PAINWeek Journal Vol. 2, Q 2 by PAINWeek

vol. 2 q 2 2014

OPIOID-INDUCED HYPERALGESIAP.14 BULLYING IN MEDICINE: ARE YOU THE VICTIM OR THE PERPETRATOR?P.20 WHIPLASH: TOWARDS NEW OBJECTIVE MARKERSP.30 STIFF & STUCK: USING JOINT MOBILIZATION TO RESTORE MOVEMENT AND REDUCE PAINP.36 DIABETES AND GASTROINTESTINAL PAINP.42

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

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

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

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

Neonatal Opioid Withdrawal Syndrome ■ Prolonged use of Butrans during pregnancy can result in neonatal opioid withdrawal syndrome which may be life-threatening to the neonate if not recognized and treated, and requires management according to protocols developed by neonatology experts

Application Site Skin Reactions ■ In rare cases, severe application site skin reactions with signs of marked inflammation including “burn,” “discharge,” and “vesicles” have occurred Anaphylactic/Allergic Reactions ■ Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post-marketing experience

Interactions with Central Nervous System Depressants Application of External Heat ■ Hypotension, profound sedation, coma, ■ Avoid exposing the Butrans application site and Addiction, Abuse, and Misuse respiratory depression, or death may result if surrounding area to direct external heat sources. ■ Butrans contains buprenorphine, a Schedule III Butrans is used concomitantly with other CNS There is a potential for temperature-dependent controlled substance. Butrans exposes users to depressants, including alcohol or illicit drugs that increases in buprenorphine released from the the risks of opioid addiction, abuse, and misuse. can cause CNS depression. Start with Butrans 5 system resulting in possible overdose and death As modified-release products such as Butrans mcg/hour patch, monitor patients for signs of Use in Patients with Gastrointestinal Conditions deliver the opioid over an extended period of sedation and respiratory depression, and ■ Avoid the use of Butrans in patients with paralytic time, there is a greater risk for overdose and consider using a lower dose of the concomitant ileus and other GI obstructions. Monitor patients death, due to the larger amount of buprenorphine CNS depressant with biliary tract disease, including acute present. Addiction can occur at recommended Use in Elderly, Cachectic, and Debilitated pancreatitis, for worsening symptoms doses and if the drug is misused or abused. Patients and Patients with Chronic Assess each patient’s risk for opioid addiction, Pulmonary Disease abuse, or misuse prior to prescribing Butrans, and ■ ADVERSE REACTIONS Closely monitor elderly, cachectic, and debilitated monitor all patients during therapy for the ■ Most common adverse reactions (≥5%) reported patients, and patients with chronic obstructive development of these behaviors or conditions. by patients treated with Butrans in the clinical pulmonary disease because of the increased risk Abuse or misuse of Butrans by placing it in the trials were nausea, headache, application site of life-threatening respiratory depression. mouth, chewing it, swallowing it, or using it in pruritus, dizziness, constipation, somnolence, Consider the use of alternative non-opioid ways other than indicated may cause choking, vomiting, application site erythema, dry mouth, analgesics in patients with chronic obstructive overdose and death and application site rash pulmonary disease if possible Life-Threatening Respiratory Depression QTc Prolongation ■ Serious, life-threatening, or fatal respiratory ■ Avoid in patients with Long QT Syndrome, family depression has been reported with modifiedVisit history of Long QT Syndrome, or those taking release opioids, even when used as Butrans.com Class IA or Class III antiarrhythmic medications for more information recommended, and if not immediately recognized or to print the Butrans Hypotensive Effects and treated, may lead to respiratory arrest and Trial Offer and Butrans ■ Butrans may cause severe hypotension, including death. The risk of respiratory depression is Savings Cards orthostatic hypotension and syncope in greatest during the initiation of therapy or ambulatory patients. Monitor patients during following a dose increase; therefore, closely dose initiation or titration monitor patients for respiratory depression. The first transdermal system to Proper dosing and titration of Butrans are Use in Patients with Head Injury or deliver 7 days of buprenorphine essential. Overestimating the Butrans dose when Increased Intracranial Pressure ■ Monitor patients taking Butrans who may be converting patients from another opioid product can result in fatal overdose with the first dose. susceptible to the intracranial effects of CO2 Accidental exposure to Butrans, especially in retention for signs of sedation and respiratory children, can result in respiratory depression and depression. Avoid the use of Butrans in patients with impaired consciousness or coma death due to an overdose of buprenorphine

WARNINGS AND PRECAUTIONS

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

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

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

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

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

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

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

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

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

following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1)]. 10 OVERDOSAGE Clinical Presentation Acute overdosage with BUTRANS is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations. Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. Naloxone may not be effective in reversing any respiratory depression produced by buprenorphine. High doses of naloxone, 10-35 mg/70 kg, may be of limited value in the management of buprenorphine overdose. The onset of naloxone effect may be delayed by 30 minutes or more. Doxapram hydrochloride (a respiratory stimulant) has also been used. Remove BUTRANS immediately. Because the duration of reversal would be expected to be less than the duration of action of buprenorphine from BUTRANS, carefully monitor the patient until spontaneous respiration is reliably re-established. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects as buprenorphine continues to be absorbed from the skin. After removal of BUTRANS, the mean buprenorphine concentrations decrease approximately 50% in 12 hours (range 10-24 hours) with an apparent terminal half-life of approximately 26 hours. Due to this long apparent terminal half-life, patients may require monitoring and treatment for at least 24 hours. In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal. The severity of the withdrawal produced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient with an opioid antagonist, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Addiction, Abuse, and Misuse Inform patients that the use of BUTRANS, even when taken as recommended, can result in addiction, abuse, and misuse, which could lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share BUTRANS with others and to take steps to protect BUTRANS from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting BUTRANS or when the dose is increased, and that it can occur even at recommended doses [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Exposure Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store BUTRANS securely and to dispose of unused BUTRANS by folding the patch in half and flushing it down the toilet. Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of BUTRANS during pregnancy can result in neonatal opioid withdrawal syndrome, which may be lifethreatening if not recognized and treated [see Warnings and Precautions (5.3)]. Interaction with Alcohol and other CNS Depressants Inform patients that potentially serious additive effects may occur if BUTRANS is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a health care provider. Important Administration Instructions Instruct patients how to properly use BUTRANS, including the following: 1. To carefully follow instructions for the application, removal, and disposal of BUTRANS. Each week, apply BUTRANS to a different site based on the 8 described skin sites, with a minimum of 3 weeks between applications to a previously used site. 2. To apply BUTRANS to a hairless or nearly hairless skin site. If none are available, instruct patients to clip the hair at the site and not to shave the area. Instruct patients not to apply to irritated skin. If the application site must be cleaned, use clear water only. Soaps, alcohol, oils, lotions, or abrasive devices should not be used. Allow the skin to dry before applying BUTRANS. Hypotension Inform patients that BUTRANS may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position). Driving or Operating Heavy Machinery Inform patients that BUTRANS may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in BUTRANS. Advise patients how to recognize such a reaction and when to seek medical attention. Pregnancy Advise female patients that BUTRANS can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant. Disposal Instruct patients to refer to the Instructions for Use for proper disposal of BUTRANS. Patients can dispose of used or unused BUTRANS patches in the trash by sealing them in the Patch-Disposal Unit, following the instructions on the unit. Alternatively, instruct patients to dispose of used patches by folding the adhesive side of the patch to itself, then flushing the patch down the toilet immediately upon removal. Unused patches should be removed from their pouches, the protective liners removed, the patches folded so that the adhesive side of the patch adheres to itself, and immediately flushed down the toilet. Instruct patients to dispose of any patches remaining from a prescription as soon as they are no longer needed. Healthcare professionals can telephone Purdue Pharma’s Medical Services Department (1-888-726-7535) for information on this product. Distributed by: Purdue Pharma L.P., Stamford, CT 06901-3431 Manufactured by: LTS Lohmann Therapy Systems Corp., West Caldwell, NJ 07006 U.S. Patent Numbers 5681413; 5804215; 6264980; 6315854; 6344211; RE41408; RE41489; RE41571. © 2014, Purdue Pharma L.P. This brief summary is based on BUTRANS Prescribing Information 303135-0B, Revised 04/2014 (A)

GUEST EDITOR ROGER PUBLISHER Aventine

B. FILLINGIM PhD

Co. 6 Erie Street, Montclair, NJ 07042

ART DIRECTOR DARRYL

FOSSA

EDITORIAL DIRECTOR DEBRA

WEINER

EDITORIAL BOARD

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

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

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

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

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

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

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

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

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

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

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

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

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

/ PWJ / Q2 / 2014 11 | GUEST EDITOR’S LETTER by roger b. Fillingim

FEATURES

14 | PAIN&CHEMICAL DEPENDENCY

OPIOID-INDUCED HYPERALGESIA by sanford m. Silverman

20 | NADDI

BULLYING IN MEDICINE: are you the victim or the perpetrator? by lisa McElhaney

36 | PHYSICAL THERAPY

STIFF&STUCK: using joint mobilization to restore movement and reduce pain by erica Sigman

42 | DIABETES&PAIN

DIABETES AND GASTROINTESTINAL PAIN by michael m. Bottros / narendren

Narayanasamy

56 | PUNDIT PROFILE with kevin l. Zacharoff

30 | MUSCULOSKELETAL

WHIPLASH: towards new objective markers by james m. Elliott

8 | PWJ | www.painweek.org

Q2 | 2014

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

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

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

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

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

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

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

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

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

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

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

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

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

Adverse Reaction

RELISTOR N = 165

Placebo N = 123

Abdominal Pain

47 (28.5%)

12 (9.8%)

Flatulence

22 (13.3%)

7 (5.7%)

Nausea

19 (11.5%)

6 (4.9%)

Dizziness

12 (7.3%)

3 (2.4%)

Diarrhea

9 (5.5%)

3 (2.4%)

Hyperhidrosis

11 (6.7%)

8 (6.5%)

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

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

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

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

ROGER B.

FiLLiNGiM PhD

T his 4th issue of PWJ provides an abundance of valuable information across several topics of importance to the frontline practitioner. The variety of clinical conditions addressed serves as a reminder of the broad array of issues faced by providers in offering high quality and well-informed clinical care to patients suffering from chronic pain. Those of us in the pain field are fond of quoting statistics attesting to the staggering societal impact—100 million people are experiencing chronic pain, costing the US economy more than $600 billion annually. Chronic pain is not one condition; as is made clear in this issue of PWJ, chronic pain comprises multiple conditions that present many different challenges. Knowledge represents the best weapon the frontline practitioner can bring to his or her battle against the manifold chronic pain conditions affecting patients. Therefore, enjoy these articles, and continue to fight the good fight.

a motor vehicle accident do not experience persistent pain, Dr. Elliott notes that a substantial minority (~25%) never fully recover. Considerable research has focused on the psychosocial and behavioral factors predicting chronic WAD symptoms, and biological factors have been downplayed. Individuals who fail to recover show increased fatty infiltrates on MRI, suggesting a potential biological mechanism. This article discusses the available imaging methods that can be used to better capture these changes and calls for a more comprehensive biopsychosocial model to conceptualize WAD. Dr. Erica Sigman addresses the use of joint mobilization to improve mobility and reduce pain. She provides a clear description of the different grades and notes that joint mobilization has been found to be an effective adjunctive treatment for different forms of pain. In addressing how it might improve both mobility and pain, Dr. Sigman makes the important point that it can impact central pain processing, thereby reducing pain and improving mobility in people with centralized pain. A case example is included, which illustrates the use of joint mobilization to treat pain due to thoracic outlet syndrome. Dr. Sanford Silverman discusses the phenomenon of opioid-induced hyperalgesia (OIH ) in which opioids have the effect of increasing rather than reducing pain. While the adverse personal and societal effects of opioids have received abundant attention in recent years, OIH is often missing from this conversation, even though there is abundant preclinical and clinical evidence. Dr. Silverman distinguishes OIH from opioid tolerance, since the latter but not the former can be overcome by increasing the dose of opioid. Information about neurobiology and the methods for diagnosis and treatment all will help the frontline practitioner recognize and manage the underappreciated clinical issue that is OIH. Lisa McElhaney opens the discussion of bullying in the healthcare setting. Several examples are provided, including a physician bullying a coworker to falsify medication dosages and a patient providing sexual favors to physicians in exchange for pain medications. Bullying occurs in multiple directions and obviously can negatively impact the workplace setting. Practitioners should be aware of these issues and take steps to prevent bullying and maintain a nonhostile work environment.

The increasing prevalence of diabetes is well known, and pain We want to thank all of the contributing authors for sharing their associated with diabetic neuropathy is recognized as a significant knowledge and expertise with us. There is much to be learned in clinical concern. Most attention has focused on painful symptoms these pages. We expect that these articles will answer some quesin the extremities; however, as Drs. Michael Bottros and Narendren tions while raising new ones. If you have feedback, or if there are Narayanasamy note, chronic abdominal pain due to gastrointestinal other topics you would like to see in future issues of PWJ, please involvement in diabetes is common yet underdiagnosed. Their article let us know. highlights the high prevalence of GI symptoms in diabetes, including abdominal pain. Several sources of diabetes-related GI symptoms are — ROGER B. FILLINGIM PHD reviewed, including gastroparesis, esophageal symptoms, nonalcoholic fatty liver disease, and enteropathy. Diagnostic and treatment considerations for each of these conditions are provided. Dr. James Elliott presents the complex and controversial topic of whiplash associated disorders ( WAD). While most people who experience Q2 | 2014

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Michael M. Bottros MD

P.42

James M. Elliott PhD, PT

P.30

Lisa McElhaney

P.20

Erica Sigman PT, DPT, OCS

P.36

Sanford M. Silverman MD

P.14

Michael Bottros is Assistant Professor of Anesthesiology, Division of Pain Medicine, in the Department of Anesthesiology at Washington University School of Medicine in St. Louis, Missouri. He is founding Director, Acute Pain Service, at Barnes-Jewish Hospital, St. Louis. His interests include treatments of both chronic and acute pain, and development of various pain care paths across hospitals. He has been interviewed on television and satellite radio, and lectured nationally and internationally on various pain conditions and their respective treatment options. Narendren Narayanasamy, MD, a Fellow in Pain Medicine at the Washington University School of Medicine, is coauthor with Dr. Bottros on this article.

James Elliott is Assistant Professor in the Department of Physical Therapy and Human Movement Sciences, Feinberg School of Medicine at Northwestern University in Chicago, Illinois, and the Principal Investigator of the Neuromuscular Imaging Research Lab (www.nirl.nu). He is also an Honorary Senior Fellow at the School of Health and Rehabilitation Sciences, the University of Queensland, Australia. His research program endeavors to identify the mechanisms underlying the development/maintenance of chronic pain-related disability following traumatic spinal injuries...in particular, motor vehicle collisions.

Lisa McElhaney is the National Vice President of NADDI, the National Association of Drug Diversion Investigators, in Lutherville, Maryland. She is a sworn veteran of the Broward Sheriff’s Office in Fort Lauderdale, Florida, and is a Detective Sergeant in the agency’s Public Corruption Unit. She has specialized in pharmaceutical and designer drug investigations, prosecutions, and education for most of her 25-year career.

Erica Sigman is a physical therapist at the faculty practice on the Health Science Campus for the University of Southern California’s (USC) Division of Biokinesiolgy and Physical Therapy. She specializes in treating patients with headaches, temporomandibular joint-related issues, orthopedic disorders, and chronic pain. Dr. Sigman is board certified by the American Board of Physical Therapy Specialties as an Orthopedic Clinical Specialist. Additionally, she is an Instructor of Clinical Physical Therapy and the Coordinator of the Orthopedic Physical Therapy Residency Program at USC.

Sanford Silverman is CEO and Medical Director of Comprehensive Pain Medicine in Pompano Beach, Florida. He is Clinical Assistant Professor in the Department of Surgery, Division of Anesthesiology, at Nova Southeastern University in Davie, Florida, and Affiliate Assistant Professor of clinical biomedical science at Charles E. Schmidt College of Medicine, Florida Atlantic University in Boca Raton. Dr. Silverman is the immediate past president of the Florida Society of Interventional Pain Physicians and president-elect of the Broward County Medical Association.

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“Since tolerance is characterized by decreasing efficacy of a drug, it can be overcome by increasing the dose...OIH cannot be overcome by increasing dosage, however, because OIH is a form of pain sensitization induced by the drug...” by SANFORD

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M. SiLV RMAN MD

www.painweek.org | PWJ | 15

As early as the nineteenth century, OIH was observed in patients receiving morphine for pain. It was recognized that a potent analgesic such as morphine could actually result in an increase in pain, as observed by Albutt in 1870:

“At such times I have certainly felt it a great responsibility to say that pain, which I know is an evil, is less injurious than morphia, which may be an evil. Here experience is needed. Does morphia tend to encourage the very pain it pretends to relieve? ...in the cases in question, I have much reason to suspect that a reliance upon hypodermic morphia only ended in that curious state of perpetuated pain.”1

*Sir Thomas Clifford Albutt (1836–1925): a British physician, researcher, and the author of Medical Thermometry.

PAiN&CHEMICAL DEPENDENCY

abstract: In the United States there is an epidemic of chronic pain that parallels the everincreasing utilization of opioids. This increase in opioid use has led to misuse and abuse and has left in its wake thousands of fatalities. Yearly, there are greater than 15,000 deaths.2 Although the general consensus is that opioids can be prescribed safely and effectively with prudent risk mitigation strategies, certain side effects/complications can be difficult to treat. Addiction, abuse, and diversion are usually the focus of such efforts, and become relatively straightforward when investigated. However, other side effects to opioid therapy can be somewhat difficult to assess and even more so to treat. Opioid-induced hyperalgesia (OIH), related to but different from tolerance, is one such complication of opioid therapy. There is preclinical and clinical evidence for such, as well as the clinical implications for the pain practitioner.3

TOL RANC VS PAiN S NSiTiZATiON Tolerance is a pharmacologic concept. It occurs when there is a progressive lack of response to a drug thus requiring increased dosing. Tolerance can occur with a variety of drugs including opioids.4,5 Tolerance may not only develop to the analgesia provided by opioids but also to the undesirable side effects which are seen with opioid administration, such as pruritus, nausea, sedation, and respiratory depression. Sensitization to pain occurs in several areas of the nervous system involving the transmission of pain. Peripheral mechanisms have been well documented with respect to neural injury involving mediators of inflammation. This is known as primary hyperalgesia and is seen clinically with peripheral nerve injuries. Secondary hyperalgesia, on the other hand, occurs “downstream” from the initiating nociceptive stimulus and peripheral injury. In the spinal cord, wide dynamic Q2 | 2014

range neurons become sensitized through a variety of mechanisms that may be mediated by neurotransmitters, such as calcitonin gene-related peptide, vasoactive intestinal peptide, dynorphin, cholecystokinin, neuropeptide Y, and N-methyl-D-aspartate ( NMDA).6 Since tolerance is characterized by decreasing efficacy of a drug, it can be overcome by increasing the dose. Unlike tolerance, OIH cannot be overcome by increasing dosage, however, because OIH is a form of pain sensitization induced by the drug, which occurs within the central nerve system (CNS). It is a pro-nociceptive process that is related to, but different from, tolerance. Pain is worsened with increased opioid dosing and is improved by reducing or eliminating the opioid. Tolerance is a necessary condition for OIH, but the converse is not true. Clinically this is an important distinction that has obvious ramifications with respect to continued use of opioids in a given patient. www.painweek.org | PWJ | 17

PAIN&CHEMICAL DEPENDENCY

“Significant pain reduction has been demonstrated in patients who have been detoxified from high-dose opioids.” Laboratory (preclinical) evidence exists for OIH. In several animal more often than not initially increase the dose of opioid to offset studies, a progressive reduction in baseline pain threshold has been what they believe is tolerance. If the patient responds positively to seen following administration of opioids through both intravenous such an increase, and sustains this over a period of time, then the and intrathecal routes.7-10 Supporting evidence has shown that OIH diagnosis of tolerance is likely. However, if there is no improvement occurs clinically outside the laboratory, and is seen after intraoper- or it is transient, then the clinician must consider OIH. ative remifentanil infusion, resulting in decreased opioid efficacy.11 Significant pain reduction has been demonstrated in patients who There are other signs and symptoms that may be helpful in diagnoshave been detoxified from high-dose opioids.12 When challenged ing OIH. Typically, the pre-existing pain condition will be exacerwith cold pressor tests, opioid addicts maintained on methadone bated. The pain pattern will become more diffuse and less localized. demonstrated increased pain sensitivity.13 The clinician must rule out further progression of the disease or increased demand, which is perceived by the patient as increased need for medication (often referred to as pseudotolerance). N UROBiOLOGY OF HYP RALG SiA There are several proposed mechanisms, many of them overlapping, In fact, most patients who are utilizing chronic opioid therapy are that may explain the phenomenon of OIH. The 3 most commonly mildly hyperalgesic, particularly to acute pain. For example, a scenario with which most interventional pain physicians are familiar is proposed are: when a patient on chronic opioid therapy presents for a procedure. Very often they do not tolerate even the local anesthetic and are less 1. The central glutamate system tolerant of the acute pain experienced during the procedure. They 2. Elevated spinal dynorphin levels 3. Descending facilitation often present with intolerance to acute surgical pain. Many surgeons have discovered that these patients often require more opioid for a Glutamate is an excitatory neurotransmitter that plays a central longer time postoperatively then the typical opioid naïve patient. role in several disease states including chronic pain and chemical dependency. The excitatory neurotransmitter NMDA binds to recep- However, if a patient on chronic opioid therapy (often at moderate to tors throughout the CNS. With prolonged opioid administration, high doses) presents with diffuse pain, then OIH should be considNMDA receptors become activated. This activation can be inhibited ered. If an increase in opioid fails to address the problem, then OIH with NMDA receptor antagonists and has been demonstrated to should be considered. If a reduction in opioid produces concomitant reduction in pain, then certainly OIH is likely. prevent the development of tolerance and OIH.14,15

Spinal dynorphin levels may increase with continued infusion of µ-receptor agonists. This in turn leads to increased levels and the release of spinal excitatory neuropeptides, such as calcitonin gene-related peptide from primary afferents.16

e e

OIH TR ATM NT STRAT Gi S When treating a chronic pain patient, it is important to recognize that multimodal therapy produces the best results. Rational polypharmacy to include nonopioid medications should be utilized, particularly in Descending facilitation may influence OIH through subsets of neu- treating neuropathic pain. This in turn provides an opioid sparing rons (on and off cells) in the rostral ventromedial medulla, which effect, reducing the total opioid dose and the concomitant opioid side have the unique response to opioids.17,18 In addition, lesioning of effects. Interventional pain medicine along with behavioral therapy these descending pathways in animals has been shown to prevent can accomplish similar goals in reducing pharmacotherapy. increases seen in excitatory neuropeptides.19 If these options are not feasible, then the clinician may consider the following approaches: DiAGNOSiNG OPiOiD-INDUC D HYP RALG SiA When a chronic pain patient demonstrates lack of efficacy to a given 1. Opioid rotation to a different chemical class of opioid medication, the most common response is to increase the dose of that 2. Utilize NMDA receptor antagonists (ketamine, mematine) medication. The presumed mechanism is tolerance. With opioids, 3. Reduce or eliminate the opioid and evaluate change in pain however, does the lack of efficacy equal tolerance or OIH? Clinicians 4. Utilize opioids with unique properties that may mitigate OIH

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e e

OPiOiDS WiTH UNiQU PROP RTi S Methadone is often utilized to treat chronic pain. It is a racemic mixture in which the D isomer is an NMDA receptor antagonist. Methadone displays incomplete cross tolerance unique from other µ-receptor agonists, which may create a niche role for it in the treatment of OIH and other forms of intractable pain, particularly neuropathic pain. Incomplete cross tolerance of methadone has also led to its association with multiple overdose deaths due to inappropriate escalation of the dose or combining it with other opioids and CNS depressants.20 Buprenorphine has been used to treat chronic pain and has been available in the US since the early 1980s. Commercially available forms for chronic pain include a parenteral form (Buprenex®) and a transdermal delivery system (Butrans®). Buprenorphine has shown to be intermediate in its ability to induce pain sensitivity in opioid addicts maintained on methadone and control patients not utilizing opioids.13 Buprenorphine is a partial agonist at the µ-receptor but an antagonist at the k-receptor. Spinal dynorphin is a known k-receptor agonist that has been implicated in OIH. Thus, buprenorphine may be unique in its ability to treat chronic pain and OIH via k antagonism.

TR ATM NT CONSiD RATiONS Weaning patients from high-dose opioid medications can be time-consuming and sometimes impractical. For example, patients often will experience more pain during the weaning process until eventually they break through the hyperalgesic barrier. Physicians will often have to adjust combinations of extended-release and short-acting opioids during the weaning process. Patients may become frustrated and eventually give up. Breaking the cycle of pain and hyperalgesia is an attractive option for the pain practitioner. Medically supervised withdrawal from highdose opioids utilizing sublingual buprenorphine is rapid and effective. Sublingual buprenorphine is approved for the treatment of opioid dependence. It requires a waiver from the Substance Abuse Mental Health Administration and the Drug Enforcement Administration. Patients who suffer from OIH can be transitioned to sublingual buprenorphine just as patients suffering from opioid addiction are. The buprenorphine can then be weaned accordingly.

CONCLUSiONS Opioid therapy can be very effective for chronic nonmalignant pain. However, like any other therapy, side effects and complications can occur. The physician should have an exit strategy when initiating opioids for the treatment of chronic pain. The potential for dealing with complications such as opioid dependence, addiction, abuse, and OIH are very real, and the pain practitioner must be prepared for these challenges. As the number of patients treated with chronic opioids increases, so do the complications. OIH should be considered in the differential diagnosis when patients fail to respond to opioid therapy, as part of a comprehensive assessment and informed consent/ agreement. Q2 | 2014

References

1. Albutt C. On the abuse of hypodermic injections of morphia. Practitioner. 1870;5:327–331. 2. Centers for Disease Control and Prevention. CDC vital signs: prescription painkiller overdoses in the US . November 2011. Available at: www.cdc.gov/VitalSigns/ PainkillerOverdoses/index.html. 3. Silverman S. Opioid induced hyperalgesia: clinical implications for the pain practitioner. Pain Physician. 2009;12:679–684. 4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Press; 1994. 5. Compton P, Rollin M, Gallagher MD, et al. The neurophysiology of pain and interfaces with addition. In: Principles of Addiction Medicine. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:1286–1287. 6. Yaksh TL , Malmberg AB . Central pharmacology of nociceptive transmission. In: Wall P, Melzack R, eds. Textbook of Pain. 3rd ed. Edinburgh, UK: Churchill Livingstone; 1994:165–200. 7. Mao J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain. 2002;100:213–217. 8. Mao J, Price D, Mayer D. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain. 1995;62:259–274. 9. Celerier E, Rivat C, Jun Y, et al. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology. 2000;92:465–472. 10. Celerier E, Laulin JP, Corcuff JB, et al. Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: a sensitization process. J Neurosci. 2001;21:4074–4080. 11. Guignard B, Bossard AE, Coste C, et al. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000;93:409–417. 12. Baron MJ, McDonald PW. Significant pain reduction in chronic pain patients after detoxification from high dose opioids. J Opioid Manag. 2006;2:277–282. 13. Compton P, Charuvastra VC , Ling W. Pain intolerance in opioid-maintained former opiate addicts: effect of long acting maintenance agent. Drug Alcohol Depend. 2001;63:139–146. 14. Trujillo KA , Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science. 1991;251:85–87. 15. Marek P, Ben Eliyahu S, Gold M, et al. Excitatory amino acid antagonists (kynurenic acid and MK-801) attenuate the development of morphine tolerance in the rat. Brain Res. 1991;547:77–81. 16. Gardell LR , Wang R, Burgess SE, et al. Sustained morphine exposure induces a spinal dynorphin-dependent enhancement of excitatory transmitter release form primary afferent fibers. J Neurosci. 2002; 22:6747–6755. 17. Barbaro NM , Heinricher MM , Fields HL . Putative pain modulating neurons in the rostral ventral medulla: reflex-related activity predicts effects of morphine. Brain Res. 1986;366:203–210. 18. Heinricher MM , Morgan MM , Fields HL . Direct and indirect actions of morphine on medullary neurons that modulate nociception. Neuroscience. 1992;48:533–543. 19. Morgan MM , Heinricher MM , Fields HL . Circuitry linking opioid-sensitive nociceptive modulatory systems in periaqueductal gray and spinal cord with rostral ventromedial medulla. Neuroscience. 1992;47:863–871. 20. Centers for Disease Control and Prevention. CDC vital signs: use and abuse of methadone as a pain killer. Available at: http://www.cdc.gov/vitalsigns/ MethadoneOverdoses/.

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“ Our society appears to reward humiliating and demeaning experiences, promoting a winner or loser mentality that encourages dominance and aggression.”

Are you the victim or the perpetrator

ANeY H L e c LISA M

NADDi

abstract: The increase of litigation in the healthcare industry has brought attention to issues of workplace safety and the behaviors of medical professionals. Not only has there been an increase in reported cases of patients being aggressive or violent towards healthcare professionals, there has also been an increase in reported cases of staff members being aggressive towards each other. Bullying contributes to deficiencies in the healthcare workplace. Whether the healthcare professionals are on the contributing or the receiving end of the mistreatment, there are significant decreases in job satisfaction and increases in job-induced stress, anxiety, and a desire to leave employment, thus generating numerous legal repercussions for not only the retention of medical staff, but correspondingly the aptitude of the staff to focus on and provide accurate medical treatment. the societal expectations of the law enforcement profes- actions conveying fear of retribution if they “don’t” perform their

sion and the healthcare profession are focused on 2 basics principles: duties a certain way and express conditions of emotional or physical to help those individuals in need and to do no harm. For the most intimidation and perceived bullying in their workplace. There are part through the years, these 2 professions have worked shoulder many types of victims, and some have described a slow and deliberto shoulder to combat a variety of unpleasant circumstances, often ate transition from the status of “victim” to “perpetrator.” calling upon each other for assistance. As industry oversight has increased in the last few decades, law enforcement has been called upon more to investigate criminal violations within the healthcare WHAT iS BULLYiNG? field. Oftentimes the allegations are related to an issue of the diver- The Merriam-Webster Dictionary definition of bullying: to treat sion of pharmaceutical drugs, a property crime, or an act of domestic another abusively, to affect by means of force or coercion, or to use violence. More recent demands, however, have required in-depth browbeating language or behavior.1 investigations into the activities of rogue practitioners, their staff, and their business practices. Our society appears to reward humiliating and demeaning experiences, promoting a winner or loser mentality that encourages domDuring the course of various criminal investigations into the activ- inance and aggression. This attitude has been supported since the ities of medical professionals, law enforcement has discovered a pat- period of the gladiators and is still popular in today’s reality televitern of coercion or bullying—both internal and external to the sion programs. While communities often attribute bullying behavpractice. Countless individuals interviewed defend their improper ior to adolescents, in truth incidents of violence have increased in

Q2 | 2014

www.painweek.org | PWJ | 21

NATIONAL ASSOCIATION OF DRUG DIVERSION INVESTIGATORS

both schools and workplaces in the past few decades. As a result, greater focus has been directed to and acutely studied on the social interactions in these environments. The term bullying has become more recognized as a form of harassment, and has been acknowledged within a variety of workplace environments.

often requires viable consequences for any noncompliance. The aggression is often passive and indirect, involving acts of disparaging treatment, such as engaging in bad-mouthing and gossip. Incidents of sexual harassment and physical coercion between colleagues are not new to the healthcare industry. The consequences most often revolve around a fiscal impact to the target employee Bullying behavior consists of 4 basic types of abuse: emotional, verbal, such as the threat of loss of their job or position in the workplace. physical, and cyber.2 Incidents of bullying behavior often begin in the The bullying behavior usually begins with a subtle approach that early phases of personal development and usually end when individ- appears as a voluntary acceptance and gradually escalates to a situals being bullied become assertive and learn skills to protect them- uation through coercion where the targeted individual is afraid selves. The societal hierarchies create an environment conducive to of any confrontation which will cause an act of reprisal. Thus the the influences of power and control, and expectations of subservience. behavior continues and as such becomes a workplace norm that, More often than not, the bullied feel somewhat responsible for being unchallenged, “validates” the perpetrator. targeted and accept their perceived fate, convinced that they do not have any options available to them. The perpetrator of the behavior usually justifies their actions as necessary to complete their respective goals. The sense of empowerment that builds within the perpetrator often fuels the escalation of the bullying behavior, which is often displayed in the presence of BULLYiNG B HAViOR While bullying behavior in the workplace has been going on for cen- other employees, seeking validation of the bully’s perceived power. turies, it has only gained recognition in the past decade. In 2010 the The other employees, not wanting to draw the same treatment from Workplace Bullying Institute surveyed 1069 people of whom 98% the perpetrator, generally ignore the behavior as a personal interacsaid they were targets of workplace bullying.2 The survey sought tion between the targeted employee and the aggressor. Coworkers to establish if the targets felt personal shame or stigma attached to frequently will listen to complaints from the victim and encourage them to report the behavior or deal with it, but they will not intertheir bullying, and the following results were reported: fere with the activity, fearing reprisal. ● 35% believed that “somehow I might have deserved While the employers set the workplace tone, most develop an avoidthe criticisms” ance of issues that may interfere with the productivity of the busi● 28% blamed themselves for “not being able to counter ness. The bullied often attempt to do their job without disrupting or confront” the bully the status quo of the workplace and make efforts to deal with the ● 22% were embarrassed from “allowing it to happen to me” ● Only 13% felt no shame, saying they “did not invite or bullying behavior. This bullying behavior can include various forms deserve the assaults” and degrees of verbal taunts, public humiliation, threats of reprisal, and acts of segregation from other employees. The study did not define whether the perpetrators of the bullying behavior were internal colleagues of the recipient’s workplace or if the individuals were encountered by the employees during the course of their regular business obligations.

Another survey3 provided several key findings from participants: ● 37% of workers have experienced bullying firsthand ● 72% of bullies are bosses ● 60% of bullies are men ● 57% of targets are women, and women bullies target women in 71% of cases This survey also determined that bullying is 4 times more prevalent than illegal harassment and more than half (62%) of employers ignore the problem. A large percentage (40%) of the bullied individuals never inform their employers of the activity, and only a small number (3%) file lawsuits.

iNT RNAL WORKPLAC BULLYiNG Internal workplace bullying— or staff-on-staff aggression—is driven by the offenders’ need to control the target employee and

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“AN OFFiCe ADMiNiSTRATOR SeT UNReACHABLe GOALS FOR OFFiCe PRODUCTiON, CONTiNUOUSLY PeNALiZiNG THe eMPLOYeeS’ PAY FOR NOT ReACHiNG THe SeT GOALS.”

EXAMPL S Specific examples of internal bullying include an anesthesiologist who required a coworker to enter false amounts into the dose administration logs of patients; 2 previous employees who had challenged the entries were subsequently transferred from the “elite” operating room team to undesirable shifts. The coworker, not wanting to experience the same fate as the previous employees, committed a felony violation and falsified the records. In another instance, an office administrator set unreachable goals for office production, continuously penalizing the employees’ pay for not reaching the set goals. This practice was a violation of federal wage laws. The employees expressed a need to remain employed and thus endured the fiscal cuts. Q2 | 2014

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NATIONAL ASSOCIATION OF DRUG DIVERSION INVESTIGATORS

A constant environment of harassment will leave the target individual feeling agitated, anxious, and waiting for bad things to happen; the bullying behavior will in fact create a problem employee who will suffer from emotional and social problems. Historically the targeted individual receives little assistance or sympathy from coworkers or human resources employees; the belief is that the behavior isn’t illegal and the employees need to work it out amongst themselves.

e e

XT RNAL BULLYiNG External forms of bullying behavior—or patient-on-professional aggression—are generally driven by perpetrators with a desire for money or drugs who influence the providers or their staff with assurances of either remuneration or retribution to gain their way. Patients can often become assertive when they feel their needs are not being met, applying pressure to the practitioner or the staff in an effort to obtain specific requests. The aggression commonly involves direct verbal abuse and at times, severe physical violence driven by determination to obtain desired drugs or treatment.

“PATieNTS CAN OFTeN BeCOMe ASSeRTiVe WHeN THeY FeeL THeiR NeeDS ARe NOT BeiNG MeT, APPLYiNG PReSSURe TO THe PRACTiTiONeR OR THe STAFF iN AN eFFORT…TO OBTAiN DeSiReD DRUGS OR TReATMeNT.”

and recurring training for personnel. Mechanisms must be in a position to identify and accurately respond to bullying practices, and awareness checks should be performed for acts of psychological violence, psychological harassment, personal harassment, status-blind harassment, mobbing events, or emotional abuse in the workplace.4 Law enforcement often provides security training to businesses in an effort to reinforce the professional responsibilities of providing a safe working environment for their employees, as well as appropriate prescribing practices. A prevention plan is extremely important to protect the business’ interests, to provide a safe and secure working environment, and to fulfill any local, state, and government requirements. The prevention plan is often combined with an ethics or sexual harassment policy and assists in the development of a strong organizational risk management strategy.

CONCLUSiON Bullying decreases performance and productivity in the healthcare workplace, leading to job dissatisfaction. Stress and anxiety increase, making staff retention difficult. Employee aptitude declines and legal repercussions arise. By applying the necessary steps to prevent bullying activity, the practitioner also secures the business’ reputation, principles, and integrity. To maintain a secure, nonhostile work environment it is important to plan for unforeseen incidents and to make sure that all personnel are aware of the applicable policies and properly trained in prevention and response procedures.

EXAMPL S Specific examples of external bullying include documented incidents of female patients providing sexual favors to physicians who illegally compensate the patient with pain medications. Regrettably if the physician decides to refuse to provide the requested drugs or to cease future demands, the physician is threatened with a sexual misconduct complaint to the licensing board. In most instances, the illegal cycle of dispensing continues until law enforcement becomes involved. Another example focuses upon racketeers who manipulate practitioners and their staff with more money than either could earn in a normal clinical situation. These organizations have been investigated by law enforcement for acts related to insurance fraud, illegal drug distribution, and money laundering activities. Once the cycle of activity begins, unless it is immediately reported by the receiver, it will continue, and there rarely is an easy exit for the practitioners.

PR V NTiON PLANS According to the Workplace Bullying Institute, every healthcare organization should have steps in place to handle bullying threats or security vulnerabilities. Basic security measures include policies, a defined prevention plan, mandatory reporting and documentation,

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References

1. “Bullying.” Merriam-Webster’s Collegiate Dictionary. 11th ed. Springfield, MA: Merriam-Webster Inc; 2003. 2. Workplace Bullying Institute. Self-defeating stigma an integral part of workplace bullying. November 9th, 2010. Available at: http://www.workplacebullying. org/2010/11/09/shame/. 3. Workplace Bullying Institute. Results of the 2007 WBI U.S. Workplace Bullying Survey. Available at: http://www.workplacebullying.org/wbiresearch/wbi-2007. 4. Ferris PA . The role of the consulting psychologist in the prevention, detection, and correction of bullying and mobbing in the workplace. Consult Psychol J. 2009;61(3):169–189.

Q2 | 2014

NOW APPROVED

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

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

NEW

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

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

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

•

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

NEW

Dosed as 2 tablets, twice a day.1 •

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

Visit xartemisxr.com/pwj

to discover a new approach to managing acute pain.

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

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

•

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

•

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

•

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

•

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

CONTRAINDICATIONS •

ADVERSE REACTIONS

XARTEMIS XR is contraindicated in patients with:

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

Serious adverse events may include respiratory depression and hepatotoxicity.

•

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

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

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

BRIEF SUMMARY - Consult full prescribing information before use.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

by JAMES

M. LLiOTT PhD, PT

MUSCULOSK L TAL

“ whiplash associated disorders (WAD) from motor vehicle collisions afflict over 4 million Americans annually… reducing Quality of life and costing $30 billion for medical and rehabilitative care.” Data from the Centers for Disease Control indicates that millions of adult drivers and passengers are treated in US emergency departments annually for whiplash as the result of a motor vehicle collision. While it is expected that over half will recover within the first months postinjury, a quarter will never fully recover. Estimated costs for medical and rehabilitative care for those patients with poor functional recovery are in the billions per year and no conservative treatments have shown to positively influence their outcomes. Unfortunately, in the vast majority of whiplash cases, structural damage on objective imaging is rarely present. Currently, the prevailing opinion is that poor functional recovery is largely influenced by social, psychological, and behavioral factors and not biological. While this may be the case in some, emerging evidence (from the author’s lab) demonstrates the rapid and early expression of muscle fatty infiltrates on MRI, signs of disturbed descending control, and muscle weakness in the individuals with whiplash associated disorders and poor functional recovery. The individuals that recover spontaneously following whiplash do not manifest such signs and symptoms, suggesting a more severe injury with a biological etiology in the chronic group. This article discusses the need for an integrated biopsychosocial model of these disorders and implications for clinical imaging research informing assessment and ultimately management options. abstract:

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hiplash associated disorders (WAD) from motor vehicle collisions (MVC) afflict over 4 million Americans annually, tremendously reducing their quality of life and costing $30 billion for medical and rehabilitative care.1 A majority of patients with WAD recover within 2 to 3 months postinjury with a fairly uncomplicated clinical presentation.2 At the other end of the spectrum is a group of patients (25%) that never fully recover, demonstrating a more complex clinical picture including severe pain-related disability,3 neck muscle degeneration,4 sensory deficits,5 muscle weakness,6 and psychological distress.7 A number of psychosocial factors, including coping, expectations, anxiety, and depression have been identified as prognostic of WAD recovery.2 The pathophysiology underlying their chronic debilitating symptoms is unknown, and the current best multimodal treatments have not shown to positively influence the rate of functional recovery of both acute and chronic WAD.8-11 Furthermore, no structural cause of the acute or chronic disorder has been found, and traditional clinical imaging approaches yield inconsistent findings. However, our previous and preliminary MRI work is at odds with this long-held position. We have observed and quantified MRI findings of muscle degeneration in the neck that is specific to the 25% with poor functional recovery.4 Such findings of muscle degeneration were not present in those that nominate full recovery or in those with chronic nontraumatic idiopathic neck disorders,12 suggesting traumatic factors do play a role. It’s difficult to determine cause and effect, and the precise mechanisms underlying muscle degeneration and their influence on long-term recovery are unknown…at this time.

Due to the recurrent (and in some cases persistent) nature of symp- PATHOM CHANiCS OF TH WHiPLASH EV NT toms in some subjects with traumatic3,13 and nontraumatic14 neck Whiplash injuries from a typical low-speed rear-end MVC are disorders, our research remains focused on establishing a set of quan- defined by energy transfer to the cervical spine resulting from tifiable measures to improve our understanding of the neuromuscular acceleration-deceleration forces that typically occur with rear-end mechanisms underlying chronic WAD. We further aim to accurately vector impacts, with and without seat safety systems such as active and consistently characterize the patient’s persistent pain-related head restraints or energy absorbing seats.16 Such forces, while sigdisability, all the while appreciating the biopsychosocial factors that nificantly reduced with active head restraints,16 can lead to the rapid can, and likely do, contribute to the clinical course. Such practice development of nonphysiological stresses (producing an ephemcould circumvent the delivery of unnecessary and costly treatments eral S-shaped curve) on the cervical spine, which could result in that could contribute to iatrogenic disability15 in patients expected to injury to many disparate regional tissues—facet joint capsules, fully recover and could also provide foundation for the exploration discs, vascular tissues, dorsal root ganglia, nerve roots, and/or the and development of more informed treatment strategies aimed at spinal cord.17-28 The effect of head position at the time of impact retarding, if not preventing, the expression of persistent pain for has also been studied, and it has been determined that injury to a number of vulnerable tissues, including the vertebral artery 29 and high-risk patients.

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the craniocervical ligamentous tissues,30 are more likely to occur if imaging.34 It may be also possible to determine the severity of the the head is rotated. Despite this knowledge, the consistent identifi- traumatic event, which may be contributing to their pain and discation of laboratory defined lesions with available imaging technol- ability and thus increase odds for developing a chronic condition. ogy in patients with whiplash remains poor.31,32 Radiography lacks This work is also well underway. sensitivity for ruling out bony lesions and the images lack the detail to quantify the often suspected strain to zygapophyseal joint capsules and/or injured discs. Computed tomography (CT ) can identify AVAiLABL MRi M THODS AND some cervical spine fractures but, to our knowledge, there are no POT NTiAL CLiNiCAL UTiLiTY longitudinal studies to determine the prevalence of osseous fractures following a MVC . MAGN TiZATiON TRANSF R RATiOS: MiCROSCOPiC SCAL Conventional MRI has largely failed to consistently reveal the Magnetization transfer ratios (MTR) are being studied as semi-quanaxiomatic soft-tissue lesions in patients with traumatic whiplash.33 titative metrics for mild and traumatic brain injury41,42 and peripheral The lack of specificity may relate to the widespread, and arguably neuropathy43 and are used clinically in diagnostic studies of neuronal unnecessary,34 use of generic clinical protocols (typically with mag- degeneration in multiple sclerosis,44 Alzheimer’s,45-49 and Parkinson’s nets at lower field strengths) and limitations in the resolution of the disease.50,51 MTR is an indirect measure of tissue stability, relying on produced images.35 The advent of higher-field systems (3 Tesla and the exchange of magnetically saturated hydrogen molecules (protons) greater) has provided a foundation for measuring physiologic pro- between water and solid tissue structures.52,53 MTR can be used as a measure to characterize the demyelination/degeneration of spinal cesses that could be associated with injured tissues.36,37 pathways in patients with spinal cord injury (SCI ) as a means to assess Recent MRI evidence from our research across 2 continents (Aus- prognosis of functional rehabilitation.54 Magnetization transfer imagtralia and North America) has identified the unique expression of ing provides a more sensitive and specific marker of neural pathway neck muscle degeneration (fatty infiltrates) between 4 weeks and pathology in the cervical cord when compared to traditional T1- and 3 months postwhiplash from a MVC .4 Interestingly, muscle changes T2-weighted signals. MTR measures of the dorsal and ventrolateral were not present in patients with lower levels of initial pain or in spinal pathways in SCI have shown to be predictive of sensory and patients with chronic nontraumatic neck pain,12 suggesting trau- motor disability levels, suggesting a noninvasive MRI measure of matic factors play a role in altering the structure of the neck mus- cord degeneration and determination of impairment is possible.54 cles. Furthermore, the presence of a posttraumatic stress disorder MTR could also provide a sensitive measure of cellular level changes ( PTSD) response mediated the relationship between initial pain in the spinal cord, brain, and muscle tissues in patients with varying levels and the development of neck muscle fat.4 While preliminary, levels of pain-related disability from a variety of neuromusculoskeletal the relationship between symptoms of PTSD (a psychological find- disorders (eg, spinal pain and/or concussion).4,55,56 ing) and objective longitudinal data for muscle degeneration (a physical pathology), suggests multiple neuropsychobiological factors influence recovery rates. Support for a neuropsychobiologic link is MUSCL FAT: MiCRO- AND MACROSCOPiC SCAL available. While the acute chemical response to traumatic or stress- The quantification of muscle fatty infiltrates on T1-weighted imaging ful events are beneficial, ongoing systemic stress can have a negative in chronic whiplash55-57 is interesting as such findings were not feaimpact at the level of the skeletal muscle system.38 Under the influ- tured in those with chronic idiopathic neck pain12 and their expression ence of excessive sympathetic nervous system outflow, intramyo- (between 4 weeks and 3 months postinjury event) appears unique to cellular oxidative stresses39 may be responsible for the observed those who develop chronic whiplash-related pain.4 It is suggested muscle changes.39 The persistent presence of oxidative stress can that these muscle changes represent a biologic basis for the transition dramatically affect skeletal muscle contractility as well as induce to chronic pain following whiplash injury. While the mechanisms the expression of fibrotic tissues that have been observed in other remain unclear, it is possible that other available MRI techniques painful conditions (such as fibromyalgia40 ) and possibly the fatty (MTR) could further help quantify earlier physiologic changes at muscle changes observed in traumatic neck pain.4 the spinal cord and muscle cell that may precede observable muscle changes on T1-weighted sequences. An earlier detection could prove Our group has worked towards combining available MRI sequences essential for identifying the presence of select physiologic changes in for identifying patients determined to be at high risk of poor func- spinal cord functioning with subsequent changes in muscle physioltional recovery. A comprehensive set of sequences provides both a ogy and the development of chronic pain-related disability. microscopic and macroscopic view of the muscle system. Such findings, in tandem with clinical self-report measures of pain-related disability, psychosocial risk factors, and psychological responses, FAT/WAT R S PARATiON IMAGiNG could improve our ability to characterize high-risk patients. Accord- There are several ways to measure the fat composition in various tisingly, a more informed management schema could be explored, sues on MRI. One is to include a dual acquisition method, where an developed, and tested in clinical trials. This noninvasive methodol- image is primarily water (fat suppressed)58 and a standard image is also ogy may afford the clinician the ability to triage patients with confi- collected (fat and water). The challenge with this type of acquisition dence and avoid costs associated with unwarranted and unnecessary remains its reliance on the uniform frequency difference between

e e

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water and fat across the whole volume of excitation, which is often difficult to obtain especially at higher magnetic fields (3 Tesla and above). A fat suppressed acquisition using a short tau inversion recovery (STIR) sequence is possible, but the quantity of fat has to be assumed.59 An alternative is the Dixon method,60 where data is collected at an echo time when water and fat are out of phase and at an echo time when water and fat are in phase. The data can be collected and combined in such a way that they generate a fat and water image. This has been applied successfully in the liver and musculoskeletal system using an iterative least squares solution called IDEAL.61,62 The method we have used in our studies collects multiple different echo times sufficiently spaced on the unit circle to provide adequate phase information for the variable projection ( VARPRO)a algorithm, which generates a globally optimal solution for the water/fat decomposition.63,64

CONCLUSiONS The observed temporal alterations in muscle structure and function in traumatic neck disorders provides preliminary evidence for an objective marker of chronic WAD. Current studies indicate that the physiologic measures assessed with a combination of available imaging protocols show promise for detecting patients that may be at risk for transitioning from acute to chronic WAD-related disability. While such measures hold promise for helping to characterize the patient at risk for developing along a trajectory of chronicity, they also provide hope for informing best clinical practice through novel assessment and management regimens that avoid suggestions of WAD being purely driven by psychosocial factors, as opposed to a combined set of identifiable (and modifiable) biopsychosocial factors.65 Furthermore, clinicians across many disciplines may be able to draw from these findings to improve outcomes among a majority of their patients that are determined to be following a trajectory of functional recovery by advising them to allow natural recovery to occur, thereby circumventing the delivery of unnecessary, and costly, treatments that have been suggested to contribute to iatrogenic disability.15

5. Sterling M, Jull G, Vicenzio B, et al. Sensory hypersensitivity occurs soon after whiplash injury and is associated with poor recovery. Pain. 2003;104:509–517. 6. Sterling M, Jull G, Vicenzio B, et al. Development of motor dysfunction following whiplash injury. Pain. 2003;103:65–73. 7. Sterling M, Jull G, Kenardy J. Physical and psychological factors maintain longterm predictive capacity post-whiplash injury. Pain. 2006;122:102–108. 8. Jull G, Sterling M, Kenardy J, et al. Does the presence of sensory hypersensitivity influence outcomes of physical rehabilitation for chronic whiplash? A preliminary RCT. Pain. 2007;129:28–34. 9. Jull G, Kenardy J, Hendrikz J, et al. Management of acute whiplash: a randomized controlled trial of multidisciplinary stratified treatments. Pain. 2013;154:1798–1806. 10. Lamb SE, Gates S, Williams MA , et al. Emergency department treatments and physiotherapy for acute whiplash: a pragmatic, two-step, randomised controlled trial. Lancet. 2013;381:546–556. 11. Michaleff ZA , Maher CG, Lin CW, et al. Comprehensive physiotherapy exercise programme or advice for chronic whiplash (PROMISE ): a pragmatic randomised controlled trial. Lancet. 2014:S0140–6736(14)60457–8. [Epub ahead of print.] 12. Elliott J, Sterling M, Noteboom JT, et al. Fatty infiltrate in the cervical extensor muscles is not a feature of chronic, insidious-onset neck pain. Clin Radiol. 2008;63:681–687. 13. Carroll LJ, Holm LW, Hogg-Johnson S, et al. Course and prognostic factors for neck pain in whiplash-associated disorders ( WAD): results of the Bone and Joint Decade 2000–2010 Task Force on Neck Pain and Its Associated Disorders. J Manipulative Physiol Ther. 2009;32:S97-S107. 14. Carroll LJ, Hogg-Johnson S, van der Velde G, et al. Course and prognostic factors for neck pain in the general population: results of the Bone and Joint Decade 2000–2010 Task Force on Neck Pain and Its Associated Disorders. Spine (Phila Pa 1976). 2008;33:S75–82. 15. Cote P, Soklaridis S. Does early management of whiplash associated disorders assist or impede recovery. Spine (Phila Pa 1976). 2011;36(25 suppl):S275-S279. 16. Ivancic PC , Sha D, Lawrence BD, et al. Effect of active head restraint on residual neck instability due to rear impact. Spine (Phila Pa 1976). 2010;35:2071–2078. 17. Grauer JN, Panjabi MM , Cholewicki J, et al. Whiplash produces an S-shaped curvature of the neck with hyperextension at lower levels. Spine (Phila Pa 1976). 1997;22:2489–2494. 18. Guez M, Hildingsson C, Rosengren L, et al. Nervous tissue damage markers in cerebrospinal fluid after cervical spine injuries and whiplash trauma. J Neurotrauma. 2003;20:853–858. 19. Kaneoka K, Ono K, Inami S, et al. Motion analysis of cervical vertebrae during whiplash loading. Spine (Phila Pa 1976). 1999;24:763–769; discussion 770. 20. Martin D, Schoenen J, Lenelle J, et al. MRI -pathological correlations in acute traumatic central cord syndrome: case report. Neuroradiology. 1992;34:262–266.

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37. Sterling M, McLean SA , Sullivan MJ, et al. Potential processes involved in the initiation and maintenance of whiplash-associated disorders: discussion paper 3. Spine (Phila Pa 1976). 2011;36:S322–329.

59. Bydder GM , Steiner RE, Blumgart LH, et al. MR imaging of the liver using short TI inversion recovery. J Comput Assist Tomogr. 1985;9(6):1084–1089.

38. Passatore M, Roatta S. Influence of sympathetic nervous system on sensorimotor function: whiplash associated disorders ( WAD) as a model. Eur J Appl Physiol. 2006;98:423–449. 39. Jenkins RR . Exercise and oxidative stress methodology: a critique. Am J Clin Nutr. 2000;72:670S-674S. 40. Gerdle B, Forsgren MF, Bengtsson A, et al. Decreased muscle concentrations of ATP and PCR in the quadriceps muscle of fibromyalgia patients—a 31 P- MRS study. Eur J Pain. 2013;17(8):1205–1215 41. Bagley LJ, McGowan JC , Grossman RI, et al. Magnetization transfer imaging of traumatic brain injury. J Magn Reson Imaging. 2000;11:1–8. 42. McGowan JC, Yang JH, Plotkin RC, et al. Magnetization transfer imaging in the detection of injury associated with mild head trauma. AJNR Am J Neuroradiol. 2000;21:875–880. 43. Sinclair CD, Morrow JM , Miranda MA , et al. Skeletal muscle MRI magnetisation transfer ratio reflects clinical severity in peripheral neuropathies. J Neurol Neurosurg Psychiatry. 2012;83:29–32. 44. Filippi M, Rovaris M. Magnetisation transfer imaging in multiple sclerosis. J Neurovirol. 2000;6 suppl 2:S115–120. 45. Hanyu H, Asano T, Iwamoto T, et al. Magnetization transfer measurements of the hippocampus in patients with Alzheimer’s disease, vascular dementia, and other types of dementia. AJNR Am J Neuroradiol. 2000;21:1235–1242.

60. Dixon WT. Simple proton spectroscopic imaging. Radiology. 1984;153(1):189–94. 61. Reeder SB, Wen Z, Yu H, et al. Multicoil Dixon chemical species separation with an iterative least squares estimation method. Magn Reson Med. 2004;51:35–45. 62. Reeder SB, Pineda AR , Wen Z, et al. Iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL): application with fast spinecho imaging. Magn Reson Med. 2005;54:636–644. 63. Hernando D, Kellman P, Haldar JP, et al. Estimation of water/fat images, B0 field map and T2* map using VARPRO. In Proceedings of the 16th Annual Meeting of ISMRM . Toronto, Canada. 2008:1517. 64. Elliott JM , Walton D, Rademaker A. Quantification of cervical spine muscle fat: a comparison between T1-weighted and multi-echo gradient echo imaging using a variable projection algorithm ( VARPRO). BMC Medical Imaging. 2013;11:13–30. 65. Dufton JA , Bruni SG, Kopec JA . Delayed recovery in patients with whiplash-associated disorders. Injury. 2012;43:1141–1147. Endnotes a. Saurabh Shah, PhD, implemented the VARPRO algorithm and acquisition sequence in the cardiovascular R&D team located at Northwestern University.

46. Hanyu H, Asano T, Sakurai H, et al. Magnetization transfer measurements of the hippocampus in the early diagnosis of Alzheimer’s disease. J Neurol Sci. 2001;188:79–84. 47. Hanyu H, Shimizu S, Tanaka Y, et al. Differences in magnetization transfer ratios of the hippocampus between dementia with Lewy bodies and Alzheimer’s disease. Neurosci Lett. 2005;380:166–169. 48. Kabani NJ, Sled JG, Chertkow H. Magnetization transfer ratio in mild cognitive impairment and dementia of Alzheimer’s type. Neuroimage. 2002;15:604–610.

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by Erica

SiGMAN PT, DPT, OCS

“ Physical therapists…play a significant role in minimizing

the economic burden of chronic pain…and promote optimal movement strategies, thereby decreasing pain and improving QOL.”

by Erica

SiGMAN PT, DPT, OCS

PHYSiCAL THERAPY

abstract: Joint mobilization and manipulation techniques are used frequently by physical therapists in order to improve mobility and decrease pain. Joint mobilization, however, affects more than just the joints. Recent evidence demonstrates how these techniques go beyond the local level and into the central nervous system. This commentary describes techniques and highlights supporting evidence for the use of this type of manual therapy in the treatment of patients with chronic pain. Chronic and centralized pain is a growing problem, calling for innovative and

cost-effective approaches to management. The prevalence of pain in the public is upwards of 100 million with the estimated healthcare cost being more than $600 billion per year in America alone.1 Chronic pain is also responsible for hundreds of thousands of lost work days and greatly impacts overall quality of life (QOL). In fact, persons with migraine have been shown to have QOL that is worse than or equal to persons with arthritis, asthma, diabetes, or depression.1,2 Physical therapists are a part of many comprehensive pain programs that are more cost-effective than traditional medical treatment approaches3 and play a significant role in minimizing the economic burden of chronic pain. While there are many treatment techniques employed by physical therapists, joint mobilization and manipulation are widely used to supplement the plan of care in order to restore pain-free mobility and promote optimal movement strategies, thereby decreasing pain and improving QOL.

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Figure: Maitland Grades of Mobilization

Resting Position

Tissue Resistance

Anatomic Limit

Joint Range of Movement

Mobilization and Manipulation Defined

How Does It Work? Proposed Mechanisms of Action

The Guide to Physical Therapy Practice defines joint mobilization as “a manual therapy technique comprised of a continuum of skilled passive movements to the joints and/or related soft tissues that are applied at varying speeds and amplitudes, including a small amplitude/high velocity therapeutic movement.” While there are varying grades of mobilization that can be performed, all grades have the potential to create change in the central nervous system. Joint mobilization activates mechanoreceptors which activate afferent neurons that engage synapses in the dorsal column of the spinal cord. Once this happens, the message is sent up to the thalamus in the brainstem and then to the somatosensory cortex in the brain. The different grades of mobilization are illustrated in the Figure (above).

Before understanding the mechanisms by which joint mobilization and manipulation can help decrease pain, it’s important to review the potential mechanisms of chronic musculoskeletal pain. Smart et al describes the different types of pain nicely.4 Nociceptive pain occurs with the activation of peripheral receptive terminals of primary afferents in response to a noxious stimuli. An example is facet dysfunction in the cervical spine. Inflammation of the facet joint causes pain with movement. No pain is present at rest or in a neutral spinal position. Pain is usually localized to one side of the cervical spine and reproduced with particular movements and/or postures. Peripheral neuropathic pain is initiated and/or caused by a primary lesion or dysfunction in the peripheral nervous system. An example is cervical radiculopathy, which presents as pain in the cervical spine and affected upper extremity due to impingement of a nerve at the level of the root. In this case, the pain is more widespread, burning/ radiating in nature, but still related to particular movements and positions that impinge upon the affected nerve root. Centralized pain, in contrast to nociceptive and peripheral neuropathic pain, is fairly constant. This pain is persistent due to altered pain processing in the central nervous system. Another way to think of it: the pain is lasting longer than what is to be expected given the involved tissues

Grades I and II activate type one cutaneous mechanoreceptors and play a role in gating pain. Therefore grades I and II are used primarily to help decrease pain at that region. Grade III moves into more tissue resistance, activating more of the muscle and joint mechanoreceptors. Grade IV is sustained motion into end range, changing joint capsule extensibility. Therefore grades III and IV are used to directly improve joint mobility. A grade V mobilization is a low amplitude/high velocity thrust technique, otherwise termed manipulation. Q2 | 2014

www.painweek.org | PWJ | 39

PHYSICAL THERAPY

“Joint mobilization and manipulation can change central processing by optimizing movement through improving painfree range of motion, appropriately altering muscle activity, and improving proprioception.”

and/or injury. A very clear example of this is phantom limb pain, where a person continues to experience sensation and pain in a limb that has been amputated. There is a healthy sample of evidence supporting the use of joint mobilization and manipulation to treat nociceptive and peripheral neuropathic pain. For the purpose of this article, we will concentrate on how joint mobilization and manipulation can aide in the management of centralized pain.

decreasing muscle tone and spasm.6,7 Joint mobilization and manipulation produces impulses in muscle spindle afferents, which help to silence gamma motor neurons, thereby improving pain-free mobility by decreasing muscle tone and spasm.7,8 In addition to silencing unwanted muscle tone, joint mobilization and manipulation has also been shown to facilitate appropriate muscle activation and timing in cases where these impairments lead to pain.1,6,7 For example, persistent low back pain has been shown to be associated with weakness and improper timing of the lumbar multifidi and transverse abdominis.9-11 Ultrasound studies show an increase in the thickness of these muscles with exercise after spinal manipulation. This improvement of muscle function is positively correlated with decreased pain and improved disability.9

How does a person get to the point of having persistent and centralized pain? If an injury occurs, whether it’s a macro- or microtrauma, it alters movement in an effort to avoid pain. This altered movement strategy can impair joint mobility and alter muscle activity, which ultimately affects and changes central processing of that particular body region.5 Similarly, if there is impaired joint mobility Finally, we can improve movement and normalize central processin the absence of pain (for example, in the case of decreased ankle ing by improving joint and body proprioception.5 A classic example mobility after a sprain 3 years earlier), it can alter movement, which of disturbed proprioception in a case of chronic pain is a whiplash changes central processing and can facilitate the development of type of injury, where there is inflammation and pain. This changes persistent pain.5 Regardless of the pathway, the alteration in central muscle spindle sensitivity, which disturbs the afferent activity in the processing has been shown to play a large role in centralized pain. region. This alters cortical representation and muscle function of the Joint mobilization and manipulation can change central process- cervical spine, which leads to disturbances in head-neck awareness, ing by optimizing movement through improving pain-free range postural stability, oculomotor control, and neck movement control. of motion, appropriately altering muscle activity, and improving This cascade of events contributes to prolonged pain, dizziness, and proprioception. headache.12,13 Since joint mobilization and manipulation activates proprioceptive afferents, it is a great adjunct to exercise and balance Mobilization and manipulation can increase pain-free range of training, in order to improve movement void of dysfunction and/ motion and mobility by improving joint capsule extensibility and or pain.14

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Case Example A 25-year-old female diagnosed with right thoracic outlet syndrome reported having pain for 2 years, taking 60 mg of Cymbalta® daily, and using Lidoderm® patches as needed. Upon the initial physical therapy evaluation, she reported pain on the right side, which started in the periscapular region and traveled down the posterior aspect of the brachium, into the medial aspect of the forearm and last 2 digits of the hand. She stated that her pain averaged 7/10 and ranged from 4 to 8/10, and was “burning” and “achy.” She also mentioned allodynia in the forearm and hand. Aggravating factors included sitting or typing more than 30 minutes and any weight-bearing through the right upper extremity. The outcome questionnaire used was DASH, the Disabilities of the Arm, Shoulder, and Hand scale. Her score indicated 58.3% disability of the right arm due to pain. The neurologic screen, including upper extremity deep tendon reflexes, dermatome and myotome testing, was symmetric and normal bilaterally. Cervical spine range of motion was only slightly limited; however, her arm pain was reproduced with flexion, right rotation, and left sidebend. The patient attended a total of 6 physical therapy visits, 30-minutes each, over the course of 2.5 months. Treatment included patient education regarding ergonomics, activity pacing, and ways to unload her right upper extremity in all functional positions. Additionally, she was placed on an exercise program focusing on postural strengthening and endurance training, cardiovascular endurance, relaxation techniques, diaphragmatic breathing, and movement reeducation. Manual therapy techniques included manipulation to the thoracic spine and cervicothoracic junctional region, joint mobilization of the right first rib, and soft tissue mobilization to the scalenes and pectoralis minor. The patient was then taught how to perform similar mobilization techniques at home using tennis balls, a foam roll, and a towel. After 2.5 months the patient’s average pain was decreased to 3/10 and the pain ranged from 0 to 4/10. Her pain was located proximally and never extended distal to the elbow. DASH improved to only 20% disability. Cervical spine range of motion was pain-free and she was able to sit and type for up to 1.5 hours without symptoms. Additionally, she had not taken Cymbalta or any other pharmacological treatment for approximately a month.

Conclusion

References 1. Institute of Medicine. Relieving Pain in America: a Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press; 2011. 2. Torrance N, Smith BH, Bennett MI, et al. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain. 2006;7(4):281–289. 3. Gatchel RJ, Okifuji A. Evidence-based scientific data documenting the treatment and cost-effectiveness of comprehensive pain programs for chronic nonmalignant pain. J Pain. 2006;7(11):779–793. 4. Smart KM , Blake C, Staines A, et al. Clinical indicators of ‘nociceptive’, ‘peripheral neuropathic’ and ‘central’ mechanisms of musculoskeletal pain. A Delphi survey of expert clinicians. Man Ther. 2010;15:80–87. 5. Butler DS, Mosley LG. Explain Pain. Adelaide, Australia: Noigroup Publications; 2003. 6. Coronado RA , Gay CW, Bialosky JE, et al. Changes in pain sensitivity following spinal manipulation: a systematic review and meta-analysis. J Electromyogr Kinesiol. 2012;22(5):752–767. 7. Pickar JG. Neurophysiological effects of spinal manipulation. Spine J. 2002;2:357–371. 8. Martinez-Segura R, De-la-Llave-Rincón AI, Ortega-Santiago R, et al. Immediate changes in widespread pressure pain sensitivity, neck pain, and cervical range of motion after cervical or thoracic thrust manipulation in patients with bilateral chronic mechanical neck pain: a randomized controlled trial. J Orthop Sports Phys Ther. 2012;42(9):806–814. 9. Koppenhaver SL , Fritz JM , Hebert JJ, et al. Association between changes in abdominal and lumbar multifidus muscle thickness and clinical improvement after spinal manipulation. J Orthop Sports Phys Ther. 2011;41(6):389–399. 10. MacDonald DA , Dawson AP, Hodges PW. Behavior of the lumbar multifidus during lower extremity movements in people with recurrent low back pain during symptom remission. J Orthop Sports Phys Ther. 2011;41(3):155–164. 11. Teyhen DS, Bluemle LN, Dolbeer JA , et al. Changes in lateral abdominal muscle thickness during the abdominal drawing-in maneuver in those with lumbopelvic pain. J Orthop Sports Phys Ther. 2009;39(11):791–798. 12. Kristjansson E, Treleaven J. Sensorimotor function and dizziness in neck pain: implications for assessment and management. J Orthop Sports Phys Ther. 2009;39(5):364–377. 13. O’Leary S, Falla D, Elliott JM , et al. Muscle dysfunction in cervical spine pain: implications for assessment and management. J Orthop Sports Phys Ther. 2009;39(5):324–333. 14. Haavik H, Murphy B. The role of spinal manipulation in addressing disordered sensorimotor integration and altered motor control. J Electromyogr Kinesiol. 2012;22:768–776. 15. Aure OF, Nilsen JH, Vasseljen O. Manual therapy and exercise therapy in patients with chronic low back pain. Spine. 2003;28(6):525–532. 16. Evans R, Bronfort G, Nelson B, et al. Two-year follow-up of a randomized clinical trial of spinal manipulation and two types of exercise for patients with chronic neck pain. Spine. 2002;27(21):2383-2389.

Joint mobilization and/or manipulation has been found to be an effective adjunct to the treatment of chronic and persistent pain. Both Aure and Evans found a combination of manual therapy and exercise to be more beneficial than manual therapy alone.15,16 There are many healthcare practitioners who perform joint mobilization and manipulation techniques, and it’s important for patients and those referring to make sure the techniques are being performed as a part of a comprehensive treatment program. Q2 | 2014

www.painweek.org | PWJ | 41

by Michael

M. BOTTROS MD/Narendren NARAYANASAMY MD

DiAB T S&PAiN

“Neuropathy of the GI system could manifest as nausea, bloating, abdominal pain, vomiting, diarrhea, constipation, and delayed gastric emptying.” abstract: An epidemiological world survey estimated an over-

all prevalence of 2.8% diabetics in the year 2000. By 2030, this number is estimated to increase to 4.4% worldwide, with the United States ranking third among all countries.1 The metabolic derangement of diabetes afflicts multiple organ systems. Neuropathy of the gastrointestinal (GI) system could manifest as nausea, bloating, abdominal pain, vomiting, diarrhea, constipation, and delayed gastric emptying. The purpose of this review on diabetes is to understand: 1) Gastric emptying physiology; 2) Pathophysiology of gastric neuronal degeneration and gastroparesis; 3) GI symptom prevalence; 4) Clinical overview of GI sequelae to diabetes

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DIABETES&PAIN

GASTRiC FUNCTiONAL ANATOMY Effective gastric emptying is accomplished by the coordinated action of the stomach and proximal small intestine at a structural and molecular level. A cascade of events takes place when food particles enter the fundus, which primarily accommodates the contents without increasing intragastric pressure. This process is enabled mainly by the release of nitric oxide ( NO) via vagal efferent output. Following gastric distension, the interstitial cells of Cajal ( ICC) generate slow waves in smooth muscles. A membrane potential gradient is established that ultimately triggers rapid circumferential and longitudinal contractions of smooth muscles that sweep throughout the body and antrum of the stomach. Macrophages that are normally present in the gastric lining exert oxidative protective effects on the gastric mucosa by expressing antioxidants like heme oxygenase-1, which produces carbon monoxide. Gastric emptying finally occurs by antral contractions and from enterogastric reflexes and release of hormones like cholecystokinin from the duodenum. Food particles less than 3 mm in size enter the duodenum by a filtration process from antral contractions.2

GASTROPAR SiS PATHOPHYSiOLOGY A major GI complication of diabetes is gastroparesis, which was originally thought to be a direct result of delayed gastric emptying. However, there seems to be an inconclusive correlation between symptoms and gastric emptying, with weak diagnostic evidence to demonstrate the abnormality in relation to gastroparesis. Abdominal pain experienced by diabetics could be due to discordant GI contractions as a result of autonomic neuropathy. Myenteric and submucous plexus of the enteric nervous system govern normal gut function by maintaining a balance between the excitatory neurotransmitters, acetylcholine and substance P, and the inhibitory neurotransmitters, vasoactive intestinal peptide ( VIP), and NO generated from nitric oxide synthase (nNOS). Advanced glycation products formed due to increased oxygen radicals produced in diabetes could inhibit the myenteric plexus decreasing n NOS production.2 Studies also show altered chemical coding leading to neuronal remodeling. These changes occur in the stomach, caecum, ileum, and proximal colon in 2 phases, an initial neuronal loss followed by a later regeneration.3 These neuronal changes could be seen as early as 1 week (proximal colon) of diabetes. The inhibitory neurons (n NOS, VIP and neuropeptide Y) are affected severely while the cholinergic excitatory neuronal density is increased leading to heightened contractility in diabetes. Further, a sensory neuropeptide, calcitonin gene-related peptide (CGRP) that is colocalized with the excitatory neurotransmitter substance P is decreased in diabetes. Another factor that is thought to contribute to gastroparesis in diabetes is loss of ICC that is damaged from impaired upregulation of the antioxidant heme oxygenase-1. Further, a survival factor for ICC, the insulin-like growth factor-1, is deficient, and relative insulin deficiency in diabetes causes smooth muscle atrophy that leads to ICC depletion causing gastric dysrhythmias (bradygastria and/or tachygastria). Decreased gastric secretion, blunted pancreatic polypeptide response, reduced pyloric relaxation, and vagus nerve dysfunction are other manifestations of diabetic neuropathy.2

e e

GI SYMPTOM R Vi W iN DiAB T S Upper and lower gastrointestinal symptoms are highly prevalent in patients with diabetes. A population-based survey of 15,000 adults to determine the prevalence of GI symptoms in diabetes showed that the duration of diabetes or the type of treatment were not significantly associated with the prevalence. Five symptom complexes were analyzed: esophageal, upper dysmotility, any bowel symptoms, diarrhea, and constipation symptom complex. A significant association of symptoms of fecal incontinence, dysphagia, and vomiting with odds ratios (OR) of 2.74, 2.71, and 2.51, respectively, at a 95% confidence interval were shown in patients with diabetes.4 Poor glycemic control could also be associated with a higher prevalence of symptoms in diabetes. Age and sex adjusted OR for symptoms such as lumpy or hardy stools (OR 3.75), urgency (OR 3.12), and upper GI dysmotility (OR 1.97) were shown to be independent risk factors in patients with

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poor glycemic control.4 In a multiple logistic regression analysis, glycemic control as represented by the HbA1C estimation was shown to be the only independent risk factor for the prevalence of upper GI symptoms.5 Further, patients with HbA1C values >8% had higher prevalence of these symptoms compared to patients with HbA1C <6% suggesting that strict glycemic control could play a significant role in decreasing the prevalence of bothersome GI symptoms in diabetic patients.

GASTROPAR SiS: clinical overview

PR S NTATiON Gastroparesis is largely prevalent in women (82%) with a mean age of occurrence at 34 years of age.6 Slow gastric emptying was seen more commonly in women than men, suggesting a decreased threshold in the development of gastroparesis in women. The reason for the gender susceptibility to this pathology is unknown. The clinical presentation is highly variable with mostly nonspecific symptoms. Usually, patients complain of abdominal pain or discomfort that is burning, vague, or crampy in nature. Very few patients localize this pain to the epigastric region; symptoms usually occur after a meal or during nighttime sleep. See Table 1 for possible etiologies for chronic abdominal pain. DiAGNOSiS

SCINTIGRAPHY—Abnormal gastric emptying still remains the only objective method to demon-

strate neuromuscular abnormality of the GI system in diabetic gastroparesis. The most commonly used method is scintigraphy, which is the radiographic measurement of a solid meal tagged with a radiolabeled compound at specific time points from the time of intake. The amount of food particles measured as a percentage is used to indirectly estimate normal vs abnormal gastric emptying time. The disadvantages of this test are that it is relatively expensive, involves exposure to some radiation, and is not standardized across medical centers in the country.1 Other possible tests used in the diagnosis of gastroparesis are: Gastric emptying breath test using 13C: 89% sensitive and 80% specific ● Gastroduodenal manometry: expensive and invasive, uncomfortable, with very limited availability ● Transabdominal ultrasound: requires technical expertise, with limited availability ●

MRI: expensive and correlates well with scintigraphy ● Nondigestible capsules: 87% sensitive and 92% specific, designed to record pH, temperature, and pressure ●

TR ATM NT NUTRITION —Though there are no randomized controlled trials done to validate the importance of diet in the management of gastroparesis, studies in healthy volunteers show that fatty foods could slow gastric emptying. Frequent small meals, chewing well, less fiber, and a low-fat diet are some recommendations to improve gastric emptying. Further, patients are encouraged to consume more liquid-based meals such as stew and soups, as this diet seems to preserve gastric emptying.2 NONPHARMACOLOGIC —These

options are generally used as adjuvants to medications:

Biofeedback therapy Relaxation therapy ● Physical and occupational therapy ● Cognitive and behavioral strategies including guided imagery Q2 | 2014

●

Acupuncture Transcutaneous electrical nerve stimulation (time consuming and some patients find it challenging to operate the device) www.painweek.org | PWJ | 45

DIABETES&PAIN

“Chronic abdominal pain due to GI involvement in diabetes is prevalent, underdiagnosed, and a complex symptomatology to manage and treat. Hence, it is imperative for healthcare providers to have an in-depth understanding of this entity.” Table 1. Differential Diagnosis for Chronic Abdominal Pain7 Pathology

Comments

Peptic ulcer disease

Epigastric burning pain related to meals

Inflammatory bowel disease

Diffuse abdominal pain, confirmed by upper and lower GI endoscopy

Chronic appendicitis

Underdiagnosed; right lower quadrant pain, retrocolic appendiceal inflammation diagnosed by digital rectal examination

Diverticular disease and diverticulosis

Usually diagnosed incidentally during colonoscopy or sigmoidoscopy

Nephrolithiasis

Intermittent abdominal pain, migratory symptoms, hemoglobin or red blood cells in the urine, stones or pelvicalyceal distension seen in ultrasound

Abdominal aortic aneurysm or mesenteric ischemia

DM II is prone to develop atherosclerosis, confirmed by ultrasound of abdominal aorta or CT of abdomen

Infectious diseases

Patients on hemodialysis are susceptible to tuberculosis, yersiniosis, Whipple’s disease, helminthic or other tropical GI infectious diseases presenting with chronic abdominal pain

Partial intestinal obstruction

Incarcerated hernia, intra-abdominal adhesions, and partial intussusception

Painful rib syndrome (rare)

Common in women; lower chest, upper abdomen, or coastal margin discomfort, rib pressure reproduces pain

Wandering spleen syndrome (rare)

Torsion of the structures (including blood vessels) that attach to the spleen leading to splenic infarcts and abdominal pain

Abdominal migraines (rare)

Usually have concomitant migraine headaches

Eosinophilic gastroenteritis (rare)

Present with abdominal pain, nausea, vomiting, and diarrhea; histopathology of tissue biopsy needed to confirm diagnosis

The Fitz-Hugh–Curtis syndrome (rare)

Right upper quadrant pain in young women due to perihepatic inflammation from Chlamydia trachomatis or Neisseria gonorrhoeae infection

Hereditary angioedema (rare)

C1 esterase inhibitor defect, present in young adolescents as colicky abdominal pain with nausea, vomiting, and diarrhea associated with mucosal swelling, usually dissipates spontaneously in 2 to 4 days

Abdominal malignancies or metastatic disease to abdomen (rare)

Associated systemic symptoms

Somatization disorder (rare)

Psychogenic in origin

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

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

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

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

(feno

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Use this Nalfon 400 mg capsule for identification.

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

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Rx ONLY

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

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

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

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

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

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

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

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

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

PHARMACOLOGIC —The

medical management of gastroparesis is listed in Table 2.

Table 2. Treatment of Gastroparesis8 Prokinetics

Antiemetics

Adjuvants

»» Metoclopramide (central and peripheral dopamine-2 receptor antagonist, only FDA-approved drug for gastroparesis) »» Domperidone (peripheral dopamine-2 receptor antagonist, investigational drug) »» Erythromycin (motilin receptor agonist)

»» Compazine (phenothiazine derivatives) »» Ondansetron (serotonin 5-HT3 receptor antagonist) »» Metoclopramide and domperidone (dopamine receptor antagonist) »» Diphenhydramine, promethazine, meclizine (H1 receptor antagonist) »» Lorazepam (benzodiazepines)

»» Nortriptyline, amitriptyline (tricyclic antidepressants) »» Gabapentin, levetiracetam (anticonvulsants)

e e

INT RV NTiONS Botox injection of the pylorus to relax its resistance may be considered to decrease gastric emptying. However, randomized controlled trials failed to validate the usefulness of this injection.8 ● Gastric electrical stimulation (GES): in patients with refractory nausea and vomiting in gastroparesis, the FDA approved implantation of a low energy and high frequency GES device in 2000. ●

Note: No specific study has evaluated the use of these adjuvants. However, these agents have been used with reasonable success for neuropathic pain.

Electrodes are connected to the antrum that stimulate autonomic vagal function allowing for more gastric accommodation, and possibly modulate gastric biomechanical activity. This modality has been shown to improve quality of life and nutritional status. The downside of GES is that it is invasive and predisposes to complications related to implantation of the electrode and the generator.8

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SOPHAG AL COMPLiCATiONS OF DiAB T S: clinical overview In long-standing diabetes, the myenteric plexus that constitutes the autonomic innervation of the esophagus could be affected causing diabetic neuropathy as seen in gastroparesis. This neuronal degeneration along with structural remodeling of the esophageal musculature could result in spontaneous contractions, abnormal peristalsis, and reduced lower esophageal sphincter tone predisposing diabetic (DM I and II ) patients to develop esophageal dysmotility, dysphagia, GERD, and heartburns. The prevalence of esophageal dysmotility and GERD were shown to be as high as 63% and 41%, respectively. However, only a minority of patients seem to present with symptoms of dysphagia and heartburn.9-11

DiAGNOSiS Tests used in the diagnosis are12: Esophageal pH monitoring and conventional manometry ● Wireless Bravo ® pH capsule (newer modality with impedance pH monitoring) ● Catheter-based technique (detects acid and nonacid reflux in the esophagus) ●

Q2 | 2014

High-resolution manometry (uses multipressure sensors that project spatiotemporal esophageal pressure changes) ● Impedance manometry (direct manometric measurement of a bolus) ●

www.painweek.org | PWJ | 51

DIABETES&PAIN

TR ATM NT Table 3 summarizes treatment options. Table 3. Treatment of Esophageal Complications of Diabetes12 Prokinetic drugs

Metoclopramide and proton pump inhibitors

Erythromycin

2-week course reduces mean esophageal transit and gastric emptying time in DM II

Consumption of sufficient fluids

Prevents pill-induced esophagitis

NONALCOHOLiC FATTY LiV R DiS AS (NAFLD): clinical overview

e e

NAFLD commonly develops in obese patients as well as those with DM II. It is defined as hepatic steatosis confirmed by histology and imaging in the absence of secondary causes like significant alcohol intake, steatogenic medications, or hereditary causes.13 NAFLD is the most common cause of chronic liver disease in North America. Most patients remain asymptomatic, while some present with malaise and right upper quadrant pain. Acanthosis nigricans may be present in children. Hepatomegaly is usually the only sign in patients with NAFLD.12

DiAGNOSiS The exclusion criteria to diagnose NAFLD are listed in Table 4. Confirmatory tests of NAFLD are shown in Table 5. Table 4. Exclusion Criteria for the Diagnosis of NAFLD12 Exclusion Criteria

Comment

Alcohol intake

>20 gm/day

Nutritional causes

Total parenteral nutrition and rapid weight loss

Metabolic

Glycogen storage disorders

Chronic hepatitis C

Especially genotype 3

Other chronic liver diseases

Autoimmune, Wilson’s, and hemochromatosis

Endocrine

Polycystic ovarian syndrome, hypopituitarism and hypothyroidism

TR ATM NT12 Lifestyle modification and weight loss ● Insulin sensitizing agents ● Vitamin E ●

52 | PWJ | www.painweek.org

Incretin mimetics Omega-3 fatty acids ● Bariatric surgery ● ●

Q2 | 2014

Table 5. Diagnosis of NAFLD12 Liver biopsy

Confirmatory diagnosis of NAFLD

Novel biomarker cytokeratin-18 fragment

78% sensitive and 87% specific

Transient elastography

Noninvasive measure of liver stiffness, high failure rate in obese individuals

NAFLD fibrosis score

Evaluate the presence of fibrosis in NAFLD by using 6 variables: »» Age »» BMI »» Hyperglycemia »» Platelet count »» Albumin »» Aspartate aminotransferase/alanine aminotransferase ratio: 90% sensitive and 60% specific to rule out 67% sensitive and 97% specific to rule in

eNTeROPATHY: clinical overview Autonomic neuropathy and fibrosis of intestinal musculature are common in patients with long-standing diabetes. This enteropathy could present as constipation (60%), diarrhea (due to small intestinal bacterial overgrowth [SIBO]), or fecal incontinence.11

DiAGNOSiS12 Tests for fecal incontinence: endoanal ultrasound, anorectal manometry

●

Hydrogen breath test for SIBO: 40% sensitive and 80% specific

TR ATM NT Table 6 summarizes the treatment options of enteropathy. Table 6. Treatment of Enteropathy12 Constipation

Diarrhea

»» Symptom relief, correction »» Hydration, exercise, increased fiber of fluid and electrolyte »» Lactulose and osmotic laxatives for deficits, improvement of severe cases nutrition and glycemic »» Lubiprostone stimulates colonic control water and electrolyte secretion »» Antidiarrheal agents should through activation of type 2 chloride be avoided; may precipitate channels in enterocytes »» Prucalopride, a selective 5-HT4-receptor toxic megacolon agonist enhances colonic transit

Q2 | 2014

Fecal Incontinence

SIBO

»» Loperamide

»» Rifaximin: shown to eradicate bacterial overgrowth in up to 84% of patients

www.painweek.org | PWJ | 53

DIABETES&PAIN

CONCLUSiON Chronic abdominal pain due to GI involvement in diabetes is prevalent, underdiagnosed, and a complex symptomatology to manage and treat. Hence, it is imperative for healthcare providers to have an in-depth understanding of this entity. While significant advances have been made in demonstrating the pathophysiology of gastroparesis, the treatment options are limited. Basic and clinical science research are warranted in formulating and validating drugs with specific targets: insulin-like growth factor-1, oxidation, ICC , n NOS, and immune cells.2 Further, ongoing regenerative medicine research could offer promising solutions in the future with respect to restoration of the deranged molecular and structural integrity of the GI system in diabetes.

References

1. Wild S, Roglic G, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047–1053. 2. Kashyap P, Farrugia G. Diabetic gastroparesis: what we have learned and had to unlearn in the past 5 years. Gut. 2010;59(12):1716–1726. 3. Chandrasekharan B, Srinivasan S. Diabetes and the enteric nervous system. Neurogastroenterol Motil. 2007;19(12):951–960. 4. Bytzer P, Talley NJ, Leemon M, et al. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. Arch Intern Med. 2001;161:1989–1996. 5. Kim JH, Park HS, Ko SY, et al. Diabetic factors associated with gastrointestinal symptoms in patients with type 2 diabetes. World J Gastroenterol. 2010;16(14):1782–1787. 6. Keld R, Kinsey L, Athwal V, et al. Pathogenesis, investigation and dietary and medical management of gastroparesis. J Hum Nutr Diet. 2011;24(5):421–430. 7. Panagoulias G, Tentolouris N, et al. Abdominal pain in an adult with type 2 diabetes: a case report. Cases J. 2008;1:154. 8. Tang DM , Friedenberg FK . Gastroparesis: approach, diagnostic evaluation, and management. Dis Mon. 2011;57(2):74–101. 9. Gustafsson RJ, Littorin B, Berntorp K, et al. Esophageal dysmotility is more common than gastroparesis in diabetes mellitus and is associated with retinopathy. Rev Diabet Stud. 2011;8:268–275. 10. Wang X, Pitchumoni CS, Chandrarana K, et al. Increased prevalence of symptoms of gastroesophageal reflux diseases in type 2 diabetics with neuropathy. World J Gastroenterol. 2008;14:709–712. 11. Lluch I, Ascaso JF, Mora F, al. Gastroesophageal reflux in diabetes mellitus. Am J Gastroenterol. 1999;94:919–924. 12. Krishnan B, Babu S, Walker J, et al. Gastrointestinal complications of diabetes mellitus. World J Diabetes. 2013;4(3):51–63. 13. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–2023.

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Q2 | 2014

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

with

Kevin L. Zacharoff MD, FACPE, FACIP, FAAP

Kevin L. Zacharoff is Faculty Clinical Instructor, at SUNY Stony Brook School of Medicine, Department of Preventive Medicine, in New York, and Director of Medical Affairs at Inflexxion, Inc.

56 | PWJ | www.painweek.org

Q2 | 2014

“When I was in junior high school, in print shop I printed up business cards that said Kevin Zacharoff, Young Doctor.” What inspired you to become a healthcare provider? I was that kid who wanted to be a doctor from the beginning—since I was 7 years old. When I was in junior high school, in print shop I printed up business cards that said Kevin Zacharoff, Young Doctor. I never had to worry about what my career was going to be, just how to get there. Why did you focus on pain management? When you’re treating someone for pain, there’s a certain connection between you and the patient that’s different than other medical conditions. It’s almost as if, at that given time, you have only one patient. It’s that focus that I like best. In all caps— FOCUS. I liked giving all of myself to one patient at a time. Who were your mentors? My mentors have always been my patients. There have been many times in my career that I got “schooled” about what I thought I had down to a science. I’ve had many professional people to look up to in my career, but the ones I remember most are the patients—they taught me the art of medicine. If you weren’t a healthcare provider, what would you be? A radio disc jockey. When the medical school applications went out, there was an application to the Connecticut School of Broadcasting standing by just in case. I was a DJ for 4 years in college and I love music.

Q2 | 2014

What is your most marked characteristic? What I want on my tombstone: that I care. It’s okay if nobody remembers me as the smartest, just the most caring. What do you consider your greatest achievement? Being a father to my daughter. Nothing else even comes close…except maybe being a good husband to my wonderful wife (she might read this...). What is your favorite language? Music. If you had to choose one book, one film, and one piece of music to take into space for an unde‑ termined amount of time, what would they be? The book would be Stephen King’s The Stand. The film would be One Flew Over the Cuckoo’s Nest. The song, Stairway to Heaven What would you like your legacy to be? That I treated people with respect more than not, that I was generous to a fault, and that I cared about everything I did. What is your motto? “I’d rather be me.”

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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).

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

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

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

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

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

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