Intractable Pain Clinics he founded in West Covina, CA. He is a member of the American Academy of Pain Medicine, the American Academy of Pain Management, the American Pain Society, and the American Society of Addiction Medicine. He is presently editor in chief emeritus of the Practical Pain Management journal and continues to be active on its editorial board. He has authored more than 300 medical books and articles.

Kathryn Walker is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland (UMD) School of Pharmacy in Baltimore. As a faculty member at UMD School of Pharmacy, she practices as a clinical pharmacist at Union Memorial Hospital on the Palliative Medicine consult team. She is also a member of the American Society of Pain Educators and has been awarded the certified pain educator (CPE) credential.

Stephen J. Ziegler is associate professor of Public Policy at Indiana University–Purdue University in Fort Wayne, IN. Trained as both a social scientist and an attorney, Dr. Ziegler conducts research and consults on the topics of opioid risk management (ensuring access while preventing abuse) and the impact of drug regulation and enforcement on the treatment of pain.

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It has always been tempting for practitioners to think that they can look into someoneâ&#x20AC;&#x2122;s eyes and tell if the patient is sincere or will misuse pain medications.

BEHAVIORAL

e

STEVEN D. PASSiK PHD/TED W. JON S PHD, CPE

by

abstract: Risk assessment is the term given to the evaluation of individuals prior to the prescribing of opioids for chronic pain in an attempt to predict future misuse, abuse, or diversion of opioids. Our purpose here is to review briefly some history of risk assessment, its current status, and where we think the field should be headed in the future.

We need not belabor the statistics on the opioid abuse problem in our country to date. The Centers for Disease Control and Prevention (CDC) has reported that overdose deaths from prescription medications have tripled over the last decade, and in

2009 there were a half million visits to emergency departments related to prescription medication overdoses. Risk assessment has been promoted as one tactic of many to help curtail this problem. The logic, with which we agree, is that if there is increased scrutiny and discernment by prescribers before the initiation of opioids, this will go a long way towards helping reduce the misuse, addiction, diversion, and overdoses. To this end, some states such as Washington and our own state of Tennessee have now legislatively mandated that those treating chronic pain with opioids must use some form of risk assessment in evaluating patients.

“Risk is not a permanent characteristic of the patient. Risk varies across time.”

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Q3 | 2013

he field of risk assessment began with “red-flag lists.”

Portenoy1 offered one of these: a list of behaviors that were thought to be indicative of potential misuse of medications.

Other authors followed with additional red-flag lists. Practitioners were then faced with a wide array of red-flag behaviors or characteristics, such as calling the practitioner by his or her first name, having no primary care provider (PCP), being a smoker, forging prescriptions, stealing medications from another patient, and selling prescription drugs. Such red-flag lists offered characteristics and behaviors for practitioners to watch for, but patient actions and “symptoms” were not scored or weighted. Although practitioners could use previously existing drug or alcohol abuse screening tools such as the CAGE (4 questions: C u t - d o w n A n n o y e d G u i l t y Eye-opener), the Michigan Alcohol Screening Test (MAST), the Drug Abuse Screening Test (DAST), and the Screening Instrument for Substance Abuse Potential (SISAP), these did not apply well to a population of chronic pain patients in whom nonpathologic physical dependence is often the norm. Thus, these screening tools were of limited value (although they are sometimes still used today in some settings).

Screening tools designed specifically for use with chronic pain patients began emerging within the last 10 years. These included the Screener and Opioid Assessment for Patients with Pain (SOAPP, 2004); the Pain Medication Questionnaire (PMQ, 2004); the Opioid Risk Tool (ORT, 2004); the Diagnosis, Intractability, Risk, Efficacy instrument (DIRE, 2006); and the SOAPP-revised (SOAPP-R, 2008). These measures helped clinicians predict future misuse of opioid medications by enabling the calculation of scores with norms, and cut-offs were used to place patients in categories of low, medium, or high risk for future medication aberrant behaviors.

IN OUR GeOGRAPHiCAL AReA, SOMe PRACTiTiONeRS SeeMeD TO USe THe ALGORiTHM NUMBeR OF MiSSiNG TeeTH + NUMBeR OF TATTOOS + NUMBeR OF PeOPLe ACCOMPANYiNG THe PATieNT iN THe WAiTiNG ROOM DiViDeD BY NUMBeR OF LeVeLS OF DiSK PATHOLOGY TO DeTeRMiNe RiSK.

Meanwhile, many clinicians have continued to rely on clinical intuition or gut instinct.

It has always been tempting for practitioners to think that they can look into someone’s eyes and tell if the patient is sincere or will misuse pain medications. Some practitioners have used idiosyncratic methods to assess risk. In our geographical area, some practitioners seemed to use the algorithm “number of missing teeth + number of tattoos + number of people accompanying the patient in the waiting room divided by number of levels of disk pathology” to determine risk. Bronstein and others2 have found that, despite the strength of conviction by prescribers, the accuracy in predicting the results of a urine drug test (UDT) is generally no better than chance.

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here are two competing issues in evaluating predictive tools. One is sensitivity—the degree to which a given measure correctly identifies a person who will engage in medication aberrant behavior. However, sensitivity needs to be balanced with the other competing issue, selectivity—the degree to which a person will probably not engage in medication aberrant behavior. If a practitioner rates every pain patient as high risk, then he or she will be correct 100% of the time for those patients who show future medication aberrant behavior.

The interests of good patient care, as well as those of third-party payers, suggest that this is not usually a reasonable approach.

Again, sensitivity needs to be balanced with selectivity. To most clinical practitioners, however, sensitivity far outweighs selectivity. Their thinking is that it is more important to be sure to identify those who will have problems (and subject a few extra patients to increased monitoring in the process). Safety seems to be the watchword in the usual course of patient care.

A question also arises with current riskassessment tools in terms of exactly what behaviors these measures are trying to predict. While early risk assessment tools focused on identifying the presence of drug addiction, current pain practice finds that there are many behaviors outside of outright addiction that reflect problems and should bring a trial use of opioids to an end. These behaviors include overuse of pain medication, the use of illicit drugs (even if these are not being used in an addictive manner), multiple missed appointments, and argumentativeness with staff.

Thus, some risk assessment tools are expected to predict behaviors that they were not originally designed to predict.

Current risk assessment tools vary in 4 ways: they tap different content areas, they gather information in different ways, they give different weights to the information found, and they differ in opaqueness, that is, the ability for the respondent to determine what the right answer is. The risk tools we use today diverge across all of these dimensions and are therefore likely to give somewhat different results.

Moore et al3 offered the first study in which different riskassessment tools were compared; his associates4-6 have followed his initial study with additional comparative research. The data from these studies are displayed in the Table. Some data were converted in order to display all in a similar format. www.painweek.org | PWJ | 7

BEHAVIORAL

There are various ways to calculate accuracy of prediction. In the analysis shown here, patients who were rated as low or low-medium risk on any risk measure were categorized as low risk. Patients who were rated as medium, medium-high, high, or very high risk were categorized as high risk. This dichotomous categorization allowed different risk-measure ratings to be compared.

Patients rated as high risk who later were discharged from opioid

Because of the increasing pressure bearing on the issue of opioid prescribing, certain clinical practices are indicated when using written risk assessments. Clinicians should give risk assessment questionnaires or surveys to patients with the explanation, “this is not a process to determine whether opioids are to be offered.” Instead, risk assessments should be used to determine what sorts of opioids should be used and what degree of treatment monitoring is indicat-

Table Summary of Risk Assessment Comparisons: Correct Prediction of Discharge from Opioid Treatment Risk Assessment Tool

Moore 2009 N=48

Jones 2011 N=51

Jones 2012—Study 1 N=132

Jones 2012—Study 2 N=263

Jones 2013 N=196

Clinical interview, experienced

77%

—

70%

71%

76%

Clinical interview, inexperienced

—

—

—

43%

—

SOAPP

73%

—

—

—

—

SOAPP-R

—

—

32%

39%

60%

ORT

45%

30%

29%

35%

48%

ORT by interview

—

57%

—

—

—

PMQ

—

—

44%

51%

—

DIRE

17%

—

—

—

—

DIRE = Diagnosis, Intractability, Risk, Efficacy ORT = Opioid Risk Tool PMQ = Pain Medication Questionnaire SOAPP = Screener and Opioid Assessment for Patients with Pain SOAPP-R = SOAPP-revised

treatment for medication aberrant behavior were counted as a correct prediction. Likewise, patients who were rated as low risk but who later were discharged from opioid treatment for medication aberrant behavior were counted as an incorrect prediction. The rates of correct prediction for each measure in each study are shown in the Table.

These data indicate that, in our population, most written risk measures were generally poor at identifying persons who later were discharged for medication aberrant behavior or violation of the treatment agreement. In our studies, a clinical interview by an experienced clinician was the best method to identify future discharge from treatment.

ed for each patient in the early stages of treatment. In other words, risk assessment should not be a pass-fail test for the use of opioids.

Opioids may be able to be used safely with individuals who are rated as high risk if there is enough structure involved in the patient’s treatment. Reassuring a patient about the purpose and use of a risk assessment tool before it is given will likely increase its validity and accuracy. In addition, written risk measures need to be crafted as simply as possible with low literacy in mind. Clinicians should review the patient’s answers and perhaps review the questionnaire together with the patient. Again, the more a written risk measure can be opaque to the respondent—when it is not clear what the right answer is—the more likely that it will offer greater validity and accuracy in results.

Another issue to be addressed in the risk assessment field is the incorporation of data from state prescription monitoring programs (PMPs) and urine or saliva drug testing results. Most current risk here are several take-home messages from the over- assessment tools do not include such information, but these sources all findings on risk assessment tools to date. The data above offer very important and even critical data in making risk assessment indicate that clinical interviews—when done by some clini- predictions. Formal algorithms are needed to join data from PMPs cians—can offer superior results in identifying those patients and UDT results with written risk measures. A patient who obtains a who will engage in medication aberrant behavior. However, low risk score on the ORT or SOAPP-R, but is positive for an illicit this does the field of pain treatment little good since at this time there drug on a UDT is no longer low risk, particularly if the patient did are not nearly enough experienced clinicians or psychologists available not reveal having taken an illicit drug to the clinician ahead of time. for pain practices. Thus, the field as a whole will likely need to contin- Various sources of other objective data need to be incorporated into ue to rely on written risk assessment questionnaires of some sort. the risk assessment process for it to be as valuable as it can be.

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We see two important and emerging issues in the field of risk assessment. The first is the issue of reviewing and changing a patient’s risk as treatment goes on. Risk is not a permanent characteristic of the patient. Risk varies across time. In addition, probably the best predictor of how a patient will use opioids is his or her actual use of opioids. If a patient is able to use opioids without medication aberrant behavior for a period of time—3 months, 6 months, 1 year—then it would seem that a lowering of risk score may be in order. While a few patients may need ongoing close monitoring to continue to do well, many are showing by their behavior that they are able to take opioids and not engage in medication aberrant behavior. If a highrisk patient does well in treatment and shows no medication aberrant behavior, how long does he or she remain labeled as high risk? We would advocate for a process in which patients can lower their initial risk rating with “time for good behavior.” Particularly when patients are being administered UDTs at a frequent rate, third-party payers will likely appreciate the chance for higher-risk patients to have their risk reduced at some point so that the high degree of monitoring can also be decreased to some degree. How and when risk lowering is done should be addressed by those in the risk assessment field.

The second and perhaps more important issue is for practitioners to use risk ratings to drive treatment decisions. Risk assessment is not

References 1. Portenoy RK. Opioid therapy for chronic nonmalignant pain: current status. In: Fields HL, Liebeskind JC, eds. Progress in Pain Research and Management. Vol 4. Seattle, WA: IASP Press; 1994:267.

2. Bronstein K, Passik SP, Muntz L, et al. Predicting abnormal urine drug testing in patients on chronic opioid therapy. Poster presented at: PAINWeek 2010; September 8–11, 2010; Las Vegas, NV. 3. Moore TM, Jones T, Browder JH, et al. A comparison of common screening methods for predicting aberrant drug-related behavior among patients receiving opioids for chronic pain management. Pain Med. 2009;10(8):1426-1433.

4. Jones T, Passik SD. A comparison of methods of administering the opioid risk tool.

J Opioid Manag. 2011;7(5):347–352.

5. Jones T, Moore TM, Levy J, et al. A comparison of various risk screening methods for patients receiving opioids for chronic pain management. Clin J Pain. 2012;28(2):93–100.

6. Jones T, Moore TM. Preliminary data on a new risk assessment tool: the brief risk interview. J Opioid Manag. 2013;9(1):19–27.

Bibliography Adams LL, Gatchel RJ, Robinson RC, et al. Development of a self-report screening instrument for assessing potential opioid medication misuse in chronic pain patients. J Pain Symp Manag. 2004;27(5):440–459.

Belgrade MJ, Schamber CD, Lindgren BR. The DIRE score: predicting outcomes of opioid prescribing for chronic pain. J Pain. 2006;7(9):671–681.

Butler SF, Fernandez K, Benoit C, et al. Validation of the revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R). J Pain. 2008;9(4):360–372.

THe RiSK LeVeL OF A PATieNT SHOULD HAVE A DiR CT BeARiNG ON THe CHOiCe OF OPiOiDS PReSCRiBeD AND ON THe FReQUeNCY OF MONiTORiNG.

e

Butler SF, Budman SH, Fernandez K, et al. Validation of a screener and opioid assessment measure for patients with chronic pain. Pain. 2004;112(1-2):65–75.

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.

just a checkbox to show that an evaluation was completed and to pass third-party inspection. The risk level of a patient should have a direct bearing on the choice of opioids prescribed and on the frequency of monitoring. The current thinking in the field holds that higher-risk patients should have more limited access to short-acting opioids. Also, higher-risk patients should have increased monitoring as evidenced by more frequent UDTs, pill counts, and checks of their PMPs. Such patients may even be seen on a biweekly or weekly basis for a time.

We fear that the current legislative emphasis on risk assessment may only focus practitioners on “checking a box” for completion, rather than focusing on the clinical implications and decisions associated with a risk rating.

We look forward to ongoing discussions of these issues with members of the healthcare community and to the future developments of the important topic of risk assessment.

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www.painweek.org | PWJ | 9

“The importance of pain centralization can’t be overstated…

…a new vocabulary is emerging as well as rethinking about old terms.”

e

Forest T NNANT MD, DRPH

by

abstract: The

most important discovery for pain management in the past generation is that a painful, peripheral injury can permanently imprint the memory of pain in the central nervous system (CNS).1-3 It is therefore most fitting that centralization of pain be included in PAINWeek’s journal launch.

be overstated. A new vocabulary is emerging as well as rethinking about old terms.3 For example, the terms neuroinflammation and neurogenesis were hardly uttered a couple of years ago, whereas today they form the foundation of our understanding and treatment of centralized pain. Our challenge today is to educate all concerned The importance of pain centralization can’t parties about centralized pain.

“Centralized is the consensus term meaning that pain initially started in the periphery and migrated into the CNS.” Q3 | 2013

www.painweek.org | PWJ | 11

NEUROLOGY

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e

ee

HOW C NTRALiZ D PAiN D V LOPS f a peripheral painful injury doesn’t heal, inflammatory mediators and possibly electronic signals from the injury site enter the spinal cord and CNS4-11 (Figure 1).

Microglial cells activate and produce neuroinflammation.5-7,9 Neuron hyperexcitability known as central sensitization occurs.10 Glutamate and other excitatory amino acids are released in the inflammatory process, causing tissue destruction in the CNS. In this process, memory of the pain somehow becomes permanently im-

Figure

How Centralized Pain Develops

e e

 CHEMICAL AND/OR ELECTRONIC SIGNALS ENTER CNS

 MICROGLIAL CELL ACTIVATION

 NEUROINFLAMMATION

 RELEASE OF EXCESS GLUTAMATE/ NEUROTOXINS

 CELL DEATH, APOPTOSIS, REFORMATION

e

There are 3 basic time frames or patterns whereby centralized pain develops after nerve injury:

1. 6

to 8 Weeks Postinjury

The classic situation is surgery.14 It has long been observed that if postoperative pain continues for about 6 to 8 weeks, it becomes persistent. The same applies to traumatic injuries.

2. Progressive

INJURED PERIPHERAL NERVES

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TiM FROM INJURY TO ONS T OF C NTRALiZ D PAiN

Transition From Peripheral Pain

Some patients have intermittent peripheral pain that slowly transforms into centralized pain. The process may take months or years. It may be precipitated by some event, such as trauma or infection. Patients will give a history that they were doing well until they rather suddenly developed constant, daily pain.

Their description may be instructive. For example, they will say things like, “I was doing OK until suddenly the pain took me over,” or “I just got worse over time until one day I couldn’t get out of bed.”

3. Instant

Development

Some patients have a sudden, unexpected, severe injury such as a gunshot or fall, and permanent pain begins almost at the instant the injury occurs. Patients may report the onset of severe, constant pain at the time of injury that subsequently never varies over time despite many therapies and interventions including surgery.

COMPLiCATiONS There are 3 major basic complications from centralized pain:

 IMPRINTING OF PAIN SENSATION

1. Immobility Fatigue, depression, physical impairments, and inability to carry out activities of daily living may occur.

printed.1,4,11 The inflamed, hyperexcited tissue in the CNS causes excess efferent electronic signals manifested by allodynia.12,13 Centralized pain, with its underlying neuroinflammation and hyperexcitable cells, displays a characteristic clinical profile that can be recognized and diagnosed. As with other diseases, centralized pain can be mild, moderate, or severe.

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2. Hormonal A most serious complication is osteoporosis, which can lead to spinal collapse. It is due to excess pituitary–adrenal overstimulation and elevated cortisol serum levels. Muscle wasting and a catabolic state due to deficiencies of testosterone and other hormones can occur.

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3. Mental

Deterioration

Neuroinflammation causes tissue destruction and cellular loss that may result in losses of memory, reading ability, attention span, and logical thinking.15,16 Dementia can occur, resulting in the need for domiciliary care. There appears to be considerable loss of brain tissue in severe cases.17-20

e

e e terminology clarification

C NTRALiZ D VS C NTRAL PAiN: Centralized has recently emerged as the consensus term meaning that pain initially started in the periphery and migrated into the CNS. It may also begin de novo in the CNS.21 The latter type of pain disorders include fibromyalgia, irritable bowel syndrome, interstitial cystitis, vulvodynia, prostatitis, and temporal mandibular joint disorder.3,4,19 At this time, central pain remains the term for pain that arises after a known, recognized CNS disease such as stroke, multiple sclerosis, or Parkinson’s disease.

CLiNiCAL DiAGNOSiS OF C NTRALiZ D PAiN

e

e

A diagnosis of centralized pain is made by history and physical examination. As of yet, there is no confirmatory diagnostic laboratory or x-ray test, but there are several supportive laboratory tests (see Figure 2). The clinical hallmarks are 4-fold: (1) constant pain (“never leaves”); (2) poor response to peripheral pain treatments such as local anesthesia, corticoid injections, needling, massage, or electrotherapy; (3) severe insomnia; and (4) excess sympathetic discharge. Allodynia is common and may be described as burning, itching, tingling, or feelings of spiders or bugs crawling on the skin. Physical evidence includes a lack of pain on pressure to the pain site and the finding of excess sympathetic discharge. The latter is produced because centralization of pain causes a loss of efferent, sympathetic control of electrical discharges.12,13 This is clinically manifested by a number of signs of excess electrical sympathetic discharge including hypertension, tachycardia, hyperreflexia, dilated pupil (mydriasis), hyperhidrosis, and vasoconstriction (cold hands or feet).

e

SUPPORTiV LABORATORY FiNDiNGS

Figure

Clinical and Diagnostic Characteristics of Centralized Pain

Constant pain ■

Poor or no response to peripheral treatments such as corticoid injections, acupuncture, topical anesthetics, or electromagnetic measures ■

Peripheral pain site shows no swelling, redness, edema, or pain on pressure ■

Periodic episodes of allodynia, burning, hyperalgesia ■

Severe insomnia ■

Neuroinflammation as evidenced by elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) ■

Overstimulation of the pituitary as evidenced by high serum levels of pituitary and/or adrenal hormones, particularly corticotropin (ACTH) or cortisol ■

Excess sympathetic discharge as evidenced by tachycardia, hypertension, mydriasis, hyperhidrosis, hyperreflexia, and vasoconstriction (cold hands and feet)

Although not diagnostic of centralized pain, there are some laboratory tests that support the history and physical symptoms and perhaps give some idea of disease severity. Also, these tests, when repeated over time, provide biologic markers to assess whether treatment is effective. The inflammatory markers of erythrocyte sedimen- pituitary–adrenal overstimulation is present.22-24 ACTH is the main tation rate (ESR) and C-reactive protein (CRP) should be assessed pituitary hormone that regulates the adrenal glands. If ACTH or in every patient with centralized pain. Although these inflammatory cortisol is too high, it means that inflammation and pain are out of markers don’t pinpoint the source of inflammation, elevated test re- control and there is overstimulation of the pituitary–adrenal system. sults indicate the presence of inflammation in the body, and some A low ACTH or cortisol level likely means that overstimulation has of it must be considered to be in the CNS. Serum corticotropin gone on so long that the pituitary–adrenal system can’t keep up with (ACTH) and cortisol levels will give you an excellent idea whether the immunologic demands being made on it by centralized pain.22-24 Q3 | 2013

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NEUROLOGY

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M DiCAL TR ATM NT Currently available neuropathic agents, antidepressants, antiinflammatory agents, and opioids do a satisfactory job of controlling centralized pain if they are aggressively deployed. The goal is to control pain and help the patient become capable of participating in normal activities of daily living including eating, sleeping, dressing, toileting, and socialization. Secondary goals are normalization of serum hormones and inflammatory markers.

New agents that show promise in animals are currently being clinically investigated to control glial cells and neuroinflammation.

These include minocycline, pentoxifylline, and acetazolamide.

to be deficient, particularly testosterone, cortisol, and pregnenolone, should be replaced.25,26 Neurogenic hormones and neuroprotective agents are new therapies in treatment of centralized pain. CNS inflammation is a progressive, tissue-destructive process, and, if not controlled, brain tissue degeneration will occur.16-20 New agents that show promise in animals are currently being clinically investigated to control glial cells and neuroinflammation. These include minocycline, pentoxifylline, and acetazolamide.27-31 Some hormones, called neurohormones, have been shown in animal studies to produce neuroprotective and neurogenetic (growth) effects.32 Early clinical trials with these hormones demonstrate significant promise in stabilizing and protecting the patient with centralized pain from deteriorating. In the author’s experience, they usually reduce or even eliminate opioid use. These agents are human chorionic gonadotropin, progesterone, pregnenolone, and oxytocin.32-39

e

e

CAS STUDi S

with a clinical diagnoses of centralized pain (Given here are 4 common situations)

CASE-1—postsurgery

A 65-year-old woman had her left hip replaced because standard medical and physical measures failed to relieve her pain. Unfortunately, surgery and a hip implant also did not relieve her pain. She has now suffered constant pain in the hip for over 5 years. Postoperatively she has been unsuccessfully treated with corticoid injections, electrical stimulation, topical lidocaine, and prolotherapy. At the time of evaluation by the author she claimed excruciating pain, but pressure and palpation over the pain site did not elicit pain. She could hardly ambulate. Her Insomnia and anxiety will almost always have to be treated in mod- erythrocyte sedimentation rate (ESR) was elevated to 65 mm/h (normal erate or severe cases. The efferent, sympathetic discharge of central- under 30 mm/h), C-reactive protein was 3.3 mg/dL (normal under .80 ized pain causes not only insomnia but also intense feelings of anxiety. mg/dL), and cortisol was 21.3 mcg/dL (normal is 4-20 mcg/dL). TreatConsequently, these patients will demand to take a benzodiazepine or ment has consisted of hydrocodone–acetaminophen (10-325 mg) 6 to 8 other muscle relaxant such as carisoprodol or baclofen. Interestingly, times a day and glutamine 500 mg three times a day, a protein diet, and the administration of a stimulant such as amphetamine or one of its stretching. Her pain has diminished, and she has some pain-free hours. analogues may seem counterintuitive, but stimulants may significant- She can physically and mentally function well enough to work. ly reduce anxiety and pain. The mechanism is probably dopamine enhancement. Topical application of morphine, ketamine, and cari- COMMENTARY soprodol is very comforting to many patients with centralized pain.

This is presumably because topicals neutralize the constant sympa- The term failed surgery is often a misnomer because the surgery may thetic electrical discharges that bombard the skin in centralized pain. have been technically perfect. In this case, surgery didn’t relieve pain because the pain may have centralized prior to the operation. In A diet with adequate protein is essential because the amino acids in other cases, the “nerve injury” of surgery, per se, may contribute to protein are the building blocks of most neurotransmitters, muscle, centralization. Surgery pain needs to be aggressively treated in the and some hormones (such as endorphins and ACTH). Food and perioperative period to prevent centralization, which commonly sets dietary supplements that are anti-inflammatory such as fish oil and in about 6 to 8 weeks postsurgery. green vegetables should be recommended. Hormones that are found

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CASE-2—chronic back pain

COMMENTARY

Eleven years before evaluation by the author, a 39-year-old man de- Pain and inflammation can remain in the periphery as well as develop veloped severe lumbar spine pain following multiple sports injuries. He a centralized component. Amputations are the classic example. In had a lumbar laminectomy, which did not relieve his pain. His attempts these situations both sites have to be treated. at treatment after surgery included epidural corticoids, chiropractic manipulation, transcutaneous electrical CASE-4—genetic autoimmune nerve stimulation (TENS), and opioids disease with adulthood pain Figure Good Reasons to Make a Clinical Diagnosis at standard dosages. Magnetic resof Centralized Pain onance imaging of his spine showed A 29-year-old woman with an Asian degenerative changes including disc Pacific heritage was referred for seprotrusions and spinal stenosis. His vere, constant “pain all over.” Before pain remained constant, and an applireferral she didn’t have a specific cation or injection of lidocaine into or diagnosis other than nondescriptive over his pain site did not relieve pain. “myofascial pain.” On evaluation she Determine if patient needs testing for He has multiple cytochrome P450 deproved to have hyperextension of fects and requires a high daily opioid joints. She gave a history of a ruptured inflammatory markers and serum hormone levels dosage for symptomatic pain control. uterus during pregnancy, periodic feHe requires testosterone replacement. vers, gastrointestinal pain, and arthralHe was prescribed pregnenolone and gias. Joint pain and fevers had begun Eliminate useless peripheral treatment measures human chorionic gonadotropin, which during childhood. She has cytochrome has lessened his pain and allowed him P450 defects of 2D6 and 2C9. A diagto reduce opioid dosages while mainnosis of Ehlers-Danlos syndrome has Avoid mislabeling patients as drug seekers, taining gainful employment. been assigned to her. Her pain treatpseudo-addicts, or mentally ill ment has consisted of opioids, human chorionic gonadotropin, and oxytocin.

COMMENTARY She has responded well in that she has some pain-free hours and can carry on The chronic low back pain patient is Justify aggressive pharmacologic treatments a marital relationship, attend school, the most common patient with cenand work part-time. tralized pain seen in clinical practice. A diagnosis of centralized pain Provide a definitive diagnosis to help settle should be assigned when the pain is COMMENTARY disability and worker’s compensation claims constant and when peripheral treatments such as paraspinal or epidural Patients with genetic autoimmune corticoids, topical lidocaine, or physdiseases are beginning to attend Establish a solid reason to prescribe opioids ical manipulation do not relieve pain. pain practices. Symptoms such as This patient appears to benefit from recurrent infections, arthralgias, feand help satisfy regulators adjunctive hormone treatments. ver, headache, and gastrointestinal complaints begin in childhood. Many children with these diseases are deCASE-3—amputation Educate about centralized pain to all scribed as sickly but are never given concerned parties including family, pharmacists, a specific diagnosis. The patient may While serving in the Middle East, a subsequently develop severe, cen45-year-old male veteran had an regulators, legal community, and tralized pain in adulthood. These above-knee amputation owing to injuthird-party payers conditions include a group of entities ries from an incendiary device explothat are given various names such as sion. His stump pain has been constant Ehlers-Danlos syndrome, Marfan synand excruciating over a 7-year period drome, Behçets disease, Still’s disease, despite multiple surgeries to remove ganglions. He didn’t respond to standard opioid dosages so he was Schmidt’s syndrome, ankylosing spondylitis, and systemic lupus eryreferred to the author. At the time of evaluation his leg was too sensi- thematosus. Although each may have a specific genetic defect and tive to touch. It was swollen, reddened, and trembling. His only serum characteristic signs and symptoms such as hyperextendable joints, hormone abnormality was low pregnenolone. He has been symptom- endocrinopathies, or spine defects, the manifestations usually overlap, atically treated with a long-acting opioid and a short-acting opioid for sometimes making it difficult to assign a specific genetic label. A combreakthrough pain. He receives a replacement dose of pregnenolone monality, however, is the development of centralized pain because along with medroxyprogesterone. He greatly benefits from an electro- many autoimmune, genetic syndromes attack certain joints, linings, magnetic instrument, which administers a pulsed radio wave and drives nerves, and tendons beginning in childhood and progress in severity a topical corticoid (iontophoretic type) into the stump. With this treat- over many years. ment regimen he has far less pain and some pain-free hours.

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NEUROLOGY

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MULTiDiSCiPLiNARY CAR AND FAMiLY INVOLV M NT

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Centralized pain is a progressive tissue-destructive process that requires care by a professional team because this process interferes with every aspect of a person’s well-being. Our psychologists, nurses, physical therapists, podiatrists, pharmacists, and social workers need to have a thorough understanding of the physiology and medical treatments for centralized pain as well as the economic and cultural setting in which the patient resides to contribute their specialized skill (see Figure 3). Patients with centralized pain require a lifetime of multidisciplinary care, whether that care is provided under one roof by a single practice with multidisciplinary staff or managed through a community-based referral system.

The serious complications of centralized pain require that the family of these patients be educated and included as an integral part of the therapeutic process. Severe forms of centralized pain may produce such significant mental deterioration in the patient that custodial care may be needed. Families simply have to know about pain and the healing process in order to be prepared.

SUMMARY Research over the last 2 decades has elucidated the mechanism by which a nerve injury in peripheral tissue can lead to neuroinflammation and imprinting of pain in the memory of CNS cells. Knowing that the severe forms of centralized pain produce suffering and disability, pain practitioners should make great effort to make a clinical diagnosis and develop treatment plans for all patients with centralized pain.

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2. Watkins LR, Maier SF. When good pain turns bad.

Curr Dir Psychol Sci. 2003;12(6):232–236.

3. Tracey I, Bushnell MC. How neuroimaging studies have challenged us to rethink: Is chronic pain a disease?

J Pain. 2009;10(11):1113–1120.

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4. Henry DE, Chiodo AE, Yang W. Central nervous system reorganization in a variety of chronic pain states: a review. PM R. 2011;3(12):1116–1125.

5. Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci.

2009;10(1):23-36.

6. Banati RB. Brain plasticity and microglia: is transsynaptic glial activation in the thalamus after limb denervation linked to cortical plasticity and central sensitization?

J Physiol Paris. 2002;96(3-4):289-299.

patients with acute, chronic and episodic pain. Schmerz (Berlin Germany). 2005;19(2):109–116.

24. Tennant F, Hermann L. Normalization of serum cortisol concentration with opioid treatment of severe chronic pain. Pain Med. 2002;3(2):132–134.

25. Rhodin A, Stridaberg M, Gordh T. Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term oral opioid treatment. Clin J Pain.

2010;26(5):374–380.

7. Banati RB. Visualising microglial activation in vivo.

Glia. 2002;40(2):206-217.

26. Vuong C, Van Uum SH, O’Dell LE, et al. The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev. 2010;31(1):98–132.

8. Mika J. Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. Pharmacol Rep. 2008;60(3):297-307.

27. Asiedu M, Ossipov MH, Kaila K, et al. Acetazolamide and midazolam act synergistically to inhibit neuropathic pain. Pain. 2010;148(2):302–308.

9. Hains LE, Loram LC, Weiseler JL, et al. Pain intensity and duration can be enhanced by prior challenge: initial evidence suggestive of a role of microglial priming. J Pain.

2010;11(10):1004–1014.

28. He Y, Appel S, Le W. Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res. 2001;909(12):187–193.

10. Latremollier A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895–926.

29. Ledeboer A, Sloane EM, Milligan ED, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation.

Pain. 2005;115(1–2):71–83.

11. May A. Chronic pain may change the structure of the brain. Pain. 2008;137(1):7–15.

12. Roberts J, Ossipov MH, Porreca F. Glial activation in the rostroventromedial medulla promotes descending facilitation to mediate inflammatory hypersensitivity. Eur J Neurosci. 2009;30(2):229–241.

13. Vera-Portocarrero LP, Zhang E-T, Ossipov MH, et al.

Descending facilitation from the rostral ventromedial medulla maintains nerve injury-induced central sensitization.

Neuroscience. 2006;14(4):1311–1320.

14. Perkins FM, Kehlet H. Chronic pain as an outcome of surgery: a review of predictive factors. Anesthesiology.

2000;93(4):1123-1133.

15. Rodriguez-Raecke R, Niemeier A, Ihle K, et al. Brain gray matter decrease in chronic pain is the consequence and not the cause of pain. J Neurosci. 2009;29(44):13746– 13750.

16. Duric V, McCarson KE. Persistent pain produces stress-like alterations in hippocampal neurogenesis and gene expression. J Pain. 2006;7(8):544–555.

17. Apkarian AV, Sosa Y, Sonty S, et al. Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J Neurosci. 2004;24(46):10410–10415.

18. Teutsch S, Herken W, Bingel U, et al. Changes in brain gray matter due to repetitive painful stimulation.

Neuroimage. 2008;42(2):845-849.

19. Kuchinad A, Schweinhardt P, Seminowicz DA, et al. Accelerated brain gray matter loss in fibromyalgia. J Neurosci. 2007;27(15):4004–4007.

20. Buckalew N, Haut MW, Morrow L, et al. Chronic pain is associated with brain volume loss in older adults: preliminary evidence. Pain Med. 2008;9(2):240–248.

21. Cook DB, Lange G, Ciccone DS, et al. Functional imaging of pain in patients with primary fibromyalgia. J Rheumatol. 2004;31(2):368–378.

22. Moore RA, Evans PJ, Smith RF, et al. Increased cortisol excretion in chronic pain. Anesthesia. 1983;38(8):788–791.

30. Mika J, Osikowicz M, Makuch W, et al. Minocycline and pentoxifylline attenuate allodynia and hyperalgesia and potentiate the effects of morphine in rat and mouse models of neuropathic pain. Eur J Pharmacol. 2007;560(23):142–149.

31. Vale ML, Benevides VM, Sachs D, et al. Antihyperalgesic effect of pentoxifylline on experimental inflammatory pain. Br J Pharmacol. 2004;143(7):833–844.

32. Roglio I, Bianchi R, Gotti S, et al. Neuroprotective effects of dihydroprogesterone and progesterone in an experimental model of nerve crush injury. Neuroscience.

2008;155(3):673–685.

33. Schumacher M, Sitruk-Ware R, De Nicola AF. Progesterone and progestins: neuroprotection and myelin repair.

Curr Opin Pharmacol. 2008;8(6):740–746.

34. Thomas AJ, Nockels RP, Pan HQ, et al. Progesterone is neuroprotective after experimental acute spinal cord trauma in rats. Spine. 1999;24(20):2134–2138.

35. Guth L, Zhang Z, Roberts E. Key role for pregnenolone in combination therapy that promotes recovery after spinal cord injury. Proc Natl Acad Sci. 1994;91(25):12308– 12312.

36. Hirono M, Igarashi M, Matsumoto S. The direct effect of HCG upon pituitary gonadotrophin secretion.

Endocrinology. 1972;90(5):1214–1219.

37. Rao CV. An overview of the past, present, and future of nongonadal LH/hCG actions in reproductive biology and medicine. Semin Reprod Med. 2001;19(1):1–119.

38. Lei ZM, Rao CV. Neural actions of luteinizing hormone and human chorionic gonadotropin. Semin Reprod Med. 2001;19(1):103–109.

39. Lukacs H, Hiatt ES, Lei ZM, et al. Peripheral and intracerebroventricular administration of human chorionic gonadotropin alters several hippocampus-associated behaviors in cycling female rats. Horm Behav.

1995;29(1):42–58.

23. Strittamatter M, Bianchi O, Ostertag D, et al. Altered function of the hypothalamic-pituitary-adrenal axis in

Q3 | 2013

— Oliver Wendell Holmes

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“Consider the purpose of the skin Q3 | 2013

—to keep things out of our body and protect our systemic circulation.” www.painweek.org | PWJ | 19

PHARMACOTHERAPY

by

e

e

KATHRYN A. WALK R PHARMD, BCPS, CPE/MARY LYNN MCPH RSON PHARMD, BCPS, FASPE, CPE

abstract: Although

the oral route is preferred for delivering medications, alternate routes are often required to manage pain in a palliative care setting. Frequently it is not feasible to use the oral route because of a patient’s disease progression, physical limitations, or mental status changes. This article will focus on using the topical or transdermal route effectively. Careful consideration of patient- and medication-related factors is required before deciding that a topical or transdermal product is appropriate for a patient.

“Not every drug is suitable for topical or transdermal administration—no matter how creative we get…”

20 | PWJ | www.painweek.org

Q3 | 2013

however, they are less likely to be effective in conditions requiring deep penetration to reach the site of pain, such as hip pain. onsider the purpose of the skin—to keep things out of our body and protect our systemic circulation. Not every drug is suitable for topical or transdermal administration.

No matter how creative we get with dosage formulations, the drug must still pass through the skin to work. This is why not every medication can be compounded into a cream, slathered on, and expected to work. Medications that are likely to favor topical use are usually lipid soluble with molecules small enough to be absorbed.

An important distinction between topical and transdermal analgesics is their location of action and method of absorption. Topical products are designed to be placed at the site of the painful area and to act locally to relieve pain in the immediate area. Common formulations include patches, lotions, and creams. Transdermal products, although applied to the skin and also available in patches, absorb into the systemic circulation and produce central effects.

One important caution with all topical and transdermal products is that heat increases absorption. This means application of direct heat sources (for example, hot water bottles) to the area where the medication is being applied should be avoided. Another important factor to consider in using topical products is the integrity of the skin: never apply them to broken or damaged skin. Patients should be reminded to avoid the use of sunscreens, moisturizers, insect repellents, and other products that may change the characteristics of the skin and alter absorption of the medication. Patients should always be educated on proper administration and told not to put occlusive dressings over medication.

Topical lidocaine patches are indicated to be worn for 12 hours and then removed for 12 hours. However, many pain providers direct patients to wear them for an entire day. In a small study of 20 patients, the group was divided into those who wore lidocaine patches continuously and those who replaced them every 12 or 24 hours. Serum drug levels were 186 ng/mL (in the every 24-hour group) and 225 ng/ mL (in the every 12-hour group), which is almost one-seventh the concentration required to produce antiarrhythmic effect (that is, 1500 ng/mL) and one-twenty-fifth the concentration for toxicity (5000 ng/ mL). The authors also reported no sensory alterations at the site of patch administration.7 Lidocaine patches are generally well tolerated with mild skin reactions being the only significant adverse effect.

Capsaicin is an older pain medication option that is used topically for neuropathic pain. It is made from the component that makes chili

OVeRALL, CAPSAiCiN iS NOT AN iDeAL AGeNT TO USe GiVeN iTS ADVeRSe eFFeCTS AND LACK OF SUSTAiNeD BeNeFiT.

peppers spicy. The exact analgesic mechanism is not completely clear, but capsaicin seems to act as a counterirritant and causes a depletion of substance P at the neuron. Initially, patients will experience pain, burning, and irritation when they apply capsaicin cream. This initial reaction can last 1 to 2 weeks and is related to the release of substance P; after repeated applications and depletion of substance P, the irritation is lessened and analgesia is achieved. In one trial of patients with mild osteoarthritis pain, capsaicin was shown to provide modest pain relief; only after about 4 weeks was maximum benefit achieved. However, the relief was not sustained. Most important, the dropout rate was 19.3% vs 10.7% in the placebo group because of the high adverse event rate (54% vs 15%). Additionally, the NNT in this trial was 8.1.8 There are no trials directly comparing capsaicin to oral or topical nonsteroidal anti-inflammatory drugs (NSAIDs); however, the NNT is 3.1 for topical NSAIDs and 5.3 for topical salicylates in osteoarthritis.9 Overall, capsaicin is not an ideal agent to use given its adverse effects and lack of sustained benefit. It is also not ideal for patients who are not able to carefully apply it because it can cause extreme irritation if the cream contacts eyes or other mucous membranes. Patients must always be counseled to wash their hands carefully immediately after use.

opical lidocaine patches (5%) are indicated for postherpetic neuralgia (PHN) and should be placed on the area of pain. Up to 3 patches can be placed at a time; they can be cut to fit the area of pain, if needed. Data from studies on PHN report that in comparison to other agents, lidocaine patches have a number-needed-to-treat (NNT) of 4.4, making them a competitive option compared with other standard analgesics such as opioids (NNT 2.7), tricyclic antidepressants (NNT 4), gabapentin (NNT 3.2–5), and capsaicin (NNT 5.3).1 A 2007 Cochrane Review did not find evidence that lidocaine patches should be a first-line option for PHN, although the reviewers concluded that these patches may provide benefit to patients on an individual basis.2 Topical lidocaine patches have also been studied for other neuropathic pain conditions such as diabetic polyneuropathy, low back pain, myofascial pain, and knee osteoarthritis.3-6 These studies, though limited in scope and duration, reported significant improvements in pain indices with minimal adverse effects. It is reasonable to think that lido- Wouldn’t it be great to have an anti-inflammatory effect on a locaine patches may be helpful for localized painful conditions; calized area while avoiding systemic adverse events for which oral Q3 | 2013

www.painweek.org | PWJ | 21

PHARMACOTHERAPY

NSAIDs are so notorious? Topical diclofenac would seem to be the solution; however, the product information contains the same strict boxed warnings as do oral NSAIDs about cardiovascular (CV) and gastrointestinal (GI) risks. A close look at the data indicates that the topical preparations available for diclofenac have less than 5% of the bioavailability of an oral 50-mg tablet. Does this mean that the adverse events are lessened as well? Studies have not given us concrete answers for this, so each clinician is left to make choices for individual patients based on the patient’s risk profile. Given our limited choices for anti-inflammatory options in patients with risk factors, using topical NSAIDs may be an option with careful monitoring in low-risk patients to provide relief.

However, there is not currently any clinical data to support that claim. It remains to be seen whether topical NSAIDs will allow safer use of anti-inflammatory agents in patients with CV disease, peptic ulcer disease, a history of NSAID-induced upper GI bleeding, or in those on concurrent antiplatelet or anticoagulation therapy.

GiVeN OUR LiMiTeD CHOiCeS FOR ANTi-iNFLAMMATORY OPTiONS iN PATieNTS WiTH RiSK FACTORS, USiNG TOPiCAL NSAiDS MAY Be AN OPTiON WiTH CAReFUL MONiTORiNG iN LOW-RiSK PATieNTS TO PROViDe ReLieF.

are 100 times less potent that COX-2 inhibitors.12 They are known to have poor efficacy in chronic pain states and are only appropriate for acute self-limiting aches, sprains, and strains. Topical salicylates have been associated with severe toxicity and deaths after topical application and also accidental or deliberate ingestion. The adverse event profile of topical salicylates is comparable to oral NSAIDs and must be considered when recommending the use of these products.

Patients receiving anticoagulants or who have any other risk factors that would limit NSAID use (for example, peptic ulcer disease) should not be using topical salicylates.

Opioids can be compounded for topical administration and applied to relieve pain associated with wound care or burns. Topical opioids act on peripheral opioid receptors that are expressed in inflamed tissue and have very limited systemic absorption. They are not available as commercial products but can be compounded using the formula 10 mg IV morphine (10 mg/mL) compounded in 8 g of intrasite gel and applied to the wound 1 to 3 times daily as needed. The only common side effects that have been reported are Diclofenac is available in a topical gel irritation at the site of application. There are (Voltaren®) that is applied using a dosing conflicting opinions in the literature regardcard to measure the amount (dose) of gel ing the use of topical opioids; however, most dispensed from the tube. After squeezing the experienced palliative clinicians consider this correct amount onto the dosing card, the an excellent option for palliative patients.13 card is used to apply the gel to the painful area. Diclofenac gel is indicated for relief of osteoarthritic pain in Topical opioids can be especially useful for avoiding IV analgesics in joints; however, it cannot be applied to every painful joint. The dos- patients who have difficulty taking oral medications and/or require ing recommendations limit the total amount to be applied per day to local analgesia for wound care. The challenges that remain in using 32 mg. Upper extremities are dosed at 4 g and lower extremities at 2 g, topical opioids are that there are no clear recommendations regardapplied 4 times daily. This correlates to choosing 2 knees or 1 knee ing differences between opioids, optimal dosing and escalation, interand 2 elbows for the day! The gel formulation has been shown to sig- vals of administration, or possible differences in the vehicles used in nificantly improve pain, function, and movement, compared with pla- compounding. cebo, after 12 weeks of treatment for pain related to osteoarthritis.10 Pennsaid® is a topical solution formulation of diclofenac and similarly indicated for the pain related to osteoarthritis of the knee. It is applied by counting drops; 10 drops at a time are placed on the knee 4 times daily for a total daily dose of 40 drops. Bathing and showering is not recommended for 30 minutes after administration to allow for absorption. This formulation has also been shown to significantly improve pain, function, and stiffness compared with placebo for pain related to osteoarthritis of the knee. It was also compared to oral diclofenac and produced comparable pain relief.11 Salicylates are a class of topical analgesics that can be purchased over the counter. Trolamine salicylate is the active ingredient in products such as Aspercreme® and Myoflex® cream whereas methyl salicylate is the active ingredient in BenGay® and Icy Hot®. Topical salicylates are thought to act as counterirritants and interfere with transcription factors and kinases involved in the inflammatory process. They do not appear to affect the cyclooxygenase (COX) enzymes because they

22 | PWJ | www.painweek.org

entanyl is a very lipid-soluble synthetic opioid that facilitates rapid diffusion across the blood–brain barrier and allows for transdermal absorption and a systemic analgesic effect. Transdermal fentanyl (TDF) is indicated only for patients with moderate to severe chronic pain who are tolerant to the equivalent of a 25-mcg/hour patch for more than 1 week. It is not appropriate to use this delivery system to treat patients with a changing pain picture such as postoperative or intermittent pain. TDF is applied for 3 days and is available in many dosages (12, 25, 50, 75, and 100 mcg/h). Approximately 15% of patients experience end-of-dose failure on the third day and may require changing patches every 48 hours.

Q3 | 2013

When a patch is placed, reliable analgesia does not occur until 12 to Transdermal buprenorphine (Butrans®) is another product available 24 hours; therefore, an equivalent opioid should be used in the first to provide systemic analgesia for patients with moderate to severe 12 hours to prevent the patient from suffering unnecessarily. Manu- chronic pain. It is available in 5-, 10-, and 20-mcg/hour patches that facturers’ guidelines for conversion to and from oral morphine are can be worn for 7 days. The application site should be on the trunk considered very conservative in converting to TDF and are not de- and rotated (not reused for 21 days). For opioid-naïve patients and signed for converting from TDF to oral morphine. A more clinically those using less than 30-mg oral morphine equivalents, the 5-mcg/ relevant equivalent dose can be determined using this conversion: hour patch should always be the starting dose. If the patient is tolerant 1 mcg/hour TDF is approximately equivalent to 2 mg oral morphine to 30- to 80-mg oral morphine equivalents, then the 10-mcg/hour per day. Therefore if the patient was taking a long-acting oral prod- patch may be started after titrating the patient down to 30 mg of oral uct such as MS Contin 45 mg PO twice daily, a 50-mcg/hour TDF morphine per day. Buprenorphine is a partial opioid agonist, which should be placed when the patient takes the last dose of MS Contin. explains the caution needed to avoid symptoms of withdrawal when That would provide equivalent coverage for the first 12 hours while converting opioid-tolerant patients on full-agonist therapy. The parthe TDF achieves analgesia onset. If titration is appropriate, it can be tial agonism may also be responsible for some advantages over full-agdone 3 days after application and every 6 days, if needed, thereafter. If onist opioids: the lower abuse potential, the less danger of overdosing, a patient receiving TDF requires rotation to another opioid, the same and the fewer withdrawal symptoms with discontinued use. conversion can be used to calculate an oral morphine dose. When the patient is in possession of the new opioid product, the patch can be We hope this review of pearls related to using topical and transderremoved. However, for the first 12 hours only, the rescue short-act- mal analgesic will stick with you as you care for patients in pain and ing opioid should be used because the fentanyl is still providing anal- strive to relieve suffering. gesia during this time. At 12 hours, 50% of the long-acting dose may be given, and at 24 hours, the full dose may be given with confidence References 1. Davies PS, Galer BS. Review of lidocaine patch 5% studies in the treatment of postherpetic neuralgia. Drugs. 2004;64(9):937–947.

BUPReNORPHiNe iS A PARTiAL OPiOiD AGONiST, WHiCH eXPLAiNS THe CAUTiON NeeDeD TO AVOiD SYMPTOMS OF WiTHDRAWAL WHeN CONVeRTiNG OPiOiD-TOLeRANT PATieNTS ON FULL-AGONiST THeRAPY.

2. Khaliq W, Alam S, Puri N. Topical lidocaine for the treatment of postherpetic neuralgia. Cochrane Database Syst Rev. 2007;(2):CD004846.

3. Barbano RL, Herrmann DN, Hart-Gouleau S, et al. Effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in diabetic polyneuropathy. Arch Neurol. 2004;61(6):914–918.

4. Gimbel J, Linn R, Hale M, et al. Lidocaine patch treatment in patients with low back pain: results of an open-label, nonrandomized pilot study. Am J Ther. 2005;12(4):311–319.

5. Affaitati G, Fabrizio A, Savini A, et al. A randomized, controlled study comparing a lidocaine patch, a placebo patch, and anesthetic injection for treatment of trigger points in patients with myofascial pain syndrome: evaluation of pain and somatic pain thresholds. Clin Ther. 2009;31(4):705–720.

6. Burch F, Codding C, Patel N, et al. Lidocaine patch 5% improves pain, stiffness, and physical function in osteoarthritis pain patients: a prospective, multicenter, open-label effectiveness trial. Osteoarthritis Cartilage. 2004;12(3):253–255.

7. Gammaitoni AR, Alvarez NA, Galer BS. Pharmacokinetics and safety of continuously applied lidocaine patches 5%. Am J Health Syst Pharm. 2002;59(22):2215–2220.

8. Altman R, Aven A, Holmburg C. Capsaicin cream 0.025% as monotherapy for osteoarthritis: a double-blind study. Semin Arthritis Rheum. 1994;23(suppl 3):25–33.

9. Mason L, Moore RA, Derry S, et al. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ. 2004;328(7446):991.

that the TDF is no longer contributing to analgesia. If a patient requires IV fentanyl, the dose is equivalent to the strength of the patch.

The approach to starting and stopping continuous infusions should be similar as the strategy described above for oral long-acting opioids in considering the first 12 to 24 hours carefully.

There are 3 types of opioid patches available, and in most cases, they are clinically equivalent. A gel-containing reservoir in the patch holds the drug in the gel, allowing it to be diffused through the adhesive protective layer. Another type of patch combines the fentanyl in the adhesive itself. The matrix membrane system incorporates the fentanyl in a matrix layer behind a rate-controlling membrane in another layer of adhesive. Fentanyl patches utilize a patient’s body fat to absorb and properly distribute the opioid so that less of an analgesic effect is seen in cachectic patients or those with poor fat stores.14 Q3 | 2013

10. Barthel HR, Haselwood D, Longley S 3rd, et al. Randomized controlled trial of diclofenac sodium gel in knee osteoarthritis. Semin Arthritis Rheum. 2009;39(3):203–212.

11. Simon LS, Grierson LM, Naseer Z, et al. Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis. Pain. 2009;143(3):238–245.

12. Altman R, Barkin RL. Topical therapy for osteoarthritis: clinical and pharmacologic perspectives. Postgrad Med. 2009;121(2):139–147.

13. LeBon B, Zeppetella G, Higginson IJ. Effectiveness of topical administration of opioids in palliative care: a systematic review. J Pain Symptom Manag. 2009;37(5):913–917.

14. Heiskanen T, Matzke S, Haakana S, et al. Transdermal fentanyl in cachectic cancer patients. Pain. 2009;144(1-2):218–222.

www.painweek.org | PWJ | 23

Your patients may not have to face chronic pain alone

There i thera s no AB-ra peuti ted ce OPAN A® ER quivalent to with I NTAC ®

OPANA® ER (oxymorphone HCl) Extended-Release tablets, CII with INTAC® Technology are the only oxymorphone extended release tablets that are designed to be crush resistant.*2 *The clinical significance of INTAC® technology or its impact on abuse/misuse liability has not been established.

Generic oxymorphone HCl ER products are available but are not designed to be crush-resistant and are not therapeutically equivalent to OPANA® ER with INTAC® Widely available on managed care plans for 9 out of 10 covered patients.3

INDICATION OPANA® ER is an opioid agonist indicated for the relief of moderate to severe pain in patients requiring continuous around-the-clock opioid treatment for an extended period of time.

Adverse reactions reported at (≥2%) in placebo-controlled trials were: nausea, constipation, dizziness, somnolence, vomiting, pruritus, headache, sweating increased, dry mouth, sedation, diarrhea, insomnia, fatigue, appetite decreased, and abdominal pain.

Please see adjacent pages for Brief Summary of full Prescribing Information, including boxed WARNING, for OPANA® ER. Learn more at opana.com References: 1. OPANA® ER [package insert]. Chadds Ford, PA: Endo Pharmaceuticals Inc; 2012. 2. Data on file, DOF-OP-57. Endo Pharmaceuticals Inc; 2012.

3. Data on file, DOF-OP-64. Endo Pharmaceuticals Inc; 2013.

Rx Only DEA Order Form Required.

OPANA® is a registered trademark of Endo Pharmaceuticals Inc. INTAC® is a registered trademark of the Grünenthal Group. © 2013 Endo Pharmaceuticals Inc. All Rights Reserved. Malvern, PA 19355 OP-02714/April 2013 www.opana.com 1-800-462-ENDO (3636)

Brief Summary (For full Prescribing Information including Dosage and Administration, and Patient Information, refer to package insert.)

WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, ACCIDENTAL EXPOSURE, and INTERACTION WITH ALCOHOL Abuse Potential OPANA ER contains oxymorphone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit (see Warnings and Precautions). Assess each patient’s risk for opioid abuse or addiction prior to prescribing OPANA ER. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depressive disorder). Routinely monitor all patients receiving OPANA ER for signs of misuse, abuse, and addiction during treatment (see Drug Abuse and Dependence).

Life-threatening Respiratory Depression Respiratory depression, including fatal cases, may occur with use of OPANA ER, even when the drug has been used as recommended and not misused or abused (see Warnings and Precautions). Proper dosing and titration are essential and OPANA ER should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Monitor for respiratory depression, especially during initiation of OPANA ER or following a dose increase. Instruct patients to swallow OPANA ER tablets whole. Crushing, dissolving, or chewing OPANA ER can cause rapid release and absorption of a potentially fatal dose of oxymorphone.

Accidental Exposure Accidental ingestion of OPANA ER, especially in children, can result in a fatal overdose of oxymorphone (see Warnings and Precautions).

Interaction with Alcohol The co-ingestion of alcohol with OPANA ER may result in an increase of plasma levels and potentially fatal overdose of oxymorphone (see Warnings and Precautions). Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while on OPANA ER. INDICATIONS AND USAGE OPANA ER is indicated for the relief of moderate to severe pain in patients requiring continuous, around-the-clock opioid treatment for an extended period of time.

Limitations of Usage OPANA ER is not intended for use: • As an as-needed (prn) analgesic • For pain that is mild or not expected to persist for an extended period of time • For acute pain • For postoperative pain unless the patient is already receiving chronic opioid therapy prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time.

CONTRAINDICATIONS OPANA ER is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma or hypercarbia • Known or suspected paralytic ileus • Moderate and severe hepatic impairment (see Clinical Pharmacology, Warnings and Precautions).

• Hypersensitivity (e.g. anaphylaxis) to oxymorphone, any other ingredients in OPANA ER, or to morphine analogs such as codeine (see Adverse Reactions).

WARNINGS AND PRECAUTIONS Abuse Potential OPANA ER contains oxymorphone, an opioid agonist and a Schedule II controlled substance. Oxymorphone can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing OPANA ER in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain.

Assess each patient’s risk for opioid abuse or addiction prior to prescribing OPANA ER. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use.

Misuse or abuse of OPANA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the opioid and pose a significant risk that could result in overdose and death (see Overdosage).

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.

Life Threatening Respiratory Depression Respiratory depression is the primary risk of OPANA ER. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.

Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO2) retention

from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status (see Overdosage).

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of OPANA ER, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with OPANA ER and following dose increases. Instruct patients against use by individuals other than the patient for whom OPANA ER was prescribed and to keep OPANA ER out of the reach of children, as such inappropriate use may result in fatal respiratory depression.

To reduce the risk of respiratory depression, proper dosing and titration of OPANA ER are essential (see Dosage and Administration). Overestimating the OPANA ER dose when converting patients from another opioid product can result in fatal overdose with the first dose. Respiratory depression has also been reported with use of modified-release opioids when used as recommended and not misused or abused.

To further reduce the risk of respiratory depression, consider the following: • Proper dosing and titration are essential and OPANA ER should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

• Instruct patients to swallow OPANA ER tablets intact. The tablets are not to be crushed, dissolved, or chewed. The resulting oxymorphone dose may be fatal, particularly in opioid-naïve individuals.

• OPANA ER is contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression (see Contraindications).

Accidental Exposure Accidental consumption of OPANA ER, especially in children, can result in a fatal overdose of oxymorphone.

Interaction with Alcohol The co-ingestion of alcohol with OPANA ER can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on OPANA ER therapy (see Clinical Pharmacology).

Elderly, Cachectic, and Debilitated Patients Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance compared to younger, healthier patients. Therefore, monitor such patients closely, particularly when initiating and titrating OPANA ER and when OPANA ER is given concomitantly with other drugs that depress respiration (see Warnings and Precautions).

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 OPANA ER, as in these patients, even usual therapeutic doses of OPANA ER may decrease respiratory drive to the point of apnea (see Warnings and Precautions). Consider the use of alternative non-opioid analgesics in these patients if possible.

Interactions with CNS Depressants and Illicit Drugs Hypotension, profound sedation, coma, or respiratory depression may result if OPANA ER is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of OPANA ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient’s use, if any, of alcohol or illicit drugs that cause CNS depression. If OPANA ER therapy is to be initiated in a patient taking a CNS depressant, start with a lower OPANA ER dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant (see Drug Interactions).

Use in Patients with Hepatic Impairment A study of OPANA ER in patients with hepatic disease indicated greater plasma concentrations than those with normal hepatic function (see Clinical Pharmacology). OPANA ER is contraindicated in patients with moderate or severe hepatic impairment. In patients with mild hepatic impairment reduce the starting dose to the lowest dose and monitor for signs of respiratory and central nervous system depression (see Dosage and Administration).

Hypotensive Effect OPANA ER 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). Monitor these patients for signs of hypotension after initiating or titrating the dose of OPANA ER. In patients with circulatory shock, OPANA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of OPANA ER in patients with circulatory shock.

Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking OPANA ER 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 OPANA ER. OPANA ER 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 OPANA ER in patients with impaired consciousness or coma.

Use in Patients with Gastrointestinal Conditions OPANA ER is contraindicated in patients with paralytic ileus. Avoid the use of OPANA ER in patients with other GI obstruction.

The oxymorphone in OPANA ER 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.

Use in Patients with Convulsive or Seizure Disorders The oxymorphone in OPANA ER 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 OPANA ER therapy.

Avoidance of Withdrawal Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) in patients who have received or are receiving a course of therapy with an opioid agonist analgesic, including OPANA ER. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing OPANA ER, gradually taper the dose (see Dosage and Administration). Do not abruptly discontinue OPANA ER. Driving and Operating Machinery OPANA ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of OPANA ER and know how they will react to the medication.

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Respiratory Depression (see Warnings and Precautions) • Chronic Pulmonary Disease (see Warnings and Precautions) • Head Injuries and Increased Intracranial (see Warnings and Precautions) • Interactions with Other CNS Depressants (see Warnings and Precautions) • Hypotensive Effect (see Warnings and Precautions) • Gastrointestinal (see Warnings and Precautions) • Seizures (see Warnings and Precautions) Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of oxymorphone hydrochloride extended-release tablets was evaluated in a total of 2011 patients in open-label and controlled clinical trials. The clinical trials enrolled of patients with moderate to severe chronic non-malignant pain, cancer pain, and post surgical pain. The most common serious adverse events reported with administration of oxymorphone hydrochloride extended-release tablets were chest pain, pneumonia and vomiting.

The following table lists adverse reactions that were reported in at least 2% of patients in placebo-controlled trials (N=5).

Adverse Reactions Reported in Placebo-Controlled Clinical Trials with Incidence ≥2% in Patients Receiving OPANA ER. MedDRA Preferred OPANA ER Placebo Term (N=1259) N=461) Nausea 33% 13% Constipation 28% 13% Dizziness (Excl Vertigo) 18% 8% Somnolence 17% 2% Vomiting 16% 4% Pruritus 15% 8% Headache 12% 6% Sweating increased 9% 9% Dry mouth 6% <1% Sedation 6% 8% Diarrhea 4% 6% Insomnia 4% 2% Fatigue 4% 1% Appetite decreased 3% <1% Abdominal pain 3% 2% The common (≥1% to <10%) adverse drug reactions reported at least once by patients treated with oxymorphone hydrochloride extended-release tablets in the clinical trials organized by MedDRA’s (Medical Dictionary for Regulatory Activities) System Organ Class Eye disorders: vision blurred Gastrointestinal disorders: diarrhea, abdominal pain, dyspepsia General disorders and administration site conditions: dry mouth, appetite decreased, fatigue, lethargy, weakness, pyrexia, dehydration, weight decreased, edema Nervous system disorders: insomnia Psychiatric disorders: anxiety, confusion, disorientation, restlessness, nervousness, depression Respiratory, thoracic and mediastinal disorders: dyspnea Vascular disorders: flushing and hypertension Other less common adverse reactions known with opioid treatment that were seen <1% in the oxymorphone hydrochloride extended-release tablets trials include the following: Bradycardia, palpitation, syncope, tachycardia, postural hypotension, miosis, abdominal distention, ileus, hot flashes, allergic reactions, hypersensitivity, urticaria, oxygen saturation decreased, central nervous system depression, depressed level of consciousness, agitation, dysphoria, euphoric mood, hallucination, mental status changes, difficult micturition, urinary retention, hypoxia, respiratory depression, respiratory distress, clamminess, dermatitis, hypotension.

Post-marketing Experience The following adverse reactions have been identified during post approval use of OPANA ER. Because these reactions 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.

Nervous system disorder: amnesia, convulsion, memory impairment

DRUG INTERACTIONS Alcohol Concomitant use of alcohol with OPANA ER can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on OPANA ER therapy (see Clinical Pharmacology).

CNS Depressants Concurrent use of OPANA ER and other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, hypotension, profound sedation, or coma. Monitor patients receiving CNS depressants and OPANA ER for signs of respiratory depression and hypotension. When such combined therapy is contemplated, reduce the initial dose of one or both agents.

Mixed Agonist/Antagonist Opioid Analgesics Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) may reduce the analgesic effect of OPANA ER or may precipitate withdrawal symptoms in these patients. Avoid the use of mixed agonist/antagonist analgesics in patients receiving OPANA ER. Cimetidine Cimetidine can potentiate opioid-induced respiratory depression. Monitor patients for respiratory depression when OPANA ER and cimetidine are used concurrently.

Anticholinergics Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of respiratory and central nervous system depression when OPANA ER is used concurrently with anticholinergic drugs.

USE IN SPECIFIC POPULATIONS Pregnancy The safety of using oxymorphone in pregnancy has not been established with regard to possible adverse effects on fetal development. The use of OPANA ER in pregnancy, in nursing mothers, or in women of child-bearing potential requires that the possible benefits of the drug be weighed against the possible hazards to the mother and the child.

Prolonged use of opioid analgesics during pregnancy may cause fetal-neonatal physical dependence.

Teratogenic Effects (Pregnancy Category C) There are no adequate and well-controlled studies of oxymorphone in pregnant women. OPANA ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see Use in Specific Populations).

Oxymorphone hydrochloride administration did not cause malformations at any doses evaluated during developmental toxicity studies in rats (≤25 mg/kg/ day) or rabbits (≤50 mg/kg/day). These doses are ~3-fold and ~12-fold the human dose of 40 mg every 12 hours, based on body surface area. There were no developmental effects in rats treated with 5 mg/kg/day or rabbits treated with 25 mg/kg/day. Fetal weights were reduced in rats and rabbits given doses of ≥10 mg/ kg/day and 50 mg/kg/day, respectively. These doses are ~1.2-fold and ~12-fold the human dose of 40 mg every 12 hours based on body surface area, respectively.

There were no effects of oxymorphone hydrochloride on intrauterine survival in rats at doses ≤25 mg/kg/day, or rabbits at ≤50 mg/kg/day in these studies (see Non-teratogenic Effects, below). In a study that was conducted prior to the establishment of Good Laboratory Practices (GLP) and not according to current recommended methodology, a single subcutaneous injection of oxymorphone hydrochloride on gestation day 8 was reported to produce malformations in offspring of hamsters that received 15.5-fold the human dose of 40 mg every 12 hours based on body surface area. This dose also produced 20% maternal lethality.

Non-teratogenic Effects Oxymorphone hydrochloride administration to female rats during gestation in a pre- and postnatal developmental toxicity study reduced mean litter size (18%) at a dose of 25 mg/kg/day, attributed to an increased incidence of stillborn pups. An increase in neonatal death occurred at ≥5 mg/kg/day. Post-natal survival of the pups was reduced throughout weaning following treatment of the dams with 25 mg/kg/day. Low pup birth weight and decreased postnatal weight gain occurred in pups born to oxymorphone-treated pregnant rats given a dose of 25 mg/kg/ day. This dose is ~3-fold higher than the human dose of 40 mg every 12 hours on a body surface area basis.

Labor and Delivery OPANA ER is not for use in women during and immediately prior to labor, where shorter acting analgesics or other analgesic techniques are more appropriate (see Indications and Usage). Occasionally, opioid analgesics may prolong labor through by temporarily reducing the strength, duration, and frequency of uterine contractions. However, these effects are not consistent and may be offset by an increased rate of cervical dilatation which tends to shorten labor.

Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. An opioid antagonist, such as naloxone, should be available for reversal of opioidinduced respiratory depression in the neonate in such situations.

Nursing Mothers It is not known whether oxymorphone is excreted in human milk. Because many drugs, including some opioids, are excreted in human milk, caution should be exercised when OPANA ER is administered to a nursing woman. Monitor infants who may be exposed to OPANA ER through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.

Pediatric Use The safety and effectiveness of OPANA ER in patients below the age of 18 years have not been established.

Geriatric Use Of the total number of subjects in clinical studies of oxymorphone hydrochloride extended-release tablets, 27% were 65 and over, while 9% were 75 and over. No

overall differences in effectiveness were observed between these subjects and younger subjects. There were several adverse events that were more frequently observed in subjects 65 and over compared to younger subjects. These adverse events included dizziness, somnolence, confusion, and nausea. On average, age greater than 65 years was associated with a 1.4-fold increase in oxymorphone AUC and a 1.5-fold increase in Cmax. Initiate dosing with OPANA ER in patients 65 years of age and over using the 5 mg dose and monitor closely for signs of respiratory and central nervous system depression when initiating and titrating OPANA ER. For patients on prior opioid therapy, start at 50% of the starting dose for a younger patient on prior opioids and titrate slowly.

Hepatic Impairment Patients with mild hepatic impairment have an increase in oxymorphone bioavailability of 1.6-fold. In opioid-naïve patients with mild hepatic impairment, initiate OPANA ER using the 5 mg dose and monitor closely for respiratory and central nervous system depression. OPANA ER is contraindicated for patients with moderate and severe hepatic impairment (see Contraindications, Warnings and Precautions), and Dosage and Administration). For patients on prior opioid therapy, start at the 50% of the dose for that a patient with normal hepatic function on prior opioids and titrate slowly.

Renal Impairment Patients with moderate to severe renal impairment were shown to have an increase in oxymorphone bioavailability ranging from 57-65% (see Clinical Pharmacology). Start opioid-naïve patients with the 5 mg dose of OPANA ER and titrate slowly while closely monitoring for respiratory and central nervous system depression (see Dosage and Administration). For patients on prior opioid therapy, start at 50% of the dose for a patient with normal renal function on prior opioids and titrate slowly.

Neonatal Opioid Withdrawal Syndrome Chronic maternal use of oxymorphone during pregnancy can affect the fetus with subsequent withdrawal signs. Neonatal withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration and severity of neonatal withdrawal syndrome vary based on the drug used, duration of use, the dose of last maternal use, and rate of elimination drug by the newborn. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts.

DRUG ABUSE AND DEPENDENCE Controlled Substance OPANA ER contains oxymorphone, a mu opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioids including fentanyl, hydromorphone, methadone, morphine, oxycodone and tapentadol. OPANA ER can be abused and is subject to criminal diversion (see Warnings and Precautions).

The high drug content in extended release formulations adds to the risk of adverse outcomes from abuse and misuse.

Abuse All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the counter drug to get ”high”, or the use of steroids for performance enhancement and muscle build up.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug seeking”behavior is very common to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts.

In addition, abuse of opioids can occur in the absence of true addiction.

OPANA ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests as required by state law, is strongly advised.

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 Abuse of OPANA ER OPANA ER is for oral use only. Abuse of OPANA ER poses a risk of overdose and death.

This risk is increased with concurrent abuse of OPANA ER with alcohol and other substances. Taking cut, broken, chewed, crushed, or dissolved OPANA ER enhances drug release and increases the risk of over dose and death.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. 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, buprenorphine, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

OPANA ER should not be abruptly discontinued (see Dosage and Administration).

If OPANA ER is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (see Use in Specific Populations).

OVERDOSAGE Clinical Presentation Acute overdosage with oxymorphone is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, sometimes, pulmonary edema, bradycardia, hypotension, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations.

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.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxymorphone overdose. Such agents should be administered cautiously to patients who are known, or suspected to be, physically dependent on OPANA ER. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

Because the duration of reversal would be expected to be less than the duration of action of oxymorphone in OPANA ER, carefully monitor the patient until spontaneous respiration is reliably re-established. OPANA ER will continue to release oxymorphone adding to the oxymorphone load for up to 24 hours after administration, necessitating prolonged monitoring. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be given as directed in the product’s prescribing information.

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, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No evidence of carcinogenic potential was observed in rats. No evidence of carcinogenic potential was observed in mice.

Mutagenesis Oxymorphone hydrochloride was not mutagenic when tested in the in vitro bacterial reverse mutation assay (Ames test) at concentrations of ≤5270 μg/plate, or in an in vitro mammalian cell chromosome aberration assay performed with human peripheral blood lymphocytes at concentrations ≤5000 μg/ml with or without metabolic activation. Oxymorphone hydrochloride tested positive in both the rat and mouse in vivo micronucleus assays.

Impairment of fertility The dose of oxymorphone that produced no adverse effects on reproductive findings in female rats is 0.6-fold the human dose of 40 mg every 12 hours on a body surface area basis.

STORAGE AND HANDLING Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).

[See USP Controlled Room Temperature].

Dispense in tight container as defined in the USP, with a child-resistant closure (as required).

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) Abuse Potential Inform patients that OPANA ER contains oxymorphone, a Schedule II controlled substance that is subject to abuse. Instruct patients not to share OPANA ER with others and to take steps to protect OPANA ER from theft or misuse.

Accidental Exposure Instruct patients to take steps to store OPANA ER securely. Accidental exposure, especially in children, may results in serious harm or death. Advise patients to dispose of unused OPANA ER by flushing the tablets down the toilet.

CAUTION: Federal law prohibits dispensing without prescription.

Manufactured for: Endo Pharmaceuticals Inc. Malvern, PA 19355 Manufactured by: Pharmaceutical Manufacturing Research Services Inc. Horsham, PA 19044 INTAC® is a registered trademark of the Grünenthal Group © 2013 Endo Pharmaceuticals Inc. All rights reserved Rev. August 2012 OP-02431e(1)

Your partner in Your partner in pain management pain management Join us at booth Join us at booth

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Š2013 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. Š2013 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

PAIN-40023 PAIN-40023

August 2013 August 2013

Printed in USA. Printed in USA.

by Jan

e

CHAMB RS NFMCPA President

CHRONIC PAIN IS A NATIONAL CRISIS. THE MILLION AMERICANS WHO ARE LIVING WITH CHRONIC PAIN CONDITIONS FACE INCREASING CHALLENGES TO ACCESSING APPROPRIATE HEALTH CARE, AND THEY NEED CHANGES IN POLICY, TREATMENTS, EDUCATION, AND SUPPORT.

100+

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PAINWeek provides a valuable forum for healthcare providers to learn new skills, understand current research, share personal insights, and contribute to the overall improvement of the delivery of better health care for the very large population of persons who live with chronic pain.

COMMON SYMPTOMS OF FIBROMYALGIA

1 Migrating and unexplained body-wide pain

2 Tenderness to touch

3 hronic pain is a national crisis. The 100+ million Americans who are living with chronic pain conditions face increasing challenges to accessing appropriate health care, and they need changes in policy, treatments, education, and support. The National Fibromyalgia & Chronic Pain Association (NFMCPA) advocates for patients and educates healthcare professionals on local and national levels, using the recommendations from the Institute of Medicine (IOM) Report titled Relieving Pain in America, which was mandated by Congress in 2010. Calling for a cultural change in how chronic pain is regarded, diagnosed, treated, researched, and taught, the January 16, 2013, IOM Report provides a blueprint for reducing both the societal impact ($560–$635 billion annually) and the personal suffering (1 in 3 people) of chronic pain illnesses.

The NFMCPA believes that supporting and developing initiatives to advance the IOM Relieving Pain in America Report recommendations will have a profound effect on the estimated 12 to 16 million Americans who suffer from fibromyalgia, a chronic pain Q3 | 2013

Cognitive difficulties (“fibro fog”)

4 Unrefreshed sleep

5 Chronic fatigue

6 Sore throats and swollen lymph nodes

7 Environmental sensitivity (lights, sounds, chemicals)

8 Lack of well-being

9 Heightened fight-or-flight response (easily startled)

illness. Fibromyalgia (FM) can be a primary illness or it can be secondary to many other conditions such as temporomandibular joint disorder (TMJD), irritable bowel syndrome (IBS), vulvodynia (VD), interstitial cystitis (ICD), migraine, lupus, neck pain, headaches, heart rate variability, rheumatoid arthritis, and postural or orthostatic tachycardia syndrome (POTS). While FM symptoms range from mild to disabling, secondary fibromyalgia is often undiagnosed.

People with FM often have hyper joint mobility, hypervigilance, and a reduced tolerance of negative stress. A perpetual pain generator (tissue or joint damage) can increase fibromyalgia symptoms. Managing the symptoms of overlapping conditions reduces FM symptoms. Depression can coexist with, but is not a cause of, fibromyalgia.

PAINWeek provides a valuable forum for healthcare providers to learn new skills, understand current research, share personal insights, and contribute to the overall improvement of the delivery of better health care for the very large population of persons who live with chronic pain. PAINWeek supports the IOM recommendations to educate healthcare providers about new research and treatment practices. While the NFMCPA educates about fibromyalgia and associated chronic pain illnesses at PAINWeek, we also learn from other attending participants and organizations. Advancing the holistic approach to helping people achieve well-being, PAINWeek events replace the less-effective Cartesian model of health care. The National Fibromyalgia & Chronic Pain Association is pleased to participate in this professional educational forum. www.painweek.org | PWJ | 29

Gary W. JAY MD, DAAPM, FAAPM

by

In the first part of this migraine review article, we will look at the epidemiology of this diathesis, as well as the International Headache Society’s diagnostic criteria, some of which are possibly contradictory as well as nosologically questionable.

The 5 phases of a migraine headache are then described, followed by the pathophysiology of migraine. abstract:

“It is estimated that more than 30 million people in the United States have one or more migraine headaches a year.”

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EXPERT OPINION

ePiDeMiOLOGY

Table Migraine Classification

t is estimated that more than 30 million people in the United States have one or more migraine headaches a year.

Furthermore, migraine is found in 18% of females and 6% of males.1 Migraine accounts for 64% of severe headaches in women and 43% in men. About 75% of all people who experience migraine are women. One in 6 American women has migraine headaches.2 It was long ago that it was believed that there was no difference between migraine incidence and prevalence in young boys and girls before puberty. In fact, the incidence of migraine with aura peaks in boys at about age 5 and in girls at about age 12 to 13. The incidence of migraine without aura peaks in boys at age 10 to 11 and in girls at age 14 to 17.3 Before puberty, both the prevalence and incidence of migraine are higher in boys than in girls. After age 12, the prevalence increases in both males and females, peaking at 30 to 40 years. The female-to-male ratio increases from 2.5:1 at puberty to 3.5:1 at age 40.4 The incidence of migraine changes over time, with decreased attack severity and frequency after menopause in about two-thirds of women. For most women with migraine, the attacks stop during pregnancy, as might be expected, because during pregnancy there are no significant peaks and troughs of estrogen. On the other hand, some women may manifest migraine at this time. While the onset of migraine after age 50 is rare, it can also begin even after age 60.

e

e

MiGRAiN DiAGNOS S: nosology

Migraine without aura (common migraine) Probably migraine without aura Migraine with aura (classic migraine) Probably migraine with aura Chronic migraine Chronic migraine associated with analgesic overuse Childhood periodic syndromes that may not be precursors to or associated with migraine Complications of migraine

The Table shows the Migraine Classification.5 Note that the category “probably migraine without aura” (or other types of migraine) is questioned by some headache specialists. “Migrainous disorder not fulfilling above criteria” is also questionable because if the situation doesn’t fulfill the noted criteria, how can it be a migraine?

Migrainous disorder not fulfilling above criteria Hemicrania continua

The International Headache Society (IHS) criteria for migraine without aura5 note that migraine without aura (about 75%–80% of migraine) is formally diagnosed according to the following:

At least 5 lifetime attacks that fulfill the following: The headache must have 2 of the following 4 characteristics: Be moderate to severe in intensity Have a throbbing quality Be unilateral Be aggravated by activity In addition, at least 1 of the following 2 is necessary: Nausea and/or vomiting Photophobia and phonophobia

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The IHS criteria for migraine with aura5 (15%–20% of migraine attacks) are as follows:

Different from migraine without aura by the presence of: A period of local neurologic symptoms preceding the headache, including: Visual, sensory, or speech issues Visual symptoms such as scotoma or seeing zigzag lines (fortification spectra) Sensory auras such as numbness or tingling in the face or fingers Possible speech difficulties

Q3 | 2013

The new appendix criteria for chronic migraine by the IHS6 are interesting in their inconsistency, as follows:

The official definition of MOH, as revised in the appendix criteria,6 is as follows:

Headache (tension-type or migraine) on 15 or more days per month for at least 3 months

Headache on 15 or more days per month

Headache occurring in a patient who has had at least 5 IHS-defined migraine attacks Headache on 8 or more days in a month, if the headaches have fulfilled: IHS criteria for migraine, or Are treated and relieved by triptan/ergot before the expected development of symptoms fulfilling IHS migraine criteria No medication overuse headache (MOH) as defined by IHS 8.2

Regular overuse for more than 3 months of one or more acute/ symptomatic treatment drugs as defined under subforms of 8.2 (of the second edition definitions): Ergotamine, triptans, opioids, or combination analgesic medications on 10 or more days per month on a regular basis for more than 3 months Simple analgesics OR any combination of ergotamine, triptans, analgesics, or opiates on 15 or more days per month on a regular basis for more than 3 months without overuse of any single class alone Headache that has developed or markedly worsened during medication overuse

Defining chronic migraine as consisting of both migraine and tension-type headache is problematic and unexpected. In 25 years of treating patients with migraine, this author has never seen a chronic migraine One study shows that 75.2% of chronic migraine patients use patient who didn’t have MOH. In fact, this phenomenon was first and an average of 3 to 4 tablets of analgesics, mostly simple analgesics, possibly best known as chronic daily headache. “isolated or in combination with other substances, such as caffeine.”8

The IHS criteria for chronic migraine and MOH5 consist of what headache specialists used to call combination headache, in which patients had migraine, tension-type headache, analgesic rebound, and vasoconstrictor rebound headache, or 3 of the 4 at the same time.

Some new information is coming to light:

Overuse of symptomatic medication is considered one of the most important risk factors for migraine progression7: Opiates—critical dose of exposure is about 8 days per month (in men more so than women) Barbiturates—critical dose of exposure is about 5 days a month (in women more so than men) Triptans—migraine progression is seen in patients with a high frequency of migraine at baseline who are taking medications 10 to 14 days per month The effect of nonsteroidal anti-inflammatory drugs (NSAIDs) varies with headache frequency, inducing migraine progression in patients with a high baseline frequency of headaches7 Medications containing barbiturates or opioids are associated with a 2-fold increase in risk for progression to transformed migraine In patients with episodic migraine, the annual incidence of transformed migraine is 2.5% To catch up a bit, as nosology changes for good or bad, transformed migraine is the term for what happens when episodic migraine changes or is transformed to chronic migraine. MOH is a risk factor for transformed migraines, as is duration of the disease, life stress, female gender, and even brain injury.

Q3 | 2013

Lastly, the diagnosis of “probable migraine” per the IHS5 indicates that a headache is missing one of the features needed to fulfill all criteria for a migraine. I will leave the sense of such a definition to the reader.

When treating chronic migraine with MOH, Diener suggests counseling followed by topiramate or onabotulinumtoxinA, and then admission to a detoxification program if necessary. He feels that counseling would be sufficient in 50% of patients.9 The author notes that treatment with the Raskin protocol in an interdisciplinary headache center is more appropriate.10 Finally, prior to dealing with the actual migraine headache, it is important to understand that children who experience physical and emotional abuse or neglect are more likely to have migraine and headaches as adults. There appears to be a “dose-response relationship between abuse and headache.” Growing evidence suggests that genes are involved in either increased vulnerability or resilience in response to early stressful experiences.11-13

e

MiGRAiN

here are 5 phases of migraine, although not every attack or every person has all phases. The phases are prodrome (premonitory symptoms), aura, headache, resolution, and postdrome.

The prodrome can be found in up to 80% of migraineurs. It begins 24 hours before the headache.14 Symptoms typically include autonomic nervous system (ANS) aspects such as fatigue, yawning, changes in appetite, increased energy, frequent urination, difficulty with memory, loss of concentration, cold hands, irritability, and hypersexuality www.painweek.org | PWJ | 33

EXPERT OPINION

or hyposexuality. The real issue is that patients don’t recognize these things for what they are, so the physician must specifically ask about prodrome symptoms. If recognized, treatment can begin soon after the onset of headache.15

WHeN THe MiGRAiNe BeCOMeS SeVeRe, SOMe PATieNTS DeVeLOP ALLODYNiA, OR PAiN FROM NONPAiNFUL STiMULi. THeiR HAiR MAY HURT (CePHALGiC) AND/OR THeY MAY DeVeLOP eXTRACePHALGiC PAiN iN THe CHeST, eXTReMiTieS, OR BACK MUSCLeS.

The headache can last 4 to 72 hours if it isn’t aborted by an appropriate medication (ie, a triptan or ergot). The pain can begin as mild and diffuse and become moderate to severe. Typical associated symptoms include nausea, vomiting, photophobia, and phonophobia. While the typical adult migraine is unilateral, it may be bilateral in some migraineurs who experienced bilateral migraine as children and who did not develop unilateral migraine as they grew older. It is most important to begin treatment as soon as possible.16,17

migraine-pain free with triptan treatment. Burstein, who demonstrated sensitization of the trigeminovascular pathway, showed that the use of an NSAID preceding triptans by an hour optimizes triptan treatment if CA exists.20,21 The migraine postdrome, or postheadache period, is described by most patients as a “hangover” with symptoms including cognitive difficulties, dizziness, fatigue, and concern that the headache may recur.

The postdrome may last 24 to 48 hours.

There are some forms of migrainous aura that indicate the need for a full neurologic workup, at least the first time they occur. These may include motor symptoms/hemiplegic aura, brain symptoms (such as severe dysarthria, vertigo, syncope, bilateral sensory changes), prolonged aura (>60 minutes), atypical aura (such as “Alice-in-Wonderland” or hallucinatory changes), changes in perception of time and space, as well as migralepsy or a seizure associated with migraine.

There appears to be a relationship between migraine and epilepsy.

Patients with one disorder are at least twice as likely to have the other.22 In the Epilepsy Family Study, 44% of patients reported physician diagnosed migraine, higher than the prevalence in the general population. In another study, 14% of adult patients with seizures had identified diagnoses of migraine, with migraine induced seizures in 1.7%.23 Some of these patients had better treatment results with a combination of antimigraine and anticonvulsant medications.

A genetically determined dysfunction of ion channels (calcium, sodium/potassium) seems to point to a common underlying mechanism for both paroxysmal disorders. There are mutations in the 3 known genes for familial hemiplegic migraine that can cause epilepsy.24 Alterations of cortical hyperexcitability as a possible pathologic mechanism underlying the onset of migraine and epileptic attacks has been noted.25

PATHOPHYSiOLOGY igraine is primarily a neurogenic process with secondary vascular changes (via cortical-spreading depression [CSD]).26 The interictal migraineur has a state of neuronal hyperexcitability in the cerebral (primarily occipital) cortex, which has been demonstrated by functional magnetic resonance imaging (fMRI).27 Patients with epilepsy have similar interictal neuronal irritability, which may help explain the increased susceptibility of the migrainous brain to headaches.28

When the migraine becomes severe, some patients develop allodynia, or pain from nonpainful stimuli. Their hair may hurt (cephalgic) and/ or they may develop extracephalgic pain in the chest, extremities, or back muscles. The development of allodynia suggests or even indi- The brain of the migraineur is genetically more excitable and more cates central sensitization, a physiologic state in which central neu- vigilant than the brain of a person without migraine. The brain of the rons transmit noxious sensory signals independent of sensory signals migraineur is genetically more excitable and more vigilant than the from the periphery.18 brain of a person without migraine.29,30 The brain of a migraineur doesn’t extinguish sensory stimuli as rapidly or as completely as Guy et al19 found that modalities of cephalgic and extracephalgic the brain of those without migraine.18,31 In one study, fMRI of cutaneous allodynia (CA) were different, with extracephalgic CA be- 12 patients with migraine compared with that of 12 healthy controls ing mostly thermal and cephalgic CA mostly mechanical, suggest- demonstrated that patients with migraine, but not controls, had ing different mechanisms for the two. Further, whether a patient highly significant hypoactivity in the nucleus cuneiformis, part of the shows signs of CA is a predictor of whether that patient can become descending pathway for pain signals.32

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In 1944 Leão expressed his theory of CSD, a well-defined wave of neuronal excitation in the cortical gray matter spreading from the site of origin at an average of 4 mm per minute (range 2–6 mm/ min).33 The ensuing cellular depolarization causes the primary cortical phenomena (aura phase), the basis of which is the release of potassium or glutamate from neuronal tissue that depolarizes adjacent tissue, which in turn then releases more neurotransmitters and thus propagates the CSD. Positron emission tomography (PET) scans show moderately reduced blood flow during a migrainous aura, but the spreading oligemia does not correspond to specific vascular territories, an important point.34 The flow is reduced secondary to reduction in metabolism. CSD pre-

THe BRAiN OF THe MiGRAiNeUR iS GeNeTiCALLY MORe eXCiTABLe AND MORe ViGiLANT THAN THe BRAiN OF A PeRSON WiTHOUT MiGRAiNe.

sumably induces clinical manifestations of the migraine aura. The spreading oligemia can be clinically silent (migraine without aura; that is, CDS may not be involved in migraine without aura).34,35

causes leakage of the blood–brain barrier (BBB), allowing potassium, nitric oxide, adenosine, and other products released by CSD to reach and sensitize the dural perivascular trigeminal afferent endings.36 Increased activity of matrix metalloproteinase-2 (MMP-2) is found in migraineurs.37-39 It is thought that there is a migraine generator—the trigeminal nucleus caudalis (Sp5C). In animal models of migraine, a number of receptor systems mediating c-Fos expression are within the trigeminal nucleus caudalis. Intracranial, unmyelinated C and A delta fibers of the trigeminal nerve transmit pain stimuli from the meninges to the trigeminal nucleus caudalis. Peripheral nerve endings surround meningeal vessels (the trigeminal vascular system) and contain neuroactive neuropeptides (CGRP, SP, and NKA). Activation of the trigeminovascular system promotes a meningeal sterile inflammatory response via the release of algetic neuropeptides by peripheral second-order neuronal endings.

Orthodromic conduction along the trigeminovascular fibers transmits information centrally with induction of immediate early c-Fos genes within postsynaptic Sp5C neurons as a marker of stimulation of the trigeminal ganglion. At least 10 receptors modulate c-Fos expression in the Sp5C: serotonin receptors 5-HT1B, 5-HT1D, 5-HT1F, and 5-HT2B; neurokinen-1 (NK-1); γ-aminobutyric acid type A (GABAA); N-methyl-D-aspartate (NMDA); AMPA receptors (group III metabotropic glutamate receptors), and opioid mu receptors. C-Fos expression is a marker of cephalgic nociception.40 The significant amount of CGRP in animals and humans in the trigeminal ganglion and the trigeminal nucleus caudalis indicate that they are the likely sites of action of CGRP in migraine. Immunohistochemical studies have detected 5-HT1D receptors in trigeminal sensory neurons, including peripheral projections to the dura and within the trigeminal nucleus caudalis and solitary tract, while 5-HT1B receptors are present on smooth muscle cells in meningeal vessels. These findings indicate that triptans (selective 5-HT1 agonists) decrease headache by abolishing neuropeptide release in the periphery and blocking neurotransmission by acting on second-order neurons in the trigeminocervical complex.41-43 References

Activation of the trigeminovascular system from CSD stimulates nociceptive neurons on dural blood vessels to release plasma proteins and algetic substances, including calcitonin gene-related peptide (CGRP), substance P (SP), vasointestinal peptide (VIP), and neurokinen A (NKA). This yields a sterile inflammatory state accompanied by continued vasodilation and increasing pain. Initial cortical hyperperfusion in CSD is partly mediated by release of trigeminal and parasympathetic neurotransmitters from perivascular nerve fibers, while delayed meningeal blood flow increase is mediated by a trigeminal–parasympathetic brainstem connection. Altered descending modulation in the brainstem may contribute to the headache phase of migraine, leading to a loss of inhibition or enhanced facilitation, resulting in trigeminal neuron hyperexcitability.32 CSD upregulates genes including those encoding cyclooxygenase 2 (COX-2), tumor necrosis factor–alpha (TNF-α) interleukin-1 beta (IL1β), gelanin, and metalloproteinases. Activation of metalloproteinase Q3 | 2013

1. Lipton RB, Cady RK, Stewart WF, et al. Diagnostic lessons from the spectrum study.

Neurology. 2002;58(suppl 6):S27–S31.

2. Lipton RB, Scher AI, Kolodner, K, et al. Migraine in the United States: epidemiology and patterns of health care use. Neurology. 2002;58(6):885–894.

3. Stewart WF, Linet MS, Celentano DD, et al. Age- and sex-specific incidence rates of migraine with and without visual aura. Am J Epidemiol. 1991;134(10):1111–1120.

4. Hsu LC, Wang SJ, Fuh JL. Prevalence and impact of migrainous vertigo in mid-life women: a community-based study. Cephalalgia. 2011;31(1):77–83.

5. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders. 2nd ed. Cephalalgia. 2004;24(suppl 1):1–160.

6. Headache Classification Committee; Olesen J, Bousser MG, Deiner HC, et al. New appendix criteria for a broader concept of chronic migraine. Cephalalgia.

2006;26(6):742–746.

7. Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology. 2008;71(22):1821–1828.

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8. Krymchantowski AV. Overuse of symptomatic medications among chronic (transformed) migraine patients: profile of drug consumption. Arq Neuropsiquiatr.

2003;61(1):43–47.

9. Diener H. Controversies in headache medicine detoxification for MOH is not necessary. Paper presented at: 53rd Annual Scientific Meeting of the American Headache Society; 2011; Washington, DC. 10. Jay GW. The Headache Handbook: Diagnosis and Treatment. Boca Raton, FL: CRC Press; 1999.

11. Buse DC. Study suggests a causal relationship between childhood adversity and migraine. Neurology Reviews. 2011;51(10):1579–1580.

12. Tietjen GE, Brandes JL, Peterlin BL, et al. Childhood maltreatment and migraine (part I). Prevalence and adult revictimization: a multicenter headache clinic survey. Headache.

2010;50(1):20–31.

13. Tietjen GE, Brandes JL, Peterlin BL, et al. Childhood maltreatment and migraine (part II). Emotional abuse as a risk factor for headache chronification. Headache.

2010;50(1):32–41.

14. Cady RK, Schreiber CP, Farmer KU. Understanding the patient with migraine: the evolution from episodic headache to chronic neurological disease. A proposed classification of patients with headache. Headache. 2004;44(5):426–435.

15. Luciani R, Carter D, Mannix L, et al. Prevention of migraine during prodrome with naratriptan. Cephalalgia. 2000;20(2):122–126.

16. Schoenen J. Deficient habituation of evoked cortical potentials in migraine: a link between brain biology, behavior and trigeminovascular activation? Biomed Pharmacother. 1996;50(2):71–78.

17. Lipton RB, Scher AI, Kolodner K, et al. Migraine in the United States: epidemiology and patterns of health care use. Neurology. 2002;58(6):885–894.

18. Aurora SK, Barrodale PM, Tipton RL, et al. Brainstem dysfunction in chronic migraine as evidenced by neurophysiological and positron emission tomography studies. Headache. 2007;47(7):996–1003.

19. Guy N, Marques AR, Orliaguet T, et al. Are there differences between cephalic and extracephalic cutaneous allodynia in migraine patients? Cephalalgia. 2010;30(7):881– 886.

20. Bernstein C, Burstein R. Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology. J Clin Neurol. 2012;8(2):89–99.

between brain biology, behavior and trigeminovascular activation? Biomed Pharmacother. 1996;50(2):71–78.

32. Moulton EA, Burstein R, Tully S, et al. Interictal dysfunction of a brainstem descending modulatory center in migraine patients. PloS One. 2008;3(11):e3799.

33. Leão AA. Spreading depression of activity in the cerebral cortex. J Neurophysiol.

1944;7:359–390.

34. Yokota C, Kuge Y, Hasegawa Y, et al. Unique profile of spreading depression in a primate model. J Cereb Blood Flow Metab. 2002;22(7):835–842.

35. Hauge AW, Asghar MS, Schytz HW, et al. Effects of tonabersat on migraine with aura: a randomised, double-blind, placebo-controlled crossover study. Lancet Neurol.

2009;8(8):718–723.

36. Richter F, Lehmenkühler A. Cortical spreading depression (CSD): a neurophysiological correlate of migraine aura. Schmerz. 2008;22(5):544–550.

37. Mannello F. New implications of the proteolytic balance between matrix metalloproteinases and their tissue inhibitors in migraine with and without aura. Clin Chim Acta.

2009;409(1-2):1–3.

38. Gonçalvesa FM, Martins-Oliveira A, Lacchini R, et al. Matrix metalloproteinase (MMP)-2 gene polymorphisms affect circulating MMP-2 levels in patients with migraine with aura. Gene. 2013;512(1):35–40.

39. Martins-Oliveira A, Speciali JG, Dach F, et al. Different circulating metalloproteinases profiles in women with migraine with and without aura. Clin Chim Acta. 2009;408(12):60–64.

40. Mitsikostas DD, Sanchez del Rio M. Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine. Brain Res Brain Res Rev. 2001;35(1):20–35.

41. Smith D, Hill RG, Edvinsson L, et al. An immunocytochemical investigation of human trigeminal nucleus caudalis: CGRP, substance P and 5-HT1D-receptor immunoreactivities are expressed by trigeminal sensory fibres. Cephalalgia. 2002;22(6):424–441.

42. Sexton PM, McKenzie JS, Mason RT, et al. Localization of binding sites for calcitonin gene-related peptide in rat brain by in vitro autoradiography. Neuroscience.

1986;19(4):1235–1245.

43. Ma W, Chabot JG, Powell KJ, et al. Localization and modulation of calcitonin gene-related peptide-receptor component protein-immunoreactive cells in the rat central and peripheral nervous systems. Neuroscience. 2003;120(3):677–694.

21. Jakubowski M, Levy D, Goor-Aryeh I, et al. Terminating migraine with allodynia and ongoing central sensitization using parenteral administration of COX1/COX2 inhibitors.

Headache. 2005;45(7):850–861.

22. Silberstein SD, Lipton RB. Headache and epilepsy. In: Ettinger AB, Devinsky O, eds. Managing Epilepsy and Co-existing Disorders. Boston: Butterworth-Heinemann; 2002:239–254.

23. Velioglu SK, Ozmenoglu M. Migraine-related seizures in an epileptic population.

Cephalalgia. 1999;19(9):797-801.

24. Haan J, Terwindt GM, van den Maagdenberg AM, et al. A review of the genetic relation between migraine and epilepsy. Cephalalgia. 2008;28(2):105–113.

25. Piccinelli P, Borgatti R, Nicoli F, et al. Relationship between migraine and epilepsy in pediatric age. Headache. 2006;46(3):413–421.

26. Cutrer FM, Charles A. The neurogenic basis of migraine. Headache. 2008;48(9):1411– 1414.

27. Waeber C, Moskowitz MA. Therapeutic implications of central and peripheral neurologic mechanisms in migraine. Neurology. 2003;61(8 suppl 4):S9–S20.

28. Welch KM. Contemporary concepts of migraine pathogenesis. Neurology. 2003;61(8 suppl 4):S2–S8.

29. Schoenen J. Neurophysiological features of the migrainous brain. Neurol Sci. 2006;(27 suppl 2):S77–S81.

30. Coppola G, Pierelli F, Schoenen J. Is the cerebral cortex hyperexcitable or hyperresponsive in migraine? Cephalalgia. 2007;27(12):1427–1439.

31. Schoenen J. Deficient habituation of evoked cortical potentials in migraine: a link

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PUBLIC POLICY & REGULATION

e e

STEPHEN J. Zi GL R PHD, JD

by

abstract: Federal

and state governments have intervened in prescribing for well over a century. The following article profiles 5 interventions designed to reduce the harms associated with prescription drug abuse. However, the potential for “medicolegal iatrogenesis” (patient harm stemming from governmental intervention) is raised, as well as the need to maintain the delicate balance between ensuring access to opioids while preventing their abuse and harm.

One of the primary purposes of government is to protect the health, safety, and welfare of its citizens. Pursuant to this laudable goal, governments at all levels in the United States have created laws and regulations in an effort to protect people from a wide range of potentially harmful products and services. This certainly was the case in the late 1800s when opioids were essentially unregulated and virtually anyone could hold themselves out as a healthcare provider.1

Today, although many things have changed, the challenges associated with ensuring access to opioids while simultaneously preventing their abuse remain the same. Recent data indicate an alarming increase in opioid-related deaths2 while at the very same time an estimated 100 million people in the United States suffer from chronic pain.3 Although recent government interventions to address the harms associated with opioid abuse have expanded, efforts to simultaneously ensure access have not. In an effort to advance balanced policy,4 the following article explores 5 governmental interventions in prescribing and discusses their potential for what I term medicolegal iatrogenesis (patient harm stemming from governmental intervention). The article concludes by recommending greater involvement by prescribers in the regulatory process.

“Intervention must be influenced by the active participation of all stakeholders, including prescribers.”

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criminal, civil, and administrative penalties for its violation.10 At its inception, the CSA recognized that drug abuse was primarily a public health issue, not exclusively a law enforcement problem.9,12 Although the DEA is the primary drug enforcement agency at the federal level, drug enforcement also exists at the state level and among several

overnmental efforts to prevent morbidity and mortality associated with the use and distribution of pharmaceutical drugs is nothing new. In 1906, the federal government passed the Pure Food and Drug Act in an effort to “prevent the ‘manufacture, sale, or transportation of adulterated or misbranded…drugs, medicines, and liquors.’ ”5 Prior to the act, opioids such as morphine and heroin were freely available and at times sold by “hawkers and door-to-door peddlers.”6,7 In 1914, the federal government passed the Harrison Act and relied on the taxing authority in the US Constitution to help control drug distribution.1,6 Over the next 6 decades, Congress passed an assortment of drug control laws until 1970, the year the federal Controlled Substances Act (CSA) was enacted into law.8 The CSA consolidated a wide range of existing drug laws into one federal scheme and divided drugs into Schedules I through V based on medical use and potential for harm.9 The CSA and its subsequent regulations would require prescribers to apply for and maintain a license with the federal Drug Enforcement Administration (DEA) and abide by federal and state rules concerning the prescribing and dispensing of controlled substances.10

IN THe CONTeXT OF PReSCRiPTiON DRUGS, THe CSA AND iTS STATe COUNTeRPARTS ReMAiN POWeRFUL TOOLS TO PUNiSH OFFeNDeRS FOR PHARMACeUTiCAL DiVeRSiON AND PReVeNT OTHeRS FROM DiVeRTiNG.

diverse, overlapping laws and jurisdictions (for example, local, county, and state police). In fact, the overwhelming majority of drug enforcement occurs at the state and local levels, not the federal level.13

In the context of prescription drugs, the CSA and its state counterparts remain powerful tools to punish offenders for pharmaceutical diversion and prevent others from diverting. Some prescribers, patients, and nonpatients have engaged in patently criminal conduct.14 And while no drug law is capable of deterring all types of diversion, there is evidence that drug laws and regulations have negatively influAny action, or inaction, always has the potential for neg- enced prescribing behavior by increasing fear of investigation among ative outcomes in both medicine and government. Since the term prescribers,15,16 even though data also suggest that the likelihood of medical iatrogenesis11 has been used to characterize harm stemming investigation or prosecution is very low.17 from medical treatment, I propose that the term medicolegal iatrogenesis be used to describe harm to patients stemming from well-in- The law enforcement model takes a punitive approach to drug contended governmental interventions. Each one of the governmental trol by enforcing laws created by a legislative branch.12 At times, the interventions in prescribing that appear below has its merits, as well coercive ability of government can deter, prevent, or reform behavas its limitations, and each one has the ability to reduce harm as well ior.18 However, the punitive approach should not be the exclusive or as result in medicolegal iatrogenesis. Although some overlap among predominant treatment for what is otherwise a public health probmodels does occur (for example, penalties), 4 different intervention lem.19 Finally, in light of the separation of powers and the functions models will be examined here: Criminal Law Enforcement, Pre- associated with each branch of government,18 it would be difficult to scription Drug Monitoring Programs (PDMPs or, more frequently, expect law enforcement (an executive branch agency) to create balPMPs), Dosage Triggers with Mandatory Pain Consults, and Pill anced policies when its primary function is the enforcement of laws created by a legislative body (the legislative branch).

Mill Legislation.

1. criminal

law enforcement

The law enforcement model serves as the leading tool to control the use and distribution of both licit and illicit drugs in the United States.

At the federal level, the CSA of 1970 provides the authority to impose Q3 | 2013

2. prescription

drug monitoring programs

PMPs are leading tools among regulators to help reduce pharmaceutical diversion.20 Historically, PMPs consisted of handwritten, triplicate forms in which a copy was retained by the prescriber and www.painweek.org | PWJ | 41

PUBLIC POLICY & REGULATION

another by the pharmacist, and the final form would eventually find unclear how these pain consultants would be compensated for their its way to the appropriate state agency.20,21 Many of these earlier time. Third, some physicians may simply opt out of treating chronic models only tracked Schedule II drugs, which in turn led some pre- pain, which in turn decreases the number of healthcare providers, inscribers to write for lower scheduled drugs or even over-the-counter creases costs, and decreases access.33 drugs (OTCs), thereby avoid the reporting requirements (and the scrutiny).21-23 Over time, states abandoned the multiple-copy format and moved towards an electronic data transfer system, a model that 4. helped reduce the time lag associated with data entry and the use of handwritten copies. States also expanded reporting requirements beyond Schedule II drugs,20 and while most of the states now have Another governmental intervention in prescribing concerns federal operational electronic PMPs, there are many variations and challeng- and state efforts to eliminate pill mills. Pill mill is a pejorative term es associated with them.21,24 For instance, not all PMPs are located defined in a proposed law as “a doctor’s office, clinic, or healthcare in identical state agencies25; many clinicians are unaware of the pro- facility that…routinely prescribes or dispenses controlled substances grams or have difficulty accessing them; patient privacy and delivery of care issues have been raised; and monitoring has a negative impact on legitimate prescribing behavior.20,25 Despite their challenges, PMPs have enormous potential to reduce pharmaceutical diversion, provided that they are “constructed and implemented properly” to help maintain balance so that efforts to reduce harm do not come at the expense of patients (medicolegal iatrogenesis).20,25

pill mill legislation

3. dosage

triggers with mandatory pain consults

In 2007, Washington State introduced opioid dosing guidelines for prescription pain medication in an effort to reduce the occurrence of injuries and deaths associated with opioids. This advisory guideline was “developed as an educational tool for primary care providers,” and called for clinicians to seek a pain consultation whenever a patient reached a dosage level of 120-mg morphine equivalent dose (MED) per day.26 To facilitate use of the guideline, the state provided an online opioid dosing calculator that enabled clinicians to determine whether the opioid they were prescribing reached the 120-mg threshold that would in turn trigger a pain consultation.27 In 2010, the Washington state legislature passed ESBH 2876, a law which would significantly alter the way pain was treated and opioids were prescribed in the state.28 Instead of asking prescribers to seek a consultation, the new law and its concomitant regulations required it.

Regulations have already been adopted by various agencies, and the guidelines further clarify that “acute pain, cancer pain, surgery-related pain, or end-of-life or hospice care” are exempted from the rules.29,a Remarkably, the original lead sponsor of ESBH 2876 had only proposed a continuing medical education (CME) requirement for prescribers (personal communication, Representative Jim Moeller, September 6, 2011), not a mandatory consultation requirement based on a dosage trigger.30 It is also worth mentioning that while the CME-only approach was rejected by some members of the Washington medical community, voluntary prescriber education remains a key component of another federal intervention in prescribing: the FDA’s Risk Evaluation and Mitigation Strategy (REMS) for extended-release opioids.31 Several groups and individuals remain concerned about the negative impact of this intervention, particularly as it relates to the consultation requirement. First, a mandatory pain consultation is required once a patient reaches 120 mg MED per day, and there are well over 15,000 patients at or above this triggering threshold.32 Second, it is

42 | PWJ | www.painweek.org

PiLL MiLL iS A PeJORATiVe TeRM DeFiNeD iN A PROPOSeD LAW AS A DOCTOR’S OFFiCe, CLiNiC, OR HeALTHCARe FACiLiTY THAT… ROUTiNeLY PReSCRiBeS OR DiSPeNSeS CONTROLLeD SUBSTANCeS OUTSiDe THE SCOPe OF THe PReVAiLiNG STANDARDS OF MeDiCAL PRACTiCe iN THe COMMUNiTY iN ReLATiON TO THe PReSCRiBiNG OR DiSPeNSiNG OF CONTROLLeD PReSCRiPTiON DRUGS.

outside the scope of the prevailing standards of medical practice in the community in relation to the prescribing or dispensing of controlled prescription drugs.”34 This definition appeared in the federal Pill Mill Crackdown Act of 2011, a proposed federal law that would amend the CSA by: (1) increasing the term of imprisonment and fines for violations involving Schedule I and II substances; (2) enhancing the penalty if the recipient of the controlled substance was under the age of 21; (3) providing for the alternative distribution of forfeited funds; and (4) criminalizing those considered to be “operators,” defined as “any practicing physician affiliated with a pill mill; or any owner, director, officer, or partner of a pill mill.”34 Both congressional versions of the Pill Mill Crackdown Act were referred to committee, and it is unlikely that they will become law anytime soon.

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However, several individual states have passed their own pill mill acts.

For instance, a unanimous Florida legislature passed House Bill 7095, which became effective July 1, 2011. The 98-page law targeting pill mills modified several existing practices related to prescribers, clinics, controlled substances, pharmacies, drug distributors, and even the state’s PMP. The Florida law significantly restricted onsite dispensing by practitioners and required the return of existing controlled substances and their buy-back by wholesalers. The statute also went so far as to list legitimate medical practice requirements, practices that are often absent in pill mills (for example, conducting a physical examination, taking a medical history, developing a treatment plan, creating a controlled substance agreement).35

5. risk

model has the potential for overlap and may not be mutually exclusive (for example, criminal law enforcement could lead to noncriminal sanctions, and PMPs could detect criminal behavior leading to criminal prosecution).c Moreover, each model has the potential to not only reduce harm but also result in medicolegal iatrogenesis. Maintaining the principle of balance in any governmental intervention is essential when creating good public policy,d and it is a policy that can and should be influenced by prescribers.

evaluation and mitigation strategies

A fifth and final governmental intervention concerns the FDA REMS initiative. The overarching purpose of REMS is to ensure the safe use of approved drugs and biologics so that the benefits outweigh the risks.36 One of the primary tools to achieve this end is education.37 While the FDA Amendments Act of 2007 provided the basis for the FDA to require REMS,38 these types of strategies have actually existed in various forms over the past decades (for example, the requiring of patient package inserts by the FDA in 1970 for oral contraceptives).

The 2007 law enabled the FDA to require REMS as a condition of a drug’s approval and subsequent approval if postmarketing surveillance indicated the need for a REMS. Current REMS could include medication guides (the most common), a communication plan (for example, letters to healthcare providers or professional societies), an implementation plan for manufacturers, timetables for assessment of the REMS, and/or Elements to Assure Safe Use (EASU), the last of which could involve special training or certification, dispensing restrictions, and patient registries).36,39 Faced with increasing evidence of harm associated with the use of prescription opioids, and concerned about the need to ensure appropriate access, the FDA created 2 sets of shared opioid REMS. One set of REMS would cover transmucosal immediate-release fentanyl (TIRF) medicines, and the other set, extended-release/long-acting (ER/LA) opioids. While the REMS for TIRF medicines include, among other things, medication guides and patient registries, opioids falling within the ER/LA shared class require only medication guides and voluntary, not mandatory, education of prescribers. The FDA decided to not make education a condition of renewed DEA licensure out of concern that mandatory education would increase costs and perhaps result in the substitution of less effective, non-ER/LA medications.36 Manufacturers of ER/LA opioids will bear the cost of educating prescribers consistent with the FDA Educational Blueprint, as well as the maintenance of websites and call centers that currently exist to assist prescribers with information and patient registration (if necessary).40 A list of opioids falling within the ER/LA shared class and their REMS is available at the FDA website.36

At times, the government may indeed be the problem instead of the solution,41 but in the end it is our government. Fortunately, there are many things that prescribers and policymakers can do to help bring about balanced policy and avoid medicolegal iatrogenesis. First, prescribers can get involved in the regulatory and policy-making process. Prescribers, or any healthcare professionals, have the ability to influence both legislation and subsequent regulation.

Contacting their representatives, state medical associations, and regulatory boards about the need for balanced prescription drug policy is a good start. Scientific evidence is always helpful, but we must also realize that political evidence and political considerations may carry their own weight in the policy-making process.

Governmental intervention in prescribing will always exist (as it should). But each intervention must strive not only to maintain the balance between ensuring access and preventing harm but also to be influenced by the active participation of all stakeholders, including prescribers.

References 1. Starr P. The Social Transformation of American Medicine: The Rise of a Sovereign Profession and the Making of a Vast Industry. New York, NY: Basic Books; 1982:80, 91, 128–129.

2. Paulozzi LJ, Ryan GW. Opioid analgesics and rates of fatal drug poisoning in the United States. Am J Prev Med. 2006:31:506–511.

3. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press; 2011.

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. Hamburg MA, Sharfstein JM. The FDA as a public health agency. N Engl J Med. 2009;360(24):2493–2495.

6. McBride DC, Terry-McElrath Y, Harwood H, et al. Reflections on drug policy. J Drug Issues. 2009;39(1):71–88.

7. Musto DF. The American Disease: Origins of Narcotic Control. 3rd ed. New York, NY: Oxford University Press; 1999:2–3, 10, 21.

The preceding 5 models represent a small sample of the many different types of governmental interventions in prescribing.b Each Q3 | 2013

8. US Congress. Controlled Substances Act. 21 USC 801. 1970.

www.painweek.org | PWJ | 43

PUBLIC POLICY & REGULATION

9. Spillane JF. Debating the Controlled Substances Act. Drug Alcohol Depend. 2004;76:17–29.

10. Behr DJ. Prescription drug control under the Federal Controlled Substances Act: a web of administrative, civil, and criminal law controls. Wash Univ J Urban Contemp Law. 1994;45:41–119.

32. Fishman SM, Webster LR. Unintended harm from opioid prescribing guidelines. Pain Med. 2009;10(2):285–286.

33. Haddad A. “An Act Relating to Pain Management” passes the Washington State legislature. Topics Pain Manage. 2011;26(8):7–10, 12.

11. Hofer TP, Hayward RA. Are bad outcomes from questionable clinical decisions preventable medical errors? A case of cascade iatrogenesis. Ann Intern Med. 2002;137:327–333.

34. 112th US Congress. Pill Mill Crackdown Act of 2011 (S.1760). Introduced October 20, 2011. http://www.govtrack.us/congress/bills/112/s1760. Accessed July 15, 2012.

12. Courtwright DT. The Controlled Substances Act: how a “big tent” reform became a punitive drug law. Drug Alcohol Depend. 2004;76:9–15.

35. Florida State House. HB 7095. An act relating to prescription drugs. 2011. http:// flsenate.gov/Session/Bill/2011/7095. Accessed February 1, 2013.

13. Miller GJ. Drugs and the Law: Detection, Recognition, Investigation. 3rd ed. Charlottesville, VA: Matthew Bender & Company; 2005:529.

36. US Food and Drug Administration. Approved Risk and Evaluation Strategies (REMS). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm. Last updated January 31, 2013. Accessed September 22, 2012.

14. Cicero TJ, Kurtz SP, Surratt HL, et al. Multiple determinants of specific modes of prescription opioid diversion. J Drug Issues. 2011;41(2):283–304.

15. Ziegler SJ, Lovrich, NP. Pain relief, prescription drugs, and prosecution: a four-state survey of chief prosecutors. J Law Med Ethics. 2003;31(1):75–100.

16. Simoni-Wastila L, Ross-Degnan D, Mah C, et al. A retrospective data analysis of the impact of the New York triplicate prescription program on benzodiazepine use in Medicaid patients with chronic psychiatric and neurologic disorders. Clin Ther.

2004;26(2):322–336.

17. Goldenbaum DM, Christopher M, Gallagher RM, et al. Physicians charged with opioid analgesic-prescribing offenses. Pain Med. 2008;9(6):737–747.

18. Marlowe DB. Judicial supervision of drug-abusing offenders. J Psychoactive Drugs.

2006;(suppl 3):323–331.

19. Joranson DE, Gilson AM. Wanted: a public health approach to prescription opioid abuse and diversion. Pharmacoepidemiol Drug Saf. 2006;15(9):632–634.

20. Gilson AM, Kreis PG. The burden of the nonmedical use of prescription opioid analgesics. Pain Med. 2009;10(suppl 2):S89–S100.

21. Fishman SM, Papazian JS, Gonzalez S, et al. Regulating opioid prescribing through prescription monitoring programs: balancing drug diversion and treatment of pain. Pain Med. 2004;5(3):309–324.

22. Gilson AM. Prescription monitoring as a public health intervention: a review of the literature. Presented at: Conference on Prescription Monitoring Research Update; April 2-3, 2009; Boston, MA. http://www.thci.org/Opioid/apr09docs/presentations/Gilson. pdf. Accessed February 1, 2013.

23. 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.

37. Zacharoff K. Opioid REMS update. Presented at: PAINWeek 2012; September 7, 2012; Las Vegas, NV. 38. US Food and Drug Act Administration Amendments of 2007 (FDAAA) of 2007. http:// www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/ significantamendmentstothefdcact/foodanddrugadministrationamendmentsactof2007/ default.htm. Accessed February 1, 2013.

39. Nicholson SC, Evanyo K, Salinas GD, et al. Extended-release/long-acting opioid REMS may fill the need for prescribers’ appropriate use education. J Opioid Manag.

2012;8(4):212–216.

40. TIRF REMS Access Program Home. https://www.tirfremsaccess.com/TirfUI/rems/ home.action. Accessed September 22, 2012.

41. President Ronald Reagan. Inaugural Address; January 20, 1981; Washington, DC. Endnotes a. To see which patients and prescribers are exempt by agency, see: http://www. doh.wa.gov/PublicHealthandHealthcareProviders/HealthcareProfessionsandFacilities/ PainManagement.aspx. b. To see several other existing or proposed models at the state level, see the National Conference of State Legislatures, Denver, Colorado, at: http://www.ncsl.org/issues-research/health/prevention-of-prescription-drug-overdose-and-abuse.aspx. c. For a discussion of penalties and agency discretion, see Ziegler SJ, Lovrich NP. Pain relief, prescription drugs, and prosecution: a four-state survey of chief prosecutors. J Law Med Ethics. 2003;31(1):75–100.Oxford University Press; 1999:2–3, 10, 21. d. Spillane JF. Debating the Controlled Substances Act. Drug Alcohol Depend. 2004;76:17–29.

24. Perrone J, Nelson LS. Medication reconciliation for controlled substances—an “ideal” prescription-drug monitoring program. N Engl J Med. 2012;366:2341–2343.

25. Fishman SM. Prescription drug monitoring programs serve a vital clinical need. Pain Med. 2011;12:845.

26. Department of Labor & Industries, Washington State. Interim Evaluation of the Washington State Interagency Guideline on Opioid Dosing for Chronic Non-Cancer Pain. http:// www.agencymeddirectors.wa.gov/Files/AGReportFinal.pdf. Published August 31, 2009.

Accessed February 1, 2013.

27. Washington State Agency Medical Directors Group. Interagency Guideline on Opioid Dosing for Chronic Non-Cancer Pain: An Educational Pilot to Improve Patient Care and Safety with Opioid Treatment. http://www.agencymeddirectors.wa.gov/Files/OpioidGdline.pdf. Updated 2010. Accessed February 1, 2013.

28. Washington State House Bill ESHB 2876. Effective June 10, 2010. http://apps.leg. wa.gov/billinfo/summary.aspx?year=2010&bill=2876. Accessed September 16, 2012.

29. Washington State Agency Medical Directors Group. 2010 Opioid Dosing Guidelines. http://www.agencymeddirectors.wa.gov/opioiddosing.asp. Accessed February 1, 2013.

30. Haddad A. Conversation: Alex Cahana, MD, on Washington State’s new law on pain care and opioid prescribing and the relevance of measurement-based care. Topics Pain Manage. 2011;26(9):7–10, 12.

31. US Food & Drug Administration. FDA introduces new safety measures for extended-release and long-acting opioid medications [press release]. http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm310870.html. Published July 9, 2012.

Accessed February 1, 2013.

44 | PWJ | www.painweek.org

Q3 | 2013

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46 | PWJ | www.painweek.org

Q3 | 2013

PUNDIT PROFILE /BARBARA L. KORNBLAU

What inspired you to become a healthcare provider?

What is your most marked characteristic?

My passion. When I am passionate about a cause, no one can stop me.

My mother took me to work with her long before we started to observe “Take Your Daughter to Work Day.” My mother worked in a nursing home. That led me to become a candy striper and work at a camp with children with cerebral palsy. I wanted to help people live better lives.

What do you consider your greatest achievement?

Why did you focus on pain management?

I have experienced chronic pain most of my life.

Focusing on pain management began as shameless selfishness. I needed to know what the options were for my own life since most healthcare providers I saw did not know how to help me. I realized many other people were in the same situation with the lack of knowledgeable providers.

Who were your mentors?

I have been lucky to have had many mentors along the way. Three stand out. My father, Sol Kornblau. Dr. Judith Leavitt, a professor of History of Medicine and Public Health and Women’s Studies at the University of Wisconsin–Madison. And Dr. Reba Anderson, an occupational therapy colleague.

My father instilled in me the values of social justice in remarkable ways. We worked together on many causes, the last one when in honor of his 90th birthday.

I took courses from Dr. Leavitt and I babysat for her children. She was an incredible role model as a professional woman and a great mother. She allowed me to take upper level courses as a sophomore, encouraged high academic standards, and taught me to write. She also taught me to do qualitative research before such a thing formally existed, and she instilled confidence in me. She helped me develop my love of history as the context for the study of health. She also showed me how to be a good mother.

Dr. Anderson convinced me that I needed to teach. I’d never planned to teach. She convinced me that I could do anything professionally. I credit her for many of the things I ended up doing.

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

“Success is the best revenge.”

Too many people in my life have told me I would never be able to do something. That has always motivated me to succeed at whatever that “something” was.

I came to Washington, DC, as a Robert Wood Johnson Health Policy Fellow. We were told not to expect to change the world. After my fellowship, I put together a blueprint to include people with disabilities in the Affordable Care Act every place that race and ethnicity appeared. This included health disparities, cultural competence, public health data collection, training of health professionals, and other areas, with the ultimate goal of improving the health of people with disabilities. I put a coalition together, and led the coalition to successfully include these provisions in the Affordable Care Act. What is your favorite language?

Sign language. I used to run a pro bono legal clinic for the deaf. I learned sign language early in my career.

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?

The film would be The Wizard of Oz to remind me “There’s no place like home.” The book would be Toward a Meaningful Life: The Wisdom of the Rebbe. This book provides me with spiritual guidance and meaning to life. The music would be Vivaldi’s Four Seasons. It’s calming, and it keeps me on task.

What would you like your legacy to be?

I saw things that were unjust and tried to change them. I made a difference in improving the world for people with disabilities.

What is your motto?

“Success is the best revenge.” Too many people in my life have told me I would never be able to do something. That has always motivated me to succeed at whatever that “something” was.

I am a healthcare provider and a lawyer. I’ve also been a professor. To me they go hand in hand. I can’t imagine being one without the other. I suppose if I were not a healthcare provider, I would be just a lawyer or just a professor.

Q3 | 2013

www.painweek.org | PWJ | 47

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PLEASE GRALISE ME! Help control the agony of PHN

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

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

Important Safety Information GRALISE is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

Antiepileptic drugs (AEDs) including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Across all GRALISE clinical trials, the other most common adverse reactions (â&#x2030;Ľ 2%) are somnolence, headache, peripheral edema, diarrhea, dry mouth, and nasopharyngitis.

Dosage adjustment of GRALISE is necessary in patients with impaired renal function. GRALISE should not be administered in patients with a creatinine clearance rate < 30 mL/min or in patients undergoing hemodialysis.

Because every moment counts in PHN Please see adjacent page for Brief Summary of Prescribing Information. Full Prescribing Information and Medication Guide are available at GRALISE.com.

References: 1. GRALISE [prescribing information]. Newark, CA: Depomed Inc.; December 2012. 2. Sang CN, et al. Gastroretentive gabapentin (G-GR) formulation reduces intensity of pain associated with postherpetic neuralgia (PHN). Clin J Pain. 2013;29:281-288. 3. Data on file, Depomed Inc.

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