PAINWeek Journal, Vol 3, Q2

vol. 3 q 2 2015

HORMONES: TESTING AND TREATMENT IN CHRONIC PAIN MANAGEMENTP.18 NIGHTMAREP.26 THE COMPLEX PAIN PATIENTP.36 MY ACHING FEETP.44

HYSINGLA™ ER:

The first and only once-daily hydrocodone with abuse-deterrent properties and no acetaminophen

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND CYTOCHROME P450 3A4 INTERACTION Addiction, Abuse, and Misuse HYSINGLA ER 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 HYSINGLA ER, 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 HYSINGLA ER. Monitor for respiratory depression, especially during initiation of HYSINGLA ER or following a dose increase.

Instruct patients to swallow HYSINGLA ER tablets whole; crushing, chewing, or dissolving HYSINGLA ER tablets can cause rapid release and absorption of a potentially fatal dose of hydrocodone [see Warnings and Precautions (5.2)].

Accidental Ingestion Accidental ingestion of even one dose of HYSINGLA ER, especially by children, can result in

a fatal overdose of hydrocodone [see Warnings and Precautions (5.2)].

Neonatal Opioid Withdrawal Syndrome Prolonged use of HYSINGLA ER 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)].

Cytochrome P450 3A4 Interaction The concomitant use of HYSINGLA ER with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.

In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration.

Monitor patients receiving HYSINGLA ER and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.11), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].

Please see Additional Warnings and Precautions on the following pages.

Please read Brief Summary of Full Prescribing Information on the following pages, including Boxed Warning.

Hysingla ER: The same opioid molecule your hydrocodone patients are familiar with

• •

One tablet daily provides 24 hours of hydrocodone delivery Formulated with properties intended to make the tablet more difficult to misuse and abuse – The in vitro data demonstrate that Hysingla ER has physical and chemical properties that are expected to deter intranasal and intravenous abuse. The data from the clinical abuse potential studies, along with support from the in vitro data, also indicate that Hysingla ER has physicochemical properties that are expected to reduce intranasal abuse and oral abuse when chewed –

• • •

However, abuse of Hysingla ER by the intravenous, intranasal, and oral routes is still possible

– With parenteral abuse, the inactive ingredients in Hysingla ER can result in death, local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury Proven effective in a clinical trial Contains no acetaminophen Flexibility of 7 dosage strengths: 20, 30, 40, 60, 80, 100, and 120 mg tablets – The starting dose for patients who are not opioid tolerant is Hysingla ER 20 mg orally every 24 hours.

Opioid-tolerant patients are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid. Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

INDICATIONS AND USAGE Hysingla ER (hydrocodone bitartrate) 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 risks of overdose and death with extended-release opioid formulations, reserve Hysingla ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

• Hysingla ER is not indicated as an as-needed analgesic.

CONTRAINDICATIONS • Hysingla ER 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 and gastrointestinal obstruction, hypersensitivity to any component of Hysingla ER or the active ingredient, hydrocodone bitartrate.

WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse • Hysingla ER contains hydrocodone, a Schedule II controlled substance. Hysingla ER exposes users to the risks of opioid addiction, abuse, and misuse.

As extended-release products such as Hysingla ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydrocodone present. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing

For more information, visit HysinglaER.com

Hysingla ER, and monitor all patients during therapy for the development of these behaviors or conditions.

Abuse or misuse of Hysingla ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the hydrocodone and can result in overdose and death.

Dosage and Administration • Hysingla ER tablets must be taken whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth.

Crushing, chewing, or dissolving Hysingla ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death.

Titration and Maintenance of Therapy • Continually re-evaluate patients receiving Hysingla ER to assess the maintenance of pain control and the relative incidence of adverse reactions as well as monitoring for the development of addiction, abuse, or misuse.

hydrocodone reengineered

Life-Threatening Respiratory Depression • Serious, life-threatening, or fatal respiratory depression has been reported with modified-release opioids, even when used as recommended, and if not immediately recognized and treated, may lead to respiratory arrest and death. The risk of respiratory depression is greatest during the initiation of therapy or following a dose increase; therefore, closely monitor patients for respiratory depression. Proper dosing and titration of Hysingla ER are essential. Overestimating the Hysingla ER dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of Hysingla ER, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone.

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

Interactions with Central Nervous System Depressants • Hypotension, profound sedation, coma, respiratory depression, or death may result if Hysingla ER is used concomitantly with other CNS depressants, including alcohol or illicit drugs that can cause CNS depression.

Start with a lower Hysingla ER dose than usual (i.e., 20-30% less), monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant.

Use in Elderly, Cachectic, and Debilitated Patients and Patients with Chronic Pulmonary Disease • Closely monitor elderly, cachectic, and debilitated patients, and patients with chronic obstructive pulmonary disease because of the increased risk of life-threatening respiratory depression. Consider the use of alternative non-opioid analgesics in patients with chronic obstructive pulmonary disease if possible.

Use in Patients with Head Injury and Increased Intracranial Pressure • Monitor patients closely who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or impaired consciousness). Opioids may obscure the clinical course in a patient with a head injury. Avoid the use of Hysingla ER in patients with impaired consciousness or coma.

Hypotensive Effect • Hysingla ER may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. Monitor patients during dose initiation or titration. In patients with circulatory shock, Hysingla ER

may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Hysingla ER in patients with circulatory shock.

Gastrointestinal Obstruction, Dysphagia, and Choking • Use caution when prescribing Hysingla ER for patients who have difficulty swallowing, or have underlying gastrointestinal disorders that may predispose them to obstruction, dysphagia, or choking. Consider use of an alternative analgesic in these patients.

Decreased Bowel Motility • Hysingla ER is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.

Monitor for decreased bowel motility in post-operative patients receiving opioids. The administration of Hysingla ER may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

Hydrocodone may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis.

Cytochrome P450 3A4 Inhibitors and Inducers • Concomitant use of CYP3A4 inhibitors may prolong opioid effects. Use with CYP3A4 inducers may cause lack of efficacy or development of withdrawal symptoms. If co-administration is necessary, evaluate patients frequently and consider dose adjustments until stable drug effects are achieved.

Driving and Operating Machinery • Hysingla ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.

Interaction with Mixed Agonist/Antagonist Opioid Analgesics • Avoid the use of mixed agonist/antagonist analgesics in patients who have received or are receiving Hysingla ER, as they may reduce the analgesic effect and/or precipitate withdrawal.

QTc Interval Prolongation • QTc prolongation has been observed following daily doses of 160 mg of Hysingla ER. Avoid use in patients with congenital QTc syndrome. This observation should be considered in making clinical decisions regarding patient monitoring when prescribing Hysingla ER in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong QTc interval. In patients who develop QTc prolongation, consider reducing the dose.

ADVERSE REACTIONS • Most common treatment-emergent adverse reactions (≥5%) reported by patients treated with Hysingla ER in the clinical trials were constipation, nausea, vomiting, fatigue, upper respiratory tract infection, dizziness, headache, and somnolence.

Please see Additional Warnings and Precautions on the preceding pages.

Please read Brief Summary of Full Prescribing Information on the following pages, including Boxed Warning.

©2015 Purdue Pharma L.P., Stamford, CT 06901-3431 B9935-A 4/15

BRIEF SUMMARY OF PRESCRIBING INFORMATION (For complete details please see the Full Prescribing Information and Medication Guide.)

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND CYTOCHROME P450 3A4 INTERACTION Addiction, Abuse, and Misuse HYSINGLA™ ER 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 HYSINGLA ER, 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 HYSINGLA ER. Monitor for respiratory depression, especially during initiation of HYSINGLA ER or following a dose increase. Instruct patients to swallow HYSINGLA ER tablets whole; crushing, chewing, or dissolving HYSINGLA ER tablets can cause rapid release and absorption of a potentially fatal dose of hydrocodone [see Warnings and Precautions (5.2)].

Accidental Ingestion Accidental ingestion of even one dose of HYSINGLA ER, especially by children, can result in a fatal overdose of hydrocodone [see Warnings and Precautions (5.2)].

Neonatal Opioid Withdrawal Syndrome Prolonged use of HYSINGLA ER 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)].

Cytochrome P450 3A4 Interaction The concomitant use of HYSINGLA ER with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Monitor patients receiving HYSINGLA ER and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.11), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].

4 CONTRAINDICATIONS HYSINGLA ER 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 and gastrointestinal obstruction • Hypersensitivity to any component of HYSINGLA ER or the active ingredient, hydrocodone bitartrate 5 WARNINGS AND PRECAUTIONS 5.1 Addiction, Abuse, and Misuse HYSINGLA ER contains hydrocodone, a Schedule II controlled substance.

As an opioid, HYSINGLA ER exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9.1)]. As extended-release products such as HYSINGLA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydrocodone present. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed HYSINGLA ER 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 HYSINGLA ER, and monitor all patients receiving HYSINGLA ER 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 HYSINGLA ER for the proper management of pain in any given patient. Abuse or misuse of HYSINGLA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the hydrocodone and can result in overdose and death [see Drug Abuse and Dependence (9.1), and Overdosage (10)]. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing HYSINGLA ER. 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, life-threatening, 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 (10.2)]. 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 HYSINGLA ER, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with HYSINGLA ER and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of HYSINGLA ER are essential [see Dosage and Administration (2.1, 2.2)]. Overestimating the HYSINGLA ER dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of HYSINGLA ER, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone.

5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of HYSINGLA ER 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.

5.4 Interactions with Central Nervous System Depressants Hypotension, profound sedation, coma, respiratory depression, and death may result if HYSINGLA ER 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 HYSINGLA ER 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 HYSINGLA ER is made, start with a lower HYSINGLA ER dose than usual (i.e., 20-30% less), 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 HYSINGLA ER and when HYSINGLA ER 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 preexisting respiratory depression for respiratory depression, particularly when initiating therapy and titrating with HYSINGLA ER, as in these patients, even usual therapeutic doses of HYSINGLA ER 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 Use in Patients with Head Injury and Increased Intracranial Pressure In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the possible respiratory depressant effects of opioid analgesics and their potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Furthermore, opioid analgesics can produce effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries. Monitor patients closely who may be susceptible to the intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury. Avoid the use of HYSINGLA ER in patients with impaired consciousness or coma. 5.8 Hypotensive Effect HYSINGLA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Monitor these patients for signs of hypotension after initiating or titrating the dose of HYSINGLA ER. In patients with circulatory shock, HYSINGLA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of HYSINGLA ER in patients with circulatory shock. 5.9 Gastrointestinal Obstruction, Dysphagia, and Choking In the clinical studies with specific instructions to take HYSINGLA ER with adequate water to swallow the tablet, 11 out of 2476 subjects reported difficulty swallowing HYSINGLA ER. These reports included esophageal obstruction, dysphagia, and choking, one of which had required medical intervention to remove the tablet [see Adverse Reactions (6)]. Instruct patients not to pre-soak, lick, or otherwise wet HYSINGLA ER 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 the mouth [see Patient Counseling Information (17)] (17)]. Patients with underlying gastrointestinal disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen are at greater risk of developing these complications. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying gastrointestinal disorders resulting in a small gastrointestinal lumen. 5.10 Decreased Bowel Motility HYSINGLA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. Opioids diminish propulsive peristaltic waves in the gastrointestinal tract and decrease bowel motility. Monitor for decreased bowel motility in post-operative patients receiving opioids.

The administration of HYSINGLA ER may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Hydrocodone may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis. 5.11 Cytochrome P450 3A4 Inhibitors and Inducers Since the CYP3A4 isoenzyme plays a major role in the metabolism of HYSINGLA ER, drugs that alter CYP3A4 activity may cause changes in clearance of hydrocodone which could lead to changes

in hydrocodone plasma concentrations. The clinical results with CYP3A4 inhibitors show an increase in hydrocodone plasma concentrations and possibly increased or prolonged opioid effects, which could be more pronounced with concomitant use of CYP3A4 inhibitors. The expected clinical result with CYP3A4 inducers is a decrease in hydrocodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. If co-administration is necessary, caution is advised when initiating HYSINGLA ER 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 (7.1)]. 5.12 Driving and Operating Machinery HYSINGLA ER may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Peak blood levels of hydrocodone may occur 14 – 16 hours (range 6 – 30 hours) after initial dosing of HYSINGLA ER tablet administration. Blood levels of hydrocodone, in some patients, may be high at the end of 24 hours after repeated-dose administration. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of HYSINGLA ER and know how they will react to the medication [see Clinical Pharmacology (12.3)]. 5.13 Interaction with Mixed Agonist/Antagonist Opioid Analgesics Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) in patients who have received, or are receiving, a course of therapy with a full opioid agonist analgesic, including HYSINGLA ER. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. 5.14 QTc Interval Prolongation QTc prolongation has been observed with HYSINGLA ER following daily doses of 160 mg [see Clinical Pharmacology (12.2)]. This observation should be considered in making clinical decisions regarding patient monitoring when prescribing HYSINGLA ER in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QTc interval. HYSINGLA ER should be avoided in patients with congenital long QT syndrome. In patients who develop QTc prolongation, consider reducing the dose by 33 – 50%, or changing to an alternate analgesic.

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)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)] • Interactions with Other CNS Depressants [see Warnings and Precautions (5.4)] • Hypotensive Effects [see Warnings and Precautions (5.8)] • Gastrointestinal Effects [see Warnings and Precautions (5.9, 5.10)] 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 1,827 patients were treated with HYSINGLA ER in controlled and open-label chronic pain clinical trials. Five hundred patients were treated for 6 months and 364 patients were treated for 12 months. The clinical trial population consisted of opioid-naïve and opioid-experienced patients with persistent moderate to severe chronic pain. The common adverse reactions (≥2%) reported by patients in clinical trials comparing HYSINGLA ER (20-120 mg/day) with placebo are shown in Table 2 below: Table 2: Adverse Reactions Reported in ≥2% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Naïve and Opioid-Experienced Patients Open-label Titration Period MedDRA Preferred Term Nausea Constipation Vomiting Dizziness Headache Somnolence Fatigue Pruritus Tinnitus Insomnia Decreased appetite Influenza

Double-blind Treatment Period

(N=905) (%)

Placebo (N=292) (%)

HYSINGLA ER (N=296) (%)

16 9 7 7 7 5 4 3 2 2 1 1

5 2 3 2 2 1 1 <1 1 2 1 1

8 3 6 3 2 1 1 0 2 3 2 3

The adverse reactions seen in controlled and open-label chronic pain 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 HYSINGLA ER in the chronic pain clinical trials were constipation, nausea, vomiting, fatigue, upper respiratory tract infection, dizziness, headache, somnolence.

The common (≥1% to <5%) adverse events reported by patients treated with HYSINGLA ER in the chronic pain clinical trials organized by MedDRA (Medical Dictionary for Regulatory Activities) System Organ Class were: Ear and labyrinth disorders tinnitus Gastrointestinal disorders abdominal pain, abdominal pain upper, diarrhea, dry mouth, dyspepsia, gastroesophageal reflux disease General disorders and administration chest pain, chills, edema site conditions peripheral, pain, pyrexia

Infections and infestations

Injury, poisoning and procedural complications Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders

bronchitis, gastroenteritis, gastroenteritis viral, influenza, nasopharyngitis, sinusitis, urinary tract infection fall, muscle strain

decreased appetite arthralgia, back pain, muscle spasms, musculoskeletal pain, myalgia, pain in extremity Nervous system disorders lethargy, migraine, sedation Psychiatric disorders anxiety, depression, insomnia Respiratory, thoracic and mediastinal cough, nasal congestion, disorders oropharyngeal pain Skin and subcutaneous tissue disorders hyperhidrosis, pruritus, rash Vascular disorders hot flush, hypertension Other less common adverse reactions that were seen in <1% of the patients in the HYSINGLA ER chronic pain clinical trials include the following in alphabetical order: abdominal discomfort, abdominal distention, agitation, asthenia, choking, confusional state, depressed mood, drug hypersensitivity, drug withdrawal syndrome, dysphagia, dyspnea, esophageal obstruction, flushing, hypogonadism, hypotension, hypoxia, irritability, libido decreased, malaise, mental impairment, mood altered, muscle twitching, edema, orthostatic hypotension, palpitations, presyncope, retching, syncope, thinking abnormal, thirst, tremor, and urinary retention.

7 DRUG INTERACTIONS 7.1 Drugs Affecting Cytochrome P450 Isoenzymes Inhibitors of CYP3A4 Co-administration of HYSINGLA ER with ketoconazole, a strong CYP3A4 inhibitor, significantly increased the plasma concentrations of hydrocodone. Inhibition of CYP3A4 activity by inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may prolong opioid effects. Caution is advised when initiating therapy with, currently taking, or discontinuing CYP3A4 inhibitors. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)]. Inducers of CYP3A4 CYP3A4 inducers may induce the metabolism of hydrocodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in hydrocodone plasma concentrations, lack of efficacy or, possibly, development of a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. If co-administration with HYSINGLA ER is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)]. 7.2 Central Nervous System Depressants The concomitant use of HYSINGLA ER 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 HYSINGLA ER 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 Warnings and Precautions (5.4)].

7.3 Interactions with Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonist analgesics (buprenorphine) may reduce the analgesic effect of HYSINGLA ER or precipitate withdrawal symptoms in these patients. Avoid the use of mixed agonist/antagonist and partial agonist analgesics in patients receiving HYSINGLA ER. 7.4 MAO Inhibitors HYSINGLA ER is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

No specific interaction between hydrocodone and MAO inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate. 7.5 Anticholinergics Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioid analgesics may increase the risk of urinary retention or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention and constipation in addition to respiratory and central nervous system depression when HYSINGLA ER is used concurrently with anticholinergic drugs. 7.6 Strong Laxatives Concomitant use of HYSINGLA ER with strong laxatives (e.g., lactulose), that rapidly increase gastrointestinal motility, may decrease hydrocodone absorption and result in decreased hydrocodone plasma levels. If HYSINGLA ER is used in these patients, closely monitor for the development of adverse events as well as changing analgesic requirements.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of HYSINGLA ER use during pregnancy. Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. In animal reproduction studies with hydrocodone in rats and rabbits no embryotoxicity or teratogenicity was observed. However, reduced pup survival rates, reduced fetal/pup body weights, and delayed ossification were observed at doses causing maternal toxicity. In all of the studies conducted, the exposures in animals were less than the human exposure (see Animal Data). HYSINGLA ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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)]. Data Animal Data No evidence of embryotoxicity or teratogenicity was observed after oral administration of hydrocodone throughout the period of organogenesis in rats and rabbits at doses up to 30 mg/kg/day (approximately 0.1 and 0.3-fold, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons).

However, in these studies, reduced fetal body weights and delayed ossification were observed in rat at 30 mg/kg/day and reduced fetal body weights were observed in in rabbit at 30 mg/kg/day (approximately 0.1 and 0.3fold, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons). In a pre- and post-natal development study pregnant rats were administered oral hydrocodone throughout the period of gestation and lactation. At a dose of 30 mg/kg/day decreased pup viability, pup survival indices, litter size and pup body weight were observed. This dose is approximately 0.1-fold the human hydrocodone dose of 120 mg/ day based on AUC exposure comparisons. 8.2 Labor and Delivery Opioids cross the placenta and may produce respiratory depression in neonates.

HYSINGLA ER is not recommended for use in women immediately prior to and during labor, when use of shorter acting analgesics or other analgesic techniques are more appropriate. HYSINGLA ER may prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. 8.3 Nursing Mothers Hydrocodone is present in human milk.

Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue HYSINGLA ER, taking into account the importance of the drug to the mother.

Infants exposed to HYSINGLA ER through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 8.4 Pediatric Use The safety and effectiveness of HYSINGLA ER in pediatric patients have not been established. Accidental ingestion of a single dose of HYSINGLA ER in children can result in a fatal overdose of hydrocodone [see Warnings and (5.2)] HYSINGLA ER gradually forms a viscous hydrogel (i.e., a Precautions (5.2)]. gelatinous mass) when exposed to water or other fluids. Pediatric patients may be at increased risk of esophageal obstruction, dysphagia, and choking because of a smaller gastrointestinal lumen if they ingest HYSINGLA ER [see Warnings and Precautions (5.9)]. 8.5 Geriatric Use In a controlled pharmacokinetic study, elderly subjects (greater than 65 years) compared to young adults had similar plasma concentrations of hydrocodone [see Clinical Pharmacology (12.3)]. Of the 1827 subjects exposed to HYSINGLA ER in the pooled chronic pain studies, 241 (13%) were age 65 and older (including those age 75 and older), while 42 (2%) were age 75 and older.

In clinical trials with appropriate initiation of therapy and dose titration, no untoward or unexpected adverse reactions were seen in the elderly patients who received HYSINGLA ER. Hydrocodone may cause confusion and oversedation in the elderly. In addition, because of the greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease and concomitant use of CNS active medications, start elderly patients on low doses of HYSINGLA ER and monitor closely for adverse events such as respiratory depression, sedation, and confusion. 8.6 Hepatic Impairment No adjustment in starting dose with HYSINGLA ER is required in patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment may have higher plasma concentrations than those with normal hepatic function. Initiate therapy with 1/2 the initial dose of HYSINGLA ER in patients with severe hepatic impairment and monitor closely for adverse events such as respiratory depression [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment No dose adjustment is needed in patients with mild renal impairment. Patients with moderate or severe renal impairment or end stage renal disease have higher plasma concentrations than those with normal renal function. Initiate therapy with 1/2 the initial dose of HYSINGLA ER in these patients and monitor closely for adverse events such as respiratory depression [see Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance HYSINGLA ER contains hydrocodone bitartrate, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. HYSINGLA ER can be abused and is subject to misuse, abuse, addiction and criminal diversion. The high drug content in the extended-release formulation adds to the risk of adverse outcomes from abuse and misuse. 9.2 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 over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get “high,” or the use of steroids for performance enhancement and muscle build up. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common to addicts and drug abusers. Drug seeking tactics include, but are not limited to, 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, people with untreated addiction, and criminals seeking drugs to sell. 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. HYSINGLA ER can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by 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 limit abuse of opioid drugs. 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 is increased with concurrent use of HYSINGLA ER with alcohol or other central nervous system depressants. Risks Specific to Abuse of HYSINGLA ER HYSINGLA ER is for oral use only. Abuse of HYSINGLA ER poses a risk of overdose and death.. Taking cut, broken, chewed, crushed, or dissolved HYSINGLA ER increases the risk of overdose and death. With parenteral abuse, the inactive ingredients in HYSINGLA ER 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. Abuse Deterrence Studies Summary The in vitro data demonstrate that HYSINGLA ER has physical and chemical properties that are expected to deter intranasal and intravenous abuse. The data from the clinical abuse potential studies, along with support from the in vitro data, also indicate that HYSINGLA ER has physicochemical properties that are expected to reduce intranasal abuse and oral abuse when chewed. However, abuse of HYSINGLA ER by the intravenous, intranasal, and oral routes is still possible. Additional data, including epidemiological data, when available, may provide further information on the impact of HYSINGLA ER on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate. HYSINGLA ER contains hydrocodone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit, including fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. HYSINGLA ER can be abused and is subject to misuse, addiction, and criminal diversion [See Warnings and Precautions (5.1) and Drug Abuse and Dependence (9)]. 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. HYSINGLA ER should be discontinued by a gradual downward titration [see Dosage and Administration (2.6)]. If HYSINGLA ER is abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, 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 Warnings and Precautions (5.3) and Use in Specific Populations (8.3)].

10 OVERDOSAGE 10.1 Symptoms 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)]. 10.2 Treatment In the treatment of HYSINGLA ER overdosage, primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. The opioid antagonist naloxone hydrochloride is a specific antidote against respiratory depression that may result from opioid overdosage. Nalmefene is an alternative opioid antagonist, which may be administered as a specific antidote to respiratory depression resulting from opioid overdose. Since the duration of action of HYSINGLA ER may exceed that of the antagonist, keep the patient under continued surveillance and administer repeated doses of the antagonist according to the antagonist labeling, 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 HYSINGLA ER. 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 antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

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

Purdue Pharma L.P. Stamford, CT 06901-3431 ©2015, Purdue Pharma L.P. U.S. Patent Numbers: 6,488,963; 6,733,783; 8,309,060; 8,361,499; 8,529,948; 8,551,520; 8,647,667 and 8,808,740.

This brief summary is based on Hysingla ER Prescribing Information 303511-0C, Revised 02/2015 (A)

Jan 30 â&#x20AC;&#x201C; Feb 6, 2016

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CONTENTS / PWJ / Q2 / 2015 14 | EXECUTIVE EDITOR’S LETTER by kevin l. Zacharoff

FEATURES

18 | KEY TOPIC

HORMONES: testing and treatment in chronic pain management by forest Tennant

26 | CLINICAL CONUNDRUM NIGHTMARE

by gary w. Jay

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THE COMPLEX PAIN PATIENT

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by darren McCoy

10 | PWJ | www.painweek.org

Q2 | 2015

RELIstoR helps provide chronic non-cancer pain patients with reliable and rapid relief from opioid-induced constipation–without compromising analgesia.1,2 • 6 out of 10 RELISTOR® (methylnaltrexone bromide) patients had at least 3 Spontaneous Bowel Movements (SBMs) per week1 • One-third of patients taking RELISTOR experienced an SBM within 4 hours of their first dose1 IndIcatIons RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain.

RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with 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 RELISTOR® (methylnaltrexone bromide) Subcutaneous Injection is contraindicated in patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation.

Cases of gastrointestinal perforation have been reported in adult patients with opioid-induced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR

in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom.

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

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

Avoid concomitant use of RELISTOR with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.

RELISTOR may precipitate opioid withdrawal in a fetus and should be used during pregnancy only if the potential benefit justifies the potential

risk to the fetus. In nursing mothers, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

In the clinical study in adult patients with opioid-induced constipation and chronic non-cancer pain, the most common adverse reactions (≥ 1%) were abdominal pain, nausea, diarrhea, hyperhidrosis, hot flush, tremor, and chills.

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

Please see Brief Summary of complete Prescribing Information for RELISTOR on the adjacent page.

References 1. Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with chronic nonmalignant pain: a randomized controlled study. J Pain. 2011;12(5):554-562.

2. RELISTOR® (methylnaltrexone bromide) Prescribing Information, Salix Pharmaceuticals, Inc. www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 For additional information, call: 1-866-669-SLXP (7597) To report adverse events, call: 1-800-508-0024 ©2015 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. REL-US-0099 v.3

The following is a brief summary only; see full Prescribing Information for complete product information.

INDICATIONS AND USAGE Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain.

Opioid-Induced Constipation in Adult Patients with Advanced Illness RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.

Limitation of use: Use of RELISTOR beyond four months has not been studied in the advanced illness population.

CONTRAINDICATIONS RELISTOR is contraindicated in patients with known or suspected gastrointestinal obstruction and patients at risk of recurrent obstruction, due to the potential for gastrointestinal perforation.

WARNINGS AND PRECAUTIONS Gastrointestinal Perforation Cases of gastrointestinal perforation have been reported in adult patients with opioid-induced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom.

Severe or Persistent Diarrhea If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their healthcare provider.

Opioid Withdrawal Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia. Take into account the overall risk-benefit profile when using RELISTOR in such patients. Monitor for adequacy of analgesia and symptoms of opioid withdrawal in such patients.

ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain The safety of RELISTOR was evaluated in a double-blind, placebo-controlled trial in adult patients with opioid-induced constipation and chronic non-cancer pain receiving opioid analgesia.

This study (Study 1) included a 4-week, double-blind, placebo controlled period in which adult patients were randomized to receive RELISTOR 12 mg once daily (150 patients) or placebo (162 patients).

After 4 weeks of double-blind treatment, patients began an 8-week open-label treatment period during which RELISTOR 12 mg was administered less frequently than the recommended dosage regimen of 12 mg once daily.

Adverse reactions in adult patients with opioid-induced constipation and chronic non-cancer pain receiving RELISTOR are shown in the following table. The adverse reactions in the table below may reflect symptoms of opioid withdrawal.

Adverse Reactions* in 4-Week Double-Blind, PlaceboControlled Period of Clinical Study of RELISTOR in Adult Patients with Opioid-Induced Constipation and Chronic Non-Cancer Pain RELISTOR Placebo 12 mg once daily n = 162 n = 150 Abdominal Pain 21% 6% Nausea 9% 6% Diarrhea 6% 4% Hyperhidrosis 6% 1% Hot Flush 3% 2% Tremor 1% < 1% Chills 1% 0% * Adverse reactions occurring in ≥ 1 % of patients receiving RELISTOR 12 mg once daily and at an incidence greater than placebo.

During the 4-week double-blind period, in patients with opioid-induced constipation and chronic non-cancer pain that received RELISTOR 12 mg every other day, there was a higher incidence of adverse reactions, including nausea (12%), diarrhea (12%), vomiting (7%), tremor (3%), feeling of body temperature Adverse Reaction

change (3%), piloerection (3%), and chills (2%) as compared to daily RELISTOR dosing. Use of RELISTOR 12 mg every other day is not recommended in patients with OIC and chronic non-cancer pain. The rates of discontinuation due to adverse reactions during the double-blind period (Study 1) were higher in the RELISTOR once daily (7%) than the placebo group (3%). Abdominal pain was the most common adverse reaction resulting in discontinuation from the double-blind period in the RELISTOR once daily group (2%).

The safety of RELISTOR was also evaluated in a 48-week, open-label, uncontrolled trial in 1034 adult patients with opioid-induced constipation and chronic non-cancer pain (Study 2).

Patients were allowed to administer RELISTOR 12 mg less frequently than the recommended dosage regimen of 12 mg once daily, and took a median of 6 doses per week. A total of 624 patients (60%) completed at least 24 weeks of treatment and 477 (46%) completed the 48-week study. The adverse reactions seen in this study were similar to those observed during the 4-week double-blind period of Study 1. Additionally, in Study 2, investigators reported 4 myocardial infarctions (1 fatal), 1 stroke (fatal), 1 fatal cardiac arrest and 1 sudden death. It is not possible to establish a relationship between these events and RELISTOR. Opioid-Induced Constipation in Adult Patients with Advanced Illness The safety of RELISTOR was evaluated in two, double-blind, placebo-controlled trials in adult patients with opioid-induced constipation and advanced illness receiving palliative care: Study 3 included a single dose, double blind, placebo-controlled period, whereas Study 4 included a 14-day multiple dose, double-blind, placebo-controlled period.

The most common (≥5%) adverse reactions in adult patients with opioid-induced constipation and advanced illness receiving RELISTOR are shown in the following table.

Adverse Reactions from all Doses in Double-Blind, PlaceboControlled Clinical Studies of RELISTOR in Adult Patients with Opioid-Induced Constipation and Advanced Illness* Adverse RELISTOR Placebo Reaction n = 165 n = 123 Abdominal Pain 29% 10% Flatulence 13% 6% Nausea 12% 5% Dizziness 7% 2% Diarrhea 6% 2% * Adverse reactions occurring in ≥ 5 % of patients receiving all doses of RELISTOR (0.075, 0.15, and 0.30 mg/kg/dose) and at an incidence greater than placebo.

The rates of discontinuation due to adverse events during the double-blind placebo controlled clinical trials (Study 3 and Study 4) were comparable between RELISTOR (1%) and placebo (2%).

Postmarketing Experience The following adverse reactions have been identified during post-approval use of RELISTOR. Because they are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal Perforation, cramping, vomiting General Disorders and Administrative Site Disorders Diaphoresis, flushing, malaise, pain. Cases of opioid withdrawal have been reported.

DRUG INTERACTIONS Other Opioid Antagonists Avoid concomitant use of RELISTOR with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.

Drugs Metabolized by Cytochrome P450 Isozymes In healthy subjects, a subcutaneous dose of 0.30 mg/kg of methylnaltrexone did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies with RELISTOR in pregnant women. The use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of intravenous methylnaltrexone during organogenesis in rats and rabbits at doses up to 20 times and 26 times, respectively, the maximum recommended human dose (MRHD) of 0.2 mg/kg/day.

RELISTOR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers It is not known whether RELISTOR is present in human milk.

However, methylnaltrexone bromide is present in rat milk. Because of the potential for serious adverse reactions, including opioid withdrawal, in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of RELISTOR have not been established in pediatric patients.

In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs such as convulsions,

tremors and labored breathing were observed, and the juvenile rats were found to be more sensitive to the adverse effects of methylnaltrexone bromide when compared to adult animals.

Juvenile dogs administered intravenous methylnaltrexone bromide for 13 weeks had a toxicity profile similar to adult dogs.

Geriatric Use In the double-blind studies, a total of 118 (14%) patients aged 65-74 years (79 methylnaltrexone bromide, 39 placebo) and a total of 108 (13%) patients aged 75 years or older (64 methylnaltrexone bromide, 44 placebo) were enrolled. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Based on pharmacokinetic data, and safety and efficacy data from controlled clinical trials, no dose adjustment based on age is recommended.

Renal Impairment No dose adjustment is required in patients with mild or moderate renal impairment. Dose reduction by one-half is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault).

Hepatic Impairment No dose adjustment is required for patients with mild or moderate hepatic impairment.

OVERDOSAGE A study of healthy volunteers noted orthostatic hypotension associated with a dose of 0.64 mg/kg administered as an intravenous bolus. Monitor for signs or symptoms of orthostatic hypotension and initiate treatment as appropriate.

If a patient on opioid therapy receives an overdose of RELISTOR, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms such as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect. Base treatment on the degree of opioid withdrawal symptoms, including changes in blood pressure and heart rate, and on the need for analgesia.

PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Administration Advise all patients to: • Inject RELISTOR subcutaneously in the upper arm, abdomen or thigh. Do not inject at the same spot each time (rotate injection sites).

• Safely dispose of needles by following the sharps disposal recommendations described in the RELISTOR Instructions for Use. • Be within close proximity to toilet facilities once RELISTOR is administered.

• Discontinue RELISTOR if treatment with the opioid pain medication is also discontinued.

Advise chronic non-cancer pain patients receiving RELISTOR for opioid-induced constipation to: • Discontinue all maintenance laxative therapy prior to initiation of RELISTOR. Laxative(s) can be used as needed if there is a suboptimal response to RELISTOR after three days.

• Inject one dose every day.

• Inform their healthcare provider if their opioid regimen is changed, to avoid adverse reactions, such as diarrhea.

Advise patients with advanced illness receiving RELISTOR for opioid-induced constipation to: • Inject one dose every other day, as needed, but no more frequently than one dose in a 24-hour period.

Gastrointestinal Perforation Advise patients to discontinue RELISTOR and to promptly seek medical attention if they develop unusually severe, persistent, or worsening abdominal pain.

Severe or Persistent Diarrhea Advise patients to discontinue RELISTOR if they experience severe or persistent diarrhea.

Opioid Withdrawal Advise patients that symptoms consistent with opioid withdrawal may occur while taking RELISTOR, including sweating, chills, diarrhea, abdominal pain, anxiety, and yawning.

Pregnancy Advise females of reproductive potential, who become pregnant or are planning to become pregnant that the use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood brain barrier.

Nursing Advise females who are nursing against breastfeeding during treatment with RELISTOR due to the potential for opioid withdrawal in nursing infants.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

To report adverse events, a product complaint, or for additional information, call: 1-800-508-0024.

Manufactured for: Under License from:

Salix Pharmaceuticals, Inc. Raleigh, NC 27615

Progenics Pharmaceuticals, Inc. Tarrytown, NY 10591

REL-RALAB56-102014

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painweekend.org

Live conference

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SAN Di GO CA March 7 ATLANTA GA March 14 SANTA CLARA CA March 28 HARTFORD CT April 11

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RAL iGH-DURHAM NC* April 18–19 COLUMBUS OH April 25 TAMPA FL* May 2–3 NASHViLL T N* June 6–7

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D NV R CO June 13 KANSAS CiTY MO June 27 N W ORL ANS LA September 26 SHORT HiLLS NJ October 3

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This activity is provided by Global Education Group. 7.o AMA Category 1 Credits™.

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MiLWAUK W I October 17 BALTiMOR M D* October 24–25 L XiNGTON KY November 7 HOUSTON TX November 14

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KEVIN L.

ZACHAROFF MD, FACPE, FACIP, FAAP

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with chronic pain, the circumstances can indeed be similar, and sometimes things related to pain and its symptomology may not be what they seem. Dr. Jay successfully drives home the point that in addition to all of the diagnostics and workup that might be done, it’s very important to look at social interaction as well, and that “Keeping one’s eyes open to what is happening in the family/relationship can alert you to tell-tale signs of things that might otherwise not be realized, or might be overlooked.” This captivating case study successfully drives that point home.

In Darren McCoy’s article on the complex pain patient, he reminds us that no two patients are the same, and that treating pain is very different than other models of medical treatment such as hypertension and diabetes. Most of us probably characterize “complex” patients as those who have multiple medical problems or multiple comorbidities. However, the physical, social, and behavioral variables that patients may have can lead to a high level of complexity as well.

Cookie cutter approaches don’t work; considerations for simplifying these complexities are welcome and offered in this article. Remember, pain is one of the few medical conditions where patients get to have a say in terms of what constitutes a successful treatment outcome.

Liana Seldin writes about something we have probably all seen many times not only in our patient encounters, but also ourselves. Let’s be real: who hasn’t had foot or ankle pain? As I age, I know that my elcome to the summer issue of PWJ! As we move into the summer bones and joints “talk to me more frequently” as my internist puts it. season, it is impossible for me to not start to get excited about the With 26 bones, 33 joints, and more than 110 muscles, tendons, and upcoming national PAINWeek conference on the other side of ligaments in the foot, it’s no surprise that this “marvel of engineering” summer, at The Cosmopolitan of Las Vegas September 8–12. I hope can easily become a source of pain if the fine balance of this frameto see you there and get a chance to chat about many things, includ- work is disrupted. Dr Seldin’s article provides an excellent review of ing PWJ and the variety of important topics covered in this issue. common types of foot-related pain, as well as their prevention and treatment. Having a podiatric perspective on this very common type I often think back to my days in training. About endocrinology, and of acute and chronic pain is a welcome addition to the PWJ. how complex the endocrine system was (or at least was to me), and how impressed I was with the intelligence and fund of knowledge of Lastly but in no way least in terms of importance is the Pundit Profile. pretty much any endocrinologist I encountered. I also took comfort Those of you not new to PWJ know about our profiles of “movers and in the fact that my career in anesthesiology and pain medicine would shakers” in our world of chronic pain and its management. For those likely enable me to steer clear of this often challenging “hormone of you reading this as your inaugural issue, please do check it out; it’s subject.” Wrong! In this issue, one of the clinicians in pain manage- a fun and insightful glimpse of people in pain management—their ment whom I hold in highest regard, Forest Tennant, sheds light on tastes, thoughts, mentors, and mantras. This issue’s Pundit Profile the fact that hormones are indeed relevant in the management and is Beth Darnall. Without giving anything away, let me say that Dr. treatment of chronic pain, and that hormone testing and treatment Darnall shows her human side and puts patients first. She is truly is “emerging as a standard practice” in the field. Of course, in this worthy of getting to know better. domain, we need to consider the impact that chronic opioid therapy can have in hormonal balance as well. In his article, Dr. Tennant Enjoy the Profile and the entire issue! I hope you find it satisfying, makes the simple case in his typical fashion that “Pain affects hor- pertinent, and most of all find some things that can impact you and mones” as do some of its treatments. Run from the endocrine system your patients in a positive way. you may try, but if you treat patients with chronic pain you need to read this article to understand the dynamics and the relationship — KEVIN L. ZACHAROFF between hormones, chronic pain, and its treatment.

Gary Jay has written an article that is a Nightmare, reminding us that sometimes, in the practice of healthcare, things may not always be what they seem. He presents a case study that is truly amazing, interesting, and also truly a nightmare. When caring for people

14 | PWJ | www.painweek.org

Kevin L. Zacharoff is Vice President of Medical Affairs, Inflexxion, and is a faculty member at SUNY Stony Brook School of Medicine.

Q2 | 2015

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Gary W. Jay MD, FAAPM

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Darren McCoy FNP-BC, CPE

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Liana Seldin DPM

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Forest Tennant MD, DrPH

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Gary W. Jay is Chief Medical Officer of AdviseClinical, a CRO in Raleigh, North Carolina. He has served as a principal investigator, key opinion leader, and pharmaceutical industry advisor and consultant. Dr. Jay was one of the 30 founding members of the American Academy of Algology (now the American Academy of Pain Medicine), which helped develop the subspecialty of pain medicine. He has written over 130 articles in peer-reviewed journals dealing with headache, pain, the autonomic nervous system, and mild traumatic brain injury; 5 textbooks; and third-party medical textbook chapters. He is currently the Immediate Past President of the Eastern Pain Association.

Darren McCoy is a nurse practitioner with Pain Consultants of East Tennessee, a multidisciplinary outpatient pain management center. He has also served as an adjunct faculty member for the College of Nursing at UT-Knoxville. He was co-presenter of “Treating the Medium-to-High Risk Patient” at PAINWeek 2011, completed his Certified Pain Educator credential in 2012, and presented a variety of sessions in the nurse practitioner track at PAINWeek 2014.

Liana Seldin is Doctor of Podiatric Medicine, Southernmost Foot and Ankle Specialists, in Miami, Florida. Dr. Seldin holds an adjunct clinical faculty position at Barry University School of Podiatric Medicine in Miami Shores, Florida.

Forest Tennant is a former US Army Medical Officer and Public Health Physician, and founder, Medical Director, Veract Intractable Pain Clinic in West Covina, California. He started a pain clinic for cancer and post-polio patients in eastern Los Angeles County, was co-author of the “Pain Patient’s Bill of Rights” section 2241.5 of the CA Division of Health and Safety code, and was instrumental in passing the “CA Intractable Pain Act.” Dr. Tennant was a professor at UCLA School of Public Health and Drug Advisor for the National Football League, LA Dodgers, and NASCAR.

16 | PWJ | www.painweek.org

Q2 | 2015

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* The Screener and Opioid Assessment for Patients with Pain (SOAPP速) and the Current Opioid Misuse Measure (COMM速) are validated measures that assess the likelihood of aberrant drug-related behavior.

Tennant MD, DrPH

by Forest

THe MAJOR COMPLiCATiON OF OPiOiDS iS HORMONe SUPPReSSiON, WHiCH iS SOMeTiMeS CALLeD ‘OPiOiDeNDOCRiNOPATHY.’

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K Y TOPiC

MANAGeMeNT AND TReATMeNT OF THe CHRONiC PAiN PATieNT DePeNDS ON NeUROPROTeCTiON AND NeUROGeNeSiS, AND THeSe PHYSiOLOGiC NeCeSSiTieS ARe HORMONALLY ReGULATeD.

abstract: Because pain is a potent stressor, it initially causes hormones to elevate in the serum; if severe pain goes uncontrolled for too long, however, hormone levels deplete in the serum. The finding of abnormal serum hormone levels serves as a biomarker of endocrinopathies, which helps inform clinicians that enhanced analgesia as well as hormone replacement may be necessary. Adequate, physiologic levels of some specific hormones are necessary for optimal analgesia, neuroprotection, and neurogenesis.

Although not a substitute for opioids, some hormone replacements may minimize their need. We know that the central nervous system produces neurohormones whose natural function is neuroprotection and neurogenesis.

Their clinical use in centralized pain states is new, and early reports indicate that they may have considerable benefit for treatment. This article reviews the current status of hormone testing and treatment in pain care.

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www.painweek.org | PWJ | 19

KEY TOPIC

testing and treatment is emerging as standard practice in ambulatory management of chronic pain. The basic underpinning of this development is the relatively recent understanding that the central nervous system (CNS), including neurons, glial cells, and the blood-brain barrier, is under hormonal control.1 Management and treatment of the chronic pain patient depends on neuroprotection and neurogenesis, and these physiologic necessities are hormonally regulated.2 Advances in laboratory technology allow for easily and rapidly obtained panels or profiles of several serum hormone concentrations at relatively modest costs.3

Research over the past 5 decades has progressively shown

show that severe pain, acute and chronic, has a profound effect on the endocrine system.8,36-48 The seminal study was done in 1964 when Shenkin,36 a Philadelphia neurologist, found that 87% of hospitalized patients with pain demonstrated elevated cortisol levels compared with 16% of those without pain. Similarly, Lascelles et al49 in 1974 found that psychiatric patients with chronic pain had elevated cortisol

❶ Some hormones facilitate, within the CNS, receptor site binding, nerve conduction, and maintenance of the blood-brain barrier.17-20 For example, opioids may not exert their maximal effect on opioid receptors if there is a hormone deficiency.18

Table 1. Major Pain Control Mechanisms of Hormones

that pain control is interdependent on adequate hormone body levels or homeostasis of certain hormones.4-14 Immune function, inflammation control, and tissue healing have long been known to be critical physiologic functions of cortisol and other hormones (Table 1).15,16 Above and beyond these basic hormonal functions are some specific CNS functions that are essential for adequate pain control:

❷ Some hormones are now known to have neuroprotective and neurogenic properties.21-31 For example, they keep nerve cells from disintegrating due to an insult such as severe pain, and they stimulate cell regrowth in the CNS, often referred to as neuroplasticity.

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WHY TH R C NT EM RG NC OF T STiNG AND TR ATM NT? Hormone testing and treatment have recently come to the forefront due to a number of reasons. The use of contemporary pharmaceuticals including opioids may entail hormone replacement to achieve endocrine homeostasis.30-35 Numerous studies dating back to 1959

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Immune facilitation Anti-inflammatory action Tissue regeneration Glucose control CNS pain functions »» Receptor binding »» Nerve conduction »» Neuroprotection »» Neuroregenesis »» Maintenance of blood-brain barrier

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EARLY TRiALS AND ANeCDOTAL RePORTS SUGGeST THAT NeUROHORMONeS MAY ReDUCe CeRTAiN ASPeCTS OF CHRONiC PAiN SUCH AS iNTeNSiTY, LeNGTH, OR SeVeRiTY OF FLAReS AS WeLL AS PReVeNT OPiOiD HYPeRALGeSiA AND ALLODYNiA. ALSO, THeY APPeAR TO HeLP MAiNTAiN OPiOiD eFFeCTiVeNeSS.

levels. Several studies since then have shown that only patients with severe pain compared to those with mild or moderate pain demonstrate abnormal hormone levels.45,50-54 Another factor that has driven the interest in hormone testing and treatment is that opioids may commonly suppress some hormones, particularly testosterone and estrogen.55-59 Pain patients who are being treated with opioids which alter their hormone levels may develop comorbidities including low libido, impaired sexual performance, depression, amenorrhea, lethargy, hyperalgesia, and hypoalgesia.58,59 A recent development that has boosted hormone testing and treatment in pain care is laboratory technology. Hormone panels of profiles consisting of 6 to 10 hormones can now be obtained rapidly.3 This rapid access makes it possible not only to screen patients, but also to assess treatment effectiveness over time. The author’s experience, to date, indicates that third-party payer approval is usually granted when the payer is informed that testing frequently results in a change in pain treatment that may be more effective clinically and possibly less expensive.

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TH 2-PHAS PHYSiOLOGiC EFF CTS OF PAiN Severe, chronic pain is a major stressor that has a profound effect on the endocrine system.1,3 Initially, pain causes the hypothalamus and pituitary to secrete hormones into the serum—including thyroid-stimulating hormone, adrenocorticotropin, and follicle-stimulating hormone—and to induce the pineal gland to secrete melatonin.36,37,48-57 Pain produces an increase of serum hormones including cortisol, pregnenolone, and testosterone, among others.

The elevation of serum hormones is phase 1. If severe pain goes uncontrolled and is disabling for a considerable period of time, the hypothalamic-pituitary-adrenal-gonadal system cannot keep up, and serum hormones may drop below their normal range.48,53,60,61 The depletion of serum hormones is phase 2. Because severe chronic pain may produce either serum hormone concentrations that are too high or too low, a finding of a hormone level outside the normal physiologic range should prompt an assessment about whether enhanced analgesia is advisable.

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HORMON S MOST CRiTiCAL iN PAiN CAR It has long been known that cortisol is essential for the control of inflammation, healing, and immunosuppression.15,16 Hydrocortisone and its various analogues have been a mainstay in pain treatment for decades, as the corticosteroids have been and continue to be used topically, systemically, intralesionally, and for epidural injection. Numerous studies have found, however, that a number of other hormones are critical for pain care, such as thyroid-stimulating hormone, pregnenolone, progesterone, estrogen, dehydroepiandrosterone ( DHEA), and testosterone.2,7,11-13 Vitamin D, whose chemical structure closely resembles that of progesterone and pregnenolone, is considered a hormone by many observers.62 It has been the realization that multiple hormones contribute to pain control that has driven the need for pain practitioners to obtain panels or profiles Q2 | 2015

of multiple hormones. Some hormones that are not listed here may contribute to pain control, but limited knowledge about them, the lack of laboratory testing availability, or clinical nonavailability make them currently impractical to test and administer in pain care.

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N UROHORMON S One of the more amazing discoveries of the past decade is that the CNS is an endocrine organ.2,11,12 It produces ≥ 6 hormones that are active within the CNS for neuroprotection and neurogenesis: pregnenolone, progesterone, DHEA , estrogen, oxytocin, and human chorionic gonadotropin. These hormones are produced independently of hypothalamic-pituitary control.3,7,13 At this time little is known or understood about production levels, reserve storage, or diurnal variation. Also, it is unknown how much they contribute to serum levels.

Two things are, however, clear and important for pain control: 1) a deficient serum level of 1 of these hormones probably represents low production by the CNS as well as in adrenals and gonads and 2) the CNS requires these hormones for neurogenesis and neuroplasticity.

Given the critical importance of neurohormones in neuroprotection and neurogenesis, consideration should be given to replacement when any neurohormone is found to be deficient on serum testing. All the neurohormones including oxytocin and human chorionic gonadotropin are currently being tested in clinical trials of chronic pain patients who have likely centralized their pain (which is often called central sensitization).63-67 Early trials and anecdotal reports suggest that neurohormones may reduce certain aspects of chronic pain such as intensity, length, or severity of flares as well as prevent opioid hyperalgesia and allodynia.23,27 Also, they appear to help maintain opioid effectiveness.11,18,30,31 www.painweek.org | PWJ | 21

KEY TOPIC

HORMONAL SeRUM ABNORMALiTieS iNDiCATe TO THe PHYSiCiAN THAT A PATieNT’S PAiN iS SeVeRe AND THAT MORe AGGReSSiVe ANALGeSiA MAY Be NeeDeD.

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HORMON SUPPR SSiON BY OPiOiDS The major complication of opioids is hormone suppression, which is sometimes called “opioid-endocrinopathy.”34,59 Opioids suppress releasing hormones in the hypothalamus. For unknown reasons they preferentially suppress gonadotropin-releasing hormone but may sometimes suppress corticotropin-releasing hormone.35,39 The usual result is the lowering of serum levels of testosterone, DHEA , and estrogen, which may occur following a brief period of elevation.35 Low levels of serum testosterone and DHEA , in both men and women, result in typical symptomatology including depression, lethargy, immobility, loss of libido, poor analgesic response, and elevated pain. The suppression of estrogen in women may result in amenorrhea or oligomenorrhea. Men may develop gynecomastia and erectile dysfunction.32,34,59 Fortunately, opioids do not often lower cortisol or pregnenolone to dangerous levels, but there are reported cases of pituitary-adrenal failure with opioids.68-72 Long-acting and intrathecal opioids suppress hormones more than short-acting opioids.32,58,59,73 The apparent, but unproven, rationale for this observation is that long-acting and intrathecal opioids continuously suppress the releasing hormone centers in the hypothalamus, whereas short-acting opioids may allow periods of nonsuppression. Rubenstein and Carpenter74 of the Kaiser Permanente Group recently surveyed 1585 men for androgen deficiency as it related to the intake of 7 opioids: codeine, hydrocodone, hydromorphone, fentanyl, methadone, morphine, and oxycodone. They found, as have others, that the long-acting opioids were more suppressive of testosterone than were the short-acting opioids. Interestingly, higher dosages of the short-acting opioids but not the long-acting opioids

22 | PWJ | www.painweek.org

were more suppressive. The opioids fentanyl, methadone, and oxycodone were more suppressive than were hydrocodone or morphine.

Although 60% to 85% of opioid treated pain patients may initially develop some hormone suppression, some patients apparently develop a tolerance to hormone suppression as serum levels of hormones may normalize after a few months of opioid administration.75 Due to the high incidence and prevalence of hormone suppression in opioid-maintained pain patients, some practitioners recommend that these patients be periodically screened for hormone deficiencies.

Under select circumstances, such as the presence of impotence and depression, hormone replacement is recommended.

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HORMON ABNORMALiTi S AS BiOMARK RS Pain, per se, may not be objectively measurable, but its effect on the endocrine system may reflect pain as an indicator. Hormonal serum abnormalities indicate to the physician that a patient’s pain is severe and that more aggressive analgesia may be needed. Although the patient’s verbal complaint of pain and need for analgesia must always be paramount in pain care, a finding of abnormal adrenocorticotropin, cortisol, or pregnenolone, for example, is a biomarker of pain severity. Foremost, however, it is an indicator that more analgesia, including neuropathic (antiseizure and antidepressant) agents or opioids, is needed (Table 2).

Table 2. Benefits of Serum Hormone Testing Uncontrolled pain biomarkers Hormone replacement need notification Treatment success monitoring Complications of hormone deficiency/excess suspicion confirmation

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WHO SHOULD B T ST D? Not every chronic pain patient needs to be tested. For example, patients who have mild to moderate painful conditions such as osteoarthritis, fibromyalgia, headaches, and carpal tunnel syndrome usually have normal hormone levels.50,51,76 The chronic pain patients who complain of severe pain on most days may be candidates for hormone testing in defined circumstances.3 Those patients who claim their pain is constant and require a sleep aid are most likely to have serum hormone abnormalities. Those whose pain is severe enough to require daily opioids are candidates for hormone testing. It is highly recommended that patients who currently take opioids and complain that their pain is still not controlled be tested for hormonal deficiencies, which may be the reason that their treatment regimen is unsatisfactory.

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MiNiMiZATiON OF OPiOiDS The administration of hormones ideally may minimize the use of opioids (Table 3). For example, if a chronic pain patient is not responding well to nonopioid measures, a hormone profile that shows deficiencies signals that a clinical trial of hormone replacement is preferable rather than simply turning to opioids (situation 1 on Table 3). If a patient is on short-acting opioids such as tramadol or hydrocodone, a hormone profile that shows deficiencies may lead to a hormone replacement trial that, it is hoped, may obviate the need for additional opioid therapy (situation 2 on Table 3). Patients who are taking opioids on a daily basis frequently show hormonal deficiencies, although the precise dosages required to produce them are unknown.73,74 It is hoped that if hormones are replaced, the patient may be able to reduce the opioids or at least stop an escalation of the daily dosage.

Although hormone replacement may minimize or reduce the need for opioids, there are currently only anecdotal reports that this may be possible.

Table 3. Case Illustrations to Minimize Opioids Situation #1—Avoid Starting an Opioid »» 34-year-old woman with fibromyalgia.

On duloxetine (Cymbalta®) and celecoxib (Celebrex®).

Had low pregnenolone and DHEA. »» Result: Pregnenolone and DHEA replacement avoided opioids.

Situation #2—Avoid a Long-Acting Opioid »» 44-year-old man with lumbar spine degeneration. On hydrocodone/acetaminophen (Vicodin®) and gabapentin (Neurontin®). Had low testosterone and pregnenolone. »» Result: Testosterone and pregnenlone replacements avoided a long-acting opioid.

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R PLAC M NT OF HORMON S The majority of chronic pain patients have normal, nondiseased glands, including pituitary, thyroid, adrenals, and gonads. Their deficiencies with severe chronic pain are physiologic, and they usually resolve with increased analgesia or subreplacement of deficient hormones. Seldom does a pain patient require a full replacement dosage of cortisol, pregnenolone, or other hormone. The exception is a pain patient with autoimmune disease or traumatic brain injury with pituitary insufficiency.77-80 It is recommended that hormones be administered only to pain patients who demonstrate deficient serum levels. At this time it is unknown if bioidentical or synthetic analogues will be the most beneficial. The starting dosages should be low and titrated upward. The author recommends that a patient’s serum level should be monitored every 3 to 4 months to ensure that the hormone levels stay in the physiologic range. If, after a few weeks, better analgesia is attained, Q2 | 2015

hormone replacement may no longer be necessary. By these simple measures, any risk of negative feedback on the glands or the induction of cancer or prostatic hypertrophy is extremely low.

Hormones are administered to ambulatory patients by oral, topical, sublingual, or intramuscular routes. Practitioners and their compounding pharmacists are currently developing novel and innovative ways to administer hormones to patients. The recommendation here is that each practitioner tailor the hormones to the individual patient, based on the resources available and the personal preferences of both patient and practitioner. Some hormones, including testosterone, have poor oral bioavailability and are therefore usually given by intramuscular or topical routes. At this time there is not sufficient data on bioavailability with most hormones to recommend a specific route of administration over the others.

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MAJOR HORMON COMPLiCATiONS Severe pain that is uncontrolled and goes on for a long period of time may cause 2 serious complications: 1) pituitary-adrenal insufficiency and 2) osteoporosis. In the former, cortisol serum levels may drop to < 1.0 µg/dL.68-72 This level should be considered an urgency in pain patients, and replacement with hydrocortisone or cortisol should be immediately started. Patients who are symptomatic with great weakness, fatigue, and immobility, and have cortisol levels <1.0 µg/dL may need an immediate injection or infusion of methylprednisolone or other potent corticosteroid as well as aggressive analgesia.72 Osteoporosis and osteopenia may be the most common complications of elevated cortisol levels. Even if the elevations are intermittent, elevated cortisol causes calcium resorption. Severe osteoporosis may occur in the spine, knees, and hips.

Chronic pain may intermittently elevate serum cortisol levels over an extremely long time period. Consequently, the chronic pain patient may develop all the signs and symptoms that are classically associated with Cushing’s syndrome or hyperadrenalism.1 Included are hypertension, hyperglycemia, truncal obesity, moon face, plethora, weakness, nephrolithiasis, and dental erosion. All of these potential developments are commonly observed in chronic pain patients.

CONCLUSiON Pain affects hormones. Hormones affect pain. Hormone testing and treatment is now a major participant in the field of pain care.

Hormone panels or profiles can now be obtained from laboratories throughout the country. Pain patients almost always report some positive, symptomatic benefit when their deficient hormones are normalized. Some hormone replacement may minimize the need for opioids. The central nervous system’s neurohormones offer neuroprotection and neurogenesis that early anecdotal reports indicate may have benefit in the suffering pain patient.

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KEY TOPIC

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20. Mechlin B, Morrow AL , Maixner W, et al. The relationship of allopregnanolone immunoreactivity and HPA-axis measures to experimental pain sensitivity: evidence for ethnic differences. Pain. 2007;131(1–2):142–152.

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

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22. Pettus EH, Wright DW, Stiein DG, et al. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res. 2005;1049:112–119.

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42. Griep EN, Boersma JW, Lenties E, et al. Function of the hypothalamicpituitary-adrenal axis in patients with fibromyalgia and low back pain. Rheumatology.

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43. Chikanza JC , Petrou P, Kingsley G, et al. Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis. Arthritis Rheum.

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45. Strittamatter M, Bianchi 0, Ostertag D, et al. Altered function of the hypothalamic-pituitary-adrenal axis in patients with acute, chronic and episodic pain. Schmerz (Berlin, Germany). 2005;19(2):109–116.

46. Chikanza JC , Petrou P, Kingsley G, et al. Defective hypothalamic response to

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47. Garofalo J, Robinson R, Gatchel R, et al. A pain severity-hypothalamic pituitary-adrenocortical axis interaction: the effects on pain pathways. J Appl Biobehav Res. 2007;12:35–42.

48. Ulrich-Lai YM , Xle W, Melj JT, et al. Limbic and HPA axis function in an animal model of chronic neuropathic pain. Physiol Behav. 2006;88:67–76.

49. Lascelles PT, Evans PR , Merskey H, et al. Plasma cortisol in psychiatric and neurologic patients with pain. Brain. 1974;97:533–540.

50. Fernandez-de-las-Penas C, Diaz-Rodriguez L, Salom-Moreno J, et al. Activation of the hypothalamic-pituitary-adrenocortical axis and sympathetic nervous system in women with carpal tunnel syndrome. Pain Med. 2014;15:1373–1378.

51. Wingenfeld K, Heim C, Schmidt I, et al. HPA axis reactivity and lymphocyte glucocorticoid sensitivity in fibromyalgia syndrome and chronic pelvic pain. Psychosom Med. 2008;70:65–72.

52. McBeth J, Silman AJ, Gupta A, et al. Moderation of psychosocial risk factors through dysfunction of the hypothalamic-pituitary-adrenal stress axis in the onset of chronic widespread musculoskeletal pain: findings of a population-based prospective cohort study. Arthritis Rheum. 2007;56:360–371.

53. Patacchioli FR , Monnazzi P, Simeoni S, et al. Salivary cortisol, dehydroepiandrosterone-sulphate (DHEA -S) and testosterone in women with chronic migraine.

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54. Sjors A, Larsson B, Karlson B, et al. Salivary cortisol response to acute stress and its relation to psychological factors in women with chronic trapezius myalgia: a pilot study. Psychoneuroendocrinology. 2009;35:674–685.

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2012;12(1):43–47.

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74. Rubinstein AL , Carpenter DM . Elucidating risk factors for androgen deficiency associated with daily opioid use. Am J Med. 2014;127(12):1195–1201.

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76. Khorami S, Muniyappa R, Nackers L, et al. Effect of chronic osteoarthritis pain on neuroendocrine function in men. J Clin Endocrinol Metab. 2006;11:4313–4318.

77. Urban RJ, Harris P, Masel B. Anterior hypopituitarism following traumatic brain injury. Brain Inj. 2005;19(5):349–358.

78. Wilkinson CW, Pogulayan KF, Petrie EC , et al. High prevalence of chronic pituitary and target-organ hormone abnormalities after blast-related mild traumatic brain injury. Front Neurol. 2012;3:1–12.

79. Agha A, Phillips J, O’Kelly P, et al. The natural history of post-traumatic hypopituitarism: implications for assessment and treatment. Am J Med. 2005;118(12):1416–1420.

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

62. Stein DG, Cebic MM . Progesterone and vitamin D hormone for treatment of traumatic brain injury in the aged. PM&R. 2001;3(601):5100–5110.

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64. Pettus EH, Wright DW, Stiein DG, et al. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res. 2005;1049:112–119.

65. Rash JA , Aguirre-Comacho A, Campbell TS . Oxytocin and pain: a systematic review and synthesis of findings. Clin J Pain. 2014;30(5):453–462.

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67. Tennant F. Clinical trial of progesterone for intractable, central pain. Presented at the meeting of the American Academy of Pain Medicine, Palm Springs, CA ; 2012.

68. Policoloa C, Stokes V, Karavitski N, et al. Adrenal insufficiency in acute oral

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www.painweek.org | PWJ | 25

by Gary

W. Jay MD, FAAPM

CLiNiCAL CONUNDRUM

“She had changed and not for the better.”

abstract: Sometimes you see a patient who has

what sounds like a bizarre story. It may seemingly be psychiatric in nature when it most definitely is not. These are patients that most physicians dislike seeing because their complexity takes a good bit of time—to make the diagnosis and determine the best treatment.

This case, which occurred in the mid-1990s, was one of those and was, indeed, a nightmare for the patient as well as her loved one.

“BC,”

a 27-year-old, right-handed Caucasian woman, came to my office with her fiancé, TF. They were living together and TF had noted significant changes in BC. When they were first engaged, BC was a vivacious woman, full of energy and enthusiasm. Now, she was not interested in much. She had changed and not for the better. BC had gained 20 pounds, and had become sloppy in appearance and in how she took care of herself in general.

According to TF, her appearance was not “spectacular,” as it used to be. He felt she had “lost the light” in her eyes, become very quiet, and had almost no personality. He told me that she could not remember or even recognize her pets or her friends.

This case, unlike the one I documented last year in PWJ (Vol 2, Q3),1 went very quickly. Within a week, the patient had put on more weight and, according to TF, “things were getting worse.” He waited until BC went to the ladies room and we were alone in the consultation room before he continued, explaining that BC used to be rather sexually demure, but lately she was asking for sex and masturbating much more frequently, as well as rubbing herself on inanimate objects.

When BC returned, and I continued taking her history, I brought up the subject of sex and she just stated that it was good.

Her neurological examination was normal. I ordered a CAT scan of her brain. (This was before MRIs became ubiquitous. Those that were available, typically in a university, were extremely expensive).

The test was read as normal.

I saw them again a week after the cerebral CAT scan results. TF noted that BC continued to “overeat” and she had gained at least 5 more pounds. He also stated that on 2 occasions he had found BC sucking on strange things: first a small metal medallion and then a key. Notably, on her second visit, BC couldn’t remember my name when I ushered her into my office.

The neurological examination was unchanged. Her blank face (with no emotion seen) made me begin to question other things. I ordered a neuropsychological test battery, which showed a normal IQ but that her executive functions were not as stable as I would have anticipated; there were indications of memory problems.

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The differential diagnosis was narrowing down.

I did some other tests on repeat neurological examination, including palmomental reflexes, jaw jerk, suck, and snout. These primitive reflexes were all positive. After the examination, I asked if BC had a history of head trauma. She denied it but sounded “disconnected” and “wrong”—words I also could use to describe my opinion of the validity of her answers.

I asked TF to find out if BC had been involved in any car accidents, to check for a police report, or an ED record. During this conversation, BC looked totally lost and uncomprehending. A little less than 2 days later, I received a call from TF. He had obtained a police report of a motor vehicle vs tree accident that occurred about 2 months before they initially came to see me. BC was the driver and had been taken by ambulance to an ED. The diagnosis was coup-contrecoup injury with rotation, with her Glasgow Coma Score initially 13 (mild brain injury) but returning to normal (15) within 2 hours.

The ED report indicated that she was amnestic for the accident, and was diagnosed with a postconcussive syndrome. TF recalled BC’s car having been struck but stated, in front of BC , that she told him someone had struck her car when she wasn’t in it. When TF asked her about it, there in my office, BC denied that she had been in an accident and denied being taken to a hospital ED —ever! www.painweek.org | PWJ | 29

CLINICAL CONUNDRUM

“…the diagnosis fell into place: Klüver-Bucy Syndrome.”

Three days later, TF called me back with further concerns: BC was still putting all sorts of strange things into her mouth. He was noticeably, and understandably, hesitant to tell me that he suspected BC of coprophagia—consumption of feces.

BC was still significantly overeating and still craving a great deal of sex, which TF again noted was just not like her. We made an appointment for a week later. But 2 days later, TF called me and reported that he had come home from work and found in his driveway a car that he didn’t recognize. The windows were fogged up and the car was “shaking like the devil.” An hour or so later BC entered their home looking very disheveled. I gave them an emergency appointment for the next day, mainly because TF was obviously at the end of his rope, and their relationship was close to over.

The next day BC again couldn’t remember my name when she and TF were escorted to my office. I questioned her regarding the motor vehicle accident. She blandly stated that she didn’t remember any such accident. TF began to get very emotional and angry. He asked her about what was going on in the car the day before, and also asked her about a possible episode of coprophagia. She stated that she hadn’t been in a car in the driveway the day before, and denied the latter.

Klüver-Bucy Syndrome The Klüver-Bucy syndrome was named after Dr. Heinrich

Klüver (1897–1979), a German-American experimental psychologist, and Dr. Paul Bucy (1904–1992), an American neuropathologist and neurosurgeon.

The first documented human case of KBS was in 1955 after humans experienced temporal lobectomies for intractable epilepsy.2 KBS was first noted in humans post meningoencephalitis in 1975.3,4 The syndrome typically results from bilateral lesions of the anterior temporal lobe, including the amygdaloid nuclei. Generally, the symptoms include5,6:

▸ Amnesia—inability to recall memories both anterograde and ▸

These 2 questions brought a diagnosis to my mind. I ordered an MRI, with and without contrast, from a local university medical center. I felt it imperative that BC have one. Although it was expensive (beyond their means), TF stated he would speak to his parents about obtaining the test with their financial help. I called, got the test scheduled for the next day, and made an appointment to see BC and TF again in 2 days.

▸

So, here is where one must decide if the problem with BC is psychiatric or physiological. Would the MRI show anything?

▸

▸ ▸

retrograde; new memories may not be formed and old memories may not be recalled, all depending on the level of destruction/ cell death Docility—exhibiting diminished fear responses or reacting with unusually low aggression, also termed “placidity” and “tameness” Hyperphagia—including eating inappropriate objects (pica) or overeating (at bulimic levels) Hyperorality—an oral tendency or compulsion to examine objects by mouth: patients may show excessive oral and tactile explorations, may engage in behaviors unacceptable in public, such as touching and licking objects Hypersexuality—heightened sex drive or a tendency to seek sexual stimulation from unusual or inappropriate objects Visual agnosia—inability to recognize familiar objects or people

Other symptoms may include: What would your diagnosis be?

Making a long story short, the MRI showed diffuse axonal injury on diffusion weighted images, particularly of the temporal lobes as well as intercerebrally. The amygdala were involved. To see scan examples (not BC’s) visit: http://regionstraumapro.com/post/20061810686 and http://virtualmedstudent.com/links/neurological/diffuse_axonal_ injury.html.

For me, the diagnosis fell into place: Klüver-Bucy Syndrome.

30 | PWJ | www.painweek.org

▸ Hypermetamorphosis—“irresistible impulse to notice and react to everything within sight”

▸ Lack of emotional response or diminished emotional affect While it is rare for a human to manifest all of the symptomatology of KBS, only 3 to 4 are diagnostic. (Nonhuman primates typically will have all or most symptoms.) Among humans the most common symptoms include: docility, hyperorality, hypersexuality, visual agnosia, and dietary changes. BC had all of these symptoms, along Q2 | 2015

“Lesions of the amygdala can also cause the patient to have impaired ability to interpret emotional aspects of facial expression.”

with apparent memory loss. Coprophagia, suspected in BC , has also been noted in those with KBS.7 Risk factors for KBS include8,9:

▸ Head injury (including mild) ▸ Herpes simplex encephalopathy ▸ Surgical lesions (especially after removal of temporal lobes for intractable epilepsy) ▸ Post epilepsy (post ictal) ▸ Dementia (especially frontotemporal dementia, or Pick’s disease, as well as Alzheimer’s disease) ▸ Cerebrovascular disease Other etiologies may include5:

▸ Neurocysticercosis—a preventable parasitic infection caused by larval cysts

▸ Neurotuberculosis ▸ Anoxic encephalopathy ▸ Herpes simplex encephalopathy ▸ Traumatic brain injury with gliosis Still other etiologies include10:

▸ Neimann-Pick disease—a group of inherited metabolic disorders that allow fat to accumulate in cells

▸ Failure to metabolize porphyria ▸ Stroke ▸ Cancer ▸ Juvenile neuronal lipofuscinosis ▸ Hypoglycemia ▸ Progressive subcortical gliosis ▸ Carbon monoxide poisoning ▸ Conditions related to autism, Rett syndrome in particular Q2 | 2015

Other Cases In typical mainstream media style, Slate, when writing about KBS, referred to its hypersexuality and stated, essentially, “how great it is!”11 In reality, things are not always so great. The KBS is neurologically not “normal” or “great.”

A 51-year-old man with epilepsy, which became intractable, had his medial temporal lobe removed. He developed KBS, becoming hypersexual and hyperoral. He became obsessed with sex (and food) and became addicted to internet porn. He ended up viewing a number of sites, with different types of sexuality, and even purchased and downloaded pornographic images of prepubescent girls. He was arrested in 2006. A psychiatrist gave him the antipsychotic quetiapine and sertraline for depression/anxiety, and his sexual obsessions disappeared. His wife noted, “he became much warmer and loving, but the medications shut off his libido. Sex became nonexistent.”

He was eventually charged with having “at least 3 images of child pornography” and he pleaded guilty. Drs. Julie and Orrin Devinsky and Dr. Oliver Sacks spoke for him at his trial and noted that these problems occurred when he had a neurological illness ( KBS) and was unable to help himself. He was sentenced to 26 months in prison, much to everyone’s frustration.12

The Limbic System and the Amygdala The amygdalae are almond-shaped gray matter structures in the anterior aspects of the temporal lobes and are set in front of each www.painweek.org | PWJ | 31

CLINICAL CONUNDRUM

“The amygdala is involved in sending motivational signals related to fear, reward, and punishment, and social as well as sexual functions.”

hippocampus. The amygdalae flank the thalamus bilaterally. The amygdala is involved in sending motivational signals related to fear, reward, and punishment, and social as well as sexual functions. It has also been associated with rage reactions and unprovoked aggression in humans with epileptiform foci detected by deep implanted brain electrodes.13 Lesions of the amygdala can also cause the patient to have impaired ability to interpret emotional aspects of facial expression. This is a link to “emotive dullness”—patients don’t respond appropriately to external stimuli and only react to the environment with a flat affect, and vocalization typically becomes less expressive. This has been linked to autism, where MRI has determined an increase in amygdala volume. The amygdala has a strong relationship with the social ability of the human being.5

tangles and beta-amyloid plaques in the amygdala. They described a 70-year-old man with progressive behavioral symptoms of hyperorality, hypersexuality, hypermetamorphosis, visual agnosia, hyperphagia, and apathy who died at age 77 of asphyxiation on a foreign object. Of note, this variant of Alzheimer’s disease with prominent amygdaloid abnormalities and a KBS phenotype was misdiagnosed as frontotemporal dementia.

BC’s Treatment

After the diagnosis of KBS was made, I started BC on carbamazepine15 200 mg TID and initially followed her weekly, with TF always along.

I later added gabapentin. BC was also started in therapy with the neuIn monkeys, destruction of or removal of both amygdalae induces a ropsychologist, a nutritionist, and a physical therapist. She continued reduction of fear and aggression as well as hypersexuality. In humans, in neuropsychological therapy for almost a year, the other therapies there is a reduction of aggression and fear, as well as the impaired for 6 to 8 weeks. She lost weight and over the year of treatment the ability to interpret emotional aspects of facial expression, hyper- other KBS symptoms abated. About a year and a half after the initial orality, hypersexuality, and more.13 There are a number of other injury, she and TF were married. published examples of KBS after amygdaloid damage. Hayman et al14 notes bilateral amygdaloid damage in a patient post cancer treatment: this patient had lesions seen on MRI post reversal of hyponatremia.

The patient had significant behavioral changes including visual agnoConclusion sia, hypersexuality, hyperorality, memory deficits, and a tendency to react to every visual stimulus.

As initially stated, BC presented as what may be perceived by many as Kile et al9 describe Alzheimer’s abnormalities of the amygdalae with a psychiatric case. I didn’t think that was true for many reasons, one Klüver-Bucy Syndrome symptoms, what they called an amygdaloid being that, even though he noted that her personality had changed, variant of Alzheimer’s disease: on necropsy, they found neurofibrillary TF was always there. While frustrated and even frightened by what

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Q2 | 2015

BC was doing, he was always caring. It has been my experience that in relationships, even bad ones, the “nonaffected” spouse or significant other (SO) has a handle on just how bad things may be. In cases where patients really “lost it” psychiatrically, the SO can sense this and frequently leaves the relationship.

It is not a secret that in about 80% to 85% of couples where a minor traumatic brain injury occurs, the SO of the patient will leave the relationship within 5 years, stating, “This is just not the person I knew.” So, while the physician is faced with what appears to be a bizarre case, it is helpful to get “silent input” from the patient’s SO. If they are truly surprised by what is happening, take a look at psychiatric issues. Also, it goes without saying, that a thorough knowledge of evaluation and treatment of patients with posttraumatic/cerebral/ cognitive/behavioral issues is needed to evaluate the patient as well as treat them. Keeping one’s eyes open to other things happening in the family/relationship can alert you to tell-tale signs of things that might otherwise not be realized, or might be overlooked.

References 1. Jay GW. If 13 clinicians can’t agree on your diagnosis…you’ve got a problem!

PWJ —PAINWeek Journal. 2014;V2/Q3:38–52.

Further Reading Anne HA , Rexer JL , Marykay PA , et al. Kluver-Bucy syndrome after bilateral selective damage of Amygdala and its cortical connections. J Neuropsychiatr Clin Neurosci.

1998;10:354–358.

Biswas A, Anand KS, Prasad A, et al. Clinico radiological profile of Kluver-Bucy Syndrome. J Assoc Physic Ind. 1998;46:318–319.

Duggal HS, Jain R, Sinha VK , et al. Post encephalitic Kluver-Bucy syndrome.

Indian J Pediatr. 2000;62:74–76.

Greenwood R, Bhalla A, Gordon A, et al. Behavioral disturbances during recovery from Herpes simplex encephalitis. J Neurol Neurosurg Psychiatr. 1983;46:809–817.

Hart RP, Kwentus JA , Fraziar RB, et al. Natural history of Kluver-Bucy syndrome after treated herpes encephalitis. South Med J. 1986;79:1376–1378.

John AA , Donald TK . Post-ictal Kluver-Bucy syndrome after temporal lobectomy.

J Neurol Neurosurg Psychiatr. 1993;56:311–313.

Kluver H, Bucy PC . Psychic blindness and other symptoms following bilateral temporal lobectomy in rhesus monkeys. Am J Physiol. 1937;119:352–353.

Marlowe WB, Mancall EL , Thomas JJ . Complete Kluver-Bucy syndrome in man.

Cortex. 1975;11:53–59.

Misra UK , Phadke RV, Seth PK . Kluver-Bucy syndrome: sequelae of tubercular meningitis. Neurol India. 1994;42:29–31.

2. Terzian H, Dalle-Ore PC . Syndrome of Kluver and Bucy reproduced in man by bilateral removal of the temporal lobes. Neurology. 1955;5:373–380.

Muller A, Baumgartner RW, Rohrenbach C, et al. Persistent Kluver-Bucy syndrome after bilateral thalamic infarction. Neuropsychiatry Neuropsychol Behav Neurol.

1999;12:136–139.

3. Ozawa H, Sasaki M, Sugai K, et al. Single-photon emission CT and MR findings in Klüver-Bucy syndrome after Reye syndrome. AmJ Neuroradiol. 1997;18(3):540–544.

Olson DA . Kluver-Bucy syndrome as a result of minor head trauma. South Med J. 2003;96:323.

4. Delgado JM . Physical Control of the Mind: Toward a Psychocivilized Society. New York, NY: Harper and Row; 1986. Available at: www.biotele.com/delgado_%20 ebook/chap14.htm.

Pradhan S, Singh MN, Pandey N. Kluver-Bucy syndrome in young children.

Clin Neurol Neurosurg. 1998;100:254–258.

5. Syndrome. Kluver Bucy Syndrome. Available at: syndrome.org/kluver-Bucy-syndrome.

Schraberg D, Welberg L. Kluver-Bucy syndrome in man. J Nerv Ment Dis. 1978;166:130–134.

6. National Institute of Neurological Disorders and Stroke. NINDS Kluver-Bucy Syndrome information page. Available at: www.ninds.nih.gov/disorders/kluver_ bucy/kluver_bucy.htm.

7. DRMARKGRIFFITHS website. High performer to hyper former: a brief overview of Kluver-Bucy syndrome. Available at: drmarkgriffiths.wordpress.com/?s=kluver+bucy.

8. Nalto K, Hashimoto T, Ikeda S. Klüver-Bucy syndrome following status epilepticus associated with hepatic encephalopathy. Epilepsy Behav. 2008;12(2):337–339.

9. Kile SJ, Ellis WG, Olichney JM , et al. Alzheimer abnormalities of the amygdala with Klüver-Bucy Syndrome symptoms: an amygdaloid variant of Alzheimer’s disease.

Arch Neurol. 2009;66(1):125–129.

10. Jha S, Patel R. Some observations on the spectrum of dementia. Neurol India.

2004;52(8):213–214.

11. Bering J. Naughty by Nature. Slate. March 3, 2011. Available at: www.slate.com/ articles/health_and_science/science/2011/03/naughty_by_nature.html.

12. Devinsky J, Sacks O, Devinsky O. Kluver-Bucy syndrome, hypersexuality, and the law. Neurocase. 2010;16(2):140–145.

13. Brain Stories. What happens if amygdala is damaged? And it’s [sic] link with Klüver-Bucy syndrome. Available at: teddybrain.wordpress.com/2013/01/09/ what-happen-if-amygdala-is-damaged/.

14. Hayman LA , Rexer JL , Pavol MA , et al. Klüver-Bucy syndrome after bilateral selective damage of amygdala and its cortical connections. J Neuropsychiatry Clin Neurosci. 1998; 10:354–358.

15. Hooshmand H, Sepdham T, Vries JK . Klüver-Bucy syndrome: Successful treatment with carbamazepine. JAMA . 1974;229:1782.

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McCoy FNP-BC, CPE

by Darren

McCoy FNP-BC, CPE

by Darren

e

FRONTLiN FOCUS

e e e e e e e e e e e e e e e e

A COMPL X PAiN PATi NT iS ON WHOS COMPLAiNTS OR R QU STS/D MANDS POS A CHALL NG TO TH TR ATM NT PROTOCOLS iN A PROViD R’S PARTiCULAR PRACTiC SiT .

Some chronic pain patient visits are seemingly simple encounters.

A provider might be asked to treat a patient with arthritic knee pain in an otherwise healthy patient not old enough for knee replacement, with pain refractory to a variety of anti-inflammatories, physical therapy, and bracing, but relieved by viscosupplementation. In that case, an opioid analgesic might seem like a very reasonable treatment option.

But unfortunately, not all encounters are straightforward. Providers who encounter patients with chronic pain complaints face a multitude of challenges, among which is deciding what to do when faced with a particularly complex case. This article is designed to empower frontline healthcare providers to recognize what constitutes a complex pain patient and understand how to simplify treatment while concurrently minimizing the risk of harm to each patient, each provider, and the public at large. abstract:

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complex case is not defined by any specific disease

e

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PAiN TR ATM NT iS...DiFF R NT process. Rather, a complex pain patient is one whose com- In some ways, treating chronic pain is like treating anything plaints or requests/demands pose a challenge to the treat- else. Those of us providing healthcare services grow accusment protocols in a provider’s particular practice site. A new tomed to encountering complex situations in any clinical provider may have a sense of apprehension upon reading environment. Many patients are living longer (though not records from prior providers or when querying the state necessarily better) as a result of advances in clinical science. controlled substance databases. The patient may have been Some of those patients take a wide array of medications receiving high doses of opioids, benzodiazepines, or tran- from a variety of well-intentioned specialists. Some patients quilizing medications from a prior provider that the new clearly thrive with specific treatments, only to have insurprovider would not have initiated and is not comfortable ance coverage changes abruptly limit their access to those continuing. The patient may have multiple pain complaints treatments. that “feed” off each other, such as mechanical back pain along with an unstable ankle resulting in gait disturbance, Additional complexity comes in the form of the wide disparrequiring a cane, resulting in wrist or shoulder pain. The ities in education, motivation to change, and personalities patient may have social circumstances that posed a chal- among the population of patients we serve. For example, lenge in prior treatment; perhaps s/he was unable to be not every diabetic patient is going to be compliant with called in for a pill count due to a lack of phone service or diet, exercise, glucose monitoring, or medication managereliance on public transportation. ment. Some patients who do not seem all that knowledgeable may actually be quite receptive to instruction and, in being These situations are not usually the result of “bad people,” so, quickly earn the trust of their providers. Conversely, but rather are the natural consequences of often well-mean- other patients may be well educated and able to compreing providers becoming involved in “bad situations” that hend instruction, but turn out to be highly manipulative of could have been avoided with rational, individualized providers and office staff, thereby earning the distrust, if patient care. If cost were of no consequence, this would not outright disdain, of their providers. not be a problem. However, addressing complex situations requires time, and time equals money in our current feefor-service environment. One study of primary care providers revealed 26% of their patient load was considered to be “complex” and required significantly more time than less-complex cases. In younger patients, the complexity was usually the result of mental health problems, including substance abuse. In older patients, the complexity was the result of multiple disease processes, medical decision making, and coordination-of-care issues.1 The Institute of Medicine concluded as far back as 1999 that “fully 80% of all medical expenses can be attributed to care of individuals with serious and complex conditions.”2

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…ADDR SSiNG COMPL X SiTUATiONS R QUiR S TiM , AND TiM QUALS MON Y iN OUR CURR NT F -FORS RViC NViRONM NT.

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HOW DiD W G T H R ?

During the 1970s, ‘80s, and ‘90s, healthcare providers began to recognize the impact of undertreated chronic pain as we saw more people returning from Vietnam, the first Gulf War, etc, having survived injuries that would have been fatal in earlier battles.3 Professional organizations dedicated to pain research were formed, such as the American Pain Society in the late ‘70s, the American Academy of Pain Medicine in the early ‘80s, and the American Society of Pain Management Nursing in the early ‘90s. Meanwhile, pharmaceutical companies began offering sustained-release formulations of opioids like morphine, fentanyl, and oxycodone.

Those sustained-release opioids were heavily marketed on the idea that treating chronic pain with opioids could be done in much the same way as the medical management of other chronic diseases such as asthma, hypertension, or diabetes. Theoretically, sustained-release medication could provide the desired therapeutic effect on a steady basis, with fewer doses per day.4 In addition, pharmaceutical marketers made it a point to explain how opioids had no organ toxicities, as opposed to treatments like acetaminophen or NSAIDs. Key opinion leaders in pain specialty organizations touted a “no therapeutic limit” model of opioid medical management and persuaded thousands of providers [this writer included] to practice that way. The Congress of the United States added fuel to the fire by decreeing 2001 to 2010 to be the Decade of Pain Control and Research.5 Patients with complaints of pain were fairly easily able to find providers who specialized in the treatment of pain, who were willing to prescribe opioid analgesics to do so, and who did so vigorously. As a result, the phrase “pain management” became virtually synonymous with “opioid management” during the late 1990s and early 2000s.

Some patients and prescribers took advantage of that “no limits” prescribing mantra and of the perceived support for pain management at state and national levels. In several states, cash-only “pill mill” businesses opened. Huge quantities of opioids were trafficked through them under the guise of legitimate pain management. Consequently, many people—some of whom had legitimate pain issues—became dependent on medications while exhibiting little, if any, functional improvement. Abuse and diversion of opioids led to growing numbers of deaths,6,7 which prompted changes in federal and state and local regulations. Additionally, groups such as Physicians for Responsible Opioid Prescribing petitioned the Food and Drug Administration to greatly curtail the ability of opioids to be prescribed long-term.8

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The combination of regulatory changes and shift in societal pressures resulted in fewer providers being willing to address chronic pain in the clinical setting. As a result, it has become more challenging for those of us who remain to sift through successes and failures, to sort through research articles and attend continuing education programs, to be able to offer the most specific treatments with the fewest risks of harm to each individual patient. Good pain management requires the provider to consider the physical, social, and behavioral strengths and weaknesses of each patient. If a provider prescribes one treatment regimen to a given patient, and a different treatment to another, the provider should be able to clearly explain what difference(s) in physical, social, or behavioral factors led to that treatment difference.

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…TH PHRAS ‘PAiN MANAG M NT’ B CAM ViRTUALLY SYNONYMOUS WiTH ‘OPiOiD MANAG M NT’ DURiNG TH LAT 1990s AND ARLY 2000s.

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PHYSiCAL COMPL XiTY Sometimes the complexity of the case comes in terms of physical comorbidities that affect a patient’s ability to take advantage of otherwise reasonable therapies for a given pain complaint. For example, a patient with chronic low back pain may also suffer from a poorly healing leg wound, or Q2 | 2015

urinary/fecal incontinence, which would preclude her from participating in the aquatic PT setting that might otherwise be helpful for the back pain. A patient may have had recent coronary artery stent placement and anticoagulant therapy, preventing that patient from being able to try a spinal interventional therapy for radiculopathy. The patient may have a seizure disorder, which limits the relative safety of some neuroadjuvant medications, or cardiac conduction issues that make some medications capable of QTc prolongation (eg, methadone) more risky.

about the perceived benefits from each drug, compared to the risks of continuing something that is not really particular helpful. A provider might encounter patients who are taking tiny doses of gabapentin, say, 100 mg at bedtime, ostensibly for neuropathic pain, but who do not find it helpful. The provider may decide, with input from that patient, whether the patient would be better off stopping the gabapentin entirely vs titrating it to give it a realistic chance at relieving pain.

Adopting a “fewer doses is better” model can help simplify Changes in our society have resulted in a “graying” popula- medication complexity with opioids as well. A patient who tion, in which the average age of patients we see has gradu- takes immediate-release morphine 30 mg every 6 hours in ally crept higher and higher. These patients have had plenty addition to extended-release morphine 15 mg every 12 hours of time to be subjected to information from the internet, would be better served by rational simplification. That from direct-to-consumer advertising during their favor- patient should be able to easily switch to extended-release ite game shows, and from infomercials for “supplements” morphine 60 mg every 12 hours with 1 immediate-release intended to make a desired change easy instead of requir- 30 mg dose a day for true activity-related pain, instead ing any behavioral changes, such as supplements for weight of routine around-the-clock dosing. The total morphine reduction instead of dietary changes. These patients often equivalent would be exactly the same, with half the number see more than one provider on a regular basis, and these of doses required. providers may not have ready access to each other’s records, even in this age of electronic medical record systems. Each In a fee-for-service model, it is easier to “write and run” than provider may be practicing evidence-based medicine to “take time and talk” about these sorts of simplifying converthe best of his or her knowledge, and may be prescribing sion. Thankfully, something as simple as viewing a patient’s regimens that could be considered appropriate, in and of daily medication schedule in a calendar format (as opposed to simply as a list scrawled on the back of an envelope) can themselves, for a given disorder. make a difference in bringing the idea of “pill burden” to the Unfortunately, a given patient may accumulate a medication front of a provider’s thought process. One study from Veterlist comprised of 10, 15, or even more individual drugs to be ans Affairs showed that the way a patient’s daily medication taken on either a daily or as-needed schedule.9 While drug regimen was presented to the admitting physician made a researchers do a good job of assessing the baseline safety substantial difference in whether a patient left the hospital and efficacy of medications among volunteers with a certain taking more medications or fewer medications.10 disease state, it must be noted that clinical trials also exclude great segments of the population. Consequently, a patient who would not have been a candidate for the clinical trial SOCiAL COMPL XiTY is the very patient who ends up getting a prescription for a Sometimes the complicating factors that bring complex given medication. Even if that medication is not particularly patients to our practices are of a social nature. A previous harmful to that patient, the drug-to-drug interactions may provider may have moved away, retired, died (or, worse, mean that one medicine is ameliorating, or “blocking,” the been indicted for some prescribing issue). The patient’s effect of the other medication. That results in a waste of family may have been displaced by some variety of disastime and money. ter (earthquake, hurricane, chemical spill). Or, the patient may have a fairly straightforward pain syndrome, but simply One of the most straightforward methods of simplifying could not afford to continue to attend a private-pay practice complex cases is to reduce the number of medications a any longer. patient takes. For example, a patient who takes a daily dose of methylprednisolone from a gastroenterologist for ulcer- Unfortunately, forces exist outside the provider-patient relaative colitis would not be likely to get added benefit from tionship that may add complexity to the plan of care. Formucelecoxib from their orthopedist for arthritic pain. As long lary coverage limitations may result in a patient needing to as the steroid had already been deemed to be a necessary find a more affordable medication option. The provider may treatment and an acceptable risk for that patient, there write a prescription for different medication, only to find would be no need to add the risks of the NSAID when it people with no clinical training or expertise are on the other likely would not provide significant additional analgesia. end of the prior authorization phone line. Other patients may have transportation problems requiring them to share rides Reducing the number of medications a patient takes with other people, some of whom may find it a convenient requires providers to take time to talk to each patient way to take advantage of the patient receiving treatment for

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FRONTLINE FOCUS

pain. Multigenerational families under one roof may place teenagers within close proximity to medications intended for elderly patients.

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B HAViORAL COMPL XiTY For reasons described earlier, there is a tendency among some providers as well as patients to assume opioids are the best treatment for pain, instead of simply one category of “tools in a toolbox.” Many providers practice in such a way that each patient they treat for pain receives prescriptions for opioids—and often the exact combination of opioids and other substances, such as benzodiazepines and other tranquilizing medications. Morbidity and mortality data bear out the problem with that approach: when every patient coming into an office is able to leave with a prescription for an opioid, benzodiazepines, carisoprodol, etc, that is a clear sign that the prescriber is not actually “treating pain.” There is no way that every patient could have the same set of risk factors.

The problems that plagued the Decade of Pain Control and Research clearly revealed that prescribing opioids has risks that must not be minimized.

Additionally, governmental or corporate restrictions may limit what can be done to treat a particular patient. Laws regarding the prescribing and dispensing of controlled substances vary considerably from state to state, so a patient moving from Oklahoma to Oregon may find it difficult to find treatment that resembles that which the patient had been accustomed to receiving. Some states place limits on the total daily dose of opioids prescribed. Other states place limits on how many days’ supply may be prescribed or dispensed. Still others have placed limits on how long certain medications may be prescribed. Additionally, some pharmacy corporations have instituted company-specific limits on how many patients each store may have under a medication agreement at any one time, thereby preventing a “new” chronic pain patient from being able to easily access what may otherwise That being said, it is also true that opioids are effective pain be a very reasonable medical management regimen. relievers, and should be considered when other treatments fail. Not every patient in pain gets relief from opioids. Of Providers may be able to navigate these social complexity those who do, not all are able to appropriately handle/secure issues by getting other staff members involved in the case the medication. Of those who report relief from opioids and management process. For example, an LPN or even an unli- who prove themselves capable of appropriately handling censed member of the staff may quickly become helpful at opioids, not all exhibit functional improvement. reminding a provider which local pharmacies are easiest to work with over the phone, which insurance plans have limits No one doubts that morphine, fentanyl, or hydrocodone on commonly prescribed medications, or how far in advance have the potential to provide pain relief. What does an indito contact a public transportation service to ensure timely vidual patient do, however, once he or she has experienced arrival of the patient for their next appointment. These little that relief? Patients for whom opioids are being considered efficiencies make the management of each patient’s case a should be required to provide some concrete examples of goals they want to accomplish. Then, from the provider’s little less taxing to the provider. standpoint, documentation should include progress toward those goals. Unless pain relief translates into meaningful functional improvement and/or goal attainment—improved sleep duration or quality, improved activity tolerance, improved interpersonal relationships, etc—opioid medication should not be continued. If patients ask for continued opioid therapy despite having failed to make functional improvement, the provider would be wise to even more strongly question the motives behind the request.

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NOT V RY PATi NT iN PAiN G TS R Li F FROM OPiOiDS. OF THOS WHO DO, NOT ALL AR ABL TO APPROPRiAT LY HANDL /S CUR TH M DiCATiON.

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2. Chrvala C, Sharfstein S, eds. Definition of serious and complex medical conditions. Committee on Serious and Complex Medical Conditions, Division of Health Care Services, Institute of Medicine. Washington, DC: National Academy Press; 1999.

3. Kerns R. PTSD and pain management. VA’s latest research. Vantage Point: Dispatches from the US Department of Veterans Affairs. March 8, 2012.

Available at: www.blogs.va.gov/ VA ntage/6060/ptsd-and-pain-management-vas-latest-research/.

4. Van Zee A. The promotion and marketing of OxyContin: commercial triumph, public health tragedy. Am J Public Health. 2009;99(2):221–227.

5. 106th Congress of the United States of America, Second Session, House Resolution 3244, Title VI, section, 1603. January 24, 2000. Available at: www.gpo.gov/fdsys/pkg/BILLS -106hr3244enr/pdf/BILLS -106hr3244enr.pdf.

6. Baumblatt J, Weideman C, Dunn J, et al. High-risk use by patients prescribed opioids for pain and its role in overdose deaths. JAMA Intern Med. 2014;174(5):796–801.

Some providers seem to go out on a limb to try to “help” a patient who has not shown a willingness to put forth much effort. It is not fair for a patient to ask a provider for a sleep aid when that patient consumes a lot of caffeine or smokes routinely. It is not fair for a patient to ask for a stimulant to help with weight loss when the provider knows all it would take is a little consistent diet and activity modification for the patient to lose a pound a week. Finally, it is not fair for a patient to ask a provider to prescribe an opioid analgesic when the medical record does not indicate significant functional improvement.

CONCLUSiONS Much of the controversy in chronic pain management comes down to the answers to these questions: Are opioids appropriate, or not? If so, how much, and for how long? Pain management with opioids, even in a seemingly straightforward case, is never easy. If it were easy, there wouldn’t be over 16,000 deaths annually from opioid-related overdoses in the US.11 Each of those deaths was accompanied by some measure of physical, social, or behavioral problem that was not appropriately addressed by the prescriber, nor understood by the deceased. The answers to these questions are never set in stone. Pain management is a dynamic process. What was once appropriate for a given patient may become inappropriate based on physical, social, and/or behavioral changes in that patient’s situation. Providers must assess these risks on an ongoing basis, and adjust the treatment of each patient based on what is known about the individual patient’s functional improvement (or lack thereof). By taking advantage of every opportunity to simplify complex regimens, providers are able to reduce the burden on individual patients, and also minimize the number of medications that could potentially be diverted into the wrong hands.

7. Glover S, Girion L. Counties sue narcotics makers, alleging ‘campaign of deception’. Los Angeles Times. May 21, 2014. Available at: www.latimes. com/local/la-me-rx-big-pharma-suit-20140522-story.html#page.

8. Physicians for Responsible Opioid Prescribing. Petition to the Food and Drug Administration for changes to opioid labeling. July 25, 2012.

Available at: www.citizen.org/documents/2048.pdf.

9. Carpenter S. Treating illness is one thing. What about a problem with many? The New York Times. March 31, 2009. Available at: agenamerica. blogspot.com/2009/03/treating-illness-is-one-thing-what.html.

10. Muir A, Sanders L, Wilkinson W, et al. Reducing medication regimen complexity. J Gen Intern Med. 2001;16(2)77–82.

11. CDC . Injury prevention & control: prescription drug overdose.

Understanding the epidemic. Available at: www.cdc.gov/drugoverdose/ epidemic/index.html.

References 1. Grant R, Ashburner J, Hong C, et al. Defining patient complexity from the primary care physician’s perspective: a cohort study. Ann Intern Med. 2011;15(12):796–801.

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Seldin DPM

by Liana

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R GiONAL PAIN SYNDROM

With 26 bones, 33 joints, and more than 100 muscles, tendons, and ligaments... the human foot is a marvel in engineering.

With each step the foot absorbs approximately 2 to 3 times body weight, and during high impact activities the workload increases to 4 to 5 times body weight. With 26 bones, 33 joints, and more than 100 muscles, tendons, and ligaments functioning together at specific angles, the human foot is a marvel in engineering.1 Any malfunction in this machinery can lead to pain, which starts a chain reaction in more proximal structures as the body avoids painful weight bearing by overusing other soft tissues and bones.

Achieving good biomechanics is key to avoiding many of the common painful conditions affecting the foot and ankle. abstract:

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REGIONAL PAIN SYNDROME

he most common form of heel pain is plantar fasciitis, accounting for more than 600,000 outpatient visits annually in the United States.2 Plantar fasciitis is most often characterized by a sharp pain along the bottom of the heel, usually the medial side. The pain tends to be worse upon applying weight to the foot after a period of rest or inactivity, most often upon first getting out of bed in the morning. Many sufferers of this condition also feel the pain after long periods of walking or standing.

This condition is also known as heel spur syndrome, though a calcaneal exostosis is not always present. In fact, visualizing a calcaneal spur on radiograph does not alone lead to a diagnosis of plantar fasciitis, which is a disease of soft tissue. Up to 19% of persons without plantar fasciitis can have heel spurs. Most infracalcaneal exostoses are not situated where the foot comes in contact with the ground and therefore do not cause pain. The calcification that we identify as a plantar heel spur can arise in 5 different locations: at the insertion of the abductor digiti minimi and flexor digitorum brevis, between the plantar fascia and these muscles, and, less frequently, within the plantar fascia and at the insertion of the short plantar ligament. This extraosseous calcification represents chronic excess tension in standing and walking, and the feeling of forceful, pathologic pulling is what the patient perceives as painful. The plantar fascia is a fibrous aponeurosis that is comprised of a lateral, central, and medial band, all of which communicate posteriorly and inferior to the infamous spur to blend with the Achilles tendon. Physical exam generally is positive tightness and pain on palpation of the medial band, where it inserts into the medial calcaneal tubercle, and less often more distally as it approaches the medial portion of the arch of the foot. A majority of plantar fasciitis sufferers are found to have tightness in the Achilles tendon as well, characterized by the inability to dorsiflex the ankle joint to 90 degrees or greater passively with the knee extended. Bending the knee releases the tension of the gastrocnemius and soleus muscles, which are also less flexible in most patients with plantar fasciitis. Consequently, as these soft tissues cannot adapt effectively during gait, microtearing occurs repetitively, particularly within the plantar fascial medial band. The cycle of injury and degeneration results in a fasciosis, which some would argue is a noninflammatory condition. As the arch of the foot flattens in relation to its resting, or nonweight-bearing position, the plantar fascia is at its most tense. Therefore, a key ingredient to managing plantar fasciitis is to reestablish elasticity of the plantar fascia in hopes of minimizing the traumatic pulling at its calcaneal insertion.

In the diagnosis of plantar fasciitis, skin lesions, such as plantar warts, calluses, and fissures, should be ruled out. Radiographs should be negative for fracture or neoplasms. Numbness or paresthesias are not pathognomonic. Ultrasonography can be used to measure the thickness of the plantar fascia, which normally should be no more than 3 mm. In individuals not responding to treatment, MRI can identify rupture of the plantar fascia, calcaneal stress fractures, or atrophy of the abductor digiti minimi associated with a local nerve entrapment.

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First and foremost, patients that adhere to a stretching regimen throughout their waking hours have better relief of poststatic dyskinesia, or pain after inactivity.

Other causes of plantar heel pain include nerve entrapment neuropathies, radiculopathies, inflammatory arthridities, bone tumors, calcaneal stress fractures, rupture of the plantar fascia, trauma, skin lesions, foreign body, heel pad syndrome, and infection of soft tissue or bone.

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the components of pronation. Other methods of decreased pathologic excessive pronation include tapings or strappings and functional orthotic devices, which can reduce the strain on the plantar fascia. Additionally, merely preventing the arch from collapsing when bearing weight via a more rigid type orthosis puts the plantar fascia at a position of less tension. Accommodative or softer devices tend to work better on patients who have higher arched, more rigid type feet.3 Oral, topical, and injected anti-inflammatories also help with pain relief, though are not substitutes for stretching and correction of biomechanical factors. Physical therapy modalities, such as ultrasound, electrical stimulation, interferential therapy, massage, and contrast baths all can aide in reducing scar tissue formation, inflammation, and pain.

Limiting high impact exercises and long-term standing and walking also allow the affected tissues to heal.

TR ATM NT OF PLANTAR FASCiiTiS Management of plantar fasciitis unfortunately requires a lot of time and effort on the part of the patient. First and foremost, patients that adhere to a stretching regimen throughout their waking hours have better relief of poststatic dyskinesia, or pain after inactivity. While mostly stretches that target the plantar aspect of the foot and the Achilles tendon and gastroc-soleus complex are generally prescribed, some patients may benefit from more extensive stretching of all posterior muscle groups of the lower extremity. Both active, gentle stretching exercises and passive stretching Other treatments include platelet-rich plasma injections,4 via a plantar fascial night splint can be of great benefit to pain laser,5 cryosurgery,6 and extracorporeal shock wave a plantar fasciitis patient. Shoe gear modification is also therapy.7 important. Patients tend to feel relief with heel heights of 1.5 inches or above, mainly because the weight bearing pressures are more distributed to more distal portions of the POST RiOR H L PAiN foot, rather than onto the heel itself. Also, raising the heel Achilles tendonitis is a pain in the back of the heel, most reduces the rearfoot’s ability to move on the frontal plane, commonly at the insertion of the Achilles tendon onto the therefore decreasing the calcaneus’ ability to evert, one of calcaneus. It can present insidiously or with acute injury.

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Plain film radiographs often show a calcification at the Achilles insertion on the posterior aspect of the calcaneus.

Like plantar fasciitis, gentle stretching exercises targeting the Achilles tendon and gastroc-soleus complex help with acute cases and as prevention of recurrence. In contrast with plantar fasciitis, however, initial treatment often entails immobilization, usually with a controlled ankle motion (CAM ) walker boot until pain is significantly improved, followed by physical therapy modalities. Recalcitrant cases can be treated with extracorporeal shock wave therapy, platelet-rich plasma injections, laser, and surgery.

increase in the divergence of the talus and calcaneus. The lateral view reveals a plantarflexion deformity of the talus, a decrease in the lateral talocalcaneal angle, the collapse of the longitudinal arch, a variable increase in the talo-first metatarsal angle, and sag at the talonavicular, naviculocuneiform, or metatarsalcuneiform joints. Decrease in the distance from the medial cuneiform to the floor compared with the contralateral foot also has been described. With advanced deformity, narrowing of the talonavicular and subtalar joints may be seen. Anterior posterior radiographs of the ankles may reveal tibiotalar arthritis, talar tilt, and calcaneofibular impingement in severe deformities. MRI is the method of choice to evaluate pathologic conditions of the posterior tibial tendon.

ARCH PAiN Plantar fasciitis can also present as pain along the arch when more distal portions of the plantar fascia are affected. In Treatments include oral or topical anti-inflammatories, addition, inflammation along the course of the tibialis pos- immobilization with a controlled ankle motion fracture terior tendon at its distal course and into its insertion along boot, cast immobilization, or physical therapy, and, for the medial aspect of the navicular bone can produce pain, long-term treatment or prevention of recurrence, functional which can often be confused with plantar fasciitis. Tibi- orthotics, ankle/foot orthoses, and surgical intervention are alis posterior dysfunction is associated with rheumatoid recommended. arthritis, injuries such as ankle sprains, diabetes, peripheral neuropathy, hypertension, obesity, or can be of idiopathic origin. Tibialis posterior tendon dysfunction can also PAiN iN TH FOR FOOT produce pain behind the medial malleolus of the ankle, in Several conditions produce pain in the “ball of the foot” and contrast with plantar fasciitis; it also tends to be more symp- are quite similar in presentation and treatment. Metatartomatic as the patient spends more time on his or her feet, salgia is pain with inflammation of the head of the affected rather than upon first bearing weight after a period of rest. metatarsal bone. Several factors can lead to metatarsalgia, Many patients with tibialis posterior dysfunction notice including high impact activities, ill-fitting shoes, excessively falling arches, or flattening of the affected foot over time. high heeled shoes, other foot deformities, such as a bunion On physical exam, patients may be unable to lift the back or arthritic condition that leads to excess pressures being of the foot standing on the affected leg. This is referred to applied to the neighboring metatarsals, being overweight, as a single leg heel rise test. and rigid cavus foot type.

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Tibialis posterior dysfunction is a degenerative process that Treatments consist of addressing any biomechanical causes consists of stages as described by Johnson and Strom.8 In with change in shoe gear and functional orthoses, paddings, stage I the length of the tendon is normal, although mild strappings, anti-inflammatories, physical therapy modalidegeneration is present. There is medial foot and ankle ties, and surgery.10 pain, swelling, and mild weakness, but no deformity. The single limb heel rise is painful, but normal. As the disease Neuroma is a condition that often mimics metatarsalgia in progresses to the second stage, a flexible planovalgus foot is presentation. The main difference is in the nature of the noted. The tendon is ruptured or functionally incompetent pain as more of a burning pain, tingling, and numbness in and shows more advanced degeneration. The “too many 1 or 2 of the toes. In both instances the patient may describe a toes sign” is present, indicating secondary deformity of the sensation of “stepping on a pebble,” especially when walking midfoot. The patient will be unable to perform a single limb barefoot, but neuroma is generally accompanied by sympheel rise, but the hindfoot remains flexible. In stage III all toms that extend distally to the toes. A neuroma is defined the signs of stage II are present, except that some component as a perineural fibroma of an intermetatarsal plantar nerve, of the hindfoot deformity is rigid. In advanced disease, there most commonly of the second and third intermetatarsal may be lateral abutment pain at the calcaneal-fibular area.8 spaces. Many sources do not consider it a true tumor. On In stage IV, later added by Myerson, there is a valgus tilt of physical exam direct pressure between the metatarsal heads the talus in the ankle mortise leading to lateral tibiotalar will replicate the symptoms, as will compression of the foredegeneration.9 In plain film radiography, there may be no foot between the finger and thumb so as to compress the distinct abnormalities in the early stages. With increasing transverse arch of the foot (Mulder’s sign), or deviation of deformity, the anterior posterior view of the foot will show the affected toes on the transverse plane (cigar sign), more lateral subluxation of the talonavicular joint. There is an notably when the forefoot is loaded or when the patient is increase in the talo-first metatarsal angle, as well as an examined standing on the affected foot.

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Treatment usually begins with anti-inflammatories, either systemic, topical, or injected. If symptoms recur, the affected nerve can be denatured with alcohol sclerosing injections11 or ablated with cryosurgery.12 Shoe gear modification and orthotic devices can be beneficial. Surgical excision is also an option.13 Differential diagnoses include capsulitis, intermetatarsal bursitis, and Freiberg’s disease (osteochondritis of the metatarsal head).

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PAiNFUL FOOT D FORMiTi S Hammertoes are contractures of the proximal interphalangeal joints of the toes, which can be painful at the dorsal aspect of the joint due to irritation from closed shoes; the tip or distal pulp of the toe because of weight-bearing pressure applied to a portion of the toe that is not anatomically equipped to accept the weight; or at the plantar aspect of the forefoot due to retrograde buckling of the proximal phalanx onto the head of the metatarsal. Hammertoes are either flexible or rigid and occur as a result of abnormal function of the tendons to the toes. Hammertoes are of genetic origin or can occur from trauma or arthritis. Friction from shoes or walking produces calluses, redness, and swelling.

biomechanics, and injury to the joint. It is a degenerative arthritis that is not age-related.

Conservative treatments for all of these foot deformities involve shoe modifications, accommodative paddings, orthotic devices, and anti-inflammatories as needed. Unfortunately, no bracing, strapping, or exercise can straighten a rigid bony deformity. In some pediatric cases, or in very flexible early onset of hammertoes, manual manipulation and splinting can reduce contractures. Surgical correction is indicated with failure of conservative therapies.

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STR SS FRACTUR S Stress fractures result from accumulated trauma from repeated submaximal loading, such as running or jumping.14 Because of this mechanism, stress fractures are common overuse injuries in athletes. Patients will complain of increasing pain with increasing activity. While the pain may subside with rest, it can be constantly present with more serious bone injury. There is usually an area of localized tenderness on or near the bone and generalized swelling to the area. Many times, stress fractures may not be seen on plain film radiographs, but subtleties, such as thickening of the bone cortex, can lead to a diagnosis. Ultrasonography,15 CT, or MRI will provide better visualization of stress fractures.

Treatments consist of adjusting the type of shoe, paddings, anti-inflammatories, and surgical correction.

Treatment consists of rest, ice, compression, elevation (or RICE); immobilization such as with a CAM walker or surMallet toes are contractures of the distal interphalangeal gical shoe or cast, and physical therapy after immobilizajoints, and clawtoes refer to involvement of both interpha- tion. Functional orthotics may be helpful in prevention of langeal joints. reinjury. Athletes are encouraged to modify their exercise programs. Moderate stress applied to the bone in a conHallux abductovalgus, or bunion, is a painful condition of trolled manner can strengthen the bone and make it less the first metatarsal-phalangeal joint. A bunion is actually susceptible to a stress fracture. an increased angle between the first and second metatarsals, leading to deviation, or in extreme cases, subluxation of the first metatarsal-phalangeal joint. The medial portion CONCLUSiON of the first metatarsal head that no longer articulates with Many painful foot and ankle conditions are attributed to the hallux proximal phalanx protrudes medially, causing anatomical deformities or acute and chronic injuries. The the visible “bump.” Over time, this incongruous joint can key to fast resolution is early diagnosis, treatment, and modbecome arthritic. Also, subchondral cysts can form especially ification of activities. on the medial eminence. The bony protrusion can be painful in closed shoes.

Hallux limitus refers to arthritis of the first metatarsalphalangeal joint that is often confused for hallux abductovalgus. In this condition, the bump is on the dorsal aspect of the big toe joint, and, as the name implies, patients find that over time, the first metatarsal-phalangeal joint loses range of motion. The end stage of this condition is hallux rigidus. With complete loss of motion due to ankylosis of the first metatarsal-phalangeal joint, patients may present without pain despite pretty remarkable radiographs. Hallux limitus/rigidus mainly is a result of structural deformities, such as either too long or too short first metatarsal, poor Q2 | 2015

References 1. Banks AS, Downey MS, Martin DE . McGlamry’s Comprehensive Textbook of Foot and Ankle Surgery. third ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.

2. Cole C, Seto C, Gazewood J. Plantar fasciitis: evidence-based review of diagnosis and therapy. Am Fam Physician. 2005;72(11):2237–2242.

3. Caselli M, Sobel E. What are the best orthotics for plantar fasciitis.

Podiatry Today. 2001;14(12).

4. Akşahin E, Doğruyol D, Yüksel HY, et al. The comparison of the effect of corticosteroids and platelet-rich plasma (PRP) for the treatment of plantar fasciitis. Arch Orthop Trauma Surg. 2012;132(6):781–785.

www.painweek.org | PWJ | 49

(fenoprofen calcium capsules, USP) 200 mg and 400 mg

Rx ONLY

REGIONAL PAIN SYNDROME

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 JR , Malanga GAinhibition , Krause DA ,Results et al.in A randomized conmode of action is unknown, 5. but it isBasford thought that prostaglandin synthetase is involved. humans demonstrate that fenoprofen has both antiinflammatory and analgesic trolled actions. Theevaluation emergence and degree of erythemic response weretherapy: measured in adult male volunteers exposed to ultraviolet irradiaof low-intensity laser plantar fasciitis. tion. The effects of Nalfon, aspirin, and indomethacin were each compared with those of a placebo. All 3 drugs demonstrated antierythemic activity. In all paArch Phys Med Rehabil.

1998;79(3):249–254. tients 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 , Fallat LM , Schwartz SM . Cryosurgery: innovative 6. in Allen corticosteroids has been studied patients BH with rheumatoid arthritis.

The studies, however, were inadequate in an 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 technique the Intreatment of plantar J Foot Ankle Surg. corticosteroid has a “steroid-sparing” effect isfor unknown. patients with osteoarthritis, the fasciitis. 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 2007;46(2):75–79. 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 7. activity,Buchbinder but mild gastrointestinal reactions (nausea, dyspepsia)J,andettinnitus occurred less frequently in patients treated with Nalfon R, Ptasznik R, Gordon al. Ultrasound-guided 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 extracorporeal shockinwave therapy forin total plantar fasciitis: randomNalfon has produced a reduction in pain intensity, an increase pain relief, improvement analgesia scores, anda 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. . 2002;288(11):1364–1372. ized controlled Good dose proportionality was observed between 200trial. mg andJAMA 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 KAsuppression , StromofDE . Tibialis posterior tendon dysfunction.

Johnson not interfere with absorption8. of Nalfon.

There is less collagen-induced platelet aggregation with single doses of Nalfon than there is with aspirin.

INDICATIONS AND USAGEClin Carefully considerRelat the potential and risks of Nalfon and other treatment options before deciding to use Nalfon. Use the Orthop Res.benefits 1989;239:196–206. 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 in patients shown hypersensitivity to fenoprofen calcium.

Nalfon should not be given to patients , Titlewho CIhave , Myerson MS . Posterior tibial tendon 9. is contraindicated Bluman EM who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to a refined classification system.

Ankle Clin.– Preexisting Asthma). Nalfon is contraNSAIDs have been reportedrupture: in such patients (see WARNINGS – Anaphylactoid Reactions,Foot and PRECAUTIONS indicated for the treatment of2007;12(2):233–249. 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 an increased of serious cardiovascular (CV)Deformities thrombotic events, infarction, and stroke, which can be 10. shown Kelikian H. risk Hallux Valgus: Allied of myocardial the Forefoot and 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 : WB Saunders; 1965. second ed.

Philadelphia, greater risk. To minimize theMetatarsalgia. potential risk for an adverse CV event in patients treated with anPA 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 thrombotic events associated with NSAID use. The concurrent GLCV. The treatment of intermetatarsal neuro-use of aspirin and an NSAID does in11. Dockery crease the risk of serious GI events (see WARNINGS - Gastrointestinal Effects). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatmas with 4% alcohol sclerosing J Footinfarction Ankleand Surg. ment of pain in the first 10-14 days following CABG surgery found an increasedinjections. incidence of myocardial 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 1999;38(6):403–408. 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 , Fallat Savoy-Moore Cryogenic neuroabla12.

Caporusso taking NSAIDs. Nalfon should be used with caution inEF patients with LM fluid ,retention, compromised R. cardiac function or heart failure. The possibility of renal involvement should be considered.

Effects –of Risk of Ulceration, Bleeding, and Perforation NSAIDs, including Nalfon, can cause serious tionGastrointestinal for the treatment lower extremity neuromas.

J Foot Ankle Surg. gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can 2002;41(5):286–290. 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, . Theat some causative in morton’s 13. Mulder increasing the likelihood of developing a seriousJD GI event time duringmechanism the course of therapy.

However, evenmetatarsalshort-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 gia. J Bonebleeding Jointwho Surg Br. 1951;33-B(1):94–95. peptic ulcer disease and/or gastrointestinal 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 14.

Viladotpatients A, Viladot Jr A. Stress fractures the foot.

Foot Ankle of fatal GI events are in elderly or de-bilitated and therefore, special care should be taken inintreating 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 Surg.

1998:4(1);3–11. 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 necro15. toxicity Banal F, been Gandjbakhch Foltz et al. Sensitivity and role in the maintenance of renal sis and other renal injury. Renal has also seen in patients inF,whom renalV,prostaglandins have a compensatory perfusion. In these patients,specificity administration ofof a nonsteroidal anti-inflammatoryin drug may cause a dose-dependent reduction in prostaglandin formation and, ultrasonography early diagnosis of metatarsal secondarily, in renal blood flow, which may precipitate overt renal decomposition. Patients at greatest risk of this reaction are those with impaired renal funcbonethose stress a pilot study 37 Discontinuation patients. JofRheumatol. tion, heart failure, liver dysfunction, takingfractures: diuretics and ACE-inhibitors, and theof elderly.

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 2009;36(8):1715–1719. 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 | albumin PWJbinding | www.painweek.org fenoprofen from plasma 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

50

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.

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NALFON ®

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

Learn More.

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

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*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

WWW. PAINEDUCATORS. References ORG 1. Wk Prescription Sales Data, 2012 2. Podiatry Today, Vol. 19, Issue 3

3. Nalfon Package Insert, July 2009 Be more than an informed clinician.

Manufactured for: Xspire Pharma Ridgeland, MS 39157 Rev. 08/2012

4. Medispan, 2012

Q2 | 2015

(fenoprofen calcium capsules) 400 mg Fast and Effective, Move On With Nalfon Safety Information Nalfon® is indicated for relief of mild to moderate pain in adults and for relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis.

Cardiovascular Risk • Non-steroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).

• Nalfon® is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms.

Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

Nalfon® is contraindicated in patients who have shown hypersensitivity to fenoprofen calcium. Nalfon® should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. Nalfon® is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. Nalfon® is contraindicated in patients with a history of significantly impaired renal function.

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. After observing the response to initial therapy with Nalfon, the dose and frequency should be adjusted to suit an individual patient's needs.

Request Information and Rx Co-pay Cards* Scan the QR code to request more information on Nalfon or to request co-pay cards. Your patients will pay no more than $15 on co-pays up to $50. *Valid for Initial Script and 5 Refills. View Complete Details.

Copyright © 2014, Xspire Pharma, Ridgeland, MS 39157

42195-308-09

(fenoprofen calcium capsules) 400 mg

What makes NALFON a unique and different non-steroidal anti-inflammatory patient option?

NALFON is Safe...

During clinical studies, Nalfon had less than 2% discontinuation rate due to gastrointestinal adverse reactions.

NALFON is Effective...

• Nalfon has more clinician use and prescriptions than any other branded NSAID with over 40 years of use and in excess of 37 million prescriptions.

• Nalfon reaches peak plasma levels within 2 hours of administration.

Peak Levels (2 hours)

0

1

2

3

90% of a single oral dose is eliminated within 24-hours as fenoprofen glucuronicle and 4-hydroxfenoprofen glucuronide, the majority urinary metabolites of fenoprofen.

4

5

6

7

8

9

NALFON is Flexible...

Unlike other commonly prescribed NSAIDs with QID dosing, Nalfon is dosed TID for better patient compliance.

NALFON is Cost Effective...

• Nalfon is covered by 90% of all commercial plans with a patient co-pay.

• Nalfon is covered by Medicare-D plans and Tri-Care.

• Only Nalfon offers patients a “Pay No More Than $15” instant pharmacy rebate.

Safety Information Nalfon® is indicated for relief of mild to moderate pain in adults and for relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis.

Cardiovascular Risk • Non-steroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).

• Nalfon® is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

For more information on Nalfon 400 mg, visit www.nalfon.com

(fenoprofen calcium capsules) 400 mg TM

Technology

• Nalfon is the only fenoprofen calcium available in a capsule preparation.

• Nalfon is rapidly absorbed with a 30-minute onset of action.

• Nalfon is readily bound to plasma proteins at 99%.

Recommended Dosing Carefully consider the potential benefits and risks of Nalfon and other treatment options before deciding to use Nalfon. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

Nalfon is indicated: • For relief of mild to moderate pain in adults.

• For relief of the signs and symptoms of rheumatoid arthritis.

• For relief of the signs and symptoms of osteoarthritis.

After observing the response to initial therapy with Nalfon, the dose and frequency should be adjusted to suit an individual patient's needs.

• The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity of the symptoms.

• Total daily dosage should not exceed 3200 mg.

• Nalfon may be administered with meals or with milk.

• The smallest dose that yields acceptable control should be employed.

(feno

profen calcium capsule s) 400 m

Disp

* NALFON 400 mg EP 123

*Not actual size

Use this Nalfon 400 mg capsule for identification.

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90 C aps Take 1 Cap Q8 H PRN rs Pain Infla a n d mma tion

Contraindications Nalfon® is contraindicated in patients who have shown hypersensitivity to fenoprofen calcium. Nalfon® should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. Nalfon® is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. Nalfon® is contraindicated in patients with a history of significantly impaired renal function.

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

After observing the response to initial therapy with Nalfon, the dose and frequency should be adjusted to suit an individual patient's needs.

Nalfon ©2011 is a registered trademark of Xspire Pharma.

WraSer Pharmaceuticals R1NF0210ZJ02

NALFON ®

(fenoprofen calcium capsules, USP) 200 mg and 400 mg

Rx ONLY

Cardiovascular Risk • Non-Steroidal Anti-Inflammatory (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (See WARNINGS).

• Nalfon® is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at great-er risk for serious gastrointestinal events (see WARNINGS).

DESCRIPTION Nalfon® (fenoprofen calcium capsules, USP) is a nonsteroidal, anti-inflammatory, antiarthritic drug. Nalfon capsules contain fenoprofen calcium as the dihydrate in an amount equivalent to 200 mg (0.826 mmol) or 400 mg (1.65 mmol) of fenoprofen. The 200 mg capsules contain cellulose, gelatin, iron oxides, silicone, titanium dioxide, and other inactive ingredients. The 400mg capsules contain gelatin, sodium lauryl sulfate, iron oxide yellow, FD&C Blue 1, titanium dioxide, FD&C Red 40, crospovidone, talc, and magnesium stearate. Chemically, Nalfon is an arylacetic acid derivative. Nalfon is a white crystalline powder that has the structural formula C30H26CaO6•2H2O representing a molecular weight of 558.65. At 25°C, it dissolves to a 15 mg/mL solution in alcohol (95%). It is slightly soluble in water and insoluble in benzene. The pKa of Nalfon is a 4.5 at 25°C. CLINICAL PHARMACOLOGY Nalfon is a nonsteroidal, anti-inflammatory, antiarthritic drug that also possesses analgesic and antipyretic activities. Its exact mode of action is unknown, but it is thought that prostaglandin synthetase inhibition is involved. Results in humans demonstrate that fenoprofen has both antiinflammatory and analgesic actions. The emergence and degree of erythemic response were measured in adult male volunteers exposed to ultraviolet irradiation. The effects of Nalfon, aspirin, and indomethacin were each compared with those of a placebo. All 3 drugs demonstrated antierythemic activity. In all patients with rheumatoid arthritis, the anti-inflammatory action of Nalfon has been evidenced by relief of pain, increase in grip strength, and reductions in joint swelling, duration of morning stiffness, and disease activity (as assessed by both the investigator and the patient). The anti-inflammatory action of Nalfon has also been evidenced by increased mobility (i.e., a decrease in the number of joints having limited motion). The use of Nalfon in combination with gold salts or corticosteroids has been studied in patients with rheumatoid arthritis. The studies, however, were inadequate in demonstrating whether further improvement is obtained by adding Nalfon to maintenance therapy with gold salts or steroids. Whether or not Nalfon used in conjunction with partially effective doses of a corticosteroid has a “steroid-sparing” effect is unknown. In patients with osteoarthritis, the anti-inflammatory and analgesic effects of Nalfon have been demonstrated by reduction in tenderness as a response to pressure and reductions in night pain, stiffness, swelling, and overall disease activity (as assessed by both the patient and the investigator). These effects have also been demonstrated by relief of pain with motion and at rest and increased range of motion in involved joints. In patients with rheumatoid arthritis and osteoarthritis, clinical studies have shown Nalfon to be comparable to aspirin in controlling the aforementioned measures of disease activity, but mild gastrointestinal reactions (nausea, dyspepsia) and tinnitus occurred less frequently in patients treated with Nalfon than in aspirin-treated patients. It is not known whether Nalfon causes less peptic ulceration than does aspirin. In patients with pain, the analgesic action of Nalfon has produced a reduction in pain intensity, an increase in pain relief, improvement in total analgesia scores, and a sustained analgesic effect. Under fasting conditions, Nalfon is rapidly absorbed, and peak plasma levels of 50 μg/mL are achieved within 2 hours after oral administration of 600 mg doses.

Good dose proportionality was observed between 200 mg and 600 mg doses in fasting male volunteers. The plasma half-life is approximately 3 hours. About 90% of a single oral dose is eliminated within 24 hours as fenoprofen glucuronide and 4'-hydroxyfenoprofen glucuronide, the major urinary metabolites of fenoprofen. Fenoprofen is highly bound (99%) to albumin. The concomitant administration of antacid (containing both aluminum and magnesium hydroxide) does not interfere with absorption of Nalfon. There is less suppression of collagen-induced platelet aggregation with single doses of Nalfon than there is with aspirin.

INDICATIONS AND USAGE Carefully consider the potential benefits and risks of Nalfon and other treatment options before deciding to use Nalfon. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Nalfon is indicated: • For relief of mild to moderate pain in adults. • For relief of the signs and symptoms of rheumatoid arthritis. • For relief of the signs and symptoms of osteoarthritis.

CONTRAINDICATIONS Nalfon is contraindicated in patients who have shown hypersensitivity to fenoprofen calcium. Nalfon should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS – Anaphylactoid Reactions, and PRECAUTIONS – Preexisting Asthma). Nalfon is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Nalfon is contraindicated in patients with a history of significantly impaired renal function (see WARNINGS – Advanced Renal Disease).

WARNINGS - CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may give a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS - Gastrointestinal Effects). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension NSAIDs, including Nalfon, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Nalfon, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Nalfon should be used with caution in patients with fluid retention, compromised cardiac function or heart failure. The possibility of renal involvement should be considered. Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation NSAIDs, including Nalfon, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.

NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or de-bilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decomposition. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of Nalfon in patients with advanced renal disease. There-fore, treatment with Nalfon is not recommended in patients with advanced renal disease. (See CONTRAINDICATIONS).

Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Nalfon. Nalfon should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS - Preexisting Asthma).

Emergency help should be sought in cases where an anaphylactoid reaction occurs. Skin Reactions NSAIDs, including Nalfon, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hyper-sensitivity. Pregnancy Starting at 30-weeks gestation, Nalfon and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. Ocular Studies to date have not shown changes in the eyes attributable to the administration of Nalfon. However, adverse ocular effects have been observed with other anti-inflammatory drugs. Eye examinations, therefore, should be performed if visual disturbances occur in patients taking Nalfon. Central Nervous System Caution should be exercised by patients whose activities require alertness if they experience CNS side effects while taking Nalfon. Hearing Since the safety of Nalfon has not been established in patients with impaired hearing, these patients should have periodic tests of auditory function during prolonged therapy with Nalfon.

PRECAUTIONS - General Nalfon cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of Nalfon in reducing inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Nalfon. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Nalfon. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Nalfon should be discontinued. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including Nalfon. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Nalfon, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Nalfon who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Nalfon should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Information for Patients - Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. 1. Nalfon, like other NSAIDs, may cause serious CV side effects, such as myocardial infarction (MI) or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). 2. Nalfon, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can oc-

cur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS - Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation).

3. Nalfon, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hy-persensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. 5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. 6. Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). 7. Starting at 30-weeks gestation, Nalfon and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur.

Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically.

If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Nalfon should be discontinued.

Drug Interactions - ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. Aspirin The coadministration of aspirin decreases the biologic half-life of fenoprofen because of an increase in metabolic clearance that results in a greater amount of hydroxylated fenoprofen in the urine. Although the mechanism of interaction between fenoprofen and aspirin is not totally known, enzyme induction and displacement of fenoprofen from plasma albumin binding sites are possibilities. As with other NSAIDs, concomitant administration of fenoprofen calcium and aspirin is not generally recommended because of the potential of increased adverse effects. Diuretics Clinical studies, as well as post marketing observations, have shown that Nalfon can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has

been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS - Renal Effects), as well as to assure diuretic efficacy. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. Phenobarbital Chronic administration of phenobarbital, a known enzyme inducer, may be associated with a decrease in the plasma half-life of fenoprofen. When phenobarbital is added to or withdrawn from treatment, dosage adjustment of Nalfon may be required. Plasma Protein Binding In vitro studies have shown that fenoprofen, because of its affinity for albumin, may displace from their binding sites other drugs that are also albumin bound, and this may lead to drug interactions. Theoretically, fenoprofen could likewise be displaced. Patients receiving hydantoins, sulfonamides, or sulfonylureas should be observed for increased activity of these drugs and, therefore, signs of toxicity from these drugs. Drug/Laboratory Test Interactions Amerlex-M kit assay values of total and free triiodothyronine in patients receiving Nalfon have been reported as falsely elevated on the basis of a chemical cross-reaction that directly interferes with the assay. Thyroidstimulating hormone, total thyroxine, and thyrotropin-releasing hormone response are not affected. Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of fenoprofen. Studies have not been conducted to determine the effect of fenoprofen on mutagenicity or fertility.

Pregnancy - Teratogenic Effects. Pregnancy Category - C Prior to 30-Weeks Gestation; Category D starting at 30-Weeks Gestation.

Starting at 30-weeks gestation, Nalfon and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. Nalfon can cause fetal harm when administered to a pregnant woman starting at 30-weeks gestation. If this drug is used during this time period in pregnancy, the patient should be apprised of the potential hazard to a fetus. There are no adequate and well-controlled studies in pregnant women. Prior to 30-weeks gestation, Nalfon should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities when given daily oral doses of 50 or 100 mg/kg fenoprofen calcium, respectively (0.15 and 0.6 times the maximum human daily dose of 3,200 mg based on body surface area comparisons). However, animal reproduction studies are not always predictive of human response. Nonteratogenic Effects Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Labor and Delivery The effects of Nalfon on labor and delivery in pregnant women are unknown. In rat studies, maternal exposure to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, increased the incidence of dystocia, delayed parturition, and decreased pup survival. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Nalfon, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness in pediatric patients under the age of 18 have not been established.

Geriatric Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

ADVERSE REACTIONS During clinical studies for rheumatoid arthritis, osteoarthritis, or mild to moderate pain and studies of pharmacokinetics, complaints were compiled from a checklist of potential adverse reactions, and the following data emerged. These encompass observations in 6,786 patients, including 188 observed for at least 52 weeks. For comparison, data are also presented from complaints received from the 266 patients who received placebo in these same trials. During short-term studies for analgesia, the incidence of adverse reactions was markedly lower than that seen in longer-term studies. Adverse Drug Reactions Reported in >1% of Patients During Clinical Trials Digestive System— During clinical trials with Nalfon, the most common adverse reactions were gastrointestinal in nature and occurred in 20.8% of patients receiving Nalfon as compared to 16.9% of patients receiving placebo. In descending order of frequency, these reactions included dyspepsia (10.3% Nalfon vs. 2.3% placebo), nausea (7.7% vs. 7.1%), constipation (7% vs. 1.5%), vomiting (2.6% vs. 1.9%), abdominal pain (2% vs. 1.1%), and diarrhea (1.8% vs. 4.1%). The drug was discontinued because of adverse gastrointestinal reactions in less than 2% of patients during premarkeing studies. Nervous System —The most frequent adverse neurologic reactions were headache (8.7% vs. 7.5%) and somnolence (8.5% vs.

6.4%). Dizziness (6.5% vs. 5.6%), tremor (2.2% vs. 0.4%), and confusion (1.4% vs. none) were noted less frequently. Nalfon was discontinued in less than 0.5% of patients because of these side effects during premarketing studies. Skin and Appen-dages—Increased sweating (4.6% vs.

0.4%), pruritus (4.2% vs. 0.8%), and rash (3.7% vs. 0.4%) were reported. Nalfon was discontinued in about 1% of patients because of an adverse effect related to the skin during premarketing studies. Special Senses—Tinnitus (4.5% vs. 0.4%), blurred vision (2.2% vs. none), and decreased hearing (1.6% vs. none) were reported. Nalfon was discontinued in less than 0.5% of patients because of adverse effects related to the special senses during premarketing studies. Cardiovascular—Palpitations (2.5% vs. 0.4%). Nalfon was discontinued in about 0.5% of patients because of adverse cardiovascular reactions during premarketing studies. Miscellaneous—Nervousness (5.7% vs. 1.5%), asthenia (5.4% vs. 0.4%), peripheral edema (5.0% vs. 0.4%), dyspnea (2.8% vs. none), fatigue (1.7% vs. 1.5%), upper respiratory infection (1.5% vs.

5.6%), and nasopharyngitis (1.2% vs. none). Adverse Drug Reactions Reported in <1% of Patients During Clinical Trials Digestive System—Gastritis, peptic ulcer with/without perforation, gastrointestinal hemorrhage, anorexia, flatulence, dry mouth, and blood in the stool.

Increases in alkaline phosphatase, LDH, SGOT, jaundice, and cholestatic hepatitis, aphthous ulcerations of the buccal mucosa, metallic taste, and pancreatitis (see PRECAUTIONS). Cardiovascular—Atrial fibrillation, pulmonary edema, electrocardiographic changes, and supraventricular tachycardia. Genitourinary Tract—Renal failure, dysuria, cystitis, hematuria, oliguria, azotemia, anuria, interstitial nephritis, nephrosis, and papillary necrosis (see WARNINGS). Hypersensitivity—Angioedema (angioneurotic edema). Hematologic—Purpura, bruising, hemorrhage, thrombocytopenia, hemolytic anemia, aplastic anemia, agranulocytosis, and pancytopenia. Nervous System—Depression, disorientation, seizures, and trigeminal neuralgia. Special Senses—Burning tongue, diplopia, and optic neuritis. Skin and Appendages—Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, and alopecia. Miscellaneous—Anaphylaxis, urticaria, malaise, insomnia, tachycardia, personality change, lymphadenopathy, mastodynia, and fever.

OVERDOSAGE Signs and Symptoms—Symptoms of overdose appear within several hours and generally involve the gastrointestinal and central nervous systems. They include dyspepsia, nausea, vomiting, abdominal pain, dizziness, headache, ataxia, tinnitus, tremor, drowsiness, and confusion. Hyperpyrexia, tachycardia, hypotension, and acute renal failure may occur rarely following overdose. Respiratory depression and metabolic acidosis have also been reported following overdose with certain NSAIDs.Treatment—To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Con-trol Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal. Alkalinization of the urine, forced diuresis, peritoneal dialysis, hemodialysis, and charcoal hemoperfusion do not enhance systemic drug elimination.

DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of Nalfon and other treatment options before deciding to use Nalfon. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with Nalfon, the dose and frequency should be adjusted to suit an individual patient's needs. Analgesia For the treatment of mild to moderate pain, the recommended dosage is 200 mg given orally every 4 to 6 hours, as needed. Rheumatoid Arthritis and Osteoarthritis For the relief of signs and symptoms of rheumatoid arthritis or osteoarthritis the recommended dose is 400 to 600 mg given orally, 3 or 4 times a day. The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity of the symptoms. Dosage adjustments may be made after initiation of drug therapy or during exacerbations of the disease. Total daily dosage should not exceed 3,200 mg. Nalfon may be administered with meals or with milk. Although the total amount absorbed is not affected, peak blood levels are delayed and diminished. Patients with rheumatoid arthritis generally seem to require larger doses of Nalfon than do those with osteoarthritis. The smallest dose that yields acceptable control should be employed. Although improvement may be seen in a few days in many patients, an additional 2 to 3 weeks may be required to gauge the full benefits of therapy.

HOW SUPPLIED Nalfon® (fenoprofen calcium capsules, USP) are available in: The 200 mg* capsule is opaque yellow No. 97 cap and opaque white body, imprinted with “RX681” on the cap and body. NDC 42195-308-10 Bottles of 100. The 400 mg* capsule is opaque green cap and opaque blue body, imprinted with “NALFON 400 mg” on the cap and “EP 123” on the body. NDC 42195-308-09 Bottles of 90 *Equivalent to fenoprofen. Preserve in well-closed containers. Store at 20° - 25° C (68° - 77° F). (See USP Controlled Room Temperature).

ATTENTION DISPENSER: Accompanying Medication Guide must be dispensed with this product.

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

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

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

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

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

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

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1 |

4 |

Interventional Pain Management: Too Much or Too Little?

Jeffrey A. Gudin, MD

Ilene R. Robeck, MD

There have been controversies about interventional techniques to treat pain.

When you look at the data that show no significant long-term benefit from these procedures it looks at outcomes from patients. These aren’t curative procedures but are certainly palliative in nature and make patients feel better. We need to better define the outcomes of these procedures. We need to be clear on the appropriate indications for doing procedures such epidural or facet joint or trigger point injections. How do we know when they’ve been beneficial and, even more importantly—or maybe most importantly—how do you know when to stop doing these things?

Not every patient with pain is a candidate for an interventional procedure. When it comes to the most common procedures like epidural steroid injection we really like to stratify our patients to those who we think might benefit from the procedure.

2 |

Myofascial Pain Syndromes R. Norman Harden, MD

Myofascial pain syndrome is a very common diagnosis in pain clinics.

We know that probably 85% of the people seen in a tertiary care pain clinic have myofascial pain syndrome either as a primary or a secondary diagnosis. Pretty much everything that we see, such as radiculopathy and nerve damage into the leg, is going to be associated ultimately with bracing and spasm of the muscles around the back—which ultimately lead to myofascial pain syndrome. So it’s very, very common. It’s also easy to identify and treat. On examination, you’ll find taut bands of muscle and in the middle of the taut band you’ll find trigger points. As you push on the point, it’s going to trigger a sensory phenomena elsewhere, usually a referred pain phenomena.

Treatment of myofascial pain syndrome is relatively simple physical therapy. Stretching, strengthening, postural correction, some hands-on techniques like myofascial release are very, very effective.

3 |

Facilitating Treatment Adherence in Pain Medicine Robert Newlin Jamison, PhD

I think it’s very important to track patients placed on opioids because these are medications that are unfortunately prone to misuse. So very careful monitoring that includes risk assessment at the very beginning and then periodic tracking with compliance checklists or urine screens is indicated. Information technology can augment that tracking by keeping people in contact while they’re in their normal environment and saving that information for their providers. We’re doing a comprehensive study with primary care physicians where we’re tracking their chronic pain patients on medication, and we’re finding that if primary care providers get periodic information about how the patients are doing and have contact with the pain specialist, they feel more confident that they can manage these patients and they can manage opioid therapy associated with the treatment Q2 | 2015

The Power of Groups: Driving Better Outcomes in Pain Management

We just don’t have enough clinicians.

Initially [the VA] thought of a group as a way to make better use of our scarce resources. But what we found is that the groups took on a life of their own in a very positive way. So now we have a pain school where we educate patients/family members about all aspects of pain in a group setting, and patients can also learn from one another. We do group cognitive behavioral therapy classes. We run an opioid safety class. We find that patients in this setting are more participatory in physical therapy, more active in terms of getting back to their lives. What I’ve seen as a clinician is that when you have somebody who’s had chronic pain and they start to have small successes, the ability to share those successes becomes therapeutic in and of itself.

There’s an excitement to sharing that’s really, I think, part of the human spirit. The groups started as a matter of necessity but have turned into something that frequently works better than one-on-one.

5 |

Marijuana and Pain Medicine: The Present and The Future Michael E. Schatman, PhD, CPE, DASPE

Cannabidiol is the future of pain medicine in that there are no side effects other than some mild anxiolysis. It has an empirical basis that is growing, particularly in pain medicine. In rat models we’ve found that cannabidiol actually turbo charges chemotherapy. It mitigates the nausea associated with it and, very importantly, it mitigates the peripheral neuropathy which 30% to 40% of all chemotherapy patients experience. A lot of patients quit chemotherapy and choose to die just because of the side effects. With cannabidiol we can get our patients to reduce their levels of opioids because of the synergy between cannabidiol and opioids, which has been empirically established. We’re just beginning to touch the surface, but physicians can’t ignore it. To do so is unethical and the AMA enjoins physicians to look at all treatment options.

6 |

Exploring Schadenfreude in the Context of Pain Therapy Richard H. Smith, PhD

We typically assume that if someone is in physical pain our automatic reaction should be empathy. That is a natural response. But there are going to be cases that provoke a different reaction. We may actually feel good about the misfortune. When asked to think about it, the clinician may be able to recount such instances—cases where they may not have felt good about someone suffering, but they didn’t feel quite so bad; that is, their empathy level was not as high. Maybe the patient is just a constant complainer about all kinds of pains. Maybe there is a feeling that pain is deserved because clinical advice has been ignored. Or there may be occasions where the patient/client relationship is the source of grief for the practitioner, and they just may not care that much about the person’s situation. And in the context of pain management, when this occurs, it has implications for how folks who are in pain are cared for. To cope with schadenfreude, it may help to acknowledge the feeling. www.painweek.org | PWJ | 55

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30 minutes

Listening to music or stories for

helped distract children from their pain1

33.2 11.6

P E R C E N T

[ In 2012 ]

P E R C E N T

of adults and

of children used complimentary health approaches—such as herbal supplements, yoga, and osteopathic manipulation2

89 patients

in an 8-week meditation program had significantly reduced pain when compared to a group just exercising3

More than

Methodone's higher risk ratio translates to

40%

72

of people with chronic pain say sleep difficulties interfere with their work

excess deaths per every

That number drops to

10,000

17%

of those without pain7

person-years of treatment 4

Nearly 1 in 4 people with chronic pain—

23 25% 6 P E R C E N T

of drug users report continuing to abuse OxyContin® despite package labeling that emphasizes its abuse-deterrent properties5

Although 72% of primary care physicians are aware of state databases that track drug prescriptions, only

53% have actually used them, and more than 1/5 indicated they were not aware of their state’s program at all6

—say they've been diagnosed with a sleep disorder compared with just

P E R C E N T

of people without chronic pain7

50% – 70% of patients with neuropathic pain conditions complain of significant sleep disturbance8

1. http://ow.ly/NJPEc 2. http://ow.ly/NJPJQ 3. http://ow.ly/NJPSe 4. http://ow.ly/NJPXm 5. http://ow.ly/NJQ3m 6. http://ow.ly/NJRXt 7. http://ow.ly/NJSmX 8. http://ow.ly/NJSxs

56 | PWJ | www.painweek.org

Q2 | 2015

The national conference on pain for frontline practitioners.

Scientific Session Chair, Joseph V. Pergolizzi, MD, and Co-chair, Srinivas Nalamachu, MD, invite you to submit abstracts for scientific posters to be presented at the 2015 National Conference.

Plan now to have your poster included! More than 2000 clinicians are gathering to foster solutions to the problem of inadequate pain control. Abstracts may be research oriented or evidence-based and relevant to frontline practitioners who treat patients in pain.

Submission Please visit www.painweek.org/scientificposters/call-for-poster-abstracts to submit abstracts electronically. The deadline for electronic submission is 5:00p Eastern, July 31. All authors will be notified via email on or around August 14.

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with

Beth Darnall PhD

Beth Darnall is a Clinical Associate Professor at Stanford University School of Medicine, Anesthesiology, Perioperative and Pain Medicine, in Palo Alto, California.

58 | PWJ | www.painweek.org

Q2 | 2015

“…I would say my patients are among my greatest mentors.”

What inspired you to become a healthcare provider?

through patient care was critical—so in that regard I would say my patients are among my greatest mentors.

I had a circuitous route into psychology and did not have a grand plan for the future until I was on postdoctoral fellowship at Johns Hopkins University.

At Hopkins, I was working with patients with catastrophic burn, amputation, spinal cord injury, and major medical concerns that required inpatient rehabilitation. From the start I was very comfortable working with people who were suffering. I found that patients readily responded to me, and this positive response validated my knowledge that I was working in the right space.

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

Why did you focus on pain management?

The field of pain has always been a natural home for me. While I love working with patients in clinic, I spend a great deal of my time conducting research studies, providing public education, and publishing because these activities allow me to reach more people and have greater impact. I have been developing video treatments, and I love that this format will allow countless patients to access specific psychobehavioral treatment.

Who were your mentors?

Dr. Stephen Wegener at Johns Hopkins University.

I also hold in high esteem several nonclinical mentors, including Dr. Lerita Coleman Brown and Dr. Tonya Palermo. Ultimately, the collective wisdom I gained

Q2 | 2015

I wear a lot of hats already: pain psychologist, NIH -funded researcher, Psychology Today columnist, and author. I recall knowing at age 11 that I would become a writer one day, but I am surprised at how it has manifested in my life. Last year I published Less Pain, Fewer Pills, and I am now writing a second book, focusing on catastrophizing in the context of pain, health, and life.

I was a semiprofessional runner and cyclist earlier in life. I was an ultramarathon trail runner when I won my first research grant in 2006. I promptly gave up competitive racing to focus on my career in pain. I still love to run, but now I do so purely for fun and relaxation, with no deadlines or performance demands—I have enough of those in other areas of my life!!

What is your most marked characteristic?

I most admire compassion in others and, while I would like to claim that as my most marked characteristic, the characteristic that others most identify in me is passion. Along with passion I would also throw in persistence, because I would have achieved little in life if I had stopped when I received the first, second, or 100th “No.”

www.painweek.org | PWJ | 59

PUNDIT PROFILE/BETH DARNALL

“[My most marked characteristic] is passion. Along with passion I would also throw in persistence, because I would have achieved little in life if I had stopped when I received the first, second, or 100th ‘No.’”

What do you consider your greatest achievement?

Overcoming fear, because it is requisite for risk-taking. To accomplish great things in life, one must repeatedly take big risks.

What is your favorite language?

The unspoken languages of emotion and energy that are interpersonally communicated: love, compassion, simpatico energy…

If you had to choose one book, one film, and one piece of music to take into space for an undetermined amount of time, what would they be?

Book: Women Who Run With the Wolves

by Clarissa Pinkola Estés.

What would you like your legacy to be?

My goal has always been to help empower others to manifest their highest potential and mission in life. Pain can stand as a critical barrier to fulfilling one’s life mission, so I am committed to helping dismantle this barrier by helping to provide rapid access to low cost, high quality pain care to all.

Knowing that I have helped another is tremendously rewarding, and even more so when the ripple-effect is considered. Each of us truly has the capacity to change the world.

What is your motto?

Have faith in yourself and, above all, live passionately.

Film: The Matrix.

Song: Imagine by John Lennon.

I love media that expand thinking around possibilities, challenge assumptions, and inspire positive change from within and without.

60 | PWJ | www.painweek.org

Q2 | 2015

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 Daily dose

Day 1

Day 2

Days 3-6

Days 7-10

Days 11-14

Day 15

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) ≥ 60 30-60 < 30 Patients receiving hemodialysis

GRALISE dose (once daily with evening meal) 1800 mg 600 mg to 1800 mg GRALISE should not be administered 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 Drug patients with events per 1000 patients Relative risk: incidence of events in drug patients/incidence in placebo patients Risk difference: additional drug patients with events per 1000 patients

1.0 3.4

5.7 8.5

1.0 1.8

2.4 4.3

3.5

1.5

1.9

1.8

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 Ear and Labyrinth Disorders Vertigo Gastrointestinal Disorders Diarrhea Dry mouth Constipation Dyspepsia General Disorders Peripheral edema Pain

GRALISE N = 359, %

Placebo N = 364, %

1.4

0.5

3.3 2.8 1.4 1.4

2.7 1.4 0.3 0.8

3.9 1.1

0.3 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 gabapentininduced pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known whether gabapentin has the ability to increase cell proliferation in other cell types or in other species, including humans.

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

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

GRALISE is indicated for the management of postherpetic neuralgia (PHN).

When your PHN patients face challenges by Night and Day

GRALISE THE NIGHT

& RELEASE THE DAY

NIGHTTIME

DAYTIME

TAKE WITH

EVENING MEAL

Once-daily GRALISE delivers 24-hour pain control, Night and Day1 • At night, when pain is at its worst 1

• Side effects that are transient1

• GRALISE is taken with the evening meal

• Dizziness (10.9%) and somnolence (4.5%) were the most common side effects, and declined during the 2-week titration period to reach sustained low levels thereafter

• In clinical trials, 9.7% of GRALISE patients

discontinued prematurely due to adverse reactions versus 6.9% for placebo4

Elderly patients experienced consistent results by Night and Day - even those over 753

• Dosage adjustment of GRALISE is necessary in patients with impaired renal function.

GRALISE should not be administered in patients with creatinine clearance <30 mL/min or in patients undergoing hemodialysis. Reductions in GRALISE dose should be made in patients with age-related compromised renal function.

Indication 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.

Important Safety Information Antiepileptic drugs, including gabapentin, the active ingredient of GRALISE, increase the risk of suicidal thoughts or behavior. Increased seizure frequency may occur in patients with seizure disorders if GRALISE is rapidly discontinued. Withdraw GRALISE gradually over a minimum of 1 week. The most common adverse reaction to GRALISE (≥5% and twice placebo) is dizziness.

Please see adjacent page for Brief Summary of Prescribing Information. Full Prescribing Information and Medication Guide are available at GRALISE.com.

References: 1. Argoff CE, Chen C, Cowles VE. Clinical development of a once-daily gastroretentive formulation of gabapentin for treatment of postherpetic neuralgia: an overview. Expert Opin Drug Deliv.

2012;9:1147-1160. 2. Data on file, 2013. Depomed Inc. 3. Gupta A, Li S. Safety and efficacy of once-daily gastroretentive gabapentin in patients with postherpetic neuralgia aged 75 years and over. Drugs Aging.

2013;30:999-1008. 4. GRALISE [prescribing information]. Newark, CA: Depomed Inc.; December 2012. © April 2015, Depomed Inc. All rights reserved. APL-GRA-0173

FOR NIGHT & DAY