PAINWeek Journal Vol 5, Q2 by PAINWeek

vol. 5 q 2 2017

arachnoiditis: taming the painful shrew p.20 abuse deterrent formulations p.30 diligence and documentation: managing the risks of prescribing controlled substances p.52 not so toxic after all! botulinum toxins in chronic pain management p.60

2017 PaiNWeeK SCHeDULe aT a GLaNCe

p.43

TIME TO DUAL

TW O O NE SOURCES SOURCE

OF PAIN OF RELIEF NUCYNTA® ER is the first and only FDA-approved long-acting opioid designed to control both nociceptive pain and the neuropathic pain associated with diabetic peripheral neuropathy (DPN). Not an actual patient.

Visit Nucynta.com for more information and to download a NUCYNTA® ER savings card

INDICATIONS AND USAGE Limitations of Use NUCYNTA ER is an opioid agonist indicated for the management of: • Because of the risks of addiction, abuse, and misuse with opioids, • pain severe enough to require daily, around-the-clock, longeven at recommended doses, and because of the greater risks of term opioid treatment and for which alternative treatment overdose and death with extended-release opioid formulations, options are inadequate reserve NUCYNTA ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate• neuropathic pain associated with diabetic peripheral release opioids) are ineffective, not tolerated, or would be neuropathy (DPN) severe enough to require daily, around-theotherwise inadequate to provide sufficient management of pain. clock, long-term opioid treatment and for which alternative treatment options are inadequate. • NUCYNTA ER is not indicated as an as-needed (prn) analgesic. NUCYNTA® ER IMPORTANT SAFETY INFORMATION WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE- THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning. • NUCYNTA ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1) • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow NUCYNTA ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (5.2) • Accidental ingestion of NUCYNTA ER, especially in children, can result in fatal overdose of tapentadol. (5.2) • Prolonged use of NUCYNTA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be lifethreatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (5.3). • Instruct patients not to consume alcohol or any products containing alcohol while taking NUCYNTA ER because co-ingestion can result in fatal plasma tapentadol levels. (5.4) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.4), (7).

Please see additional Important Safety Information, including BOXED WARNING, and Brief Summary on the following pages.

NUCYNTA® ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) CONTRAINDICATIONS NUCYNTA ER is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected gastrointestinal obstruction, including paralytic ileus • Hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product. • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse NUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse. Because extendedrelease products such as NUCYNTA 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 tapentadol 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 NUCYNTA ER, and monitor all patients receiving NUCYNTA ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Abuse or misuse of NUCYNTA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tapentadol and can result in overdose and death. Opioid are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA ER. Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential. Overestimating the NUCYNTA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in respiratory depression and death due to an overdose of tapentadol. Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal

opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol. Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUCYNTA ER with benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs. Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of NUCYNTA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: NUCYNTA ER treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of NUCYNTA ER.

NUCYNTAÂŽ ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Alternatively, consider the use of non-opioid analgesics in these patients. Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tapentadol with serotonergic drugs.Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). This may occur within the recommended dosage range. See Warnings and Precautions in full Prescribing Information for a list of symptoms associated with Serotonin Syndrome. Discontinue NUCYNTA ER if serotonin syndrome is suspected. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Severe Hypotension NUCYNTA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of NUCYNTA ER. In patients with circulatory shock, NUCYNTA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA ER in patients with circulatory shock. Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), NUCYNTA ER may reduce respiratory

drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of NUCYNTA ER in patients with impaired consciousness or coma. Risks of Use in Patients with Gastrointestinal Conditions NUCYNTA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The tapentadol in NUCYNTA ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Increased Risk of Seizures in Patients with Seizure Disorders The tapentadol in NUCYNTA ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA ER therapy. Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA ER. In these patients, mixed agonists/ antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing NUCYNTA ER, gradually taper the dose. Do not abruptly discontinue NUCYNTA ER. Risks of Driving and Operating Machinery NUCYNTA ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA ER and know how they will react to the medication. Risk of Toxicity in Patients with Hepatic Impairment A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA ER in patients with severe hepatic impairment. Reduce the dose of NUCYNTA ER in patients with moderate hepatic impairment. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA ER. Risk of Toxicity in Patients with Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known. ADVERSE REACTIONS In clinical studies, the most common (â&#x2030;Ľ10%) adverse reactions were nausea, constipation, vomiting, dizziness, somnolence, and headache.

NUCYNTAÂŽ ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) Select Postmarketing Adverse Reactions Anaphylaxis, angioedema, and anaphylactic shock have been reported very rarely with ingredients contained in NUCYNTA ER. Advise patients how to recognize such reactions and when to seek medical attention. Panic attack has also been reported. DRUG INTERACTIONS Alcohol See BOXED WARNING. Benzodiazepines and Other Central Nervous System (CNS) Depressants See BOXED WARNING. Serotonergic Drugs See Warnings and Precautions. Monoamine Oxidase Inhibitors (MAOIs) See Contraindications. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics May reduce the analgesic effect of NUCYNTA ER and/or precipitate withdrawal symptoms. Avoid concomitant use. Muscle Relaxants See BOXED WARNING and Warnings and Precautions. Diuretics Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when NUCYNTA ER is used concomitantly with anticholinergic drugs. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. NUCYNTA ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Labor or Delivery Opioids cross the placenta and may produce respiratory depression in neonates. NUCYNTA ER is not recommended for use in pregnant women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including NUCYNTA ER, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. Lactation Because of the potential for serious adverse reactions including excess sedation and respiratory depression in a breastfed infant, advise patients that breast feeding is not recommended during treatment with NUCYNTA ER.

Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible. Pediatric Use The safety and efficacy of NUCYNTA ER in pediatric patients less than 18 years of age have not been established. Geriatric Use Elderly patients (aged 65 or older) may have increased sensitivity to tapentadol. In general, use caution when selecting a dosage for an elderly patient. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of NUCYNTA ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression. Hepatic Impairment Use of NUCYNTA ER in patients with severe hepatic impairment is not recommended. In patients with moderate hepatic impairment, dosage reduction of NUCYNTA ER is recommended. Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment is not recommended. DRUG ABUSE AND DEPENDENCE See BOXED WARNING OVERDOSAGE In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. Please see Brief Summary, including BOXED WARNING, on the following pages.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This does not include all the information needed to use NUCYNTA ER safely and effectively. See full Prescribing Information for NUCYNTA ER. INDICATIONS AND USAGE NUCYNTA ER (tapentadol) 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 • neuropathic pain associated with diabetic peripheral neuropathy (DPN) severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Usage • 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 (see Warnings and Precautions), reserve NUCYNTA 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. • NUCYNTA ER is not indicated as an as-needed (prn) analgesic. WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning. • NUCYNTA ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1) • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow NUCYNTA ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (5.2) • Accidental ingestion of NUCYNTA ER, especially in children, can result in fatal overdose of tapentadol. (5.2) • Prolonged use of NUCYNTA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (5.3). • Instruct patients not to consume alcohol or any products containing alcohol while taking NUCYNTA ER because co-ingestion can result in fatal plasma tapentadol levels. (5.4) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.4), (7). CONTRAINDICATIONS NUCYNTA ER is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected gastrointestinal obstruction, including paralytic ileus • Hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product (see Adverse Reactions). • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (see Drug Interactions). WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse NUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as NUCYNTA 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 tapentadol present (see Drug Abuse and Dependence). Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA ER. 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 NUCYNTA ER, and monitor all patients receiving NUCYNTA ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of NUCYNTA ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA ER, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA ER along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of NUCYNTA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tapentadol and can result in overdose and death (see Overdosage). Opioid are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA 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). Contact the local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, 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). 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 NUCYNTA ER, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression especially within the first 24-72 hours of initiating therapy with and following dosage increases of NUCYNTA ER. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential (see Dosage and Administration). Overestimating the NUCYNTA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in respiratory depression and death due to an overdose of tapentadol. Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see Use in Specific Populations, Patient Counseling Information). Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol (see Clinical Pharmacology). Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUCYNTA ER with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see Drug Interactions). If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see Drug Interactions and Patient Counseling Information). Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of NUCYNTA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: NUCYNTA ER treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of NUCYNTA ER (see Warnings and Precautions). Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients (see Warnings and Precautions). Alternatively, consider the use of non-opioid analgesics in these patients. Monitor such patients closely, particularly when initiating and titrating NUCYNTA ER and when NUCYNTA ER is given concomitantly with other drugs that depress respiration (see Warnings and Precautions). Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tapentadol with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic

an aff tra inh su ma Se ag blo inc vo ho Dis Ad Ca fol ma an ins so rep ad fun ad av ass Se NU an ab blo (e. the of va us Ris He In (e. NU fur an Op the Ris NU ga Th Op tra Inc Th pa oth se W Av bu wh ag an an W Ad an Ris NU po W tol me Ris A he in wi wi Ph for titr Ris Us no glu me AD Th de •A •L •N •I a

antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) (see Drug Interactions). This may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue NUCYNTA ER if serotonin syndrome is suspected. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Severe Hypotension NUCYNTA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) (see Drug Interactions). Monitor these patients for signs of hypotension after initiating or titrating the dosage of NUCYNTA ER. In patients with circulatory shock, NUCYNTA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA ER in patients with circulatory shock. Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), NUCYNTA ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of NUCYNTA ER in patients with impaired consciousness or coma. Risks of Use in Patients with Gastrointestinal Conditions NUCYNTA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The tapentadol in NUCYNTA ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Increased Risk of Seizures in Patients with Seizure Disorders The tapentadol in NUCYNTA ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA ER therapy. Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA ER. In these patients, mixed agonists/ antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms (see Drug Interactions). When discontinuing NUCYNTA ER, gradually taper the dose (see Dosage and Administration). Do not abruptly discontinue NUCYNTA ER (see Drug Abuse and Dependence). Risks of Driving and Operating Machinery NUCYNTA ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA ER and know how they will react to the medication (see Patient Counseling Information). Risk of Toxicity in Patients with Hepatic Impairment A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA ER in patients with severe hepatic impairment. Reduce the dose of NUCYNTA ER in patients with moderate hepatic impairment (see Dosage and Administration and Clinical Pharmacology). Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA ER. Risk of Toxicity in Patients with Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known (see Clinical Pharmacology). ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse (see Warnings and Precautions) • Life-Threatening Respiratory Depression (see Warnings and Precautions) • Neonatal Opioid Withdrawal Syndrome (see Warnings and Precautions) • Interaction with Benzodiazepine or Other CNS Depressants (see Warnings and Precautions)

• Serotonin Syndrome (see Warnings and Precautions) • Adrenal Insufficiency (see Warnings and Precautions) • Severe Hypotension (see Warnings and Precautions) • Gastrointestinal Adverse Reactions (see Warnings and Precautions) • Seizures (see Warnings and Precautions) • Withdrawal (see Warnings and Precautions) Clinical Trial Experience Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA ER in Patients with Chronic Pain due to Low Back Pain or Osteoarthritis The most common adverse reactions (reported by ≥10% in any NUCYNTA ER dose group) were: nausea, constipation, dizziness, headache, and somnolence. The most common reasons for discontinuation due to adverse reactions in eight Phase 2/3 pooled studies reported by ≥1% in any NUCYNTA ER dose group for NUCYNTA ER- and placebo-treated patients were nausea (4% vs. 1%), dizziness (3% vs. <1%), vomiting (3% vs. <1%), somnolence (2% vs. <1%), constipation (1% vs. <1%), headache (1% vs. <1%), and fatigue (1% vs. <1%), respectively. Please see full Prescribing Information for ADRs occurring in ≥ 1% of patients. Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA ER in Patients with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy The most commonly reported ADRs (incidence ≥10% in NUCYNTA ER-treated subjects) were: nausea, constipation, vomiting, dizziness, somnolence, and headache. Please see full Prescribing Information for ADRs occurring in ≥ 1% of patients. Postmarketing Experience The following adverse reactions have been identified during post approval use of tapentadol. Psychiatric disorders: hallucination, suicidal ideation, panic attack Serotonin syndrome: Cases of serotonin syndrome, a potentially lifethreatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in NUCYNTA ER. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids (see Clinical Pharmacology). DRUG INTERACTIONS Clinically Significant Drug Interactions with NUCYNTA ER Alcohol Clinical Impact:

Concomitant use of alcohol with NUCYNTA ER can result in an increase of tapentadol plasma levels and potentially fatal overdose of tapentadol. Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy. Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Due to additive pharmacologic effect, the concomitant use of Impact: benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical The concomitant use of opioids with other drugs that affect Impact: the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.6]. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue NUCYNTA ER if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical MAOI interactions with opioids may manifest as serotonin Impact: syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]. Intervention: Do not use NUCYNTA ER in patients taking MAOIs or within 14 days of stopping such treatment Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical May reduce the analgesic effect of NUCYNTA ER and/or Impact: precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Tapentadol may enhance the neuromuscular blocking action of Impact: skeletal muscle relaxants and produce an increased degree of respiratory depression.

NUCYNTA ER (tapentadol) extended-release tablets, CII BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION (continued) Muscle Relaxants (continued) Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of NUCYNTA ER and/or the muscle relaxant as necessary. Diuretics Clinical Opioids can reduce the efficacy of diuretics by inducing the Impact: release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical The concomitant use of anticholinergic drugs may increase Impact: risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when NUCYNTA ER is used concomitantly with anticholinergic drugs. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome (see Warnings and Precautions). The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy can occur regardless of the health of the mother or the use of medications. 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. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly (see Warnings and Precautions). Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psychphysiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. NUCYNTA ER is not recommended for use in pregnant women during and immediately prior to labor. Opioid analgesics, including NUCYNTA ER, can prolong labor. Lactation Risk Summary There is insufficient/limited information on the excretion of tapentadol in human or animal breast milk. Physicochemical and available pharmacodynamic/toxicological data on tapentadol point to excretion in breast milk and risk to the breastfeeding child cannot be excluded. Because of the potential for serious adverse reactions including excess sedation and respiratory depression in a breastfed infant, advise patients that breast feeding is not recommended during treatment with NUCYNTA ER. Clinical Considerations Monitor infants exposed to NUCYNTA ER through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible. Pediatric Use The safety and efficacy of NUCYNTA ER in pediatric patients less than 18 years of age have not been established. Geriatric Use Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of NUCYNTA ER, 28% (1023/3613) were 65 years and over, while 7% (245/3613) were 75 years and over. No overall differences in effectiveness or tolerability were observed between these patients and younger patients. Elderly patients (aged 65 or older) may have increased sensitivity to tapentadol. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of NUCYNTA ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression (see Warnings and Precautions). Hepatic Impairment Use of NUCYNTA ER in patients with severe hepatic impairment (ChildPugh Score 10-15) is not recommended. In patients with moderate hepatic impairment (Child-Pugh Score 7 to 9), dosage reduction of NUCYNTA ER is recommended (see Dosage and Administration). Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) is not recommended. DRUG ABUSE AND DEPENDENCE Controlled Substance NUCYNTA ER contains tapentadol, a Schedule II controlled substance.

Abuse NUCYNTA ER contains tapentadol, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. NUCYNTA ER can be abused and is subject to misuse, addiction, and criminal diversion (see Warnings and Precautions). The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse. 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. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers, and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers 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. NUCYNTA ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal 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. Risks Specific to Abuse of NUCYNTA ER NUCYNTA ER is for oral use only. Abuse of NUCYNTA ER poses a risk of overdose and death. The risk is increased with concurrent use of NUCYNTA ER with alcohol and other central nervous system depressants. With intravenous abuse the inactive ingredients in NUCYNTA ER can result in local tissue necrosis, infection, pulmonary granulomas, embolism and death, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Dependence 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 dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. NUCYNTA ER should not be abruptly discontinued (see Dosage and Administration). If NUCYNTA ER is abruptly discontinued in a physicallydependent patient, a withdrawal 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 Use in Specific Populations). OVERDOSAGE Clinical Presentation Acute overdosage with NUCYNTA ER can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

eXeCUTiVe eDiTOR KEViN L. ZACHAROFF md, facpe, facip, faap

eeK

PUBLiSHeR PAINW

ART DiReCTOR DARRYL FOSSA

eDiTORiAL DiReCTOR DeBRA WeiNeR eDiTOR HOLLY CASTeR

Charles E. Argoff md, cpe Professor of Neurology Albany Medical College Department of Neurology Director Comprehensive Pain Center Albany Medical Center Department of Neurology Albany, ny Paul Arnstein rn, phd, acns-bc, fnp-c, faan Clinical Nurse Specialist for Pain Relief Massachusetts General Hospital Boston, ma Said R. Beydoun md, faan Professor of Neurology Director of the Neuromuscular Program Keck Medical Center of University of Southern California Los Angeles, ca Jennifer Bolen jd Founder Legal Side of Pain Knoxville, tn Paul J. Christo md, mba Associate Professor Johns Hopkins University School of Medicine Department of Anesthesiology and Critical Care Medicine Baltimore, md Michael R. Clark MD mph, mba Vice Chair, Clinical Affairs Johns Hopkins University School of Medicine Department of Psychiatry and Behavioral Sciences Director, Pain Treatment Programs Johns Hopkins Medical Institutions Department of Psychiatry and Behavioral Sciences Baltimore, md Geralyn Datz phd Affiliate University of Southern Mississippi Department of Psychology Clinical Director Southern Behavioral Medicine Associates Hattiesburg, ms

eDiTORiAL BOARD

Peter A. Foreman dds, daapm Consultant Rotorua Hospital and Private Practice Rotorua, New Zealand Gary W. Jay md, faapm, facfei Clinical Professor Department of Neurology Division: Headache University of North Carolina Chapel Hill, nc Mary Lynn McPherson pharmd, bcps, cpe, faspe Professor and Vice Chair University of Maryland School of Pharmacy Department of Pharmacy Practice and Science Hospice Consultant Pharmacist Baltimore, md Srinivas Nalamachu md Clinical Assistant Professor Kansas University Medical Center Department of Rehabilitation Medicine Kansas City, ks President and Medical Director International Clinical Research Institute Overland Park, ks Bruce D. Nicholson md Clinical Associate Professor Department of Anesthesia Penn State College of Medicine Hershey Medical Center Hershey, pa Director of Pain Specialists Lehigh Valley Health Network Department of Anesthesiology Allentown, pa

Marco Pappagallo md Director of Medical Intelligence Grünenthal usa Bedminster, nj Director Pain Management & Medical Mentoring New Medical Home for Chronic Pain New York, ny Steven D. Passik phd VP, Scientific Affairs, Education, and Policy Collegium Pharmaceuticals, Inc. Canton, ma Joseph V. Pergolizzi md Chief Operating Officer nema Research Inc. Naples, fl Robert W. Rothrock pa-c, mpa University of Pennsylvania Department of Anesthesiology and Critical Care Pain Medicine Division Philadelphia, pa Michael E. Schatman phd, cpe, daspe Editor-in-Chief Journal of Pain Research Adjunct Clinical Assistant Professor Tufts University School of Medicine Department of Health & Community Medicine Boston, ma Sanford M. Silverman md, pa CEO and Medical Director Comprehensive Pain Medicine Pompano Beach, fl Thomas B. Strouse md Medical Director Stewart and Lynda Resnick Neuropsychiatric Hospital at ucla Los Angeles, ca

Copyright © 2017, PAINWeek, a division of Tarsus Medical Group. The opinions stated in the enclosed printed materials are those of the authors and do not necessarily represent the opinions of PAINWeek or its publication staff. PAINWeek does not give guarantees or any other representation that the printed material contained herein is valid, reliable, or accurate. PAINWeek does not assume any responsibility for injury arising from any use or misuse of the printed materials contained herein. The printed materials contained herein are assumed to be from reliable sources, and there is no implication that they represent the only, or best, methodologies or procedures for the pain condition discussed. It is incumbent upon the reader to verify the accuracy of any diagnosis and drug dosage information contained herein, and to make modifications as new information arises. All rights are reserved by PAINWeek to accept, reject, or modify any advertisement submitted for publication. It is the policy of PAINWeek to not endorse products. Any advertising herein may not be construed as an endorsement, either expressed or implied, of a product or service.

vol. 5 q 2 2017

20 30 52 60 71 72 73 74 76

neurology

arachnoiditis: taming the painful shrew

by forest tennant

pharmacotherapy

abuse deterrent formulations

by sanford m. silverman

medical/legal

diligence and documentation: managing the risks of prescribing controlled substances

by michael c. barnes

key topic

not so toxic after all! botulinum toxins in chronic pain management

by ramon l. cuevas-trisan

pw next generation

with ravi prasad

clinical pearls

by douglas gourlay

pain by numbers one-minute clinician

with steven stanos, phyllis l. hendry, sophia sheikh, debra b. gordon, daniel clauw, ignacio badiola, peter yi

pundit profile

with theresa mallick-searle

2017 PaiNWeeK SCHeDULe aT a GLaNCe 10

PWJ | www.painweek.org

P. 43

Q2 | 2017

A treatment for opioid-induced constipation (OIC) for your adult patients with chronic non-cancer pain (CNCP) that may help them

GO LIKE CLOCKWORK RELISTOR tablets* deliver a reliable, rapid response, that may give your adult patients relief from OIC they can count on 1,2

% Achieved at least 3 SBMs† per week over 4 weeks

HOURS

vs 38% taking placebo (P=.005)1,2

4 4 HOURS

Patients experienced % relief within 4 hours of dosing

27% of dosing days vs 18% with placebo (P=.0001)2

HOURS

The only PAMORA not metabolized via the CYP3A4 pathway

PAMORA, peripherally acting mu-opioid receptor agonist; SBM, spontaneous bowel movement. * Three 150-mg tablets (450 mg total) once daily in the morning with water on an empty stomach at least 30 minutes before the first meal of the day.1 †

HOURS

No pharmacokinetic drug-drug interactions1

Defined as bowel movement without the use of any laxative in previous 24 hours.1

STUDY DESIGN

In a 4-week, randomized, multicenter, HOURS double-blind, placebo-controlled, phase 3 study, the efficacy of RELISTOR tablets was evaluated in 401 patients (200 RELISTOR tablets, 201 placebo) with CNCP for which they were taking opioids. All patients had OIC, defined as <3 SBMs per week and at least one additional symptom of constipation.1,2

INDICATION • RELISTOR is an opioid antagonist. RELISTOR tablets are indicated for the treatment of opioid-induced constipation (OIC) in adults with chronic non-cancer pain.

IMPORTANT SAFETY INFORMATION - RELISTOR 150-mg tablets, for oral use • RELISTOR tablets are 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 tablets 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 tablets in patients who develop this symptom. • If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR tablets and consult their healthcare provider. • Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR tablets. 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 tablets with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal. • In a clinical study, the most common adverse reactions for RELISTOR tablets (≥ 2% of RELISTOR patients and at a greater incidence than placebo) in patients with

chronic non-cancer pain were: abdominal pain (14%), diarrhea (5%), headache (4%), abdominal distention (4%), vomiting (3%), hyperhidrosis (3%), anxiety (2%), muscle spasms (2%), rhinorrhea (2%), and chills (2%). • The use of RELISTOR tablets during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier. Advise pregnant women of the potential risk to a fetus. Because of the potential for serious adverse reactions, including opioid withdrawal, in breastfed infants, advise women that breastfeeding is not recommended during treatment with RELISTOR tablets. • A dosage reduction of RELISTOR tablets is recommended in patients with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute as estimated by Cockcroft-Gault). No dosage adjustment of RELISTOR tablets is needed in patients with mild renal impairment. • A dosage reduction of RELISTOR tablets is recommended in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. No dosage adjustment of RELISTOR tablets is needed in patients with mild hepatic impairment (Child-Pugh Class A). To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Please see Brief Summary for RELISTOR tablets on adjacent page and full Prescribing Information at relistor.com. REFERENCES: 1. RELISTOR [prescribing information]. Bridgewater, NJ: Salix Pharmaceuticals. 2. Data on file, Salix Pharmaceuticals.

Tablets

The safety of RELISTOR injection was evaluated in a double-blind, placebocontrolled trial in adult patients with OIC and chronic non-cancer pain receiving opioid analgesia. This study (Study 2) included a 4-week, doubleblind, placebo-controlled period in which adult patients were randomized to receive RELISTOR injection 12 mg subcutaneously 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 injection 12 mg subcutaneously was administered less frequently than the recommended dosage regimen of 12 mg once daily. The most common adverse reactions in adult patients with OIC and chronic non-cancer pain receiving RELISTOR injection are shown in Table 5. The adverse reactions in the table below may reflect symptoms of opioid withdrawal.

BRIEF SUMMARY OF PRESCRIBING INFORMATION This Brief Summary does not include all the information needed to use RELISTOR safely and effectively. See full prescribing information for RELISTOR. RELISTOR (methylnaltrexone bromide) 150 mg tablets, for oral use. RELISTOR (methylnaltrexone bromide) injection, for subcutaneous use. 8 mg/0.4 mL methylnaltrexone bromide in single-dose pre-filled syringe. 12 mg/0.6 mL methylnaltrexone bromide in a single-dose pre-filled syringe, or single-dose vial. Initial U.S. Approval: 2008 INDICATIONS AND USAGE RELISTOR is an opioid antagonist. RELISTOR tablets and RELISTOR injection are indicated for the treatment of opioid-induced constipation (OIC) in adults with chronic non-cancer pain. RELISTOR injection is also indicated for the treatment of OIC in adults with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Limitations of Use: Use beyond four months has not been studied in the advanced illness population. CONTRAINDICATIONS RELISTOR tablets and injection are contraindicated in patients with known or suspected mechanical gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation. WARNINGS AND PRECAUTIONS Gastrointestinal Perforation Consider the overall risk benefit in patients with known or suspected lesions of the GI tract. Cases of gastrointestinal perforation have been reported in adult patients with OIC 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 Discontinue if severe or persistent diarrhea occurs during treatment. Opioid Withdrawal Consider the overall risk benefit in patients with disruptions to the bloodbrain barrier. Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR. Monitor closely for adequacy of analgesia and symptoms of opioid withdrawal. 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 clinical practice. Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain The safety of RELISTOR tablets was evaluated in a double-blind, placebo-controlled trial in adult patients with OIC and chronic non-cancer pain receiving opioid analgesia. This study (Study 1) included a 12-week, double-blind, placebo-controlled period in which adult patients were randomized to receive RELISTOR tablets 450 mg orally (200 patients) or placebo (201 patients). After 4 weeks of double-blind treatment administered once daily, patients continued 8 weeks of double-blind treatment on an as needed basis (but not more than once daily). The most common adverse reactions in adult patients with OIC and chronic non-cancer pain receiving RELISTOR tablets are shown in Table 4. Adverse reactions of abdominal pain, diarrhea, hyperhidrosis, anxiety, rhinorrhea, and chills may reflect symptoms of opioid withdrawal. Table 4: Adverse Reactions* in 4-Week Double-Blind, Placebo-Controlled Period of Clinical Study of RELISTOR Tablets in Adult Patients with OIC and Chronic Non-Cancer Pain (Study 1) RELISTOR Tablets Placebo Adverse Reaction n = 200 n = 201 Abdominal Pain** 14% 10% Diarrhea 5% 2% Headache 4% 3% Abdominal Distention 4% 2% Vomiting 3% 2% Hyperhidrosis 3% 1% Anxiety 2% 1% Muscle Spasms 2% 1% Rhinorrhea 2% 1% Chills 2% 0%

*Adverse reactions occurring in at least 2% of patients receiving RELISTOR tablets 450 mg once daily and at an incidence greater than placebo. **Includes: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort and abdominal tenderness.

Table 5: Adverse Reactions* in 4-Week Double-Blind, Placebo-Controlled Period of Clinical Study of RELISTOR Injection in Adult Patients with OIC and Chronic Non-Cancer Pain (Study 2) RELISTOR Injection Placebo Adverse Reaction n = 150 n = 162 Abdominal Pain** 21% 7% Nausea 9% 6% Diarrhea 6% 4% Hyperhidrosis 6% 1% Hot Flush 3% 2% Tremor 1% <1% Chills 1% 0%

*Adverse reactions occurring in at least 1% of patients receiving RELISTOR injection 12 mg subcutaneously once daily and at an incidence greater than placebo. **Includes: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort and abdominal tenderness. During the 4-week double-blind period, in patients with OIC and chronic non-cancer pain that received RELISTOR every other day, there was a higher incidence of adverse reactions, including nausea (12%), diarrhea (12%), vomiting (7%), tremor (3%), feeling of body temperature change (3%), piloerection (3%), and chills (2%) as compared to daily RELISTOR dosing. Use of RELISTOR injection 12 mg subcutaneously 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 2) 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 injection was also evaluated in a 48-week, open-label, uncontrolled trial in 1034 adult patients with OIC and chronic non-cancer pain (Study 3). Patients were allowed to administer RELISTOR injection 12 mg subcutaneously 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 2. Additionally, in Study 3, 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 injection was evaluated in two, double-blind, placebo-controlled trials in adult patients with OIC and advanced illness receiving palliative care: Study 4 included a single-dose, double-blind, placebo-controlled period, whereas Study 5 included a 14-day multiple dose, double-blind, placebo-controlled period. The most common adverse reactions in adult patients with OIC and advanced illness receiving RELISTOR injection are shown in Table 6 below. Table 6: Adverse Reactions from all Doses in Double-Blind, PlaceboControlled Clinical Studies of RELISTOR Injection in Adult Patients with OIC and Advanced Illness* (Studies 4 and 5) RELISTOR Injection Placebo Adverse 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 at least 5% of patients receiving all doses of RELISTOR injection (0.075, 0.15, and 0.3 mg/kg) and at an incidence greater than placebo. **Includes: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort and abdominal tenderness. The rates of discontinuation due to adverse reactions during the double-blind, placebo-controlled clinical trials (Study 4 and Study 5) were comparable between RELISTOR (1%) and placebo (2%). Postmarketing Experience The following adverse reactions have been identified during post-approval use of RELISTOR injection. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Gastrointestinal Perforation, cramping, vomiting. General Disorders and Administration 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 0.3 mg/kg of RELISTOR did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate. USE IN SPECIFIC POPULATIONS Pregnancy The use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier and should be

used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Advise pregnant women of the potential risk to a fetus. Lactation Because of the potential for serious adverse reactions, including opioid withdrawal, in breastfed infants, advise women that breastfeeding is not recommended during treatment with RELISTOR. 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. Pediatric Use Safety and effectiveness of RELISTOR tablets and injection have not been established in pediatric patients. Geriatric Use In clinical studies of RELISTOR tablets, no overall differences in effectiveness were observed. Adverse reactions were similar; however, there was a higher incidence of diarrhea in elderly patients. In clinical studies of RELISTOR injection, no overall differences in safety or effectiveness were observed between elderly patients and younger patients. Based on pharmacokinetic data, and safety and efficacy data from controlled clinical trials, no dosage adjustment based on age is recommended. Monitor elderly patients for adverse reactions. Renal Impairment In a study of subjects with varying degrees of renal impairment receiving RELISTOR injection subcutaneously, there was a significant increase in the exposure to methylnaltrexone in subjects with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute as estimated by Cockcroft-Gault) compared to healthy subjects. Therefore, a dosage reduction of RELISTOR tablets and RELISTOR injection is recommended in patients with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute as estimated by Cockcroft-Gault). No dosage adjustment of RELISTOR tablets or RELISTOR injection is needed in patients with mild renal impairment (creatinine clearance greater than 60 mL/minute as estimated by Cockcroft-Gault). Hepatic Impairment Tablets In a study of subjects with varying degrees of hepatic impairment receiving a 450 mg dose of RELISTOR tablets, there was a significant increase in systemic exposure of methylnaltrexone for subjects with moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment compared to healthy subjects with normal hepatic function. Therefore, a dosage reduction of RELISTOR tablets is recommended in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. No dosage adjustment of RELISTOR tablets is needed in patients with mild hepatic impairment (Child-Pugh Class A). Injection There was no clinically meaningful change in systemic exposure of methylnaltrexone compared to healthy subjects with normal hepatic function. No dosage adjustment of RELISTOR injection is needed for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, monitor for methylnaltrexone-related adverse reactions. OVERDOSAGE A study of healthy subjects 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. NONCLINICAL TOXICOLOGY Carcinogenesis Oral administration of methylnaltrexone bromide at doses up to 200 mg/kg/day (about 81 times the subcutaneous maximum recommended human dose (MRHD) of 12 mg/day based on body surface area) in males and 400 mg/kg/day (about 162 times the subcutaneous MRHD of 12 mg/day) in females and in Sprague Dawley rats at oral doses up to 300 mg/kg/day (about 243 times the subcutaneous MRHD of 12 mg/day) for 104 weeks did not produce tumors in mice and rats. Mutagenesis Methylnaltrexone bromide was negative in the Ames test, chromosome aberration tests in Chinese hamster ovary cells and human lymphocytes, in the mouse lymphoma cell forward mutation tests and in the in vivo mouse micronucleus test. Impairment of Fertility Methylnaltrexone bromide at subcutaneous doses up to 150 mg/kg/day (about 122 times the subcutaneous MRHD of 12 mg/day; about 3.3 times the oral MRHD of 450 mg/day) was found to have no adverse effect on fertility and reproductive performance of male and female rats. Animal Toxicology and/or Pharmacology In an in vitro human cardiac potassium ion channel (hERG) assay, methylnaltrexone caused concentration-dependent inhibition of hERG current. PATIENT COUNSELING INFORMATION See FDA-approved Patient Labeling (Patient Information). To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Based on 9502500, Rev. 07/2016 Salix Pharmaceuticals 8510 Colonnade Center Drive Raleigh, NC 27615 www.salix.com Manufactured for:

Under license from:

Progenics Pharmaceuticals, Inc. Tarrytown, NY 10591 U.S. Patent Numbers: 6,559,158; 8,247,425; 8,420,663; 8,524,276; and 8,956,651 Relistor is a trademark of Salix Pharmaceuticals or its affiliates. RELO.0036.USA.16

Global Education Group (Global) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education to physicians. Global Education Group designates this live activity for a minimum of 36.0 AMA PRA Category 1 Credit(s)TM. This activity will be approved for continuing pharmacy, psychology, nurse practitioner, nursing, and dentistry education. Applications for certification of social work NASW and family physician AAFP hours will be applied for. For more information and complete CME/CE accreditation details, visit our website at www.painweek.org.

Importance and relevance levels for this article are high! a meaningful time for me regarding how I Kevin L. Zacharoff see the year “shaping up” from a pain manOn the innovation front, botulinum toxins agement perspective. By this time, most have been used for some time for a variety featured topics for discussion, debate, and deliberation have already of medical conditions. Dr. Ramon L. Cuevas-Trisan provides us with a surfaced, setting the “hot topics” stage for the remainder of the year. detailed analysis and brief summary of published literature of known In many cases, regulatory issues may be responsible for driving this uses of botulinum toxins as a component of management and treatment chronologic phenomenon: at the beginning of the year sleeves are rolled of various chronic pain syndromes. These syndromes include headaches, up and mandates are given. Sometimes published research frames the myofascial pain conditions, low back pain, and chronic regional pain landscape, and national meeting agendas have been set, while in other syndrome. When I think about important current topics, it seems that cases media attention highlights certain subjects. 2017 has not been complementary and alternative nonopioid treatments top the list. This different: innovative treatments seem to be needed now more than ever, is why this article is so vitally important, as it sheds light on exactly and it’s clear that we also need to keep focused on potential comple- what we seem to be looking for and need — new treatment options for mentary approaches, as opposed to simply hoping for that ever-elusive patients who suffer from chronic pain. “silver bullet” of chronic pain treatment. I think this issue of PWJ does a good job of summarizing the pulse of this year’s pain environment, and This issue’s Pundit Profile is Theresa Mallick-Searle ms, np-bc, anp-bc lives up to the mission of providing meaningful information for clinicians and coincidentally, at the time I’m writing this, it is National Nurses Week. managing pain on the front line. How timely to recognize and introduce you to someone whose nursing background led her to a career in pain management. With harnessed One of the most frustrating things to me is when back pain is referred tenacity and dedication, Mallick-Searle makes a positive difference in to as a diagnosis. Back pain is the description of a symptom and its patients’ lives, and we are lucky to have her. Enjoy reading about what location. In his article, Dr. Forrest Tennant, one of the most respected led her down this path and motivates her. elder statesmen in the pain world, sheds light on one cause of back pain, arachnoiditis, which has sometimes been referred to as the “world’s Lastly is the Next Generation Profile of Dr. Ravi Prasad. I’m not sure worst” pain. Dr. Tennant informs and educates the reader about the we realize how important behavioral health is with respect to medical history, pathophysiology, and treatment of a diagnosis that was most health and particularly pain treatment. Reading about this psycholocommonly made at autopsy. The inflammatory nature of this condition is gist’s dedication will help shape the future of pain management. Just stressed, and tailored anti-inflammatory treatment approaches are also knowing there is a next generation gives me hope. discussed. This article is yet another example of how we need to understand the cause of the pain in order to manage and treat it appropriately. In my mind this issue of PWJ hits all the targets for 2017: innovative treatments, diligence to manage risk, old conditions that have new sigNext we have an article from Dr. Sanford Silverman, last issue’s Pundit nificance, and new approaches to managing old risks. As we think about Profile. Dr. Silverman takes us on a journey into new formulations of the rapidly approaching PAINWeek National Conference in Las Vegas, opioids being developed to help battle manipulation and abuse of these September 5–9, I’m sure the curriculum will mirror these subjects. I hope medications. Managing the risk of aberrant opioid related behaviors is to see you there! a tall order, and abuse deterrent formulations of opioids are considered by many to be here to stay. Pharmaceutical companies and research—Kevin L. Zacharoff md, facip, facpe, faap ers have come up with creative ways, outlined in this piece, to combat misuse. The article is well worth the read. In fact, because of its comprehensive nature, I bet that if you prescribe opioid analgesics for chronic Kevin L. Zacharoff is Pain Educator and Consultant and Faculty, Clinical Instructor at suny Stony Brook School of Medicine, Department of Preventive Medicine, in pain, you will save it for future reference. Stony Brook, New York.

Early on in medical training, something that is stressed as one of the most important aspects of safe and effective care is the practice of diligent documentation in the patient’s medical record. This not only benefits patient care, but also provides a significant amount of protection and transparency to healthcare providers. While much is written about prudent clinical approaches involving chronic opioid therapy, Michael C. Barnes, JD, provides us with a legal perspective on the subject of managing risk of prescribing controlled medications for the treatment of chronic pain. Without question, this article delivers information we need to know— how to pay attention to what needs to be done and documented to protect patients, while at the same time safeguard ourselves regarding potential regulatory and liability related issues.

PWJ | www.painweek.org

Q2 | 2017

Live Medical Conference 6.0–12.0 Ce/CMe credits PAiNWeeKeND™ ReGiONAL CONFeReNCe SeRieS

PAiN MANAGeMeNT FOR THe MAiN STReeT PRACTiTiONeR

2017

painweekend.org

ANAHeiM CA ATLANTA GA BALTiMORe MD BiRMiNGHAM AL CHARLeSTON SC CiNCiNNATi OH DALLAS TX DeNVeR CO

FT. LAUDeRDALe FL HONOLULU HI HOUSTON TX JACKSONViLLe FL KANSAS CiTY MO MiLWAUKee WI MiNNeAPOLiS MN NASHViLLe TN

NeW ORLeANS LA PiTTSBURGH PA PROViDeNCe RI RALeiGH NC SACRAMeNTO CA SALT LAKe CiTY UT SAN DieGO CA SCOTTSDALe AZ

This activity is provided by Global Education Group for 6.0–12.0 AMA PRA Category 1 Credits™. This program is planned in accordance with AANP CE Standards and Policies and AANP Commercial Support Standard.

SeATTLe WA SOUTHFieLD MI ST. LOUiS MO TAMPA FL WOODCLiFF LAKe NJ Cities/states subject to change. Refer to painweekend.org for more information.

Michael C. Barnes jd, miep

P.52

Michael Barnes is managing partner, dcba Law & Policy, in Washington, dc. He advises pharmaceutical companies, laboratories, treatment programs, and practitioners seeking to improve health outcomes and reduce risks of liability. Mr. Barnes is a founder and the chairman of the not-for-profit Center for Lawful Access and Abuse Deterrence and is a member of the advisory board for the National Rx Drug Abuse & Heroin Summit. He has authored scholarly articles and presents frequently at conferences nationwide. He contributes to U.S. News & World Report; provides analysis for cnbc, cnn, fox Business/News, and msnbc; and served as confidential counsel, White House Office of National Drug Control Policy.

Ramon L. Cuevas-Trisan md

P.60

Ramon Cuevas-Trisan is Chief of the Physical Medicine, Rehabilitation & Pain Management Service at the Veterans Affairs Medical Center in West Palm Beach, Florida.

Sanford M. Silverman md

P.30

Sanford Silverman is an Affiliate Assistant Professor, Clinical Biomedical Science, at the Charles E. Schmidt College of Medicine at Florida Atlantic University in Boca Raton. He is also ceo and Medical Director of Comprehensive Pain Medicine in Pompano Beach, Florida.

Forest Tennant md, drph, facpm, mph

P.20

Forest Tennant is a former us Army Medical Officer and Public Health Physician. He is the founder and Medical Director of Veract Intractable Pain Clinic in West Covina, California. He started a pain clinic for cancer and postpolio patients in eastern Los Angeles County, was coauthor of the “Pain Patient’s Bill of Rights” section 2241.5 of the ca Division of Health and Safety code, and 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.

PWJ | www.painweek.org

Q2 | 2017

PWJ keeps you going all year long.”

— Michael R. Clark Md, mph, mba

SCULPTURE BY EMMA CASTER-DUDZICK

“Meetings come to an end, but learning never stops.

ACCeSS PAiNWeeK 365 DAYS A YeAR PAINWeek® is an innovative single point of access designed specifically for frontline practitioners, recognized as a trusted resource for the latest pain management news, information, and education. →Visit www.painweek.org to access key opinion leader insights expressed via the following sections: ❶ Expert Opinion ❷ Key Topics ❸ One-Minute Clinician ❹ Pundit Profile ❺ PWJ—PAINWeek Journal

By Forest Tennant md, drph, facpm, mph

NeUROLOGY

abstract: The arachnoid

is the middle layer of the covering of the spinal cord and brain. The covering is usually called meninges when referring to the brain, and the lower spine covering is usually referred to as the theca or thecal sac. The outer layer of the covering is the dura and the inner layer the pia mater. The middle layer, arachnoid, was so named over a century ago because it resembles a spider web. Arachnoiditis simply means inflammation of the arachnoid. Heretofore, arachnoiditis has been a taboo subject in medical circles as it was thought to be a rare disease usually caused by medical procedures.1 Pain caused by arachnoiditis has sometimes been referred to as the “world’s worst” and the condition so hopeless that treatment wasn’t even considered.1–9

PWJ | www.painweek.org

Q2 | 2017

arachnoiditis was most often diagnosed only at autopsy.1,2,6 Tuberculosis

was a common cause.3,5 Today it is now clear that arachnoiditis is neither rare nor primarily caused by medical procedures such as spinal taps, epidural injections, or surgery. Furthermore, effective treatment regimens have been developed.10,11 Arachnoiditis may be the end result of almost all the common causes of lumbar and cervical spine pain including herniated discs, degenerative arthritis, and osteoporosis (Table 1).2,4,6 Genetic connective tissue diseases, such as Ehlers-Danlos, are prone to develop arachnoiditis. While a medical procedure may accelerate the development of arachnoiditis, some causative, underlying pathology initiates the disease.9,12,13 Arachnoiditis is now diagnosed by a typical symptom profile, physical exam, the presence of serum inflammatory markers, and magnetic resonance imaging (mri).14–16 Although its precise incidence and prevalence are unknown, arachnoiditis cases are now being discovered in every community and clinical practice that deals with low back pain. It is often overlooked and referred to by such names as low back or neck syndrome, failed back surgery syndrome, or degenerative spine disease.17 Practitioners are just beginning to understand and diagnose the condition. This article is to raise awareness that the condition can no longer be considered “rare,” and every pain practitioner must now recognize and treat it. Adhesive arachnoiditis (AA)

Although the term arachnoiditis technically means inflammation of the arachnoid lining, the term has, in the past 2 or 3 decades, also commonly included inflammation of nerve roots of the cauda equina. There are about 2 dozen nerve roots in the cauda equina.18,19 They are stringlike and hang suspended below the conus medularis (about l1). When they are inflamed and there is no evidence of arachnoid inflammation on mri, the term chronic cauda equina syndrome is sometimes used providing the patient has some symptoms such as pain and bladder or bowel dysfunction. Clinical cases that are being diagnosed today, however, almost always show mri evidence of combined nerve root and arachnoid lining inflammation.14,15 Regardless of whether the initiating cause originates in the arachnoid lining or cauda equina nerve roots, Q2 | 2017

inflammation eventually causes fibrosis, scarring, and adhesions to form between the nerve roots and arachnoid lining (Figure). At this point some nerve roots no longer free float in the spinal fluid, and severe pain and neurologic impairment develop since the neuroinflammation, fibrosis, scarring, and adhesions which form disrupt the normal neuroelectric mechanisms of the nerve roots. The cervical spine does not have free floating nerve roots as does the lumbar spine. The arachnoid lining may, however, become inflamed and be the cause of severe neck pain and disability. Criteria to diagnose cervical arachnoiditis is in the formative stage and will not be addressed here, although the author believes cervical arachnoiditis is a major cause of severe neck pain.

www.painweek.org | PWJ

NeUROLOGY

Figure. How Adhesive Arachnoiditis Develops Fortunately, the pain of arachnoiditis, regardless of stage, usually responds quite well to the standard pain therapies of today. In fact, most cases have yet to be diagnosed and are being treated with standard pain therapy.

Injury Toxin Puncture Infection Friction Compression Damage to arachnoid lining

Damage to nerve roots in cauda equina

Fibrosis and adhesions glue nerve roots and lining together

Causes of AA

Inflammation that originates in the arachnoid layer is usually due to puncture or toxin in the subdural space. Toxins may rarely be introduced by spinal taps or epidural injections. Inflammation of spinal nerve roots may include any process that causes: friction, irritation, infection, or compression of the roots. Any pathologic process that causes nerve roots to rub or cling together may initiate inflammation. Simply, nerve roots that are anatomically compressed together rather than free floating may develop inflammation due to friction. The nerve roots are actually suspended in fluid to prevent friction or adherence to each other, and to prevent the development of fibrosis, adhesions, and scars.18–20 Chronic spinal conditions such as those listed on Table 1 may initiate clinging, clumping, and neuroinflammation in suspended nerve roots. Millions of patients have a variety of these conditions and may live a long life. They are all, consequently, at risk, and an unknown number will develop cauda equina neuroinflammation and AA.

Patients with aa may well have such pain as to warrant the historical fears and dread of the disease. Apparently adhesions, which “glue” or attach nerve roots to the arachnoid lining, interrupt neuroelectric mechanisms to such a degree that severe constant pain and neurologic impairments ensue. Of particular clinical importance are the flares of aa. They routinely force a patient to bed with fear, remorse, tears, and thoughts of suicide. Mere oral breakthrough opioids are not sufficient for these severe flares of aa. The most potent opioids administered by sublingual, injection, or suppository route in combination with a corticosteroid are often required to break the flare.

Table 1. Chronic Spinal Conditions That May Cause Cauda Equina Neuroinflammation and Adhesive Arachnoiditis (aa) ▸▸ Herniated discs ▸▸ Scoliosis ▸▸ Collapsed vertebrae ▸▸ Degenerative osteoarthritis ▸▸ Spinal stenosis ▸▸ Perineural (Tarlov) cysts ▸▸ Osteoporosis ▸▸ Spondylolisthesis Other causes of AA: Surgery, radiographic dyes, infections, and medical procedures may accelerate the development of arachnoiditis if a chronic spinal condition is present. Patients with genetic, connective tissue disorders such as Ehlers-Danlos and Marfan’s syndromes commonly develop aa

Pain of AA

Historical accounts of arachnoiditis are legendary as to its severity. It was a dreaded disease commonly known to be the worst pain ever.1,3,6 It is now clear that the pain of arachnoiditis follows the usual spectrum of painful disorders in that the pain may be mild, moderate, or severe. After studying over 350 mris of arachnoiditis patients the author has concluded that the severest pain develops after adhesions form between the cauda equina nerve roots and the arachnoid lining. Lesser degrees of pain seem to be present when there is only mri evidence of nerve root inflammation and no adhesion formation. In these cases, the term chronic cauda equina syndrome is reasonable.

24 PWJ | www.painweek.org

Symptom profile

It is critical today that all practitioners who deal with spine pain be aware of the typical symptom profile of arachnoiditis in order to select back pain patients who need evaluation for arachnoiditis.17 Although all back pain causes have some symptomatic overlap, arachnoiditis cases have some rather specific symptoms (Table 2). If some of the typical symptoms are not present, arachnoiditis is likely ruled out as the cause. Typically, patients cannot sit or stand in one position for long. Q2 | 2017

Table 2. Diagnosis of Adhesive Arachnoiditis Symptoms

Physical Signs

Laboratory Findings

▸▸ Constant pain

▸▸ Can’t straight leg raise

▸▸ Elevated inflammatory markers

▸▸ Pain and weakness when standing too long; must sit or lay down

▸▸ Decreased range of motion in upper and lower extremities

▸▸Jerking/tremors in legs ▸▸ Difficulty initiating urination and/or defecation ▸▸ Intense episodes of heating/ sweating

▸▸ Weakness in legs ▸▸ Abnormal gait: slow, guarded, short steps, leans ▸▸ Asymmetry of back musculature

▸▸ Episodes of blurred vision ▸▸ Headache ▸▸ Lacerating or stabbing pain in the legs

○○ Erythrocyte sedimentation rate ○○ Cytokines (interleukins, tumor necrosis factor)

▸▸ Hyporeflexia in legs

▸▸ Burning feet

○○ C-reactive protein

MRI Confirmation (mri findings by themselves should not be used for diagnosis; there must be typical symptoms and physical findings) ▸▸ Clumped and displaced nerve roots ▸▸ Adhesions between nerve roots and arachnoid lining

▸▸ Bizarre feelings on the skin (eg, bugs crawling, water dropping, pins sticking)

Bladder dysfunction in the form of urgency, hesitancy, or incontinence will be present as the spinal nerve roots in the cauda equina have over 20 nerve connections to the bladder. Pain that radiates into the buttocks or legs will be present. Interestingly, many patients will complain of burning feet and describe bizarre pain sensations like water dripping on them or crawling insects or worms on the skin. Headaches, blurred vision, mental deterioration, and tinnitus are common due to spinal fluid flow obstruction.20

Diagnoses of aa

If a patient gives a typical symptom profile, other measures should be taken to establish the diagnosis of aa. Patients will need this specific diagnosis in order to obtain necessary diagnostic tests, medications, and possibly a disability determination. Lack of a specific diagnosis may leave the patient simply labeled a chronic back pain patient and/or a mental case: Physical examination will always show abnormal neurologic findings, but they are nonspecific in that other spinal conditions may have the same findings (Table 2). The most consistent physical findings are impairment of range of motion. For example, straight leg raising and upward arm reach may be quite restricted. A careful exam of the lower extremities may show paraparesis (partial paralysis) and even paraplegia (inability to walk). Reflexes may be reduced or be absent, and one leg or foot may be more affected than the other. Gait will likely show some abnormality. Laboratory testing is critical. Arachnoiditis is a neuroinflammatory disease that raises a variety of inflammatory markers in the serum.21–25 The recommended panel, which is now available through commercial laboratories in every Q2 | 2017

community, includes erythrocyte sedimentation rate (esr), C-reactive protein (crp), and cytokines.21,23 The cytokine panel currently being offered by many laboratories includes several interleukins and tumor necrosis factor. Myeloperoxidase and alpha-1-antitrypsin are commonly elevated, but they are evaluated only through a specialty laboratory. Myeloperoxidase is regularly elevated in arachnoiditis patients seen by this author.21 Patients who demonstrate elevated inflammatory serum markers require aggressive antineuroinflammation treatment that isn’t necessary in patients who don’t demonstrate high inflammatory markers. High markers indicate the presence of active, progressive disease that must be controlled lest the patient develop increased pain and neurologic impairments including paraparesis or paraplegia. Highly recommended is a serum hormone profile that includes cortisol, dehydroepiandrosterone (dhea), pregnenolone, progesterone, estradiol, and testosterone. If hormone levels are in normal range, it likely means the disease is not too severe. Suppressed levels, however, suggest severe pain and active, progressive neuroinflammation. It is recommended that patients with low serum hormone levels be given trials of hormone replenishment. Diagnosis of arachnoiditis and cauda equina neuroinflammation may be confirmed with a contrast mri. The mri should not, however, be solely relied upon to make the diagnosis. Old scars and inactive lesions may falsely appear to represent an active pathologic process, so mri findings need to be correlated with the typical symptoms, physical findings, and laboratory tests found in aa. Put another way, a definitive diagnosis of aa must have typical clinical symptoms, physical abnormalities, as well as MRI findings.

www.painweek.org | PWJ

NeUROLOGY

Persistent neuroinflammation and disease progression

aa is a neuroinflammatory disease that encompasses the spinal canal covering and nerve roots of the cauda equina. The nerve roots contain microglial and other glial cells that activate and produce chronic neuroinflammation.24,25 Our studies show that this inflammation is persistent but may clinically flare and then subside.21 This is analogous to the joint inflammation of rheumatoid arthritis. The pathologic consequences of persistent neuroinflammation can neither be underestimated nor assumed to be eliminated with treatment.21 Persistent neuroinflammation of the cauda equina nerve roots may, overtime, progressively impair the patient. For example, the patient’s pain may suddenly worsen or radiate into different anatomical areas. Bladder and gastrointestinal dysfunction may abruptly develop. As neuroinflammation progresses, more fibrosis, adhesions, and scarring may develop within the spinal canal producing spinal fluid flow obstruction and impairment. When this occurs, the patient will experience cerebral manifestations including headache, blurred vision, tinnitus, and reduced mental abilities that may include memory, reading, and logical thinking. The disease may progress to paraparesis or even paraplegia. For reasons that are unclear AA may restrict upper extremity range of motion and strength. AA may also progress to a generalized autoimmune disorder with arthralgias and myalgias. Although the mechanism for this is unclear, one logical explanation is drainage of neuroinflammatory waste into the general circulation.26–29 The basic and fundamental treatment for AA is control of neuroinflammation, and it is described below.

26 PWJ | www.painweek.org

Treatment

A multidisciplinary approach is needed. Arachnoiditis patients require specific exercises, dietary measures, electromagnetic treatments, family education, and psychologic counseling. The latter is necessary to support the patient and family since aa is a progressive inflammatory disease. Exercises must contain some element of stretching and walking to hopefully prevent paraparesis and paraplegia. We recommend a medical treatment regimen that has 3 components: ❶ neuroinflammation control, ❷ pain relief, and ❸ neurogenesis (nerve regrowth). Control of neuroinflammation is the foundation and most critical component of aa treatment. Without it, pain is likely to be poorly controlled and the patient too disabled to participate in exercise and other treatment efforts. Consequently, the following section is dedicated, in some detail, to our current neuroinflammation control regimen. Pain relief is essentially the standard of the day. Nonopioid analgesic agents in the neuropathic, nmda antagonist, adrenergic, and topical classes are preferred to keep the opioid dosage as low as possible. In some cases, high dose opioid therapy, opioid injections, and even intrathecal administration of opioids will be necessary. Neuromodulation may be helpful in selected cases. Acute flares are problematic. An injectable or suppository opioid, anti-inflammatory agent such as ketorolac or indomethacin, and a corticosteroid may be necessary to control a flare. Q2 | 2017

Table 3. Inflammation Control Regimen Neurogenic treatment is the new horizon in treating aa. Our approach to neurogenesis is to simultaneously utilize nutrition, exercise, electromagnetic measures, and neurohormones to hopefully stimulate nerve growth. It is hoped that the arachnoid lining and nerve roots will heal and allow normal or near normal function and permanently reduce pain and disability. There currently isn’t enough clinical evidence to make unequivocal recommendations. Our approach is to first determine serum levels of these hormones which all are produced and utilized in the cns: ❶ dehydroepiandrosterone (DHEA), ❷ estradiol, ❸ pregnenolone, ❹ progesterone, and ❺ testosterone. If any are deficient, they are replenished. We have initiated open label clinical trials with oxytocin, human chorionic gonadotropin (hcg), and human growth hormone (hgh). Our early observations are quite positive, but must await confirmation with double-blind studies and other observations before specific recommendations can be made. French investigators have reported that long-term administration of pentoxifylline may resolve fibrosis in and around the spinal cord.30–33 This approach has been utilized by this author in a few cases with positive results.

Neuroinflammation control: foundation of treatment

Inflammation of the arachnoid lining and cauda equina nerve roots are the underlying cause of the disease. Control of the inflammation, consequently, in these 2 anatomical tissue sites is critical and fundamental to successful treatment. Without inflammation control, pain relief and other measures may prove illusive, anemic, and even noneffectual. This author’s treatment of the inflammation of aa is different from that used in pain management and rheumatologic disorders. The inflammation in nerve roots is caused by microglial and qualifies for the term “neuroinflammation.”24,25 This form of inflammation does not respond to many anti-inflammatories or corticosteroids that are effective in peripheral inflammatory disorders.10,11 This form of inflammation is persistent, and it is questionable whether current pharmacologic agents can permanently eliminate it.21 An inflammation regimen used by this author is given here in some detail. It has been developed by clinical trial and error over time (Table 3). It is admittedly foreign to traditional pain management and contains some risks of bleeding, renal toxicity, and adrenal suppression that must be clearly explained to the patient and family. It is the author’s clear opinion that aa can only be treated with a potent anti-inflammatory regimen. The first agent we employ is a low dose corticosteroid initially given 3 to 5 days a week, in the afternoon because serum cortisol drops to precipitating low levels late in the day.33 Patients usually report their worst pain to occur late in the day. Second, we have found 2 anti-inflammatory agents that appear clinically effective: indomethacin and ketorolac.34,35 Both agents are known to Q2 | 2017

Starting dosages can be raised and given in greater frequency if necessary. The starting corticosteroid, anti-inflammatory agent, and microglial cell suppressor may need to be switched if there is poor clinical response or side effects. 1 Low dose corticosteroid ▸▸ Methylprednisone 4 mg or dexamethasone .5 to 1.0 mg given at 3:00p to 4:00p 3 to 5 days a week. 2 Anti-inflammatory agent ▸▸ When normal inflammatory serum markers are present: indomethacin 25 to 50 mg with meals on 3 to 5 days a week ▸▸ When elevated inflammatory markers are present: ketorolac 30 mg by injection each week (eg, Monday); repeat 2 more times in the same week with a skipped day between doses 3 Microglial suppressor ▸▸ Metformin 500 mg at bedtime 3 to 5 days a week Alternatives ▸▸ Minocycline 100 mg ▸▸ Acetazolamide 125 mg ▸▸ Pentoxifylline 400 mg

cross the blood brain barrier and enter the spinal fluid. We will administer ketorolac by injection if some serum inflammatory markers such as crp or interleukins are elevated, but, if they are normal, we start oral indomethacin, given with meals 3 to 5 days a week. We start with one ketorolac injection a week and allow a maximum of 3 injections a week for patients under age 70. A day must be skipped between injections and hemoglobin and renal function must be periodically monitored. In addition to a low dose corticosteroid and anti-inflammatory agent, we will start one of a class of agents called “microglial suppressors.” Four available agents have been shown in in vitro studies to suppress microglial neuroinflammation.36–55 These agents are metformin, minocycline, acetazolamide, and pentoxifylline. We usually start with low dose metformin given at bedtime. If metformin produces side-effects or appears ineffective, one of the other agents is selected. Acetazolamide has demonstrated some symptom reduction in patients with headache, blurred vision, and tinnitus. We believe these patients suffer from spinal fluid flow obstruction. The major goal of inflammation treatment is to bring serum inflammatory markers into normal range. We monitor serum markers every 30 to 60 days and will increase the dosage of www.painweek.org | PWJ

NeUROLOGY

one or more of the medications or switch medications to bring markers into normal range. Besides monitoring serum markers, the anti-inflammatory regimen that is prescribed must reduce baseline and flare pain and reduce episodes of sweating and heat. Once serum inflammatory markers are normal and symptoms reduce, some or all medication dosages can be reduced or even discontinued and later restarted if necessary.

Conclusions

Arachnoiditis simply means “inflammation” of the arachnoid layer of the covering of the spinal cord. In the past it has been considered a rare disease with no hope of treatment, and patients were therefore relegated to a dreadful, short life of misery. This perception must change as arachnoiditis is emerging in all communities and pain treatment facilities as a chronic, painful disabling condition in which the pain can be mild, moderate, or severe. The reasons for this change are multiple and include our ability to diagnose its presence with serum inflammatory markers and technologically advanced mris. Also, it is now clear that many common lumbar spine disorders can lead to arachnoiditis if a person lives long enough for the pathologic condition to compress or irritate and create neuroinflammation in the nerve roots of the cauda equina and/ or arachnoid lining. Medical procedures to treat the underlying spinal condition may accelerate the development of neuroinflammation in nerve roots and/or arachnoid lining. Given the potential progressive nature and severe disability caused by aa, aggressive, multidisciplinary treatment directed at inflammation control, pain relief, exercises, nutrition, electromagnetic measures, and psychologic support are necessary. The medical regimen to control neuroinflammation and pain is not one traditionally used in standard pain or rheumatologic treatment. It is based on serum monitoring to bring inflammatory markers into normal range and utilizes low dose corticosteroids, anti-inflammatory agents, and a new class of agents known as microglial suppressors. It is emphasized that neuroinflammation control is the foundation of treatment of aa, since it is a progressive neuroinflammatory disorder. Pain practitioners are urged to begin identifying undiagnosed cases of arachnoiditis and begin instituting some of the measures described here. References 1. Aldrete JA. Suspecting and diagnosing arachnoiditis. Pract Pain Mgt. 2006;6(1):72–82. 2. Quiles M, Marchicello PJ, Tsairis P. Lumbar adhesive arachnoiditis: etiologic and pathologic aspects. Spine. 1978;3:45–50. 3. Shaw MDM, Russel JA, Grossart KW. The changing pattern of spinal arachnoiditis. J Neurol Neurosurg Psychiatry. 1978;41:97–107.

Burton CV. Lumbrosacral arachnoiditis. Spine. 1978;3:24–30.

7. Jorgensen J, Hansen PH, Steenskov V, et al. A clinical and radiological study of chronic lower spinal arachnoiditis. Neuroradiology. 1975;9:139–144. 8. Bonner B, Ehni G. Spinal arachnoiditis: the post-operative variety in particular. Spine. 1978;3:40–44. 9. Haughton VM, Eldavis OP, Ho KC, et al. Arachnoiditis from experimental myelograph with aqueous contrast media. Spine. 1978;3:65–69. 10. Tennant F. Adhesive arachnoiditis. Pract Pain Manag. 2014;14(7):63–69. 11. Tennant F. Arachnoiditis: diagnosis and treatment. Prac Pain Manag. 2016; 16(5):74–87. 12. Avidan A, Gomori M, Davidson E. Nerve root inflammation demonstrated by magnetic resonance imaging in a patient with transient neurologic symptoms after intrathecal injection of lidocaine. Anesthesiology. 2002;97(1):257–258. 13. Matsui H, Tsuji H, Kanamori M, et al. Laminectomy-induced arachnoiditis: a postoperative serial MRI study. Neuroradiology. 1995;37:660–666. 14. Ross JS, Masaryk TJ, Modic MT, et al. MR imaging of lumbar arachnoiditis. AJR Am J Roentgenol. 1987;149:1025–1032. 15. Delamarter RB, Ross JS, Masaryk TJ, et al. Diagnosis of lumbar arachnoiditis by magnetic resonance imaging. Spine. 1990;15:304–310. 16. Aldrete JA. Nerve root “irritation” or inflammation diagnosed by magnetic resonance imaging. Anesthesiology. 2003;98(5):1294. 17. Tennant F. Which chronic back pain patients have arachnoiditis. J Pain. 2016;17(4):532. 18. Well EJ, Cohen MS, Massic JB, et al. Cauda equina anatomy: intrathecal nerve root organization. Spine. 1990;15:1244–1247. 19. Cohen MS, Wall EJ, Kerber CW, et al. The anatomy of the cauda equina on CT scans and MRI. J Bone Joint Surg. 1991;73-B:381–384. 20. Johanson CE, Duncan JA 3rd, Klinge PM, et al. Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Cerebrospinal Fluid Res. 2008;5:10. 21. Bilello J, Tennant F. Patterns of chronic inflammation in extensively treated patients with arachnoiditis and chronic intractable pain. Postgrad Med. 2016;92(17):1–5. 22. Bjurstrom MF, Giron SF, Griffis CA. Cerebrospinal fluid cytokines and neurotropic factors in human chronic pain populations: a comprehensive review. Pain Pract. 2014;Oct. 29:doi10.111:/papr.12252. 23. Tennant F. Erythrocyte sedimentation rate and C-reactive protein: old but useful biomarkers for pain treatment. Pract Pain Manag. 2013;13(2):61–65. 24. Streit WJ, Mack RE, Griffin WS. Microglia and neuroinflammation: a pathologic perspective. J Neuroinflammation. 2004;1:14–19. 25. O’Callgan JP, SriranT, Miller DB. Defining “neuroinflammation”. Ann NY Acad Sci. 2008;1139:318–330. 26. Laman JD, Weller RO. Drainage of cells and soluble antigen from the CNS to regional lymph nodes. J Neuroimmune Pharmacol. 2013;8:840–856. 27. Rydovik B, Holm S, Brown MD, et al. Diffusion from the cerebrospinal fluid as a nutritional pathway for spinal nerve roots. Acta Physiol Scand. 1990;138:247–248. 28. Weller RO, Djuanda E, Yow H, et al. Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol. 2009;117:1–14.

4. Monij JA. Spinal arachnoiditis disease or coincidence? Acta Neurochir 1980;53:151–160.

29. Csarr HF, Harling-Berg CJ, Knopf PM. Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol. 1992;2:259–296.

5. Kumar A, Montanero W, Wilinsky R, et al. MR features of tubercular arachnoiditis. J Comput Assist Tromog. 1993;17:127–130.

30. George C, Lefain JL, Delonion S. Case report: resolution of symptomatic

28 PWJ | www.painweek.org

Q2 | 2017

epidural fibrosis following treatment with combined pentoxifylline-tocopherol. Br J Radiol. 2004;77:885–887. 31. Delanian S, Porcher R, Balla-Mekias S, et al. Randomized placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis. J Clin Oncol. 2003;21:2545–2550.

50. Pabreja K, Dua K, Sharma S, et al. Minocycline attenuates the development of diabetic neuropathic pain: possible anti-inflammatory and anti-oxidant mechanism. Eur J Pharmacol. 2011;661(1–3):15–21. 51. Chew DJ, Carlstedt T, Shortland PJ. The effects of minocycline or riluzole treatment on spinal root avulsion-induced pain in adult rate. J Pain. 2014;15(6):664–675.

32. Lefaix JL, Delanizan S, Vozenin MC, et al. Striking regression of subcutaneous fibrosis induced by high doses of gamma rays using a combination of pentoxifylline and alpha-tocopherol: an experimental study. Int J Radiat Oncol Biol Phys. 1999;43:839–847.

52. Harvey JW, Otterson M, Yun H, et al. Acetazolamide reduces referred postoperative pain after laparoscopic surgery with carbon dioxide insufflation. Anesthesiology. 2003;99:924–928.

33. Bilello J, Tennant F. Lower serum cortisol levels in patients with arachnoiditis and chronic intractable pain (CIP). Presented at PAINWeek; Las Vegas, Nevada: 2016.

53. Radhakrishnan R, Sluka KA. Acetazolamide, a carbonic anhydrase inhibitor, reverses inflammation-induced thermal hyperalgesia in rats. J Pharmacol Exp Ther. 2005;313:921–927.

34. Aldrete JA. Epidural injections of indomethacin for post-laminectomy syndrome: a preliminary report. Anesth Analg. 2003;96(2):463–468.

54. Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov. 2008;7:168–181.

35. Nakano M, Matsui H, Miaki K, et al. Post-laminectomy adhesion of the cauda equina: inhibitory effects of anti-inflammatory drugs on cauda equina adhesion in rats. Spine. 1998;23(3):298–304.

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

36. Inyang K, Szabo-Pardi T, Price T. Treatment of chronic pain: long-term effects of metformin on chronic neuropathic pain and microglial activation. Presented at American Pain Society; Austin, Texas: 2016. 37. Dorazil-Dudzik M, Mika J, Schafer MK, et al. The effects of local pentoxifylline and propentofylline treatment on formula-induced pain and tumor necrosis factor-alpha messenger RNA levels in the inflamed tissue of the rat paw. Anesth Analg. 2004;98:1566–1573. 38. Tawfik VL, Nutile-McMenemy N, Lacroix-Fralish MI, et al. Efficacy of propentofylline, a glial modulating agent, on existing mechanical allodynia following peripheral nerve injury. Brain Behav Immun. 2007;21:238–246. 39. Liu J, Feng X, Yu M, et al. Pentoxifylline attenuates the development of hyperalgesia in a rat model of neuropathic pain Neurosci Lett. 2007;412:268–272. 40. Vale ML, Benevides VM, Sachs D, et al. Antihyperalgesic effect of pentoxifylline on experimental inflammatory pain. Br J Pharmacol. 2004;143:833–844. 41. Sweitzer SM, Schubert P, DeLeo JA. Propentofylline, a glial modulating agent, exhibits antiallodynic properties in a rat model of neuropathic pain. J Pharmacol Exp Ther. 2001;297:1210–1217. 42. Liu J, Li W, Zhu J, et al. The effect of pentoxifylline on existing hypersensitivity in a rat model of neuropathy. Anaesth Analog. 2008;106:650–653. 43. Raghavendra V, Tanga FY, DeLep JA, et al. Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rat. Neuropsychopharmacology. 2004;29:327–334. 44. Tikka TM, Kaistinaha JE. Minocycline provides neuroprotection against n-methyl-d-asparate neurotoxicity by inhibiting microglia. J Immunol. 2001;166(12):7527–7533. 45. Mika J. Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. Pharmacol Rep. 2008;60:297–300. 46. Pi R, Wenning L, Nelson TK, et al. Minocycline prevents glutamate-induced apoptosis of cerebellar granule neurons by differential regulation of p38 and akt pathways. J Neurochem. 2004;91:1219–1230. 47. Tikka T, Usenius T, Tenhunon M, et al. Tetracycline derivatives and ceftriaxone, a cephalospaorin antibiotic, protect neurons against apoptosis induced by ionizing radiation. J Neurochem. 2001;78:1409–1414. 48. Kraces RL, Pasieczny R, Larioso-Willingham, et al. Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-scavenging activity. J Neurochem. 2005;94:819–827. 49. Kelso Ml, Schef NN, Scheff SW, et al. Melatonin and minocycline for combinatorial therapy to improve functional and histopathological deficits following traumatic brain injury. Neurosci Lett. 2011;488(1):60–64.

Q2 | 2017

www.painweek.org | PWJ

By Sanford M. Silverman md

PHaRMaCOTHeRaPY

Prescription drug abuse is the fastest growing problem in the US. According to the Center for Disease Control (cdc) enough opioid pain relievers were sold in 2010 “to medicate every adult in the United States with the equivalent of a typical dose of 5 mg of hydrocodone every 4 hours for 1 month.”1 In 2011 there were 41,340 deaths from prescription drug poisonings, over 17,000 involving opioids. Prescription drug overdose was the leading cause of injury death in 2012. Among people 25 to 60 years old, prescription drug overdose caused more deaths than motor vehicle traffic crashes. The drug overdose death rate has more than doubled from 1999 through 2013.2-6 Diversion

Diversion is defined as the intentional removal of a medication from legitimate and dispensing channels.7 It is common among prescription drugs, where approximately 53% were obtained from a friend or relative, and 83.6% of those were from a single physician source.8

PWJ | www.painweek.org

Q2 | 2017

Regulatory

Several states have imposed laws which limit amounts, doses, and distributions of opioid pain medications for the treatment of noncancer pain.9-11 Sublingual buprenorphine is utilized to treat opioid use disorder. On March 29, 2016, the us Department of Health and Human Services (hhs) announced lifting the cap of 100 patients to 200 who can be treated with sublingual buprenorphine for opioid use disorder. As of July 6, 2016, hhs increased this to 275 patients.12 The Food and Drug Administration (fda) proposed a “Safe Use Initiative” in 2009 in which they proposed to identify, using a transparent and collaborative process, specific candidate cases; drugs, drug classes, and/or therapeutic situations that are associated with significant and measurable amounts of preventable harm.13 In 2012, the fda also proposed and implemented rems (Risk Evaluation and Mitigation Strategy) for extended release/long acting (er/la) opioids for the treatment of chronic noncancer pain.14 This new rems required er/la opioid analgesic companies to make training available for healthcare professionals who prescribe er/la opioid analgesics on proper prescribing practices and to distribute educational materials to prescribers and patients on the safe use of these pain medications. The er/la opioid rems is at no cost to the practitioner and is currently voluntary for prescribing er/la for noncancer pain. However, the tirf (Transmucosal Immediate Release Fentanyl) rems is mandatory for prescribers of these products.15 tirf products are fda approved and restricted to the treatment of breakthrough cancer pain.

Guidelines

Various organizations have published guidelines for the use of opioids in the treatment of noncancer pain. These are quite similar in their recommendations, and in fact the consensus from these organizations is that the level of evidence when utilizing chronic opioid therapy for the treatment of noncancer pain is fair and at times lacking.16-18 The cdc has compiled opioid guidelines for primary care physicians treating noncancer pain.19 The rationale being that primary care physicians manage a significant amount of chronic pain and have little training to do so. Across medical specialties it is believed that addiction is a common consequence of prolonged use, and that long-term opioid therapy often is overprescribed for patients with chronic noncancer pain.

Q2 | 2017

www.painweek.org | PWJ

PHaRMaCOTHeRaPY

The goal is to deter abuse, realizing it is impossible to prevent abuse.

Opioids With Abuse Deterrent Formulations (adfs)

can be added to interfere with, reduce, or defeat the euphoria associated with abuse. The antagonist can be sequestered The fda’s Abuse-Deterrent Opioids—Evaluation and Labeling and released only upon manipulation of the product. For Guidance for Industry, released in 2015, establishes the ration- example, a drug product can be formulated such that the ale and methodology for the development of er/la opioids substance which acts as an antagonist is not clinically active that contain abuse deterrent properties.20 The goal is to deter when the product is swallowed, but becomes active if the abuse, realizing it is impossible to prevent abuse. Many opioid product is crushed and injected or snorted. products are manipulated (crushed, snorted, injected, etc) to facilitate abuse. Since er/la opioids contain a large amount in ❸ Aversion—Substances can be added to the product a single delivery system(s), they are a favorite target of abusers. to produce an unpleasant effect if the dosage form is In short, the goal of an abuser is to convert an er/la opioid manipulated or is used at a higher dosage than directed. For into an immediate release (ir) one. adfs are intended to make example, the formulation can include a substance irritating manipulation more difficult or to make abuse of the manipu- to the nasal mucosa if ground and snorted. lated product less attractive or less rewarding. ❹ Delivery system (including use of depot injectable Opioid products can be abused in a variety of ways. Amongst formulations and implants)—Certain drug release designs them include being swallowed whole, crushed and swallowed, or the method of drug delivery can offer resistance to crushed and snorted, crushed and smoked, or crushed, dis- abuse. For example, sustained-release depot injectable solved and injected. It should be noted that the most common formulation or a subcutaneous implant may be difficult to form of abuse is the oral (nonmanipulated) route, which is not manipulate. addressed by adfs. ❺ New molecular entities and prodrugs—The properties ADFs can be categorized as follows: of a new molecular entity (nme) or prodrug could include the need for enzymatic activation, different receptor binding profiles, slower penetration into the central nervous system, ❶ Physical/chemical barriers—Physical barriers can preor other novel effects. Prodrugs with abuse deterrent vent chewing, crushing, cutting, grating, or grinding of the properties could provide a chemical barrier to the in vitro dosage form. Chemical barriers, such as gelling agents, can conversion to the parent opioid, which may deter the abuse resist extraction of the opioid using common solvents like of the parent opioid. New molecular entities and prodrugs are water, simulated biological media, alcohol, or other organic solvents. Physical and chemical barriers can limit drug release subject to evaluation of abuse potential for purposes of the Controlled Substances Act (csa). following mechanical manipulation, or change the physical form of a drug, rendering it less amenable to abuse. ❻ Combination—2 or more of the above methods could be ❷ Agonist/antagonist combinations—An opioid antagonist combined to deter abuse.

34 PWJ | www.painweek.org

Q2 | 2017

Premarketing Studies

The fda suggests 3 categories of study in order to obtain approval for abuse deterrence. ● Category 1—Laboratory based in vitro manipulation and extraction studies ● Category 2—Pharmacokinetic (pk) studies ● Category 3—Human abuse liability studies Category 1—Laboratory based in vitro manipulation and extraction studies

and 100 being maximum response, usually used to assess “How high are you?” ● Bipolar scale: score of 0 to 100 with 0 being minimal “disliking,” 100 being maximal “liking,” and 50 being a neutral response neither “liking or disliking” The vas should be the primary measure for drug liking because it appears to correlate most directly with potential for abuse. Other measures of particular interest include assessment of likelihood to take the drug again and assessment of overall drug liking. Category 4—Postmarketing Studies

In vitro studies should assess various simple and sophisticated mechanical and chemical ways a drug could be manipulated, such as by: ● Defeating or compromising the controlled release of an opioid from er formulations for purposes of abuse by different routes of administration ● Preparing an ir formulation for alternative routes of administration ● Separating the opioid antagonist, if present, from the opioid agonist, thus compromising the product’s abuse deterrent properties Category 2—Pharmacokinetic (PK) studies The goal of the clinical pk studies should be to understand the in vivo properties of the formulation by comparing the pk profiles of the manipulated formulation with the intact formulation and with manipulated and intact formulations of the comparator drugs through one or more routes of administration. For example, an er/la adf product should show the same or nearly the same pharmacokinetics, such as Cmax , Tmax , and auc (area under the curve), as one without adf.

Category 4 epidemiological studies are designed to measure abuse deterrence (overall and route specific abuse and abuse deterrence) in a large population. To date, no manufacturer has achieved this category labeling for abuse deterrence. How ever, there have been some postmarketing studies for adf OxyContin® (Purdue Pharma, Stamford, ct). Coplan et al measured changes in exposure to extended release oxycodone (ero, OxyContin®) prior to and after its adf reformulation.21 They looked at all exposure types (therapeutic errors, abuse, and accidental exposure) for ero, short acting (se) oxycodone, and heroin. For all types of exposure, the ero adf showed a net decrease of 26% over a 3-year period. The se oxycodone showed a 15% increase and the use of heroin increased by 37%. Decrease in all types of ero exposures were greater with increasing dose. Conclusions of this study were: ● Abuse deterrent formulations, with physicochemical barriers appear to be promising at reducing abuse and adverse outcomes from misuse. ● More consistent abuse deterrent properties and addressing heroin availability may be necessary to improvise public health benefit.

Category 3—Human abuse liability studies These studies generally are conducted in a drug experienced, recreational user population. Subjects should generally not be physically dependent and should not be currently seeking or participating in treatment for drug abuse such that participating in the study could make them vulnerable to relapse. These subjects will consume the drug in a double blinded fashion. This is often done via the oral and intranasal routes. The subjects will compare placebo, intact adf, crushed adf, and an active comparator (usually an IR formulation). In typical abuse liability studies, several instruments have been used to measure subjective responses predictive of the likelihood of abuse. These instruments include: ● Visual Analogue Scales (vas)—used for drug liking, good effects, bad effects, and other drug abuse related effects ● Profile of Mood States (euphoria, “high”) ● Unipolar scale: score of 0 to 100 with 0 being no response Q2 | 2017

Dart et al examined trends in opioid analgesic abuse and mortality in the us from the Researched Abuse, Diversion, and Addiction Related Surveillance (radars) System to describe trends between 2002 and 2013 in the diversion and abuse of oxycodone, hydrocodone, hydromorphone, fentanyl, morphine, and tramadol.22 The programs gathered data from drug diversion investigators, poison centers, substance abuse treatment centers, and college students. Heroin use was shown to increase significantly after the release of adf OxyContin, while a concomitant decrease in adf OxyContin use was observed. This increase was documented via the National Poison Data System, the American Association of Poison Control Centers, and the National Survey on Drug Use and Health (Substance Abuse and Mental Health Services Administration or samhsa. Butler et al studied abuse rates and routes of administration of reformulated adf OxyContin.23 An observational design www.painweek.org | PWJ

PHaRMaCOTHeRaPY

Since extended release long acting opioids contain a large amount in a single delivery system(s), they are a favorite target of abusers. In short, the goal of an abuser is to convert an ER/LA opioid into an immediate release (IR) one.

compared the prevalence, prescription-adjusted prevalence rates, and roa (routes of administration) patterns of past-30day abuse of oral reformulated OxyContin (orf) in the period after its introduction, to that of OxyContin before introduction. Abuse patterns for 2 comparator opioid compounds (er morphine and er oxymorphone) were assessed during the same preand post-orf periods. The primary route of nonoral abuse of er oxymorphone is by snorting and of er morphine is by injecting, thus providing relevant controls for route-specific comparisons.

Cicero et al also looked at heroin usage postrelease of reformulated OxyContin.24 They found a significant rise in heroin usage and a concomitant decrease in OxyContin usage. 70% of respondents indicated a switch to heroin, approximately 24% to other oxycodone products, and less than 15% to other opioids. Respondents were college students and a subset that was willing to give up their anonymity and participate in the interview based Researchers and Participants Interacting Directly (rapid) program. Among these 88 participants who indicated experience using pre-adf and adf OxyContin, the residual level of abuse reflected the following 3 phenomena:

The study demonstrated a substantial decrease in the use of original formulation OxyContin and a decrease in the overall usage of both adf and original OxyContin. The routes of administration showed changes in pre and post orf. Specifically, there was a net increase in oral use of 21.6%, a net decrease in insufflation (snorting) of 27.3%, a net decrease in smoking of 2.2%, and a net decrease of injection of 19.8%.

❶ Transition from nonoral routes of administration to oral use: 38 participants (43%) ❷ Successful efforts to defeat the adf mechanism leading to a continuation of inhaled or injected use: 30 participants (34%) ❸ Exclusive use of the oral route independent of formulation type: 20 participants (23%)

The same routes of administration of comparator er/la opioids (oxymorphone and morphine) were also examined. For oxymorphone there was a net decrease in oral consumption by 8.1%, a net increase in insufflation by 7%, a net increase in smoking by 1.7%, and a net increase of injection by 7%. Morphine showed no real significant changes.

Section 9.2 in the PI of any opioid product discusses abuse potential. It also denotes whether the product has abuse deterrent properties as conveyed through Category 1–3 studies required by the fda.

PWJ | www.painweek.org

Product insert (pi)—Section 9.2: Abuse

Q2 | 2017

Current adfs Available Embeda® Embeda® (Pfizer, ny) is an er/la adf of morphine. Specifically, it uses an antagonist (naltrexone) mixed with the active drug (morphine), which if crushed or manipulated releases and reduces the euphorigenic or rewarding effect of morphine. The beads use a proprietary technology of sequestered naltrexone that will not release with normal oral consumption but will after crushing or other physical manipulation. Category 3 studies show significantly less liking and euphoria of crushed Embeda consumed orally and intranasally as compared to both placebo and active comparators (er morphine and ir morphine).25–28

OxyContin® OxyContin® is an er/la oxycodone product that utilizes technology which provides significant resistance to crushing or grinding. The residual produced after such manipulation is difficult to syringe due to the formation of a gelatinous mass when liquid is added. OxyContin has abuse deterrent properties as denoted in section 9.2 of the pi.29

In Vitro Testing In vitro category 1 studies were performed to evaluate the success of different extraction methods in defeating the ER formulation. Results support that, relative to original OxyContin, there is an increase in the ability of orf to resist crushing, breaking, and dissolution using a variety of tools and solvents. The results of these studies also support this finding for orf relative to an ir oxycodone. When subjected to an aqueous environment, orf gradually forms a viscous hydrogel (ie, a gelatinous mass) that resists passage through a needle.

Clinical Liability Studies In a randomized, double blind, placebo controlled, 5 period crossover pharmacodynamic study, 30 recreational opioid users with a history of intranasal drug abuse received intranasally administered active and placebo drug treatments. The 5 treatment arms were finely crushed orf 30 mg tablets, coarsely crushed orf 30 mg tablets, finely crushed original OxyContin 30 mg tablets, powdered oxycodone hcL 30 mg, and placebo. Drug liking was measured on a bipolar drug liking scale of 0 to 100 where 50 represents a neutral response of neither liking nor disliking, 0 represents maximum disliking and 100 represents maximum liking. Response to whether the subject would take the study drug again was also measured on a bipolar scale of 0 to 100 where 50 represents a neutral response, 0 represents the strongest negative response (“definitely would not take drug again”) and 100 represents the strongest positive Q2 | 2017

response (“definitely would take drug again”). 27 of the subjects completed the study. Incomplete dosing due to granules falling from the subjects’ nostrils occurred in 34% (n=10) of subjects with finely crushed orf, compared with 7% (n=2) of subjects with finely crushed original OxyContin and no subjects with powdered oxycodone hcL.29 The intranasal administration of finely crushed orf was associated with a numerically lower mean and median drug liking score and a lower mean and median score for “take drug again” compared to finely crushed original OxyContin or powdered oxycodone hcL.29

Targiniq® Targiniq® is an er/la oxycodone product that utilizes an antagonist (naloxone) mixed with the opioid. Specifically, it uses an oxycodone:naloxone ratio of 2:1. The naloxone undergoes extensive first pass effect after oral consumption and has minimal to no effects, which allows the oxycodone to provide therapeutic analgesia. If manipulated and subsequently insufflated or injected, the naloxone antagonizes the effects of the oxycodone, thus reducing the reward and likeability to the abuser. Targiniq er has abuse deterrent properties according to section 9.2 of the pi.30

In Vitro Testing In vitro category 1 studies were performed to evaluate the success of different extraction methods in defeating the controlled-release formulation of Targiniq er and separating the oxycodone component from naloxone, a potent opioid antagonist. Laboratory test data demonstrate that Targiniq er can be crushed and dissolved in solution. However, complete separation or complete inactivation of naloxone from oxycodone was not achieved despite using various techniques and conditions.30

Clinical Abuse Potential Studies In the clinical abuse potential studies described below, drug liking was measured on a bipolar drug liking scale of 0 to 100 where 50 represents a neutral response of neither liking nor disliking, 0 represents maximum disliking and 100 represents maximum liking. Response to whether the subject would take the study drug again was measured on a unipolar scale of 0 to 100 where 0 represents the strongest negative response (“definitely would not take drug again”) and 100 represents the strongest positive response (“definitely would take drug again”). Response to subjective feeling of getting “high” was measured on a unipolar scale of 0 to 100, where 0 represents “definitely not” and 100 represents “definitely so.” www.painweek.org | PWJ

PHaRMaCOTHeRaPY

Study in Nondependent, Opioid Abusers— Intranasal (IN) Administration In a randomized, double blind, placebo and active controlled, 3 period crossover pharmacodynamic study, 23 nondependent, opioid abusers with moderate experience with opioids received in administered Targiniq er 40 mg/20 mg (finely crushed tablets),oxycodone hcL 40 mg powder (active control), and placebo treatments. in administration of finely crushed Targiniq er was associated with statistically significant lower maximum drug liking scores (P<0.001) and statistically significant lower maximum scores for “take drug again” (P<0.001), compared to powdered oxycodone hcL, and was associated with similar mean and median maximum scores for drug liking and “take drug again” compared to placebo treatment.30 The efficacy of Targiniq er was evaluated in one 12-week, randomized, double blind, placebo controlled clinical trial in opioid experienced patients with uncontrolled moderate to severe chronic low back pain. A higher proportion of patients treated with Targiniq er (55%) had at least a 30% reduction in pain score from screening to week 12 compared to placebo patients (41%). Also, a higher proportion of patients treated with Targiniq er (37%) had at least a 50% reduction in pain score from screening to week 12 compared to placebo patients (25%).30

Opana® Opana® is an er/la oxymorphone product that utilizes crush resistant intac® technology. Opana does not have labeling for abuse deterrent properties in section 9.2 of the product information. There are 2 efficacy studies for low back pain: one for opioid naïve patients and the other for opioid tolerant patients. Both studies showed statistically significant reduction in vas compared to placebo.31

Oxaydo® Oxaydo® is an ir formulation of oxycodone which uses aversion technology to reduce abuse. Specifically, it is formulated with an inactive ingredient (sodium lauryl sulfate, which is found in soap, shampoo, and other personal hygiene products) that may cause nasal burning and throat irritation when insufflated, to discourage intranasal use. Oxaydo does not have abuse deterrent properties per section 9.2. In a double blind, active comparator, crossover study in 40 nondependent recreational opioid users, drug liking responses and single-dose safety of crushed Oxaydo tablets were compared with crushed ir oxycodone tablets when subjects self-administered the drug intranasally. The presence of sequence effects resulted in questionable reliability of the second period data.

38 PWJ | www.painweek.org

First period data demonstrated small numeric differences in the median and mean drug liking scores, lower in response to Oxaydo than ir oxycodone. 30% of subjects exposed to Oxaydo responded that they would not take the drug again compared to 5% of subjects exposed to IR oxycodone. Study subjects self-administering Oxaydo reported a higher incidence of nasopharyngeal and facial adverse events and a decreased ability to completely insufflate 2 crushed tablets within a fixed time period (21 of 40 subjects). The clinical significance of the difference in drug liking and difference in response to taking the drug again reported in this study has not yet been established. There is no evidence that Oxaydo has a reduced abuse liability compared to ir oxycodone.32

Xtampza® Xtampza® is an er/la oxycodone that has physical properties which resist crushing and manipulation. Specifically, the microspheres of Xtampza er relative to ir oxycodone tablets were less susceptible to the effects of grinding, crushing, and extraction using a variety of tools and solvents. Xtampza er resisted attempts to pass the melted capsule contents or the microspheres suspended in water through a hypodermic needle.33 Xtampza er has abuse deterrent properties as listed in section 9.2. In an oral abuse liability study, Xtampza er showed the oral administration of chewed and intact Xtampza er in the fasted state was associated with statistically lower mean drug liking scores compared with crushed ir oxycodone. However, the differences for Xtampza er chewed and intact compared with crushed ir oxycodone for the “take drug again” scores were small and not statistically significant.33 In an intranasal abuse liability study, approximately 92% (n=33) of subjects had some reduction in drug liking with Xtampza er relative to crushed immediate-release oxycodone hcL. 78% (n=28) of subjects had a reduction of at least 30% in drug liking with Xtampza er compared to crushed immediate-release oxycodone hcL, and approximately 58% (n=21) of subjects had a reduction of at least 50% in drug liking with Xtampza er compared to crushed immediate-release oxycodone hcL.33

Hysingla ER® Hysingla® er is a once daily hydrocodone er/la formulation for chronic pain. It uses the same technology as OxyContin to provide a physical barrier to manipulation. Hysingla er has abuse deterrent properties per section 9.2 of the pi.34 Hysingla er is formulated with physicochemical properties intended to make the tablet more difficult to manipulate for misuse and abuse, and maintains some extended release characteristics even if the tablet is physically compromised. Q2 | 2017

It should be noted that the most common form of abuse is the oral (nonmanipulated) route, which is not addressed by ADFs.

To evaluate the ability of these physicochemical properties to reduce the potential for abuse of Hysingla er, a series of in vitro laboratory studies, pharmacokinetic studies, and clinical abuse potential studies was conducted.

drug again was measured on a unipolar scale of 0 to 100 where 0 represents the strongest negative response (“definitely would not take drug again”) and 100 represents the strongest positive response (“definitely would take drug again”).

In Vitro Testing

Intranasal Abuse Potential Study

In vitro physical and chemical tablet manipulation studies were performed to evaluate the success of different extraction methods in defeating the er formulation. Results support that Hysingla er resists crushing, breaking, and dissolution using a variety of tools and solvents and retains some er properties despite manipulation. When subjected to an aqueous environment, Hysingla er gradually forms a viscous hydrogel (ie, a gelatinous mass) that resists passage through a hypodermic needle.

In the intranasal abuse potential study, 31 subjects were dosed and 25 subjects completed the study. Treatments studied included intranasally administered tampered Hysingla ER 60 mg tablets, powdered hydrocodone bitartrate 60 mg, and placebo. Incomplete dosing due to granules falling from the subjects’ nostrils occurred in 82% (n=23) of subjects receiving tampered Hysingla ER compared to no subjects with powdered hydrocodone or placebo.

Clinical Abuse Potential Studies in Nondependent Opioid Abusers

The intranasal administration of tampered Hysingla ER was associated with statistically significantly lower mean and median scores for drug liking and “take drug again” (P<0.001 for both), compared with powdered hydrocodone.34

Two randomized, double-blind, placebo and active controlled clinical studies in nondependent recreational opioid users were conducted to characterize the abuse potential of Hysingla ER following physical manipulation and administration via the intranasal and oral routes.31 For both studies, drug liking was measured on a bipolar drug liking scale of 0 to 100 where 50 represents a neutral response of neither liking nor disliking, 0 represents maximum disliking, and 100 represents maximum liking. Response to whether the subject would take the study Q2 | 2017

Oral Abuse Potential Study In the oral abuse potential study, 40 subjects were dosed and 35 subjects completed the study. Treatments studied included oral administrations of chewed Hysingla ER 60 mg tablets, intact Hysingla ER 60 mg tablets, 60 mg aqueous hydrocodone bitartrate solution, and placebo. www.painweek.org | PWJ

PHaRMaCOTHeRaPY

Prodrug ADFs are precursors to the active opioid. They are enzymatically bio transformed in the gastrointestinal tract and therefore cannot be abused via inhalation, snorting, and smoking.

The oral administration of chewed and intact Hysingla ER was associated with statistically lower mean and median scores on scales that measure drug liking and desire to “take drug again” (P<0.001), compared to hydrocodone solution.34

environment, the manipulated Arymo ER tablets form a viscous hydrogel (ie, a gelatinous mass) that resists passage through a hypodermic needle.

The results of a similar analysis of drug liking for intact Hysingla ER relative to hydrocodone solution were comparable to the results of chewed Hysingla ER relative to hydrocodone solution. Approximately 83% (n=29) of subjects had some reduction in drug liking with intact Hysingla ER relative to hydrocodone solution. 83% (n=29) of subjects had a reduction of at least 30% in peak drug liking scores with intact Hysingla ER compared to hydrocodone solution, and approximately 74% (n=26) of subjects had a reduction of at least 50% in peak drug liking scores with intact Hysingla ER compared with hydrocodone solution. Approximately 17% (n=6) had no reduction in drug liking with intact Hysingla ER relative to hydrocodone solution.34

Oral Clinical Abuse Potential Study

Arymo™ ER® Arymo™ ER is an extended release morphine sulfate compound that can be administered every 8–12 hours. Arymo ER has physical and chemical properties expected to make abuse by injection difficult.35

In Vitro Testing In vitro physical and chemical manipulation studies were performed to evaluate the ability of different methods to defeat the ER properties. The results of this testing demonstrated that Arymo ER tablets, in comparison to morphine sulfate ER tablets, have increased resistance to cutting, crushing, grinding, or breaking using a variety of tools. When subjected to a liquid

40 PWJ | www.painweek.org

An oral abuse potential study was conducted in 39 subjects who were nondependent recreational opioid users; 38 subjects completed the study. Treatment arms included manipulated Arymo ER 60 mg tablets (taken with juice), intact Arymo ER 60 mg tablets (taken with juice), crushed 60 mg morphine sulfate ER tablets (mixed in juice), and placebo. The study demonstrated that the oral administration of manipulated Arymo ER resulted in a statistically lower mean drug liking score than the oral administration of crushed morphine sulfate ER tablets. However, the difference between manipulated Arymo ER and crushed morphine sulfate ER tablets for “take drug again” was not statistically significant, indicating that the difference in drug liking scores was not clinically meaningful.

Prodrug ADFs

Prodrug ADFs are precursors to the active opioid. They are enzymatically bio transformed in the gastrointestinal tract and therefore cannot be abused via inhalation, snorting, and smoking. Benzhydrocodone hydrochloride (KP201) is a prodrug of hydrocodone (in combination with acetaminophen) and was developed by KemPharm (KP201/APAP) as a potential ADF.36 KP201 was tested in healthy individuals and confirmed by a group of opioid-naïve subjects in clinical studies.37,38 Three human clinical abuse potential studies showed that KP201/APAP produced a significantly lower Cmax , a delay in Tmax , a decreased total exposure to hydrocodone, and a Q2 | 2017

lower incidence of hypoxia at high doses, as compared to a hydrocodone bitartrate and APAP combination for both intranasal and oral administration.36,39 The manufacturer received new drug application approval and priority review from FDA in February 2016.40

ADFs With Unique Delivery Systems Another potential strategy for deterring opioid abuse is the development of new delivery systems, such as subcutaneous implants and depot injections that provide sustained and gradual opioid release. The buprenorphine transdermal delivery system (btds; Butrans®, Purdue Pharma)41 utilizes a molecule (buprenorphine) with a high affinity for the μ-receptor. As a partial agonist, buprenorphine is a logical choice as an agent for abuse deterrence due to its lack of euphorigenic effects.

One may consider adfs for opioids as “the child guard cap,” which currently exists for all prescription pharmaceuticals (and many over the counter as well). The concept that medications contain an abuse deterrent formulation to protect others in addition to our own patients is really a public health solution to a growing epidemic. These technologies are expensive, and society (and government) must decide who will pay for them and determine whether they are mandated for use or simply recommended. Potential cost savings have demonstrated for substituting reformulated OxyContin for generic oxycodone er. Several studies in a comprehensive review have assessed the economic impact of reduced abuse, drug overdose rates, and utilization after instituting reformulated OxyContin.50,51 The prescription drug epidemic is being fought on multiple fronts. ADFs are just one weapon in that war. References

Implants could be used to treat patients with comorbid chronic pain and substance abuse, which accounts for 32% of chronic pain patients who require prescription opioids.42,43 The first subdermal implant of buprenorphine (Probuphine®, Titan Pharmaceuticals) was approved by fda in May 2016 for the maintenance treatment of opioid dependence.41 This product provides continuous low dosing of buprenorphine for up to 6 months, obviating the need for daily medication and safeguarding against illicit drug use.44–46 Although this product is approved for the treatment of opioid dependence, theoretically the same technology could be utilized in the treatment of chronic pain. Pharmacokinetic data suggests that implant buprenorphine produces lower peak plasma concentrations than sublingual administration.47 A small study of heroin dependent abusers showed that implant buprenorphine resulted in fewer positive urine tests for opioids, less withdrawal symptoms, and fewer craving events after 6 months.48 An unpublished Phase III trial demonstrated after 6 months that implant buprenorphine was noninferior to sublingual buprenorphine/naloxone in maintaining clinical stability, with no evidence of illicit opioid use (63.2% vs 53.9%, P=0.21).48 The monthly cost of such a product is high (approximately $1000), which could be an obstacle to its use.49

Conclusion

Q2 | 2017

1. Centers for Disease Control and Prevention. Vital Signs: overdoses of prescription opioid pain relievers and other drugs among women United States, 1999–2010. MMWR. 2013;62:537–542. 2. Kochanek KD, Xu J, Murphy SL, et al. Deaths: final data for 2009. Natl Vital Stat Rep. 2011;60(3):1–116. 3. CDC Vital Signs. Prescription painkiller overdoses: use and abuse of methadone as a painkiller. July 2012. Available at: https://www.cdc.gov/vitalsigns/ methadoneoverdoses/. 4. Warner M, Chen LH, Makuc DM, et al. Drug poisoning deaths in the United States, 1980–2008. NCHS Data Brief. 2011 Dec;(81):1–8. 5. National Center for Injury Prevention and Control. Division of Unintentional Injury Prevention. Policy Impact. Prescription Painkiller Overdoses. November 2011. 6.

CDC. Opioid overdose. Available at: www.cdc.gov/drugoverdose/index.html.

7. Katz NP, Adams EH, Chilcoat H, et al. Challenges in the development of prescription opioid abuse-deterrent formulations. Clin J Pain. 2007;23:648–660. 8. Substance Abuse and Mental Health Services Administration. Results from the 2013 national survey on drug use and health: summary of national findings. Based on chart available at: www.samhsa.gov/data/sites/default/files/ NSDUHresultsPDFWHTML2013/Web/NSDUHresults2013.pdf. 9. Washington State Legislature. WAC Medical Quality Assurance Commission. WAC 246–919 (850–863). 10. Governor’s Cabinet. Opiate Action Team. Ohio guidelines for prescribing opioids for the treatment of chronic, non-terminal pain 80 mg of a morphine equivalent daily dose (MED) “trigger point.” Available at: mha.ohio.gov/Portals/0/ assets/Initiatives/GCOAT/Guidelines-Chronic-Pain.pdf.

adfs are now mandated by the fda for all pharmaceutical manufacturers of er/la opioids. They are part of a broader rems strategy to mitigate overdose deaths and morbidity associated with prescription opioid use. It is important to note that adfs do not replace rems but are an integral component.

12. Federal Register. Medication assisted treatment for opioid use disorders. Available at: https://www.federalregister.gov/documents/2016/07/08/2016–16120/ medication-assisted-treatment-for-opioid-use-disorders.

The use of adfs is to protect the public and is not necessarily designed for individual patient use. In fact, if a pain practitioner suspects or diagnoses a patient with a substance used disorder, then controlled substances should not be prescribed for pain. Instead a treatment regime for chemical dependency should be implemented.

14. FDA. Questions and Answers: FDA approves a Risk Evaluation and Mitigation Strategy (REMS) for Extended-Release and Long-Acting (ER/LA) Opioid Analgesics Available at: www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ ucm309742.htm.

11. CS/CS/HB 7095: Prescription Drugs; Florida Senate; Chapter No. 2011–141.

13. FDA’s Safe Use Initiative: Collaborating to reduce preventable harm from medications. Available at: www.fda.gov/downloads/Drugs/DrugSafety/ ucm188961.pdf.

15. FDA. Approved Risk Evaluation and Mitigation Strategies Available at:

www.painweek.org | PWJ

PHaRMaCOTHeRaPY

www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsDetails. page&REMS=60.

34. Hysingla® ER prescribing information. Available at: www.accessdata.fda. gov/drugsatfda_docs/label/2014/206627s000lbl.pdf.

16. Manchikanti L, Abdi S, Atluri S, et al; American Society of Interventional Pain Physicians. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic noncancer pain: part 1—evidence assessment. Pain Physician. 2012;15(3 suppl): S1–65.

35. Arymo prescribing information. Available at: www.accessdata.fda.gov/ drugsatfda_docs/label/2017/208603s000lbl.pdf.

17. Manchikanti L, Abdi S, Atluri S, et al; American Society of Interventional Pain Physicians. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic noncancer pain: part 2—guidance. Pain Physician. 2012;15(3 suppl):S67–116. 18. Chou R, Fanciullo GJ, Fine PG, et al; American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10:113–130. 19. Dowell D, Haegerich TM, Chou R. CDC Guideline for prescribing opioids for chronic pain—United States, 2016. MMWR Recomm Rep. 2016;65(1):1–49. 20. FDA. Abuse-deterrent opioids—evaluation and labeling: guidance for industry. Available at: www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm334743.pdf. 21. Coplan PM, Kale H, Sandstrom L, et al. Changes in oxycodone and heroin exposures in the National Poison Control Data System after introduction of extended-release oxycodone with abuse-deterrent characteristics. Pharmacoepidemiol Drug Saf. 2013;22:1274–1282. 22. Dart RC, Surratt HL, Cicero TJ, et al. Trends in opioid analgesic mortality in the United Sates. N Engl J Med. 2015;372:241–248. 23. Butler SF, Cassidy TA, Chilcoat H, et al. Abuse rates and routes of administration of reformulated extended-release oxycodone: initial findings from a sentinel surveillance sample of individuals assessed for substance abuse treatment. J Pain. 2013;14(4):351–358.

36. KemPharm, Inc. completes human abuse liability program for KP201/APAP. News Release. Oct 21, 2015. Available at: investors.kempharm.com/phoenix. zhtml?c=253970&p=irol-newsArticle&ID=2099179. 37. KemPharm’s KP201 demonstrates complete metabolic cleavage of prodrug and steady-state pharmacokinetics profiles for hydrocodone, hydromorphone and acetaminophen. News Release. Available at: investors.kempharm.com/phoenix.zhtml?c=253970&p=irol-newsArticle&ID=2030673. 38. KemPharm’s KP201 demonstrates bioequivalence compared to Norco® in key pivotal clinical study. News Release. September 25, 2013. Available at: investors.kempharm.com/phoenix.zhtml?c=253970&p=irol-newsArticle&ID=2030658. 39. KemPharm, Inc. reports positive data from oral human abuse liability clinical trial of KP201/APAP. Globe News Wire. June 11, 2015. Available at: globenewswire. com/news-release/2015/06/11/743843/10138140/en/KemPharmInc-Reports-Positive-Data-From-Oral-Human-Abuse-Liability-Clinical-Trial-of-KP201- APAP.html. 40. KemPharm. FDA grants priority review to KemPharm for KP201/APAP NDA. News Release. February 10, 2016. Available at: investors.kempharm.com/phoenix. zhtml?c=253970&p=irol-newsArticle&ID=2137106. 41. Butrans prescribing information. Purdue Pharma, Stamford, CT. June 2014. 42. Katz N. Abuse-deterrent opioid formulations: are they a pipe dream? Curr Rheumatol Rep. 2008;10:11–18. 43. Ives TJ, Chelminski PR, Hammett-Stabler CA, et al. Predictors of opioid misuse in patients with chronic pain: a prospective cohort study. BMC Health Serv Res. 2006;6:46.

24. Cicero TJ, Ellis MS. Abuse deterrent formulations and the prescription opioid abuse epidemic in the United States: lessons learned from OxyContin. JAMA Psychiatry. 2015;72(5):424–429.

44. FDA New Release. FDA approves first buprenorphine implant for treatment of opioid dependence. Available at: www.fda.gov/newsevents/newsroom/pressannouncements/ucm503719.htm.

25. Stauffer J, Setnik B, Sokolowska M, et al. Subjective effects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extended-release capsules versus morphine solution and placebo in experienced non-dependent opioid users A randomized, double-blind, placebo-controlled, crossover study. Clin Drug Investig. 2009;29(12):777–790.

45. Buprenorphine implants (Probuphine) for opioid dependence. Med Lett Drugs Ther. 2016;58:94–95.

26. Setnik B, Sommerville K, Goli V, et al. Assessment of pharmacodynamic effects following oral administration of crushed morphine sulfate and naltrexone hydrochloride extended-release capsules compared with crushed morphine sulfate controlled-release tablets and placebo in nondependent recreational opioid users. Pain Med. 2013;14:1173–1186.

47. White J, Bell J, Saunders JB, et al. Open-label dose-finding trial of buprenorphine implants (Probuphine) for treatment of heroin dependence. Drug Alcohol Depend. 2009;103:37–43.

27. Setnik B, Goli V, Levy-Cooperman N, et al. Assessing the subjective and physiological effects of intranasally administered crushed extended-release morphine formulations with and without a sequestered naltrexone core in recreational opioid users. Pain Res Manag. 2013;18(4):e55-e62. 28. Webster LR, Johnson FK, Stauffer J, et al. Impact of intravenous naltrexone on intravenous morphine-induced high, drug liking, and euphoric effects in experienced, nondependent male opioid users. Drugs R D. 2011;11:259–275. 29. OxyContin® prescribing information. Available at: www.accessdata.fda.gov/ drugsatfda_docs/label/2015/022272s027lbl.pdf. 30. Targinq® product information. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2014/205777lbl.pdf. 31. Opana® prescribing information. Available at: www.accessdata.fda.gov/ drugsatfda_docs/label/2013/201655s004lbl.pdf.

46. Probuphine [package insert]. South San Francisco, CA: Titan Pharmaceutical Inc. May 2016.

48. Braeburn Pharmaceuticals. Probuphine® (buprenorphine) Implant Phase 3 Data Presented at CPDD Annual Scientific Meeting. Available at: braeburnpharmaceuticals.com/probuphine-buprenorphine-implant-phase-3-data-presented-at-cpdd-annual-scientific-meeting/. 49. Bebinger M. FDA considering pricey implant as treatment for opioid addiction. Kaiser Health News. May 25, 2016. Available at: khn.org/news/ fda-considering-pricey-implant-as-treatment-for-opioid-addiction/. 50. Kirson NY, Shei A, White AG, et al. Societal economic benefits associated with an extended-release opioid with abuse-deterrent technology in the United States. Pain Med. 2014;15:1450–1454. 51. Rossiter LF, Kirson NY, Shei A, et al. Medical cost savings associated with an extended-release opioid with abuse-deterrent technology in the US. J Med Econ. 2014;17:279-287.

32. Oxaydo® prescribing information. Available at: egalet.com/wp-content/ uploads/2014/12/USPI_OXAYDO-Oxycodone-HCL-Tablets_Egalet-FINAL28Apr2015.pdf. 33. Xtampza® prescribing information. Available at: www.xtampzaer.com/pdf/ xtampza-pi.pdf.

PWJ | www.painweek.org

Q2 | 2017

CONFeReNCe PReVieW

2017

Sept. 5â&#x20AC;&#x201C;9

The Cosmopolitan of Las Vegas

conference preview

“

PAINWeek is an excellent conference for frontline practitioners because the level of discussion is definitely at the cutting edge of science. There is so much good information that it’s not even possible to get everything in one fell swoop; it will require coming back again!” —Jennifer Hah md, ms

Launched in 2007, PAINWeek quickly ascended to become the largest US pain conference. In 2017, we invite you to celebrate and participate in a decade of unparalleled leadership that has elevated the pain management acumen of approximately 12,000 healthcare providers over the last 10 years. Celebrating our 11th year, PAINWeek remains the favorite destination for frontline practitioners to enhance their competence in pain management. Join us for a comprehensive program of a multidisciplinary curriculum, satellite events, and exhibits. To learn more and register for PAINWeek 2017, visit www.painweek.org, and follow us on Twitter® at twitter.com/painweek.

WORKSHOPS A Comedy of Errors: Methadone, Marijuana, and Buprenorphine Presented Tuesday, Sept 5 9:00a – 12:00p Registration Fee: $165 The 3 most contentious, poorly understood analgesics today are methadone, cannabis, and buprenorphine. This fast-paced workshop will equip practitioners with immediately implementable practical tips regarding when and how to use these analgesics, including dosage formulations, routes of delivery, appropriate use in therapy, drug interactions, dosage titration (up and down), opioid conversion calculations, and more. All discussions will be aimed at enhancing clinical, economic, and humanistic outcomes on the individual patient and health system level.

Managing Pain Between a Rock and a Hard Place:

Getting the Tough Jobs Done in Serious Illness Presented Tuesday, Sept 5 1:40p – 4:40p Registration Fee: $165

Patients with serious illnesses often experience painful clinical situations that are beyond the scope of usual and customary practice. Palliative care practitioners are skilled at thinking “out of the box” to get the job done, including recognizing and treating opioid induced hyperalgesia, pain in highly opioid tolerant patients, and the use of analgesics such as ketamine (by a variety of routes of administration), methadone (oral and parenteral), and lidocaine (parenteral and topical). Participants in this interactive workshop will leave with practical strategies to treat difficult pain syndromes in advanced illness, including painful wound care.

Winning the Game of Groans:

Strategies and Tactics for Preserving the Pain Practitioner’s Decision to Prescribe Controlled Medication Presented Wednesday, Sept 6 9:00a – 12:00p Registration Fee: $185 Back by popular demand, this hands-on workshop—a huge success at last year’s conference—will instruct pain practitioners on key self-audit strategies and tactics to demonstrate and document patient evaluation and monitoring when prescribing controlled medications to treat pain. Using a combination of teaching methods, faculty will present not only the “what” of quality patient evaluation and monitoring, but also the “how to” of compliance and documentation strategies. Faculty and learners will work through extensive case examples and various treatment puzzles to accomplish course objectives.

PARTiCiPATiNG ORGANIZATiONS American Headache Society (ahs) Presented Tuesday, Sept 5

Developed by the American Headache Society®, the Chronic Migraine Education Program (cmep) includes new advances and addresses acute and preventive treatment options. In addition, the cmep highlights epidemiologic data on the scope and distribution of migraine with an emphasis on diagnosing chronic migraine,

and recent insights into the mechanisms of the disorder setting the stage for improving treatment outcomes for this most disabling of headache disorders. Part 1 will cover Diagnosis of Chronic Migraine, risk factors, and prognosis. Part 2 will cover Preventive Pharmacotherapy for chronic migraine and advances in acute treatment.

American Pain Society (aps) Presented Friday, Sept 8

The theme of this year’s aps Track is Bend Don’t Break: Building Resilience Against Chronic Pain. Previous pain research emphasized identifying risk factors and pathological states. While of obvious importance, this pathology based approach neglects the importance of identifying resilience factors that protect against pain or enable individuals to respond adaptively in the face of pain. The aps Track at PAINWeek 2017 will feature 5 sessions. The first is Resilience vs Vulnerability in Chronic Pain. Next, The Biological Interface of Resilience will discuss how resilience factors may prevent the adverse biological outcomes of chronic pain. Ramping-Up Resilience for Chronic Pain: Strategies for Reducing Pain and Improving Function will emphasize novel interventions that may increase resilience. Resilience Interventions for Pain will feature multidimensional interventions to promote resilience in people with fibromyalgia. The final session is Building Brain Resilience through Mindfulness Meditation.

American Society of Pain Educators (aspe) Presented Wednesday, Sept 6 and Thursday, Sept 7

The 12th annual Pain Educators Forum will present 2 days of clinical and adult learning courses. Day 1 features Pain Terminology, which addresses how “knowing the difference makes a difference,” followed by Pain Pathophysiology Unraveled, uncovering the underlying mechanisms responsible for pain. Chronic Pain Assessment offers effective communication and evaluates screening tools. Next, Pain Diagnostics: Clinical Pearls to Improve Common Tests for Pain speaks to the importance of diagnostic testing for differential diagnosis (and their inherent limitations), followed by an extensive presentation on Pain Therapeutics. Day 2 presents Flipping the Script: Why We Need a Patient REMS Course; You’re Giving me an mi: Incorporating Motivational Interviewing into Challenging Conversations; and Who Gives a Hoot about Pedagogy, Andragogy, and Heutagogy? How Educators Can Help Learners Learn.

International Pelvic Pain Society (ipps) Presented Thursday, Sept 7

The International Pelvic Pain Society (ipps) joins PAINWeek for the first time, presenting What’s Going on Down There? Demystifying Female Pelvic Pain Syndromes. First is Don’t Dismiss Dysmenorrhea: A Systematic Approach to the Evaluation and Management of Painful Periods. Early and prompt treatment of dysmenorrhea may be an important target for prevention of central sensitization, as well as the progression to various chronic pain conditions. When Pain Is Not Sexy: Evaluation and Management of Sexual Pain in Females reveals how sexual pain fits the biopsychosocial model of pain. Pelvis Gone Wild: A Sordid Tale of Musculoskeletal Dysfunction will discuss pelvic pain conditions (endometriosis, vulvodynia, painful bladder syndrome, etc) and key abdomino-pelvic musculature. The final course, To Infinity and Beyond Pharmacotherapy: An Integrative

www.painweek.org

Approach to the Management of Female Chronic Pelvic Pain, will discuss varied integrative modalities—conventional and plantbased medicines, nutrition, movement therapies, manual bodywork, etc. Throughout the track, faculty will utilize clinical vignettes and video demonstrations.

National Association of Drug Diversion Investigators (naddi) Presented Thursday, Sept 7

The 2017 naddi Track will bring current trending information with a primary focus on drug diversion nuances. Topics will include Data Fiction—Do We Make Life and Death Decisions Based on Bad Data? and the problem it poses for the healthcare industry; Algorithms and Opioid Dosing Watch Lists and how they are used in investigations; the status of the many national Overdose Prevention Strategies and whether they are working; Opioid Counterfeits that are on the black market and the fallout on our streets; and also insight into a Pain Practice Check-Up and how law enforcement uses deviations from Standards of Practice as probable cause for search warrants.

FeATUReD TRACKS

NeW! Functional Medicine

Presented Tuesday, Sept 5 All You Need is Love: Incorporating Functional Medicine in Pain Care will teach providers about the development and implementation of an intervention that addresses the 4 key pillars of an anti-inflammatory lifestyle. In addition, there will be some exploration of how a person expresses love and feels loved, the ultimate measure of a patient’s well-being and health. Food is Medicine: A Review of the AntiInflammatory Diet will guide providers on how to implement a modified elimination diet. Use of this diet necessitates the removal of the most common causes of food reactions while monitoring clinical symptoms to see if there is an improvement in how the patient feels. During this presentation the facilitators will outline what foods to eliminate/ adjust. Looking in the Rear View Mirror: Addressing Inflammation Through Lifestyle Imbalances will guide providers on how to coach patients to change their environment and live an anti-inflammatory lifestyle by focusing on proper sleep hygiene, stress management, and how to adjust an exercise program to accommodate the individual needs and capabilities of the patient. The goal of the intervention is to educate and support self-care among chronic pain patients, not just during treatment, but for a lifetime.

NeW! Medical Cannabinoids and Medical Marijuana

Advanced Practice Provider (app) Presented Thursday, Sept 7

Presented Friday, Sept 8

Returning this year is the acclaimed Advanced Practice Provider (app) Track, focusing on practice issues surrounding pain education and management, most pertinent to nurse practitioners, physician assistants, clinical nurse specialists, and other frontline clinicians. The track, created and presented by apps for apps, will provide a full-day of diverse educational offerings, beginning with a 2-hour Case Based Learning presentation from the perspective of an interdisciplinary panel, reviewing complex case studies on common, but otherwise challenging-to-manage pain syndromes, including chronic low back pain, postherpetic neuralgia, and diabetic peripheral neuropathy. The final 3 hours of the day will be broken up into 3 separate 50 minute courses, the first of which will exam The Importance of Chart Documentation: Through the Eyes of a Chart Reviewer. Specifically, the balance of all factors associated with safe opioid prescribing will be described. Pitfalls associated with use of an ehr when caring for the chronic pain patient will be explained, along with identification of essential items that should be included in your documentation when caring for the patient with chronic pain. Blending, Melting, or Throwing Off a Cliff? Abuse Deterrent Technologies to Minimize Opioid Abuse will focus on the fda’s publication “Abuse Deterrent Opioids—Evaluation and Labeling: Guidance for Industry,” as well as discuss many of the novel technologies developed and labeled specifically to minimize the likelihood of abuse, while retaining the potential benefits of opioids in the management of pain. The Green-Eyed Martian: Do Healthcare Disparities Exist in Pain Management?, the final lecture, will explore the topic of disparities in pain management. It will define the epidemiological findings that define the scope of the problem related to disparities in pain management about race, ethnicity, and socioeconomic status. Case scenarios will be presented representing life examples. Finally, strategies to minimize disparities in healthcare when it comes to providing pain management will be identified.

The past several years have witnessed dramatic increases in the use and state-mandated legalization of medical cannabinoids, as well as a growing number of states that have legalized marijuana recreationally. Reefer Madness: Taking the Insanity Out of Medical Cannabinoids will serve as an update of what we know and what we don’t know about the safety and efficacy of medical cannabinoids for pain management. Different perspectives will be presented in this track, among them Cannabis vs Cannabinoids: The Politics of Medical Marijuana, which will discuss the tendency to equate medical cannabinoids with medical marijuana, and the distinctions between the 2 will be explored. Medical Efficacy of Cannabis Therapeutics: Focus on Pain Management will cover misinformation and lack of understanding by hcps about cannabinoids. Specifically, this course will address the discovery of the endocannabinoid system (ecs) as a modulator of nociception and the role that phytocannabinoids have on the ecs. With more acceptance and use of cannabis for a variety of medical conditions, typically pain, there comes health and societal effects, many of which have been unanticipated. Cannabis and Pain: Lessons From Colorado looks at growing pains experienced along the way, particularly with de facto legalization prior to the vote to legalize.

NeW! Physical Therapy

Presented Tuesday, Sept 5 Words Wisely Chosen: Avoiding the Unintended Nocebo Effect will teach clinicians to explain body pain in terms of anatomy and biomechanics. Alternative, descriptive terms/phrases to use during patient interactions will be offered. Exercise Prescription for Patients With Chronic Pain will discuss low exercise compliance and review guidelines and trials discussing implementation of patient coaching techniques to bridge the gap between evidence and practice to help

www.painweek.org

patients attain better function and a healthier lifestyle. At the Edge of Interaction: Applying Edge Work and Novel Movement to Painful Motion is well-suited for clinicians working or interested in fields of movement therapy, manual therapy, physical medicine, and rehabilitation as it relates to pain. Restoring Hope: The Treatment of Pelvic Pain Across the Gender Spectrum will outline interdisciplinary options to identify persons with pelvic pain and design treatment programs to restore optimal function. Lastly, the Fascial Distortion Model (FDm) gives practitioners the ability to interpret a patient’s pain complaints and direct treatment to correct fascial distortions.

NeW! Wound Care

Presented Saturday, Sept 9 This new track discusses the necessity of wound care. Each of the 2-hour sessions will inform attendees of the importance of proper care of the body’s largest organ: skin. Woundology—The Spectrum of Reasons Why the Epithelium Gets Lost reviews the major causes of wounds that may present in a practitioner’s office. The presenter will offer common sense ways to make the diagnosis and decide if treatment can be performed in the office or should be referred to a specialist. This session will provide an overview of the basic pathophysiology of several common types of wounds and sets the stage for the second session, Insult to Injury: Wound and Other Pains in a Wound Care Patient. Once a diagnosis of the etiology of a wound or related condition has been made, treatment of the pain associated with it needs to be logical, successful, and multifocal to address not just the pain but related and interrelated causes. This presentation will look at the causes of pain related to various wound conditions and discuss treatment options as well as overall pain control.

SPeCiAL iNTeReST SeSSiONS Measure for Measure:

Prescribing Guidelines, Rules, and Regulations The state of Washington was one of the first states to legislate prescribing rules for the treatment of chronic pain, a unique model that relied on the use of a dosage trigger and the necessity to calculate morphine equivalency. Following Washington’s lead, the Centers for Disease Control and Prevention (cdc) as well as other states have created their own guidelines and rules that not only vary widely but are often in conflict with each other. This presentation will discuss the recent history of prescribing guidelines, their diffusion across the United States, and their potential impact on medical practice and the treatment of pain.

Walking the Tightrope: Pain, Addiction, and Suicide Death by suicide has become a global epidemic. Every 40 seconds someone in the world dies of suicide. An estimated 804,000 suicide deaths occurred worldwide in 2012. Individuals with chronic pain commonly have significant concomitant psychiatric and medical disorders placing them at higher risk for suicide. This presentation will review current literature on the epidemiology of suicidal ideation in the pain and substance use disorder populations, and discuss assessing suicide risk and identifying modifiable mediators of pain, substance use disorder, and suicide.

As You Like It: The Business of Pain Medicine It has been estimated that approximately 30% of adults in the United States suffer from chronic or recurrent pain and this number grows annually. Pain care models have in the past evolved from unimodal/ multimodal approaches to cost effective, efficacious interdisciplinary care. Over the past few years the field of pain medicine has regressed from providing a more holistic, interdisciplinary approach to emphasizing unimodal (spinal injections, spinal cord stimulation), and at best limited multimodal (medication management, procedures) interventions. The long-term efficacy and costs of these currently standard treatments varies greatly. This presentation will provide a critical review of good vs poor evidence based pain medicine interventions and the associated costs to patients and society.

Are You Now… or Have You Ever Been? Saving Pain Medicine from Zealotry

Healthcare providers continue to incur the ire of anti-opioid zealots who have engaged in marginalization of prescribers and the millions of people who take opioids responsibly. This panel discussion will explore the many policy and ethical issues surrounding the prescribing of opioids and provide prescribers with some strategies that may help effect change and improve the lives of the people they treat.

The Story of O—A Molecule in Chains? The management of chronic pain syndromes with long-term opioid therapy remains controversial. How are clinicians supposed to responsibly sift through the miasma of evidence based data, and the chorus of cnn, cdc, and dea voices, while helping patients manage their chronic pain? This presentation separates fact from fiction, acknowledges the dilemma facing healthcare providers today, and provides practical insight to frontline practitioners grappling with this quandary.

Using Electronic Pain Assessment Programs and Innovative Technology in Pain Medicine:

Where Are We Now and Where Are We Going?

There has been a rise in interest in remotely assessing and monitoring pain and associated symptoms (eg, fatigue) as well as in the use of electronic health (eHealth) technology designed to support individuals in making lifestyle changes needed to improve pain management. Consumer demand for remote assessment programs, health ‘apps,’ and sensors has far outpaced the science needed to understand their benefits and impact. For persons with chronic pain and the providers who treat them, assessment programs, mobile apps, and activity monitors can help encourage behavioral change, including symptom monitoring, and serve as useful tools to enhance patient-provider communication. This 90-minute session will detail the content, and face validity, reliability, usability, benefits, barriers, and technical issues associated with the use of eHealth technology for persons with chronic pain and discuss future areas for clinical use. Note: Confirmed dates/times for all Special Interest Sessions will be noted in the forthcoming Schedule-at-a-Glance, available May 2017. Note: Courses and tracks are subject to change.

www.painweek.org

MONDaY/9.4

TUeSDaY/9.5

WeDNeSDaY/9.6

Session presented from 6:00p – 7:00p.

Sessions presented from 7:00a – 6:30p.

PAINWeek 101—Making the Most of Your PAINWeek Experience!

American Headache Society (AHS) Chronic Migraine Education Program

● Osteoarthritis

PART 1 (2 hours)

● Translational Complex Regional Pain Syndrome:

● Diagnosis of Chronic Migraine and Episodic Migraine

Research vs Empiricism (80 minutes)

● Transitions, Risk Factors, and Barriers to Care

● Diabetic Peripheral Neuropathic Pain

● Case Studies and Q&A

● Man on Fire Syndrome:

PART 2 (2 hours) ● Pathophysiology of Chronic Migraine and

Episodic Migraine

● Acute Treatment Strategies ● Preventive Treatment Strategies

Not certified for credit.

Behavioral Pain Management

Visit www.painweek.org for more information.

● Crisis=Opportunity: Reducing Medication Burden

While Managing Chronic Pain

● The Lesion Not Visible on the Scan ● Kissing the Wrong Frog:

Exploring Common Factors in Pain Management

● Nonpharmacologic Management of Pain:

Essential Tools for Frontline Clinicians

Health Coaching ● Pain Management Coaching: Integrative and

Complimentary Strategies for Complicated Pain

● How Pain Management Coaching Impacts Pain Outcomes

Integrative Pain Management ● Microbiome: The Link Between Nutrition and Pain ● Please Release Me!

Effective Treatment for Myofascial Pain ● Biofeedback Therapy:

Surviving and Living With Chronic Pain (80 minutes) ● Connecting the Dots in Chronic Pain ● Lessons From a County Hospital Setting: A Novel

Approach to Integrative Pain Management (80 minutes)

Master Class ● Neurogenic Thoracic Outlet Syndrome (90 minutes)

Medical/Legal ● Get Your Specimens in Order: 2017 ● Overdose! Legal Risk Mitigation and Response

(80 minutes)

PAINWeek Pop-Ups ● Pain Mechanism Theories:

From Gates to Predictive Coding

● 14 Miles from Wisdom: Things I Learned by Accident

Diagnosis and Treatment of Erythromelalgia

Interventional Pain Management ● Injections, Nerve Blocks, Pumps, and

Spinal Cord Stimulation

● Failed Back Surgery Syndrome ● Regenerative Medicine for Chronic Pain:

Who, What, and When?

● From the Torpedo Fish to HF10:

The Evolution of Neuromodulation

Master Class ● It Hurts to Be Alive:

Fibromyalgia (2 hours)

Pain Educators Forum ● Pain Terminology:

Knowing the Difference Makes a Difference!

● Pain Pathophysiology Unraveled ● Chronic Pain Assessment ● Pain Diagnostic Methods ● Pain Therapeutics (2 hours)

PAINWeek Pop-Ups ● Pharmacogenetics:

To Test or Not to Test?

● Effective Motivational Interviewing

Special Interest Sessions ● Are You Now… or Have You Ever Been? (80 minutes) ● Drinking From a Fire Hose: Educating Stakeholders at the Speed of Sound ● The Story of O— A Molecule in Chains ● Walking the Tightrope: Pain, Addiction, and Suicide ● How to Develop a Multidisciplinary Pain Program

in a Nonacademic Setting

Workshop ● Winning the Game of Groans: Strategies and Tactics for Preserving the Pain Practitioner’s Decision to Prescribe Controlled Medication (3 hours)

Special Interest Sessions ● The Regulatory Agency Will See You Now ● Itsa Schmerz! Acute Post-Op Pain Management

(80 mins)

● Measure for Measure: Prescribing Guidelines, Rules, and Regulations ● The Outer Limits: Analgesics of the Future ● Ketamine: Not Just for Horses ● Within You, Without You:

Virtual Reality for Pain Management

Workshops ● Managing Pain Between a Rock and a Hard Place ● A Comedy of Errors:

Methadone, Marijuana, and Buprenorphine (3 hours)

SPeCiaL eVeNTS *

PAINWeek 101 is a noncertified primer for first time attendees—or anyone seeking a refresher on the conference agenda, faculty, onsite technology, and venue logistics. Moderated by PAINWeek staff and faculty with Global Education Group, all questions as they pertain to course selection and CME protocol will be answered. With so much packed into the 5-day conference, PAINWeek 101 will make sure that you’re fully briefed and oriented to navigate, plan, select, and make the most of your PAINWeek experience!

Chronic Pain Syndromes

WeDNeSD aY 5:30p – 9:00p

Keynote Address and Welcome Reception THURSD aY 6:30p – 8:30p

Poster Session and Reception FRiD aY 4:00p – 5:00p

Exhibit Hall Closing Reception

*Times subject to change.

THURSDaY/9.7

Sessions presented from 7:00a – 6:30p.

FRiDaY/9.8

Sessions presented from 7:00a – 6:30p.

SaTURDaY/9.9

Saturday sessions presented from 7:00a – 4:30p.

Advanced Practice Providers

American Pain Society (APS)

Functional Medicine

● Case Based Learning:

● Resilience vs Vulnerability in Chronic Pain

● All You Need is Love:

A Multidisciplinary Review (2 hours)

● Blending, Melting, or Throwing Off a Cliff:

● The Biological Interface of Resilience ● Ramping Up Resilience for Chronic Pain:

Abuse Deterrent Technologies to Minimize Opioid Abuse

Strategies for Reducing Pain and Improving Function

● The Green-Eyed Martian: Do Healthcare Disparities Exist in Pain Management?

● Building Brain Resilience through

● Importance of Appropriate Chart Documentation:

Pitfalls to Help Avoid Litigation

Master Class ● Lost in Translation: Making Sense of Clinical

Treatment Guidelines (90 minutes)

National Association of Drug Diversion Investigators (NADDI) ● Data Fiction—Do We Make Life and Death Decisions Based on Bad Data? ● Algorithms and Opioid Dosing Watch Lists ● Balanced Pain Management & Overdose Prevention Strategies: Where Are We Now? ● Opioid Counterfeits ● Pain Practice Check-Up

Pain Educators Forum ● Flipping the Script:

Why We Need a Patient REMS Course

● You’re Giving Me an MI: Incorporating Motivational Interviewing into Challenging Conversations (90 minutes) ● ¿Donde Duele? An Introduction to Basic Medical

Spanish for Healthcare Professionals (2 hours)

PAINWeek Pop-Ups ● Is That Naloxone in Your Pocket or

Are You Just Happy to See Me?

● Pharmacogenetic Case Studies:

● Resilience Interventions for Pain

Mindfulness Meditation

International Pelvic Pain Society (IPPS) ● The Painful Uterus and the Brain:

A Systematic Approach to the Evaluation and Management of Painful Periods

● Pelvis Gone Wild: A Sordid Tale of Musculoskeletal Dysfunction ● When Pain is Not Sexy: Evaluation and

Management of Sexual Pain in Females

● Beyond Pharmacotherapy: An Integrated

Approach to Managing Female Chronic Pelvic Pain

Master Class ● Differential Diagnosis of Low Back Pain (2 hours)

Medical Cannabinoids and Medical Marijuana ● Reefer Madness:

Taking the Insanity Out of Medical Cannabinoids ● Cannabis vs Cannabinoids:

The Politics of Medical Marijuana

● Medical Efficacy of Cannabis Therapeutics

Medical Legal ● How Many Lawyers Does It Take to Keep a

Practitioner Out of Trouble?

Neurology ● Arachnoiditis: Taming the Painful Shrew ● Differential Diagnosis of Myelopathies

Test the Patient or Simply Switch the Drug?

● My Head’s Stuck in a Waffle Iron and Can’t

Pharmacotherapy

● Diagnosis and Treatment of Centralized Pain

● Opioid Conversion Calculations ● PharmasKnowGenetics vs

Pharmacogenetics Unveiled

● What’s All the “GABA” About?

Pregabalin and Gabapentin Abuse

● Rational Polypharmacy:

An Update for Specific Conditions

● HeSAID, SheSAID: The Real Facts on NSAIDs

Special Interest Sessions ● Pain Clinical Trials ● The Octopus From Hell:

Get Out! The Mystery of Occipital Neuralgia and Neuroinflammation

Pain and Chemical Dependency ● Common Threads in Pain and Chemical

Dependency (3 hours)

PAINWeek Pop-Ups ● Pharmacogenetics 101: Reviewing the Cytochrome

System & Other Genetic Variations Important in Treating Pain and Depression

● Interdisciplinary Integration of Next Generation Pharmacists

Exploring 8 Extremities of Chronic Pain

Podium Poster Presentations

● Fudin vs Gudin:

Not certified for credit

Can High Dose Prescribing Be Defended in Court?

● As You Like It: The Business of Pain Medicine ● Low Pressure Headaches:

Where is the Leak?

(For planning purposes)

Special Interest Sessions ● The Medical Stasi: Perils and Pitfalls of

Excessive Urine Drug Testing

● Opioid Sparing: Treating the Whole Patient

Incorporating Functional Medicine in Pain Care (2 hours) ● Food is Medicine: A Review of the Anti-Inflammatory Diet ● Looking in the Rear View Mirror: Addressing

Inflammation Through Lifestyle Imbalances

Master Class ● Differential Diagnosis of Low Back Pain

(2 hours) (encore)

PAINWeek Pop-Ups ● Making America Treatment-Friendly Again:

Federal Policy and Pain

● Relaxation Through Music

Palliative Care ● A Wrinkle in the Plan ● Speed Dating With the Pharmacy Ladies: Pain Management and Palliative Care ● New Drugs in Pain Management and

Palliative Care

● IV Methadone: When All Else Fails

Pharmacotherapy ● 3’s Company: COX-2 Inhibitors, Medicinal Marijuana,

and Opioid Prescribing

● Topical Opioids: The Perfect Solution for Reducing

Systemic Opioid Exposure

● The 411 on Nonprescription Analgesics:

When to Hold ‘Em, When to Fold ‘Em

Physical Therapy ● Words Wisely Chosen:

Avoiding the Unintended Nocebo Effect ● Fascial Distortion Model—Pattern Recognition

of Patients’ Subtle Hand Gestures When Describing Symptoms (2 hours)

● Exercise Prescription for Patients With

Chronic Pain

● Restoring Hope: The Treatment of Pelvic Pain

Across the Gender Spectrum

● At the Edge of Interaction: Applying Edge Work

and Novel Movement to Painful Motion

Special Interest Sessions ● Using Electronic Pain Assessment Programs

and Innovative Technology in Pain Medicine: Where Are We Now and Where Are We Going? (90 minutes)

● Born to Be Wild: Music Therapy Applications for

Neonatal Abstinence Syndrome (90 minutes)

Wound Care ● Woundology—The Spectrum of Reasons Why the

Epithelium Gets Lost (2 hours)

● Insult to Injury: Wound and Other Pains in a Wound

Care Patient (2 hours)

● The first certified-for-credit course begins on Tuesday, September 5, at 7:00a. ● The last certified-for-credit course concludes on Saturday, September 9, at 4:30p. ● All courses are 50 minutes, except where noted. PAINWeek Pop-Ups are 30 minutes.

ONLY $699

This offer expires on 7/31. Use promo code PWJ

5 Days, 120+ Hours, and 90+ Faculty In 2017, you can look forward to a week of Special Interest Sessions, Master Classes, and multidisciplinary course concentrations like the 2016 courses below.

PW17 CPREViEW 2.14.indd 7

3/20/17 5:34 PM

By Michael C. Barnes jd, miep

“Given that these [controlled prescription] medications carry these greater risks, practitioners who prescribe them have a higher duty of care and should take corresponding steps to prevent harm to their patients.”

MeDiCaL/LeGaL

b s t r a c t :

Policymakers, in their sense of urgency to stem the rate of overdose deaths ravaging their communities, may have been shortsighted in their approaches to reducing drug abuse in its entirety. For example, they focused on greater safety precautions only for opioid analgesics prescribed for pain rather than for other commonly abused controlled prescription medications (CPMs), including opioids indicated for treating addiction, benzodiazepines, sleep medications, and stimulants. In some cases, the abuse of these medications continues unabated. Additionally, while policymakers have focused heavily on limiting the supply of opioid pain relievers available for abuse, they may not have adequately accounted for demand for other substances of abuse. Analog fentanyl and heroin—widely available at relatively low prices, with variable and oftentimes dangerously high levels of potency—are increasingly contributing to the nation’s overdose epidemic. To protect their patients from developing substance use disorders and inadvertently overdosing, and to shield themselves from criminal, civil, and administrative liability, prescribers of all controlled medications—not just opioid analgesics— should be exceptionally diligent. This article sets forth principles and recommendations that a prescriber might consider in establishing policies and practices for the prescribing of all controlled medications.

54 PWJ | www.painweek.org

Q2 | 2017

controlled presciption medications CPMs, by definition, have a higher potential for abuse than noncontrolled prescription medications. Given that these medications carry these greater risks, practitioners who prescribe them have a higher duty of care and should take corresponding steps to prevent harm to their patients. Under federal and state controlled substances acts, the risks and related duties are categorized by controlled substance schedules (eg, Schedule II vs Schedule V), regardless of drug class (eg, opioid analgesic vs anticonvulsant). In other words, under federal and state controlled substances laws, the minimum steps a prescriber should take to prevent harm to the patient and the public parallels the cpm’s schedule, irrespective of the prescribed substance’s chemical type or intended use. To comply with these laws, for example, a prescriber should employ a minimal level of caution in prescribing a Schedule IV sleep medication equivalent to that used in prescribing a Schedule IV opioid pain reliever. the need to exercise caution in prescribing any controlled medication, regardless of its drug class, is illustrated by statistics showing that the abuse of controlled benzodiazepines, sleep medications, and stimulants is common. For example, 5.3 million people abused prescription stimulants in 2014.1 One in 5 college students has abused prescription stimulants.2 Overdose deaths involving benzodiazepines increased 5-fold between 2001 and 2014.3 Additionally, emergency department visits involving controlled sleep medication nearly doubled from 22,000 in 2005/2006 to more than 42,000 in 2009/2010.4 Q2 | 2017

legal standard for prescribing to satisfy the requirements of federal and state controlled substances acts, and to reduce the likelihood of harm and liability, prescribers of controlled medications should establish a legitimate medical need and prescribe in the ordinary course of professional practice for each patient.5 In fulfilling these duties, practitioners should also take reasonable steps to prevent harm www.painweek.org | PWJ

MeDiCaL/LeGaL

to the patient and the public. Finally, the practitioner should document in the medical record the patient-specific factual information underpinning medical necessity, as well as all treatment decisions and the reasons for them.

A. legitimate medical need Practitioners should assess the patient and determine that a legitimate medical need for a cpm exists before prescribing. To establish such need, practitioners should take a medical history, conduct a physical exam and a mental health exam, verify the patient’s diagnosis, and consider special population-specific risks (eg, older adults, pregnant women, or history of substance use).

B. ordinary course of professional practice Practitioners may only prescribe cpms in the ordinary course of professional practice. In other words, they should act in a manner that is consistent with the “reasonable, prudent practitioner” test.6 Under the reasonable, prudent practitioner test, practitioners should employ a level of caution that a reasonable practitioner in similar circumstances would exercise in prescribing to prevent harm to a patient.7 To meet this standard, the practitioner should counsel the patient about the risks and benefits of the cpm the practitioner is proposing for use in the patient’s treatment. This process may include reviewing a medication guide with the patient and explaining its warnings and directions. If the patient understands the risk-benefit profile and decides to proceed with the medication, the practitioner should document in the patient’s medical record that the patient comprehends his responsibilities related to medication safety. Additionally, as in all cases the practitioner should document the treatment plan. After prescribing and before renewing a prescription for a cpm, the practitioner should continue to monitor the patient to ensure the treatment is suitable (the patient’s condition is improving, absence of intolerable adverse effects, etc). If the assessment shows possible signs of drug diversion or problematic substance use, the practitioner should adjust the treatment plan by increasing the level of care vigilance and supervision (ie, kicking the patient “up,” not “out”). Immediately discharging (firing) the patient for nonadherence can result in the patient experiencing a variety of negative outcomes, including unmet medical needs, drug withdrawal, drug-seeking, or an overdose or overdose-related death after being relegated to the black market to find symptom relief. To avoid such adverse outcomes and a potential legal finding that the practitioner abandoned the patient, practitioners should employ strategies that include implementation of an exit strategy and tapering the cpm when instances of to the treatment plan or issues of safety of cpms exist.8 Generally, tapers of medications to which tolerance or dependence may be present should be done slowly. In cases of opioid dependence, buprenorphine should

56 PWJ | www.painweek.org

be considered to aid in tapering, and opioid maintenance treatment may be necessary.9

C. reasonable steps to prevent harm As part of verifying legitimate medical need and prescribing in the ordinary course of professional practice, a practitioner should take reasonable steps to prevent harm to the patient and the public. Such steps include screening the patient for history of and potential for problematic substance use before prescribing a cpm and periodically thereafter. This process typically includes reviewing the state’s prescription drug monitoring program (pdmp) data, obtaining a detailed substance abuse history of the patient and her/his family, and conducting urine drug testing (udt). There is no standard udt regimen that is suitable for all patients, so practitioners should use a principle based approach that they can adapt to meet individual patients’ specific needs. Practitioners should adopt a written policy to guide in identifying medical necessity, ordering udt, collecting and handling specimens, evaluating udt results, adjusting a patient’s treatment plan based on udt results, and maintaining a thorough medical record. Before prescribing a cpm, the practitioner should confirm that the patient has unsuccessfully tried nonpharmacologic, noncontrolled pharmacologic, and lower-scheduled pharmacologic options. This prescribing process includes assessing whether it is medically necessary for the patient to take a medication with properties that are abuse deterrent (eg, cannot be crushed and snorted or injected), diversion resistant (eg, administered via injection by a practitioner and not dispensed for take-home use), or adherence enhancing (eg, continuously delivered via long-acting implant). The practitioner should follow a cpm’s label requirements for prescribing when feasible, and document reasons for deviation if it is medically necessary to prescribe off-label. It is imperative that the practitioner be aware of and follow state laws prohibiting the off-label prescribing of certain controlled medications (eg, prescribing a buprenorphine medication approved for opioid dependence to treat the patient’s pain). Practitioners should also familiarize themselves with the cpm’s Risk Evaluation and Mitigation Strategy (rems) if one exists and be sure to comply with any specific prescribing recommendations. For example, the rems for extendedrelease and long-acting opioid analgesics recommends that practitioners provide the patient with a patient counseling document.10 Finally, the practitioner should educate the patient on proper storage and disposal of cpms to reduce the possibility of diversion, misuse, abuse, and accidental exposure to people other than the patient. Q2 | 2017

D. thorough documentation The practitioner should document in the medical record the factual information underpinning the patient’s medical need for a cpm, as well as the basis for each conclusion and treatment decision the practitioner makes. An accurate, thorough, and up-to-date medical record is essential to a practitioner’s ability to prove in a criminal, civil, or administrative proceeding that the practitioner fulfilled his legal and ethical obligations in prescribing a controlled medication. Narrative detail can help prove that the practitioner accounted for the patient’s unique medical needs in formulating and adjusting the patient’s treatment plan. The practitioner should strive to incorporate the following details into the medical record:

CPM guideline for opioid analgesics in march 2016, the cdc released the Guideline for Prescribing Opioids for Chronic Pain. The cdc Guideline provides recommendations for primary care providers who prescribe opioid analgesics for patients with chronic pain outside of active cancer treatment, palliative care, and end-of-life care.9 The document is not intended to cover pain care as a specialty practice. Reasonable and practical recommendations from the cdc Guideline that all prescribers of cpms, regardless of their practice setting, should incorporate into patients’ treatment plans include: ●● Trying nonpharmacologic and noncontrolled medications before prescribing controlled medications

●● Medical history, including special needs or risks ●● Physical exams ●● Mental health exams ●● Diagnosis ●● Unsuccessful treatments ○○ Nonpharmacologic ○○ Noncontrolled pharmacologic ○○ Lower-scheduled pharmacologic ●● Counseling on cpm risks and safety ●● Patient responsibilities form signed by the patient ●● Treatment plan ●● pmp reports ●● udt ○○ Test selections and reasons ○○ Results and actions taken ○○ When to test again ●● Copy of dated and signed prescription with DEA registration and X number (which denotes authority to prescribe buprenorphine for opioid use disorder), if applicable ●● Discussions of treatment benefits and detriments (such as how treatment has improved the patient’s life) ●● Other monitoring measures (eg, pill counts) ●● Adjustments to the treatment plan

Q2 | 2017

●● Documenting intended and actual clinical improvements ●● Counseling patients on risks and benefits ●● Starting with the lowest effective dose ●● Prescribing in low quantities for acute conditions ●● Re-evaluating benefits and harms often ●● Assessing risk factors and mitigating risks ●● Checking pdmp data before prescribing a cpm and periodically thereafter ●● Referring patients with a substance use disorder to addiction treatment Additional recommendations that are not included in the cdc Guideline but that practitioners should incorporate when prescribing cpms include: ●● Prescribing lower scheduled medications before prescribing higher scheduled medications ●● Prescribing medications with abuse deterrent properties when medically necessary (eg, when there is increased risk of aberrant drug related behavior) ●● Prescribing formulations with features that enhance adherence and reduce diversion, such as implants and injectables, when medically necessary—when a patient has had difficulty adhering to a regimen of self-administering an oral medication, or when there is a likelihood that a patient’s friend or family member may steal and consume or sell the medication It is important always to document the patient-specific reasons for prescribing a particular medication, but especially in the case of products with abuse deterrent, diversion resistant, or adherence enhancing properties, which insurers may be reluctant to cover. A patient-specific medical necessity analysis will help the patient in the event it becomes necessary to appeal an insurer’s coverage denial. www.painweek.org | PWJ

MeDiCaL/LeGaL

“Immediately discharging (firing) the patient for nonadherence can result in the patient experiencing a variety of negative outcomes, including unmet medical needs, drug withdrawal, drug-seeking, or an overdose or overdose-related death after being relegated to the black market to find symptom relief. To avoid such adverse outcomes and a potential legal finding that the practitioner abandoned the patient, practitioners should employ strategies that include implementation of an exit strategy and tapering the CPM when instances of nonadherence to the treatment plan or issues of safety of CPMs exist.”

The cdc Guideline contains some recommendations that are not well supported by scientific evidence. For example, one recommendation suggests that physicians should implement additional precautions when increasing the dosage to 50 or more morphine milligram equivalents (mme) per day and should generally avoid increasing the dosage beyond 90 mme per day.11 However, according to multiple professional organizations, including the American Academy of Family Physicians, these dose cutoffs may be arbitrarily placed.12 In some instances, they are lower than the U.S. Food and Drug Administration (fda) labeled therapeutic dose.13 In other words, the cdc Guideline recommends prescribing some opioid pain relievers at lower-than-therapeutic doses. If an individual is prescribed an opioid medication at a daily dose below the range set forth in the medication’s label, the individual may take self-measures to obtain pain relief. The individual might be forced to skip doses, hoard medication, divert the medication to the black market or worse, seek out black-market substances like heroin or counterfeit fentanyl for pain relief. Consistent with the cdc Guideline, some states are adopting dose ceilings for opioids prescribed by nonexpert practitioners.14 Practitioners in these states may find themselves in the untenable position of having to choose between compliance

58 PWJ | www.painweek.org

with the state guideline and adherence to the medical standard of care. In such scenarios, it is imperative that the practitioner thoroughly document the patient’s medical necessity and the specific reasons for not following the state’s mandatory guidelin e, as well as the basis in medical-scientific literature or standard practice for the chosen course of treatment. Additionally, the Comprehensive Addiction and Recovery Act of 2016 has required the Secretary of Health and Human Services (hhs), by July 2018, to convene a task force comprised of federal agencies and a diverse group of nongovernmental stakeholders to review and determine whether there are gaps or inconsistencies between best practices for chronic and acute pain management that have been developed by federal agencies, such as the cdc Guideline. The task force is required, within one year of convening, to propose any necessary updates to such best practices.

final recommendations in addition to the recommendations set forth above, including adopting and following written policies for udt, practitioners should consider adopting and following written policies for the prescribing of controlled medications. Such Q2 | 2017

policies should draw heavily from credible resources and include citations wherever possible. In the case of prescribing policies, sources should likely include practice guidelines, medical journal and law review articles, fda-approved medication prescribing information, and rems training materials and resources. cpm prescribing and udt policies aid in practitioner training and serve as a resource to guide practitioners through the medical decision-making and documentation processes. They provide evidence that the practitioner has been diligent in identifying the ordinary course of professional practice and in taking reasonable steps to prevent harm to patients and the public.

Published January 20, 2016. Available at: http://www.aafp.org/news/ health-of-the-public/20160120opioidguideline.html. 12. Tennant F, Ciccone TG. AAPM Raise Concerns Over CDC Opioid Guidelines. Practical Pain Management. Published February 22, 2016. Available at: www.practicalpainmanagement.com/resources/news-and-research/ aapm-raise-concerns-over-cdc-opioid-guidelines. 13. U.S. Food and Drug Administration. Tapentadol Hydrochloride Full Prescribing Information. Label. Updated June 2010.Available at: www.accessdata.fda.gov/ drugsatfda_docs/label/2010/022304s003lbl.pdf. Accessed January 13, 2017. 14. Maine Revised Statutes. Requirements Regarding Prescription of Opioid Medication. 32 M.R.S. § 2210.

By meeting the recommendations discussed in this article, we can make meaningful progress toward reducing diversion, misuse, and abuse of controlled medications. References 1. Hughes A, Williams MR, Lipari RN, et al. Prescription Drug Use and Misuse in the United States: Results from the 2015 National Survey on Drug Use and Health. Substance Abuse and Mental Health Services Administration. Published September 2016. Available at: www.samhsa.gov/data/sites/default/files/NSDUHFFR2–2015/NSDUH-FFR2–2015.htm. 2. Feliz J. New Survey: Misuse and Abuse of Prescription Stimulants Becoming Normalized Behavior Among College Students, Young Adults. Partnership for Drug-Free Kids. Published November 13, 2014. Available at: www.drugfree.org/ newsroom/adhd-survey-2014. 3. National Institute on Drug Abuse. Overdose Death Rates. National Institute on Drug Abuse. Updated January 2017. Available at: www.drugabuse.gov/ related-topics/trends-statistics/overdose-death-rates. 4. Emergency department visits attributed to overmedication that involved the insomnia medication zolpidem. The Dawn Report. August 7, 2014. Available at: www.samhsa.gov/data/sites/default/files/DAWN-SR150Zolpidem-2014/DAWN-SR150-Zolpidem-2014.pdf. 5. Drug Enforcement Administration, Department of Justice. Purpose of issue of prescription. 21 C.F.R. § 1306.04(a). 6. Gilbert v. Sycamore Mun. Hosp., 622 N.E.2d 788, 795 (Ill. 1993) (stating that the standard of care is “the authority which a reasonably prudent person, exercising diligence and discretion, in view of the principal’s conduct, would naturally suppose the agent to possess.”). McPherson v. Ellis, 287 S.E.2d 892, 895 (N.C. 1982), (stating: [a] physician or surgeon who undertakes to render professional services…he must exercise reasonable care and diligence in the application of his knowledge and skill to the patient’s case; and he must use his best judgment in the treatment and care of his patient…He is held to the standard of professional competence and care customary in similar communities among physicians engaged in his field of practice). 7. Strauss DC, Thomas JM. What does the medical profession mean by “standard of care?” J Clin Oncol. 2009;27(32):e192-e193. 8. Department of Veterans Affairs. Tapering and Discontinuing Opioids. Published 2013. Available at: www.healthquality.va.gov/guidelines/Pain/cot/ OpioidTaperingFactSheet23May2013v1.pdf. 9. Dowell D, Haegerich TM, Chou R, et. al. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. MMWR Recomm Rep. 2016;65 (No. RR-1):1–49. Available at: dx.doi.org/10.15585/mmwr.rr6501e1. 10. U.S. Food and Drug Administration. Extended-Release (ER) and Long-Acting (LA) Opioid Analgesics Risk Evaluation and Mitigation Strategy (REMS). Available at: http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm311290.pdf. 11. American Academy of Family Physicians. AAFP Offers Mixed Comments on CDC’s Opioid Prescribing Guidance. American Academy of Family Physicians.

Q2 | 2017

www.painweek.org | PWJ

By Ra

san m as-Tri v e u C n L .

Table

○○ Headaches (chronic migraine prophylaxis, occipital neuralgia) ○○ Myofascial pain syndromes (thoracic outlet syndrome, piriformis syndrome) ○○ Low back pain ○○ Lateral epicondylitis ○○ Plantar fasciitis ○○ Facial pain (trigeminal neuralgia; traumatic, atypical, temporomandibular joint pain) ○○ Intractable joint pain ○○ Raynaud’s phenomenon ○○ Postherpetic neuralgia ○○ Painful diabetic neuropathy ○○ Other focal peripheral nerve injuries ○○ Complex regional pain syndrome

KeY TOPiC

abstract: Botulinum toxins have been used for many years to manage a wide variety of chronic pain syndromes. This article will outline some of the published literature and clinical practice observations of the known uses of botulinum toxins in the management of a various chronic pain syndromes (Table). Preclinical studies will be briefly summarized to provide a theoretical construct on which to build the mounting clinical evidence showing the virtues of botulinum toxins as safe and effective analgesic biologicals.

PWJ | www.painweek.org

Q2 | 2017

botulinum toxin products commercially available for use in humans in the United States: 3 are serotype A toxins (onabotulinumtoxinA = Botox®, abobotulinumtoxinA = Dysport®, and incobotulinumtoxinA = Xeomin®) and the other is serotype B toxin (rimabotulinumtoxinB = Myobloc®). These biologicals share some basic properties but, given their manufacturing methods, biological potency assays, and final chemical composition, units of biological activity (dosing) are not interchangeable, effectiveness is not uniform in all applications, and side effect profiles are distinct for each. Neurotoxins as Neuromodulators

The emerging role of botulinum toxins in the management of complex/intractable chronic pain syndromes is linked to their potential roles as chemical neuromodulators, affecting neurogenic inflammation. In vitro as well as in vivo investigations provide insight into the potential neuromodulatory and analgesic mechanisms of botulinum toxins, where botulinum toxin type A (BtxA) has been effective in reducing the release of glutamate, calcitonin gene-related peptide (cgrp), substance P, and has resulted in a clear reduction in pain related behaviors in rats subjected to painful stimuli after pretreatment with BtxA.1–5 All these antinociceptive observations occurred in sensitized states, commonly operant in chronic neurogenic pain syndromes. The following sections will describe clinical observations of the effects of toxins in a variety of chronic pain states.

Clinical Applications Headaches Extensive clinical evidence supports the important role of onabotulinumtoxinA (Botox ®) in chronic migraine prophylaxis. This is the only purely analgesic application with approval from the Food and Drug Administration (fda) for one of the commercially available toxins in the United States.6,7 Q2 | 2017

The mechanistic effect of migraine prophylaxis is believed to be linked to neuroregulatory effects of cgrp in relation to the trigeminal ganglion.8,9 The efficacy and safety of onabotulinumtoxinA in migraine headache prophylaxis has been shown in several randomized clinical trials.10–18 Different dosing and injection site paradigms have been used for years but the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (preempt) study established preferred injection sites and intervals for onabotulinumtoxinA use in chronic migraine prophylaxis.19 One of the most critical issues remains appropriate patient selection based on the appropriate diagnosis (chronic migraine). OnabotulinumtoxinA has also been shown to be effective in the management of occipital neuralgia, a chronic headache disorder often seen in patients after trauma, mostly upper cervical flexion/extension soft tissue injuries.20–22 Successful anesthetic blockade of the greater and/or lesser occipital nerves is considered diagnostic as well as therapeutic in this condition. Unfortunately, in many instances, this therapeutic approach only provides short-term relief and a similar approach using botulinum toxin may provide longer-lasting relief. Clinical studies using botulinum toxins in tension-type headache have repeatedly failed to show favorable results.23 www.painweek.org | PWJ

KeY TOPiC

[the] study established preferred injection sites and intervals for onabotulinumtoxinA use in chronic migraine prophylaxis. One of the most critical issues remains appropriate patient selection based on the appropriate diagnosis…

Myofascial Pain Syndromes The use of botulinum toxins for the management of painful muscle syndromes dates back to the mid-90s.24,25 Trigger points are believed to affect the neuromuscular endplate with sustained contraction of sarcomeres and a compression of neighboring capillaries with subsequent local hypoxia. The established mechanism of action of botulinum toxins (presynaptic inhibition of acetylcholine release) make them an attractive option for managing intractable myofascial pain syndrome (mps). A small (n=40) randomized study comparing the efficacy between onabotulinumtoxinA and methylprednisolone injections combined with physical therapy in various mps patterns showed superiority of the toxin in terms of duration of effect.26 However, there are only a handful of small series reported, and efficacy has not been consistent. Some specific myofascial pain syndromes will be discussed below.

Forward-Head Syndrome/Thoracic Outlet Syndrome/Piriformis Syndrome A relatively common type of mps is seen in individuals who present with anterior coronal displacement of the head (forward head syndrome). This is characterized by cervical protraction, capital extension with shortened cervical paraspinals, elevated and shortened upper trapezius and levator scapula, scalene and pectoral shortening, eccentric lengthening of

64 PWJ | www.painweek.org

the rhomboids and middle trapezius, and scapular protraction and internal rotation of the shoulder girdles. These patients may initially present with neck and upper thoracic symptoms but may eventually progress to symptomatic cervicobrachialgia, presenting symptoms of thoracic outlet syndrome (tos). BtxA injections targeting shortened muscles followed by a stretching and postural exercise program often provide significant benefits in this condition. tos is an uncommon syndrome that in some cases results from compression of the neurovascular bundle elements at the superior thoracic inlet as these pass between the anterior and middle scalene muscles. It generally causes neurovascular insufficiency symptoms in the affected extremity, sometimes attributed to cervical radiculopathy or other soft tissue/nerve injuries. BtxA has been used effectively in some cases, targeting the scalenes.27 Piriformis syndrome is a type of mps affecting the piriformis muscle, a small hip external rotator that sits deep in the gluteal area. This condition is more commonly postural but may also be compressive. When postural, it is generally reactive to lumbar flexed posture due to eccentric contraction as compensation due to a sustained lumbar flexed posture. The efficacy of type A and B toxins in the management of this syndrome has been documented using precision targeting techniques, such as electromyography or fluoroscopy, to ensure proper localization of this deep muscle.28,29 (A more detailed discussion on the uses of botulinum toxins in myofascial pain syndromes may be accessed in a published textbook.30) Q2 | 2017

Low Back Pain A small number of studies have evaluated the effectiveness of onabotulinumtoxinA in low back pain. Injections described have generally targeted the paraspinals at several levels. In a small (n=31) randomized double blind placebo controlled trial, patients with lateralized back pain were injected in the paraspinals at 5 levels (L1-L5 or L2-S1).31 The results were favorable in terms of pain reduction and improvement in functional outcomes, as measured by the Oswestry Low Back Pain Questionnaire (olbpq), with noticeable changes at 3 weeks and further improvement by 8 weeks. In a larger (n=75) open extension of that same study with more heterogeneous patients (including patients with abnormal mris, radicular pain, and even failed back syndrome), the investigators repeated injections to responders at 4 month intervals, showing favorable outcomes in more than half of the subjects at 3 weeks and at 2 months.32 Another open study by the same investigators enrolled a heterogeneous group of 60 patients with chronic low back pain, including patients with bilateral pain, opioid users, and patients with neurological deficits, as well as patients with prior back surgery. The investigators reported good response in nearly two-thirds of the subjects at 4 weeks, more than half at 8 weeks, and nearly 20% by 16 weeks. 60% of the responders had radicular pain and more than two-thirds of these experienced significant improvement in that pain.33 In another very small, open, single blinded study, the investigators measured pain intensity and spasms at 1, 2, and 3 months, showing sustained, statistically significant pain relief and reduction in muscle spasms.34 Interestingly the authors reported that pain reduction occurred earlier than reduction in muscle spasm, mirroring some of the cervical dystonia literature observations. An evidence based review published in 2008 concluded that there is Level 2A evidence in support of the use of BtxA in the treatment of low back pain. Doses, techniques and follow up varies among studies making direct comparisons very difficult. They concluded that botulinum toxins are safe and appear to be useful in select patients who have failed first-line therapies, with variable degrees of efficacy.35

Lateral Epicondylitis Several studies have reported the use of botulinum toxins in lateral epicondylitis. In a randomized controlled trial (n=60) where patients received normal saline or abobotulinumtoxinA injections over the tender area (lateral epicondyle enthesis), the investigators reported significant favorable differences in pain reduction in the active group at 4 and 12 weeks.36 In contrast, another randomized controlled trial (n=40) using normal saline or onabotulinumtoxinA injections performed Q2 | 2017

intramuscularly at a point 5 cm distal to point of maximal tenderness of the lateral epicondyle in line with the midwrist, the investigators reported no significant difference in grip strength, pain, and qol at 3 months.37 This may suggest the importance of injection location. However, a more recent randomized placebo controlled trial involving patients with chronic refractory lateral epicondylitis used a single injection of either BtxA vs placebo at an intramuscular site measured in a standard fashion, distal to the lateral epicondyle. The group receiving botulinum toxin, had significant reductions in pain at rest during follow up compared to the placebo group at 4 week intervals up to 16 weeks.38 A systematic review on the use of toxins for this ailment concluded that existing literature provides support for use of BtxA injections into the forearm extensor muscles for treatment of chronic treatment-resistant lateral epicondylitis.39

Plantar Fasciitis Studies evaluating the use of botulinum toxins for the management of intractable plantar fasciitis have yielded generally positive results. However, the number of subjects has been very low. A randomized controlled trial (n=43 feet) reported that the active group had statistically significant improvements in all measures at 3 and 8 weeks.40 In addition to its small sample size the study was limited by its short duration and the lack of a conventional treatment group. A very small (n=9) open label study described one injection of abobotulinumtoxinA subfascially into the painful area of the heel.41 Subjects reported a significant reduction of pain in weight-bearing by week 6 persisting into week 14, and reduction of pain at rest at 2 weeks which persisted throughout the study period. A more recent randomized double blind controlled study included 50 patients with chronic plantar fasciitis injected with BtxA vs a similar amount of normal saline into the plantar fascia under ultrasound guidance. The active group had significant pain reduction compared to the placebo group at 3 weeks and 3 months postinjection. Additionally, plantar fascia thickness in the symptomatic foot decreased significantly in the active group.42 Another randomized controlled study compared efficacy between BtxA and corticosteroid injections in chronic plantar fasciitis and found that at 1 month, both groups had significantly improved over baseline with the toxin group showing a tendency towards superiority that became significant at the 6 month postinjection point.43

Facial Pain/TMJ Pain Botulinum toxins have been extensively used to manage craniofacial pain of numerous etiologies, including trigeminal neuralgia, atypical facial pain, and temporomandibular pain www.painweek.org | PWJ

KeY TOPiC

An open label series of 44 patients with diagnoses including temporomandibular joint syndrome, postsurgical pain syndromes, essential headache, and idiopathic trigeminal neuralgia reported favorable response in 75% of the patients. Several additional trigeminal neuralgia case series have been reported showing very favorable results. disorders. Several studies have reported the use of toxins for management of temporomandibular pain and dysfunction. In a case series of 46 subjects with temporomandibular pain treated with onabotulinumtoxinA, subjects reported significant improvements in pain, function, mouth opening, and tenderness to palpation.44 Another series of 41 patients with painful hyperactivity of the masticatory muscles treated with abobotulinumtoxinA reported various degrees of symptom control.45 The same investigators published a randomized placebo controlled study including 90 patients (60 injected with toxin and 30 placebo) with chronic facial pain treated with onabotulinumtoxinA injections into several masticatory muscles. 91% of patients who received botulinum toxin experienced significant improvements in pain as measured with a Visual Analog Scale.46 An open label series of 44 patients with diagnoses including temporomandibular joint syndrome, postsurgical pain syndromes, essential headache, and idiopathic trigeminal neuralgia reported favorable response in 75% of the patients.47 Several additional trigeminal neuralgia case series have been reported showing very favorable results.48–53 The author has followed several cases of facial pain of various etiologies with very good results, in particular one patient with very severe intractable posttraumatic facial pain treated with low doses of onabotulinumtoxinA spanning nearly 7 years (20 sessions).54 (Readers should be aware of potential of publication bias but may consider a trial of toxin injections in cases where other modalities have failed.)

66 PWJ | www.painweek.org

Intractable Joint Pain There is limited emerging evidence for the use of botulinum toxins for the management of pain in degenerative joint disease. It has been theorized that botulinum toxins may inhibit the expression of low-grade inflammatory mediators such as interleukin 1 and tumor necrosis factor-alpha.55 Clinical studies have documented safety and effectiveness in humans with various arthritides. A retrospective case series (15 joints) reported the safety and efficacy of repeat onabotulinumtoxinA intra-articular injections to manage chronic osteoarticular pain (knees, ankles, shoulders) of various etiologies.56 A review published in 2008 identified the evidence in support of the use of BtxA in the treatment of joint pain as Level 1C and 2C, identifying that variable doses, techniques, and follow-up intervals among published studies make these very difficult to compare.35 Subsequent to that publication, a prospective randomized, double blind trial compared the effects of a single intra-articular knee injection with corticosteroid (40 mg methylprednisolone), low dose onabotulinumtoxinA (100 units), and high dose onabotulinumtoxinA (200 units).57 Pain decreased (>2 point reduction in pain) in all groups but reached statistical significance only in the low dose onabotulinumtoxinA group only. All groups showed statistically significant improvements in womac scores and short-term safety was clearly shown. Based on this, onabotulinumtoxinA appears to be a safe option for intractable cases of osteoarticular pain when multiple other treatment approaches have failed.35 Q2 | 2017

The use of botulinum toxins in the management of postarthroplasty intractable pain is a particularly interesting application given the limited management options in these patients. Evidence for the use of toxins in this indication comes from case reports, personal communications, and the author’s clinical experience.

Raynaud’s Phenomenon An open series of 33 subjects with severe Raynaud’s phenomenon treated with onabotulinumtoxinA showed it to be very effective regarding analgesia and improved perfusion.58 The author has used the same protocol in a few patients with excellent results.

Postherpetic Neuralgia A randomized, double blind, placebo controlled study of 60 subjects with postherpetic neuralgia divided patients into 3 groups—1 receiving subcutaneous BtxA, another 0.5% lidocaine, and a third receiving saline injections. Compared with pretreatment, pain scores decreased at day 7 and 3 months’ posttreatment in all 3 groups with those in the toxin group decreasing more significantly compared with lidocaine and placebo groups at both time intervals posttreatment. The investigators also demonstrated an opioid sparing effect in the toxin group.59

Diabetic Neuropathy Pain The most recent revision of the guidelines for pharmacological management of neuropathic pain by the American Academy of Neurology concluded that botulinum toxins are more effective than placebo, assigning its evidence a low degree of strength with moderate to large effect size based on 2 randomized controlled trials.60

Other Focal Peripheral Nerve Injuries Botulinum toxins have been used via intradermal or subcutaneous injections in the distribution of pain in cases of meralgia paresthetica and other focal neuropathies causing small areas of intense pain.61 A recent case report showed effectiveness of botulinum toxin injected for recalcitrant intractable postthoracotomy pain.62 The author has used this technique with good results in a small number of patients. Other uses have also included carpal tunnel syndrome, postamputation stump pain, and postradiation fibrosis.

Complex Regional Pain Syndrome (CRPS) A controlled study using intradermal or subcutaneous botulinum toxin injections in this condition failed to show improvements over placebo whereas an unblinded retrospective review of individuals with crps in the upper limbs who also

The use of botulinum toxins in the management of postarthroplasty intractable pain is a particularly interesting application given the limited management options in these patients.

Q2 | 2017

www.painweek.org | PWJ

KeY TOPiC

had spasms or dystonia associated with the condition showed analgesic effects when BtxA was used intramuscularly.63,64 A small (n=9) randomized, double blind, placebo controlled crossover study reported the effects of lumbar sympathetic blocks and compared the efficacy and duration between bupivacaine and BtxA mixed with bupivacaine. Median time to analgesic failure was 71 days for the toxin group compared with fewer than 10 days for the bupivacaine group, suggesting, at least in this small sample, enhanced duration of the block’s analgesic effect.65

Other General Concepts About Botulinum Toxins

All commercially available toxins in the us carry a boxed warning indicating that their effects may spread from the area of injection to other areas of the body, producing symptoms consistent with botulinum toxin effects, including asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. However, if these products are applied properly (location, dose, dilution) and to the appropriate patient, the incidence of side effects is extremely low. Side effects are generally short-lived and self-limited. The agency also warns physicians and consumers about the fact that units of biological activity of any of the toxins are not interchangeable with units of any other botulinum toxin. All toxins are considered pregnancy Category C.

Conclusion

There is mounting evidence for the use of botulinum toxins as part of the armamentarium in the comprehensive management of a wide variety of chronic pain syndromes. Botulinum toxins appear to have direct analgesic effects as neuromodulators, attenuating nociceptive transmission in abnormally sensitized pain states without causing anesthesia. At present, there are numerous clinical trials for pain indications with several commercially available toxins and investigations into toxin modifications in order to potentially create compounds with more targeted effects as well as longer duration of action. These remarkable biologicals hold remarkable potential for the field of pain management but also carry unique complexities beyond those considered with other pharmaceuticals, including dosing, lack of interchangeability among the various existing formulations, and issues associated with their delivery methods (location, dilution). The good news is that they are not so toxic after all… References 1. Ishikawa H, Mitsui Y, YoshitomiT, et al. Presynaptic effects of botulinum toxin type A on the neuronally-evoked response of albino and pigmented rabbits iris sphincter and dilator muscles. Jpn J Opthalmol. 2000;44(2):106–109. 2.

Purkiss J, Welch M, Doward S, et al. Capsaicin-stimulated release of

68 PWJ | www.painweek.org

substance P from culture dorsal root ganglion neurons: involvement of two distinct mechanisms. Biochem Pharmacol. 2000;59(11):1403–1406. 3. Welch MJ, Purkiss JR, Foster KA. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon. 2000;38(2):245–258. 4. Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache. 2004;44(1):35–43. 5. Aoki KR. Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache. 2003;43(1):S9–15. 6. Dodick DW, Turkel CC, DeGryse RE, et al; on behalf of PREEMPT Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010;50:921–936. 7. Aurora SK, Winner P, Freeman MC, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled analyses of the 56-Week PREEMPT clinical program. Headache. 2011;51:1358–1373. 8. Durham PL. CGRP-receptor antagonists—a fresh approach to migraine therapy? N Engl J Med. 2004;350(11):1073–1075. 9. Blumenfeld A. Botulinum toxin type A: an neuromodulatory mechanism of action in migraine [commentary]. Headache. 2004;44:42–43. 10. Blumenfeld A. Botulinum toxin type A as an effective prophylactic treatment in primary headache disorders. Headache. 2003;43: 853–860. 11. Dodick DW. Botulinum neurotoxin for the treatment of migraine and other primary headache disorders: from bench to bedside. Headache. 2003;43:S25-S33. 12. Silberstein S, Mathew N, SaperJ, et al, for the BOTOX Migraine Clinical Research Group. Botulinum toxin type A as a migraine preventive treatment. Headache. 2000;40:445–450. 13. Silberstein SD, Stark SR, Lucas SM, et al. Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. 2005;80:1126–1137. 14. Silberstein SD, Gobel H, Jensen R, et al. Botulinum toxin type A in the prophylactic treatment of chronic tension-type headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study. Cephalalgia. 2006;26:790–800. 15. Aurora SK, Gawel M, Brandes JL, et al. Botulinum toxin type A prophylactic treatment of episodic migraine: a randomized, double-blind, placebo-controlled exploratory study. Headache. 2007;47:486–499. 16. Mathew NT, Frishberg BM, Gawel M, et al. Botulinum toxin type A (BOTOX ® ) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Headache. 2005;45:293–307. 17. Freitag FG, Diamond S, Diamond M, et al. Botulinum toxin type A in the treatment of chronic migraine without medication overuse. Headache. 2008;48:201–209. 18. OndoWG, Vuonf KD, Derman HS. Botulinum toxin A for chronic daily headache: a randomized, placebo-controlled, parallel design study. Cephalalgia. 2004;24:60–65. 19. Blumenfeld A, Silberstein SD, Dodick DW, et al. Method of injection of onabotulinumtoxinA for chronic migraine: a safe, well-tolerated, and effective treatment paradigm based on the PREEMPT clinical program. Headache 2010;50(9):1406–1418. 20. Kapural L, Stillman M, Kapural M, et al. Botulinum toxin occipital nerve block for the treatment of severe occipital neuralgia: a case series. Pain Pract. 2007;7:337–340. 21. Taylor M, Silva S, Cotrell C. Botulinum toxin type A (Botox) in the treatment of occipital neuralgia: a pilot study. Headache. 2008;48;1476–1481. 22. Volcy M, Tepper S, Rapoport AM, et al. Botulinum toxin type A for the treatment of greater occipital neuralgia and trigeminal neuralgia. A case report with pathophysiological considerations. Cephalalgia. 2005;25:990.

Q2 | 2017

23. Evers S. Review of botulinum toxin type A for the prophylactic treatment of chronic daily headache. Neuropsychiatr Dis Treat. 2007;3(6):761–764.

44. Freund B, Schwartz M, Symington JM. botulinum toxin: new treatment for temporomandibular disorders. Br J Oral MaxilloFac Surg. 2000;38(5):466–471.

24. Childers MK, Wilson DJ, Galate JF, et al. Treatment of painful muscle syndromes with botulinum toxin: a review. J Back Msk Rehabil. 1998;10:89–96.

45. von Lindern JJ. Type A botulinum toxin in the treatment of chronic facial pain associated with temporo-mandibular dysfunction. Acta Neurol Belg. 2001 Mar;101(1):39–41.

25. Cheshire WP, Abashian SW, Mann D. Botulinum toxin in the treatment of myofascial pain syndrome. Pain. 1994;59(1):65–69. 26. Porta M. A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of myofascial pain syndrome and pain from chronic muscle spasm. Pain. 2000;85:101–105. 27. Jordan SE, Ahn SS, Freischlag JA, et al. Selective botulinum chemodenervation of the scalene muscles for treatment of neurogenic thoracic outlet syndrome. Ann Vasc Surg. 2000;14(4):365–369. 28. Lang A. Botulinum toxin type B in piriformis syndrome. Am J Phys Med Rehabil. 2004;83:198–202. 29. Childers MK, Wilson DJ, Gnatz SM, et al. Botulinum toxin type A use in piriformis syndrome: a pilot study. Am J Phys Med Rehabil. 2002;81:1–9.

47. Borodic GE, Acquadro MA.The use of botulinum toxin for the treatment of chronic facial pain. J Pain. 2002;3(1):21–27. 48. Piovesan EJ, Teive HG, Kowacs PA, et al. An open study of botulinum-A toxin treatment of trigeminal neuralgia. Neurology. 2005;65(8):1306–1308. 49. Bohluli B, Motamedi MHK, Baghery SC, et al. Use of botulinum toxin A for drug-refractory trigeminal neuralgia: a preliminary report. Oral Surg Oral Med Oral Path Oral Radiol Endod. 2011;111(1):47–50. 50. Zuniga C, Diaz S, Piedimonte F, et al. beneficial effects of botulinum toxin type A in trigeminal neuralgia. Arq Neuro-Psiquiatr. 2008;66(3):500–503.

30. Cuevas-Trisan RL. Usos de la Toxina Botulínica en Sindromes de Dolor Miofascial. In: Micheli F, Dressler D. Toxina Botulínica: Nuevas Indicaciones Terapeúticas. 1st. Ed. Buenos Aires: Médica Panamericana; 2010:261–269.

51. Turk U, Ilhan S, Alp R, et al. Botulinum toxin and intractable trigeminal neuralgia. Clin Neuropharmacol. 2005;28(4):161–162.

31. Foster L, Clapp L, Erickson M, et al. Botulinum toxin A and chronic low back pain. Neurology. 2001;56:1290–1293.

52. Bosca-Blasco ME, Burguera-Hernandez JA, Roig-Morata S, et al. [Painful tic convulsif and Botulinum toxin] Rev Neurol. 2006;42(12):729–732.

32. Jabbari B, Ney J, Sichani A, et al. Treatment of refractory, chronic low back pain with botulinum neurotoxin A: an open-label, pilot stud. Pain Med. 2006;7(3):260–264.

53. Allam N, Brasil-Neto JP, Brown G, et al. Injections of botulinum toxin type A produce pain alleviation in intractable trigeminal neuralgia. Clin J Pain 2005;21(2):182–184.

33. Ney JP, Difazio M, Sichani A, et al. Treatment of chronic low back pain with successive injections of botulinum toxin A over 6 months. Clin J Pain. 2006;22(4):363–369.

54. Cuevas-Trisan, R. The use of botulinum toxin type A in the treatment of intractable facial pain: a case report. Abs. AAPM annual meeting – Las Vegas 9/2007.

34. Nagarajan V, Al-Shubaili A, Ayad YM, et al. Low back ache treatment with botulinum neurotoxin type A. Med Princ Pract 2007; 16:181–186. 35. Jeynes LC, Gauci CA. Evidence for the use of botulinum toxin in the chronic pain setting:A review of the literature. Pain Pract. 2008;8(4):269–276. 36. Wong SM, Hui AC, Tong PY, et al. Treatment of lateral epicondylitis with botulinum toxin: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2005;143(11):793–797. 37. Hayton MJ, Santini AJ Hughes PJ, et al. Botulinum toxin injection in the treatment of tennis elbow: a double-blind, randomized, controlled pilot study. J Bone Joint Surg Am. 2005;87(3):503–507.

55. Namazi H, Majd Z. Botulinum toxin as a novel addition to anti-arthritis armamentarium. Am J Immunol. 2005;1(2):94–95. 56. Mahowald ML, Singh JA, Dykstra D. Long-term effects of intra-articular botulinum toxin type A for refractory joint pain. Neurotox Res. 2006;9:179–188. 57. Boon AJ, Smith J, Dahm DL, et al. Efficacy of intra-articular botulinum toxin type A in painful knee osteoarthritis: a pilot study. PMR. 2010;2(4):268–276. 58. Neumeister MW. Botulinum toxin type A in the treatment of Rauynaud’s phenomenon. J Hand Surg. 2010;35A:2085–2092. 59. Xiao L, Mackey S, Hui H, et al. subcutaneous injection of botulinum toxin A is beneficial in postherpetic neuralgia. Pain Med. 2010;11(12):1827–1833.

38. Espandar R, Heidari P, Rasouli MH, et al. Use of anatomic measurement to guide injection of botulinum toxin for the management of chronic lateral epicondylitis: a randomized controlled trial. CMAJ. 2010;182(8): 768–1773.

60. Waldfogel JM, Nesbit SA, Dy SM, et al. Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: a systematic review. Neurol. 2017;10–1212. [ePub ahead of print]

39. Kalichman L, Bannuru RR, Severin M, et al. Injection of botulinum toxin for treatment of chronic lateral epicondylitis: systematic review and meta-analysis. Sem Arth Rheum. 2011;40(6):532–538.

61. Dhull P, Tewari AK, Upreti V, et al. Botulinum toxin for meralgia paresthetica in type 2 diabetes. Diab Metabol Synd Clin Res Rev. 2013;7(1):1–2.

40. Babcock MS, Foster L, Pasquina P, et al. Treatment of pain attributed to plantar fasciitis with botulinum toxin a: a short-term, randomized, placebo-controlled, double-blind study. Am J Phys Med Rehabil. 2005;84(9):649–654. 41. Placzek R, Deuretzbacher G, Meiss AL. Treatment of chronic plantar fasciitis with botulinum toxin A: preliminary clinical results. Clin J Pain. 2006;22(2):190–192. 42. Huang Y-C, Wei S-H, Wang H-K, et al. Ultrasonographic guided botulinum toxin type A for plantar fasciitis: an outcome-based investigation for treating pain and gait changes. J Rehabil Med. 2010;42(2):136–140. 43. Diaz-Llopis IV, Rodriguez-Ruiz CM, Mulet-Perry S, et al. Randomized controlled study of the efficacy of botulinum toxin type A versus corticosteroids in chronic plantar fasciitis: results at one and six months. Clin Rehabil. 2012;26(7):594–606.

Q2 | 2017

46. von Lindern JJ, Niederhagen B, Berge S, et al. Type A botulinum toxin in the treatment of chronic facial pain associated with masticatory hyperactivity. J Oral Maxillofac Surg. 2003;61(7):774–778.

62. Fabregat G, Asensio-Samper JM, Palmisani S, et al. Subcutaneous botulinum toxin for chronic post-thoracotomy pain. Pain Pract. 2013;13(3):231–234. 63. Safarpour D, Salardini A, Richardson D, et al. Botulinum toxin A for the treatment of allodynia of complex regional pain syndrome: a pilot study. Pain Med. 2010;11:1411–1414. 64. Kharkar S, Ambady P, Venkatesh Y, et al. intramuscular botulinum toxin in complex regional pain syndrome: case series and literature review. Pain Physician. 2011;14:419–424. 65. Carroll I, Clark JD, Mackey S. sympathetic block with botulinum toxin to treat complex regional pain syndrome. Ann Neurol. 2009;65(3):348–351.

www.painweek.org | PWJ

PaiNWeek salutes the next generation of frontline practitioners who embrace education as the best analgesic!

SHORT CUTS

Ravi Prasad phd Psychologist Clinical Associate Professor Stanford University

… this faith [I have] in our inherent strength is also what draws me to the field of pain psychology…

GPS San Francisco Bay Area, California Typical Day “I start each day at the hospital working alongside a team of colleagues in the Stan-

ford Comprehensive Interdisciplinary Pain Program (SCIPP). SCIPP is one of the few academic inpatient pain programs in the nation geared toward helping patients with chronic pain decrease their reliance on opioids to manage their condition and increase their use of nonpharmacologic strategies. I spend the second half of my day seeing patients in our outpatient pain center and taking care of other administrative responsibilities.” Persona “In my clinical role, I am essentially a guide: I cannot make individuals change but I can help them navigate through different approaches to dealing with the challenges in their lives. It is immensely rewarding to help patients learn that even though there may not be a cure for their pain, there are sustainable pathways to increase physical and emotional functioning and improve overall quality of life.” Social Media Habits “The days are so busy that I rarely get a chance to check in with social media feeds! When I do have downtime, I most frequently peruse Facebook and LinkedIn.” People “There are many historical figures that I highly regard. As for contemporary public figures, I would have to recognize former president Barack Obama. Regardless of my agreement/disagreement with his perspectives, I have the utmost respect for the vast barriers that he had to overcome to become the first African American president and for igniting such a high level of passion among individuals who were previously indifferent to politics.” Words “Although dated, Viktor E. Frankl’s book, Man’s Search for Meaning, is a powerful text that showcases the internal resources we possess that can help us cultivate resilience under the most atrocious circumstances. His depiction of life in a concentration camp is both emotionally moving and inspirational.” Popcorn “The first time I saw the movie Gandhi I was too young to fully appreciate it; however, watching it later in life was very powerful. I suspect that my affinity for this movie and my previously cited book and public figure all have one thing in common: they all display the immense internal power that each of us possesses as human beings. I believe that this faith in our inherent strength is also what draws me to the field of pain psychology, as my daily clinical practice involves helping individuals cultivate this force within themselves to maximize quality of life.” PAINWeek “PAINWeek is a phenomenal event that provides vast exposure to a full range of biopsychosocial interventions that are available to help improve the lives of individuals living with pain. All of the presenters possess a passion for their work that is readily palpable and quite contagious!”

Q2 | 2017

www.painweek.org | PWJ

SHORT CUTS

By Doug Gourlay md, msc, frcpc, fasam

“You can’t solve a chronic pain problem in an active, untreated addict.” If pain and chemical dependency coexist, determine which is dominant and treat the dominant disorder first. Do you have the experience AND the resources to manage this patient? When in doubt, ask for help! Either formally through consultation or informally via an organization like Ontario’s MMAP, the Medical Mentoring for Addictions and Pain for primary care practitioners. This shouldn’t mean you can’t treat pain in an active addict but rather that, in order to treat an underlying chronic pain condition—the substance use disorder—it must be simultaneously assessed and addressed. This is particularly relevant in cases where the patient does not want to address these other issues.

PWJ | www.painweek.org

Q1 | 2017

SHORT CUTS

A study

compared dorsal root ganglion (DRG) stimulation to spinal cord stimulation (SCS) for pain reduction efficacy in

152 subjects with lower extremity neuropathic pain. Treatment success was defined as a

50 %

A study surveyed the treatment goals

of 2 groups at 2 clinics in California:

patients with chronic pain and

primary care clinicians.

decrease in pain scores over 3 months. The DRG cohort achieved the success threshold in

Patient goals:

81.2 % 55.7 %

wanted less pain, and

of cases compared to just

success for the SCS treated population.1

Joint replacement surgery is riskier for women than for men. A review of

2,613 patients

with unexplained postsurgical pain found women reporting a

6.8 pain level on a 1 to 10 scale, vs 6.1 for men. Testing for sensitivity to joint replacement metal components revealed immune sensitization to the metals in

49% 38%

of the women but only

of the men.2

48% 22%

wanted accurate diagnosis.

Clinician goals differed:

41%

prioritized improved patient functionality, and

26%

emphasized minimizing risk of medication side effects.

Author’s conclusion: better patient/provider communication is needed.3

Music therapy can reduce pain following spine surgery.

30 patients

at Mount Sinai Department of Orthopedics received a

30-minute music therapy session within 72 hours of their procedure, plus standard postoperative care. They reported a drop in visual analog scale pain rating of 6.20 to 5.09.

Device maker Theranica, Ltd. reported results of a preliminary study of its new stimulation device on

patients who experienced 2 to 8 migraine attacks per month, and who avoided migraine medication for at least 60 days before the study.

229

migraine attacks were treated

with varying levels of device stimulation or placebo (sham) stimulation. Patients who received active stimulation reported at least

50%

pain reduction, compared to just

26%

who received placebo.5

a study of

200,000 patients records found that

of patients undergoing common surgical procedures had received at least 2 prescriptions for opioids in the

90 days before surgery. These patients on average spent a

1/2 day longer

30 surgical patients

in the hospital and were more likely to return to the hospital or to a rehabilitation facility in the first 30 days’ postsurgery.

5.20 to 5.87.4

Preoperative opioid use should thus be considered a risk factor for elective surgery.6

A second group of

who received only standard care reported their pain increased from

1. http://bit.ly/2oTJV0c 2. http://bit.ly/2oQBnWM 3. http://bit.ly/2ppJonF 4. http://bit.ly/2qntwS1 5. http://bit.ly/2pcMgWx 6. http://bit.ly/2pc3xiv

Q2 | 2017

www.painweek.org | PWJ

SHORT CUTS

research being done. There’s still long ways for us to go developing actual tools that can be used in the ed setting. All the tools that are currently available are not really designed for our population. As for the key message behind pain as the fifth vital sign, it’s about communication. Communicating with our patients—performing pain assessments within the ed perimeters, discussing the barriers and challenges that go along with working that environment—that’s where we can improve and where we should focus our energy so we can provide better care for patients when it comes to dealing with their pain.

What You Should Know About Evidence Based Medicine

Steven Stanos do

Evidence based medicine (ebm) is how we connect research to clinical practice. It started in the 80s and 90s as of way of looking at how studies are done and how they could be applied to clinical care, and it’s gone through a number of changes over the years. ebm is now being applied to thousands of different conditions, and I think it’s important to consider and assess “Is it accurate? Is it being used correctly? Are people or groups or stakeholders using it inappropriately in some cases?” ebm is very complex. Often the term gets thrown around and practitioners need to understand its basic components so they can judge clinical studies or guidelines when they come out and have an understanding of whether there was bias involved, how the studies were done, and which studies were looked at. The goal for the practitioner should be to become a better user of clinical and research information. The cdc guidelines for opioid prescribing were definitely an example of ebm, although they were done by a governmental body vs the usual practice where ebm guidelines are written by scientific groups or associations. The cdc has a different mission—to help protect the public. Really, the cdc guidelines were primarily done to decrease opioid abuse, heroin overdoses, and misuse of medications. There’s been trepidation from some physician and provider groups that some of the recommendations may have not been ebm, but more opinion or contextual support. I think in general the 12 recommendations are useful for physicians and providers in matters of patient assessment and monitoring, and in treating patients who develop other problems related to opioid use. But some of the evidence that they used was very low grade, and there’s a problem when the evidence is very low and recommendations are made. And if the recommendations just create fear for prescribers, if they’re misused or misinterpreted, then patients could be stigmatized and denied care from which they could benefit.

Emergency Department and Pain as the Fifth Vital Sign

Phyllis L. Hendry md, faap, facep; Sophia Sheikh md

Dr. Sheikh: With this new awareness of pain management in the Emergency Department, there’s a lot more interest and a lot more

PWJ | www.painweek.org

Dr. Hendry: Pain is important. It’s called the fifth vital sign. That partially led to patient satisfaction scores, the hcahps scores, and 2 or 3 of those are based on pain. And even though they are hospital based scores, the experience starts in the ed. So there’s talk about taking those pain components out of the patient satisfaction survey. I have mixed feelings about that because I do think pain management is important, but maybe we put a little bit too much emphasis there. It’s easy to just give an opioid and take the pain away, and what we really need to be looking at are other ways to treat pain. There’s a ton of nonpharmacological methods. We still need to be treating pain. It’s still important. But that’s the way hospitals were getting reimbursed. If you didn’t have high hcahps, it adversely affected you. Half to 78% of patients who come to the ed are there for pain related complaints, and so it is important. We do have to continue to look at that.

Challenges in Acute Pain Management Debra B. Gordon rn, dnp, faan

A common question I hear is “How do you manage acute pain in folks with chronic pain and opioid tolerance?” It’s similar to general principles: using plan of care, multimodal analgesia, utilizing a professional team, understanding what the goals are realistically in terms of recovery, not just focusing on a single thing like opioids. All patients deserve pain treatment and whether they have the disease of addiction or substance use disorder or not, they may need opioids in their lifetime. Exposing people to opioids does not cause this complicated disease, this vile psychosocial disease of addiction. Certainly, when people have that disease present, we have to be very vigilant and careful and have clear guidance about tapering opioids and looking at their risks. But there’s no evidence that using opioids to treat acute pain is going to cause relapse and probably, if anything, if we undertreat patients with opioids, it’s going to cause more problems—people will probably go out and look for illicit sources. Should we refrain from using opioids, try to detoxify patients with substance use disorder in the hospital while they’re there? There is really little evidence that has anything to do with their sobriety. In fact, it just puts them at risk for overdose and death when they leave the hospital. I think we have to use pharmacologic principles. We have to think about safety but we can safely use opioids in all patients including patients with substance use disorder. It takes multidisciplinary plans of care. It takes a multimodal approach using other strategies in addition to opioids. It’s surprising when you ask people about their addiction history, often how open and honest they’ll be. You have to establish

Q2 | 2017

trust and rapport with someone. They’ve often been through poor medical encounters where they’ve felt a lot of judgment or have been treated inconsistently. Sometimes it’s pretty obvious what brought them to the hospital. Use universal precautions, such as urine drug testing, to uncover what substances are present when people are in the hospital and appear intoxicated. And I think you have to thank patients for that open honesty and say it’s important for us to know so that we can provide better and safer care.

Pain From the Brain: The Role of Sensory Amplification Daniel Clauw md

I think it’s important for primary care providers or anyone taking care of chronic pain patients to realize that the central nervous system (cns) plays a very prominent role in pain processing. In many individuals, in whom we see that the cns is amplifying their pain, the brain is also amplifying other sensory experiences. If you encounter a patient with chronic pain who also reports that they’re sensitive to the brightness of light, the loudness of noises, odors, or even that they have a lot of side effects from drugs, those are all clues that the person is more globally sensory hyper-responsive. What that should indicate to a clinician about the patient is that part or maybe all of their pain is really coming more from the brain than from the area of the body where they’re experiencing pain. This is important because the drug and nondrug treatments that work to treat pain that is coming from the brain—conditions like fibromyalgia, irritable bowel, headache, interstitial cystitis—are entirely different than the therapies which work for pain from damage or an inflammation somewhere in the body. We refer to these as centralized pain states, in that the cns is playing a more prominent role. Physicians need to get better at identifying that symptom pattern. It should be a blinking neon light that some or much of this person’s pain is coming from the brain. It means we must switch over to some of the drugs that work primarily in the brain. The older drugs would be some of the tricyclics. The newer drugs would be the gabapentinoids, the serotonin norepinephrine reuptake inhibitors. Even cannabinoids would probably be preferred for those individuals rather than opioids or nonsteroidals. The nonpharmacologic treatment options are extremely important in these types of syndromes because drugs to treat this type of pain are not as effective as drugs we have to treat other diseases. And some of the underlying pathogenesis of central or brain pain probably is due to some of the sleep difficulties that people have. A lack of exercise can also turn up the volume control in the brain. Think about therapies like nondrug approaches to sleep hygiene. Be aggressive about getting people moving and then exercising.

and postinguinal hernia repair syndrome. They’re typically considered neuropathic pain states. They’re not the typical neuropathic pain disorders that we think of in pain management and primary care, which tend to be things like diabetic neuropathy, which affects a larger proportion of the population. They are usually postsurgical and their treatment might differ a little bit as well. The best treatment options include a multimodal approach using things like antineuropathic pain medications, as well as treating any comorbidities that these patients may have—depression, anxiety, sleep disorders. Some of the more common medications with the best evidence are things like gabapentin and pregabalin, which are usually considered the first line of therapy for these pain symptoms. Second line therapy might be antidepressants specifically like duloxetine and venlafaxine, which work in the serotonin and norepinephrine reuptake inhibitor pathway, and have been shown to be pretty successful in these patients. In general, these patients are not good candidates for opioid therapy. Most people consider opioids in these patients more as second line, and even third line. Ideally, you want to try to maximize some of the nonopioid modalities. I would tell primary care physicians to either consult or refer to pain management specialists if they have questions. Most pain management physicians are more than happy to assist. A lot of times, we see that primary care physicians are able to start patients on some of these medications, and in a lot of patients, they will do fine. They will never need to see a pain management physician. But as soon as any questions come up where it just doesn’t seem right, we’re always just a phone call away.

Dr. Yi: I’m not sure if “odd” is necessarily the right word. They’re odd in the sense that not everyone gets them after these certain types of surgeries. It’s only a subset of patients that tend to get long sequelae of pain after these surgeries. So I guess in that way it’s odd, but they are actually pretty prevalent for people that experience it. We try to emphasize a multimodal approach—medical treatment, procedural interventions, psychological interventions like cognitive behavioral therapy, graded motor imagery. These therapies benefit patients the most when they’re used in conjunction with each another. Some of the nonpharmacological therapies for these neuropathic pain syndromes would be preemptive modalities, meaning targeting pain before a noxious stimuli happens. In a lot of these cases, it will be surgery, preemptive procedures, such as a thoracic epidural or a paravertebral catheter, or different types of pec blocks for mastectomy. Those types of procedures would be alternatives to medications.

Going Beyond the Usual Neuropathic Pain Conditions Ignacio Badiola md; Peter Yi md

Dr. Badiola: Odd neuropathic pain disorders are a problem in the United States and across the world. Some of the more common ones are postmastectomy syndrome, postthoracotomy syndrome,

Q2 | 2017

www.painweek.org | PWJ

SHORT CUTS

with

theresa

mallick searle

ms, np-bc, anp-bc

PWJ | www.painweek.org

Q1 | 2016

“[If you weren’t a healthcare provider…] I would probably be a teacher. The absolutely wonderful thing about my current career is that I get to do both!”

Q What inspired you to become a healthcare provider?

When I was 17, my mother and 2 younger sisters were involved in a head-on motor vehicle accident. The 3 were taken to separate medical centers that could accommodate the level of trauma care needed. The evening of the accident and over the next 2 to 3 months, I watched doctors and nurses work tirelessly to stabilize and care for the 3 lives that meant the most to me. The dedication, attention, and level of compassion that I observed cemented in me my future life’s work.

Why did you focus on pain management?

a I sort of fell into pain management. As an or & pacu nurse, I worked closely with the Pain Service caring for their patients when undergoing interventions. I came to respect the discipline while working along with these specialty physicians doing remarkable interventions “curing” pain. After completing my advanced degree, the Pain Service at Stanford was looking to bring on their first Nurse Practitioner. For me, there was no question as to where I wanted to focus my practice. Q2 | 2017

Who were your mentors?

It is difficult to choose just 1 or 3 individuals. I try and take examples from most everyone that I interactive with, be it a close friend, colleague, supervisor, or stranger on the street, to better myself as a person and care provider. Specific individuals who I admire and I reflect on every day in my professional life are Sean Mackey, an individual who I first met as a Pain Fellow and watched grow to be one of the most respected pain researchers, leaders, and advocates for patients in our discipline. Ian Carroll, who I also initially met as a Pain Fellow, whose commitment to patients with pain is the greatest I have ever experienced. Ian’s intelligence and relentless drive to diagnose the otherwise undiagnosable, is of utmost inspiration. Finally, Wendye Robbins, one of the most talented, compassionate, and driven women that I have ever met. Her equal devotion and commitment to patients, family, friends, colleagues, and society as a whole is unequaled. Dr. Robbins is one of the first women in pain medicine that I met when starting my career, and I found her to be a true enigma. Her ability to be “all” and do “all” from physician, business women, entrepreneur, to devoted mother, wife, and friend filled me with the confidence to expand my boundaries.

www.painweek.org | PWJ

PUNDi T PROFiLe/SiLVeRMaN

“…milestones in my life that I am most proud of: completing nursing school, landing my first job at Stanford, becoming a Nurse Practitioner.” Q If you weren’t a healthcare provider, what would you be? I would probably be a teacher. The absolutely wonderful thing about my current career is that I get to do both!

about horticulture (or growing potatoes), given that I recently read The Martian. I would choose a film for pure entertainment. I really enjoy the X-Men series. Finally, I would choose a song of inspiration, maybe something from John Lennon like Whatever Gets You Through the Night.

What is your most marked characteristic?

Q What do you consider your greatest achievement?

Stubbornness, tenacity, and curiosity. My husband says, “Bulldog. When she is focused on something, she is a bulldog and will not let go.”

It is difficult for me to choose one life event as my greatest achievement. Instead I like to consider milestones in my life that I am most proud of: completing nursing school, landing my first job at Stanford, becoming a Nurse Practitioner.

What would you like your legacy to be?

I would like to be remembered as a hardworking, humble, creative, caring nurse, wife, sister, aunt, friend, and colleague. What is your motto?

If difficult, it is done at once. The impossible takes a little longer.

Theresa Mallick-Searle, MS, NP-BC, ANP-BC, is a Nurse Practitioner, Pain Medicine, at Stanford Health Care, in California.

What is your favorite language?

Sign language—reflecting the ability to communicate without words.

Q 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?

I am sure that this question is supposed to reflect something deep and profound about my personality. So since I will be heading off to space, I would choose a book of instruction. Something

78 PWJ | www.painweek.org

Q2 | 2017

GRALISE® (gabapentin) tablets Rx Only BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This does not include all the information needed to use GRALISE safely and effectively. See full Prescribing Information for GRALISE. INDICATIONS AND USAGE • GRALISE is indicated for the management of postherpetic neuralgia. • GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration. DOSAGE AND ADMINISTRATION • 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 crush, split, or chew the tablets. For recommended titration schedule, see DOSAGE AND ADMINISTRATION in full Prescribing Information. • If GRALISE dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of 1 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 mL/min or in patients on hemodialysis. CONTRAINDICATIONS GRALISE is contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients. 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. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Table 1: Risk by Indication for Antiepileptic Drugs (including gabapentin, the active ingredient in GRALISE) in the Pooled Analysis

Indication Epilepsy Psychiatric Other Total

Placebo Patients with Events Per 1000 Patients 1.0 5.7 1.0 2.4

Relative Risk: Risk Incidence of Difference: Events in Drug Additional Drug Patients Patients/Incidence Drug Patients with Events Per in Placebo with Events Per 1000 Patients Patients 1000 Patients 3.4 3.5 2.4 8.5 1.5 2.9 1.8 1.9 0.9 4.3 1.8 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 pre-existing 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. 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.

Table 2: 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 Infections and Infestations Nasopharyngitis Urinary tract infection Investigations Weight increased Musculoskeletal and Connective Tissue Disorders Pain in extremity Back pain Nervous System Disorders Dizziness Somnolence Headache Lethargy

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

2.5 1.7

2.2 0.5

1.9

0.5

1.9 1.7

0.5 1.1

10.9 4.5 4.2 1.1

2.2 2.7 4.1 0.3

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 enlargement, elevated creatine kinase, elevated liver function tests, erythema multiforme, 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 In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 mcg/mL; 1mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the Cmax at 3600 mg/day). Hydrocodone 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 the interaction at other doses is not known. Antacid (containing aluminum hydroxide and magnesium hydroxide) An antacid containing aluminum hydroxide and magnesium hydroxide reduced the bioavailability of gabapentin immediate release by approximately 20%, but by only 5% when gabapentin immediate release was taken 2 hours after the antacid. It is recommended that GRALISE be taken at least 2 hours following the antacid (containing aluminum hydroxide and magnesium hydroxide) administration. Drug/Laboratory Test Interactions False positive readings were reported with the Ames-N-Multistix SG® dipstick test for urine protein when gabapentin was added to other antiepileptic drugs; therefore, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein. USE IN SPECIFIC POPULATIONS Pregnancy Category C: GRALISE should be used during pregnancy or in women who are nursing only if the benefits clearly outweigh the risks. See full Prescribing Information for more information about use of GRALISE in pregnancy. 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. 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 in full Prescribing Information]. DRUG ABUSE AND DEPENDENCE The abuse and dependence potential of GRALISE has not been evaluated in human studies. OVERDOSAGE 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.

Relief Uninterrupted

Bring 24-hour relief into their routine

GRALISE is the only true once-a-day gabapentinoid that offers Night to Day control of PHN pain1

• Patients receiving GRALISE experienced significant pain reduction vs placebo beginning Week 1 and continuing throughout the 10-week study (P<0.05)2,3 •Average daily pain score reduction for GRALISE was -2.1 vs -1.6 with placebo (P=0.013)2 Study Design: Patients from 89 investigative sites participated in this randomized, double-blind, parallel design, placebo-controlled, multicenter clinical trial. The study period included a 1-week baseline period, followed by randomization and a 2-week titration to a once-daily dose of 1800 mg G-GR or matched placebo, followed by an 8-week maintenance-dose period, followed by a 1-week dose-tapering period. 452 patients were randomized, with 221 receiving 1800 mg of GRALISE and 231 receiving placebo.2 Primary endpoint: change in the baseline observation carried forward (BOCF) average daily pain score from the baseline week to Week 10 of the efficacy treatment period.2

Learn more today at www.Gralise.com 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.

IMPORTANT SAFETY INFORMATION ADVERSE REACTIONS The most common side effects were dizziness (10.9%) and somnolence (4.5%). USE IN SPECIFIC POPULATIONS Reductions in GRALISE dose should be made in patients with age-related compromised renal function.

WARNINGS AND PRECAUTIONS 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.

For more information about GRALISE, please see Brief Summary on the following page.

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