The Pain Practitioner - Opioid Abuse + Abuse-deterrant Formulations

Integrative Pain Management for Optimal Patient Care

The Pain Practitioner September/October 2017

Opioid Abuse

+

Abuse-deterrent Formulations Equianalgesic Dosing

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 (≼10%) 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.

Š February 2017, Depomed, Inc. All rights reserved. APL-NUCX-0029 Rev. 3

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

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.

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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.

© May 2017, Depomed, Inc. All rights reserved. APL-NUCX-0249

The Pain Practitioner SEPTEMBER/OCTOBER 2017

To access the virtual magazine, go to newsstand.aapainmanage.org

10 NOTES FROM THE FIELD Minding Our Language

By Bob Twillman, PhD, FAPM, Executive Director 11 EDITORIAL Abuse-deterrent Opioids: Tech, Yes. Talk, Too

By W. Clay Jackson, MD, DipTh, Editor-in-Chief PAGE 10

12 ANNUAL MEETING/EDUCATION Member Focus: Talking with Norm Shealy By Debra Nelson-Hogan 14 ADVOCACY Policy Is Not a Dirty Word

By Katie Duensing, JD, Director of Legislative and Regulatory Affairs 15 Will Abuse-deterrent Formulations Eliminate Opioid Abuse?

By Christine Rhodes, MS

PAGE 14

17 Are ADFs the Answer to Opioid Abuse?

By Bob Twillman, PhD, FAPM, Executive Director 19 Opioid Dosing Policy: Pharmacological Considerations Regarding Equianalgesic Dosing

By Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP; Mena Raouf, PharmD; and Erica L. Wegrzyn, PharmD

PAGE 17

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ACADEMY BOARD OF DIRECTORS President Joanna Katzman, MD, MSPH Past President Robert A. Bonakdar, MD, FAAFP Vice President W. Clay Jackson, MD, DipTh Secretary Paul Christo, MD, MBA Treasurer Kevin T. Galloway, BSN, MHA, Colonel, US Army (Retired) Directors-at-Large Alfred V. Anderson, MD, DC George D. Comerci, Jr, MD, FACP John Garzione, DPT Christian D. González, MD Michael Kurisu, DO, ABIHM Joseph Matthews, DDS, MSc Liaison to the Board Maggie Buckley

STAFF AND CONSULTANTS Executive Director Robert Twillman, PhD, FAPM Director of the State Pain Policy Advocacy Network (SPPAN) Amy Goldstein, MSW Assistant Director of Education Cathleen Coneghen Director of Legislative and Regulatory Affairs Katie Duensing, JD Member Services Manager Whitney O’Donnell Account Manager Rosemary LeMay Professional Development Project Manager MacKenzie Davis Content Consultant Debra Nelson-Hogan

THE PAIN PRACTITIONER STAFF AND CONSULTANTS Editor-in-Chief W. Clay Jackson, MD, DipTh Editor Debra Nelson-Hogan Advertising and Sales Leslie Ringe Managing Editor Cathleen Coneghen Clinical Editor Christine Rhodes, MS Art Director Peter McKinley, Pak Creative Copy Editor Rosemary Hope

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NOTES FROM THE FIELD

Minding Our Language

By Bob Twillman, PhD, FAPM, Executive Director

I try hard to manage my language related to pain management. As my colleagues will tell you, I’m a stickler for using certain terms and avoiding others, but it’s in the service of helping us maintain a proper philosophical approach to our work. I believe that words do matter, and that consistent use of certain terms can affect our behavior, for better or for worse.

With that in mind, here are some of my linguistic pet peeves.

PAINKILLERS Virtually every reference to opioid analgesics in the lay press and in publications from government agencies such as the Centers for Disease Control and Prevention uses the term “painkiller” in lieu of “opioid analgesic” or my preferred term, “pain reliever.” To me, “painkiller” is inaccurate and pejorative. It is inaccurate because opioid analgesics do not “kill” pain, either in the sense that they completely relieve the pain or that they make it go away permanently. It is pejorative because it implies that these medications are “killers,” that they cause people who use them to lose their lives. While this is true for some people, it is perhaps more often true that they give people “more life,” at least in terms of quality, if not quantity.

I prefer using “pain reliever” because this is exactly what those medications do when they are effective—they provide relief by reducing the intensity of pain experienced by the individual. Subtly, it also communicates to the person using these products therapeutically that they should expect some relief from their pain, rather than total elimination of the pain.

CHRONIC OPIOID THERAPY Another common term is “chronic opioid therapy,” which refers to opioid therapy that lasts a considerable length of time, usually 90 consecutive days or more. The problem with this term is the use of “chronic” instead of the more properly descriptive “long-term.”

Some dictionaries note that “chronic” has a negative connotation, and many of their definitions reinforce that notion.

Granted, long-term opioid therapy can have adverse consequences, but they are neither universal nor unopposed by benefits gained by using opioids.

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Have you noticed that we never refer to “chronic insulin therapy,” or “chronic statin therapy?” Why, then, should opioid therapy be labeled as being “chronic?”

I am careful to use the term “long-term opioid therapy” when writing or speaking, and I’ve considered a letter campaign aimed at convincing scientific journal editors to adopt the same convention.

The term “chronic opioid therapy” only reinforces a notion that opioids are universally undesirable and harmful.

PAIN PATIENTS/PEOPLE IN PAIN Laypeople and clinicians talk about “pain patients,” but there has been a trend to move away from similar terms throughout the medical profession.

Referring to “patients” and then further defining them by their condition (e.g., “cancer patients”) is dehumanizing and creates a stereotypical view of people with those conditions. When challenged, many people will substitute the term “people in pain,” which may be a bit better but still is not as humanizing as I’d like. “People in pain” implies a state of being, an existence only in the context of pain. Further, it seems almost inescapable, presenting an image of a person stuck in a labyrinth, unable to find a way out.

My preference: “people with pain.” In this construction, the person is primary, and the pain that that person is experiencing is presented as something that is separate from, and separable from, that individual.

If you “have” pain, it is possible to imagine

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a condition in which you no longer “have” that pain. The pain does not define the person, and it is not a state of being. It is merely a “possession” that might be left behind if the right kind of care is received.

PAIN TREATMENT VS. PAIN CARE If you’ve read my columns closely, you might have noticed this distinction.

We often appropriately talk about the treatments we provide for people with pain. However, in line with integrative medicine’s more humanistic and personcentered viewpoint, I think “treatment” doesn’t always capture the most healing aspect of our clinical work. The extent to which we “care” for a person, and to which that person feels “cared for” is very powerful, and maximizing that sense of caring also maximizes healing. I have remarked that many people with chronic pain receive too much treatment and not enough care. It is common for people with pain to have multiple treatments thrown at them without ever making a truly caring human connection with a clinician, an occurrence that is often detrimental.

My convention is to use “treatment” when I’m speaking about specific techniques, such as a chiropractic adjustment or the administration of a medication, and to use “care” when I’m talking about a holistic, person-centered, approach that is most concerned with restoring a state of total wellness.

These pet peeves are often subtle, but are ubiquitous in our discussion of pain management. I think the distinctions are important and have many implications for the ways in which we serve the people with whom we work. Being mindful of our language and what we are really saying when we use certain terms can only help move us toward achieving our goal of delivering top-quality pain care for every person with pain. ❏ Bob Twillman, PhD, is the executive director for the Academy of Integrative Pain Management.

Dr. Twillman is responsible for overseeing federal and state pain policy developments and advocating for those supporting an integrative approach to managing pain. He also serves as Chair of the Prescription Monitoring Program Advisory Committee for the Kansas Board of Pharmacy.

EDITORIAL

Abuse-deterrent Opioids: Tech, Yes. Talk, Too

By W. Clay Jackson, MD, DipTh, Editor-in-Chief

I called his family member, and was relieved to learn that no permanent neurologic damage had occurred, and that he was recovering. I gently queried the sister regarding the events of the day of the fall, searching for any clues as to the cause of his altered mentation.

“Anything different that day?”

“Nothing, doctor. I gave him the medicine, just like you said. And the new one—the long-acting one—I even cut it in half, because it was new, and I was worried it might be too strong for him.”

It was a challenging situation, the type that makes your internal warning systems tick more loudly than usual. Bill* had lung cancer metastatic to bone, and certainly had a biologic source that readily explained his complaints of uncontrolled pain. In my role as a palliative physician working in a large, multispecialty oncology center, it was my job to address his pain, and to offer decisional support as he navigated difficult courses of treatment. Challenge accepted, as this sort of work was well within my clinical scope, and formed the raison d’être of the palliative care clinic.

It was the psychosocial elements of Bill’s case that gave me pause. He was on relatively high doses of opioids (>120 morphine-equivalent daily dose [MEDD]), and also took benzodiazepines four times daily. He had suffered from bipolar disorder for many years, and had a past history of substance use disorder (but reported no active use in over a year, since the cancer diagnosis). To further complicate matters, Bill lived nearly two hours southeast of our clinic, so continuity appointments would require careful coordination with his oncology treatment team to minimize his travel burden.

I felt pressured by competing priorities.

The obligation to alleviate the patient’s pain was beyond clinical; it was moral. However, the clinical obligation to do so in the safest manner possible (or practicable) could not be ignored. Data analysis from our state board of health indicates that concomitant treatment with a benzodiazepine (BZD) and an opioid raises the risk of overdose by a

factor of 13 over the risk of overdose when taking an opioid alone (1). I was therefore reluctant to continue the BZD, especially at its dose, which was near the maximum recommended. I was also concerned about the patient following the treatment regimen (both oncologic and palliative), given the challenges with adherence that many patients with bipolar disorder encounter. Finally, given the past history of substance use disorder, I was concerned that the patient might use the opioids inappropriately, given the stressors of an ongoing struggle with a progressive cancer.

I found what I felt was a reasonable middle ground among the clinical needs that seemed impossible to completely reconcile. I discussed my concerns with Bill, as well as his sister, who was at the initial consultation. She agreed to manage his medications, in an effort to bolster tight adherence to our agreed-upon plan.

Bill agreed to lower his dose of BZD to reduce the risks of sedation or respiratory depression. And considering the patient’s past experience with substance use disorder, I switched his long-acting opioid to an abuse-deterrent formulation. I explained the rationale for my treatment plan to Bill and his sister, and they gave their “buy-in” to the plan. He agreed to follow up within three weeks.

What happened next was beyond my anticipation, even after 20 years of experience. I received a hospital discharge report from an outlying facility, describing a head injury that Bill sustained after a fall, and reduced mental status.

MY HEART SANK. A great advance in pharmaceutical technology, designed to protect the patient from harm, had not fulfilled its potential, and for the most basic of reasons—a lack of understanding on the part of the patient and his caregiver support team.

My mind whirred. Had I been careful in my explanation of how to use the new medication? Where had the breakdown in communication occurred?

Bill survived his adverse event without lasting sequelae. But I did not.

I carry its lessons to this day, into every patient encounter. I utilize the amazing technical advances that we have in our pharmaceutical toolkit, including the abuse-deterrent opioids, recognizing their power to make care safer. But I also make sure I take some extra time to talk about the tech, so that the full measure of that safety is realized. ❏ *Name and some demographic information changed to protect patient’s identity.

Reference

1. Mutter M. Tennessee Board of Health Controlled Substances Task Force; personal communication.

W. Clay Jackson, Editor-in Chief, is clinical assistant professor of family medicine and psychiatry at the University of Tennessee College of Medicine in Memphis, Tennessee, where he maintains a private practice in family and palliative medicine. He is also the medical director of Comprehensive Primary Care, and of Methodist Hospice and Palliative Services. Dr. Jackson is the associate fellowship director of palliative medicine at the University of Tennessee College of Medicine.

THE PAIN PRACTITIONER

| VOLUME 27, NUMBER 5 |

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ANNUAL MEETING/EDUCATION

Member Focus: Talking with Norm Shealy

By Debra Nelson-Hogan, Editor, Pain Practitioner

C. Norman Shealy, MD, PhD, is a neurosurgeon and one of the world’s leading experts in stress and pain management.

Dr. Shealy holds 10 patents for groundbreaking discoveries, and has published more than 300 articles and 25 books.

As one of the first physicians to specialize in pain management, he founded the Shealy Institute in 1971, the first comprehensive, holistic clinic in the country for the management of depression, migraine, fibromyalgia, and back pain, resulting in numerous pioneering treatments. Dr. Shealy, an AIPM member since 1997, spoke to us about his past and current work.

in 1972. I got my PhD in psychology, and my dissertation was actually working on biogenics, which I define as retraining the nervous system. The single most important thing is to teach the person to be in present time, most often called, “be here now.” I looked at biofeedback as proof that the mind could change the physiology of the body.

The next step is learning to balance emotions. I developed and adapted a number of gestalt and other exercises to help people get rid of their unfinished anger, guilt, anxiety, and depression.

DNH: You have been in the pain field for 53 years. What do consider your three major contributions?

CNS: Without question, the most significant as far as its impact on the world is the TENS unit, the transcutaneous electrical nerve stimulation device and the spinal cord stimulator.

In the early 1960s, after three years working on pain physiology in cats, I concluded that electrical stimulation anywhere on or in the body was the best way to relieve pain. I introduced the TENS unit and what is still being done as spinal cord stimulation.

When I introduced spinal cord stimulation, suddenly 400 people a year were coming to me. They were so damaged with unsuccessful back operations and drugs, that I was only willing to put the stimulator in 6% of them. That’s why in 1971 I decided to find a way of treating chronic pain that was not disruptive.

So my second achievement was developing what I call biogenics. I started with behavioral modification, then learned about biofeedback and autogenic training

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And the third and I believe most important contribution yet, not just for pain but for health overall, is a project measuring adrenomedullin, which is a vasodilator peptide that has a wide range of biological actions, such as reduction of oxidative stress. I believe it is the single most important chemical reaction in the body to any stress, more than adrenalin or cortisone.

Adrenomedullin increases throughout life because of repetitive stress; every time you’re stressed, chemically, physically, emotionally, your body produces adrenomedullin to help get rid of the stress response. But gradually from age 20 on, you produce more and more.

A study reported last fall noted that in the town of Acciaroli, Italy, more than one in 10 of the population of 700 is greater than 100 years old. Researchers

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found that elderly people in the region have unusually good blood circulation for their age and they have adrenomedullin levels equal to healthy 20 or 30 year olds. I thought the levels might be attributed to scalar energy, one of the most misunderstood and mystifying concepts in physics. It is called “zero point” energy and moves many times the speed of light; and although it can’t be measured, it can be produced. We exposed 28 people to 36 hours of scalar energy and found a striking reduction in adrenomedullin over a month period.

Although it is not related to pain, my fourth greatest discovery is regenerating telomeres. Under ordinary circumstances, the tips of your DNA, the telomeres, shrink 1% every year of life if you have good health habits. Your telomeres can help your body repair itself, regenerate itself, be healthier. I have demonstrated that I can regenerate those telomeres an average of 3.5% a year. My telomeres are 35 years younger than I am, and I’ve got 50 other people who’ve done this with me.

Remember, every cell in your body is reproduced many times throughout life.

As your telomeres shrink, you reach a point where you can no longer make new cells. Shortened telomeres are associated with every chronic illness, from cancer to heart disease, and so on.

We now know, pretty unequivocally, at least 80% of illnesses are the result of unhealthy habits. Those unhealthy habits, generally, go back to poor selfesteem and begin somewhere between conception and the first seven years of life. For most people, their lifelong attitude has already been determined sometimes by birth, but definitely not later than age seven.

DNH: How are you helping people make better lifestyle choices?

CNS: I endowed The Mary-Charlotte Bayles Shealy Chair of Conscientious Psychology at Missouri State University, in honor of my late wife, because I believe conscientiousness is the number one personality trait associated with longevity and health. I endowed this

ANNUAL MEETING/EDUCATION

chair several years ago to teach, train, and coax people to become more conscientious. Conscientiousness means being organized and responsible and it looks to me as if 97.3% of Americans are lacking in conscientiousness.

There are three major healing studies showing that only 2.7% of people have the most essential health habits: Number one, normal weight. Seventy percent of Americans are overweight and 5% are just plain obese. Number two, no smoking; 22% of adults still smoke. Number three, eating a minimum of five servings a day of fruits and vegetables. The average American has 2.2 and finally, 30 minutes of physical exercise five days a week. Only 10% of Americans have that one. I think if everyone adopted those four habits, within 25 years average life expectancy in this country would go up 25 years, at least.

DNH: Do you have a particular patient case you would like to share?

CNS: A 50-year-old woman was sent to my clinic in April of 1974, literally dying, moribund, with terminal metastatic breast cancer. On the 17th day of working with her using one of my biogenic exercises, this woman, who was brought into the room on a stretcher, got up and walked out free of pain. Three months later her cancer was gone, never to return. A year and a half later I was invited to speak at the hospital where she had been previously unsuccessfully treated with chemotherapy and radiation. She said to me, “Norm, I want to tell you what happened. During that exercise I suddenly realized how much I hated my family, and I decided I’m not going to let the bastards kill me.” She said, “I came home and told my husband I was going to get well.” He said, “But you’ve got cancer, you’re going to die.” She said, “I got well and he committed suicide.”

Actually, two years before she came to see me, her husband had come close to dying of a kidney failure. He had a transplant from her favorite son. She nursed him and nurtured him through that. When she developed cancer, he rejected her as if she was poison. So when she got well, this man who had no trouble for two-and-a-

half years suddenly rejected his transplant kidney and died. My basic philosophy is you cannot afford the luxury of anger, guilt, anxiety, or depression because those are the emotions that kill you.

I believe emotions cause inflammation, stress reactions, adrenomedullin increases and result in disease and finally death.

DNH: So how do we incorporate this idea into health care and healing?

CNS: I believe we are individually responsible for our habits, our beliefs, our health, and our longevity. We must become responsible and we need a different insurance coverage. I believe we need a national, one company, totally nonprofit, totally nongovernment organization that provides medical insurance, not “health insurance.”

Obviously, one of the ways to force people who have unhealthy habits is to charge them higher premiums. If you smoke, you pay twice as much as people who don’t smoke. If you’re fat, you pay twice as much as people who aren’t fat. There are certain habits that must be mandated to self-care.

There’s no reason why a person who’s not overweight and doesn’t smoke should have to pay to take care of people who have sloppy health habits, in my opinion. It sounds rough, but life is tough.

DNH: How would you suggest we manage pain for the next 50 years?

CNS: I think we need to use alternative therapies and retraining the nervous system. They are tremendous adjuncts in controlling pain. Over the years, I have worked with 30,500 chronic pain patients who failed conventional medicine. My success rate is around 85%, so 15% of these patients would not under the most extreme circumstances change their habits. They paid lip service for a brief period of time to changing, but they won’t change their habits; they’re going to continue suffering not only chronic pain, but depression and anxiety.

Basically we have to change everybody’s belief system and their habits and make people responsible for their own health. ❏

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ADVOCACY

Policy Is Not a Dirty Word

By Katie Duensing, JD, Director of Legislative and Regulatory Affairs

I know, I know. You saw the word “policy” in the title and your eyes glazed over. Or, just as likely a possibility, you felt a feeling of dull rage, the kind you can only know when you give so much of yourself to improve the lives of your patients only to have your profession regularly spoken of with disdain by policymakers.

You’re not wrong to be frustrated— it’s not an easy time to treat people living with pain—but bear with me, because that is exactly why your continued support of AIPM and our policy endeavors is so vital.

reaching hundreds of policymakers) aiming to influence more than 70 policy proposals in 30 states and federally, AIPM/SPPAN had some fantastic successes.

• Prevented dangerous opioid-related “step therapy” in Maine. LD 1031 was introduced as “An act to establish reasonable and clinically appropriate exceptions for opioid medication prescribing limits.” Considering Maine’s 100 MME/day opioid dose ceiling, it would be easy to assume this a good thing. As introduced, the bill would

It’s not an easy time to treat people living with pain, but that is exactly why your continued support of AIPM and our policy endeavors is so vital.

During the first nine months of 2017, there were 1,250 pain-related bills considered across the nation. Of those, 268 aimed to impact prescribing and dispensing of pain medication and 173 related to prescription monitoring programs. And, while we’d be the first to say that there isn’t enough attention paid toward access to integrative care, there were still 72 such bills introduced this year. If these numbers feel dizzying, it’s because they are—which is why our team watches them for you, your practice, and your patients. We ensure that these bills don’t go unnoticed, and we work tirelessly to ensure that they don’t cause negative unintended consequences for people living with pain and those practitioners who care for them.

This year, after sending more than 80 letters to various committees (thus

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have created a “medical necessity” exception to the ceiling. However, to access the “medical necessity” exception, a provider would have to confirm that no less than 16 separate actions were taken and/or treatments were tried prior to exceeding 100 MME/day, some of which were over-burdensome, costly, and outright dangerous to patients. However, the bill was substantially amended prior to passage and our concerns were resolved.

• Greatly expanded access to high quality care in Michigan in rural areas through the use of telehealth thanks to the recent passage of SB 213, a bill that we strongly supported. The new law allows a health professional to prescribe a controlled substance via telehealth if

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they ensure the patient has access to follow-up and/or emergency care.

• Secured step therapy reform in Colorado when they passed SB 203, a bill that we strongly supported. This will help to ensure that patients are able to receive the optimal medication for their particular situations, as determined by their health care providers, and will result in an overall financial savings to the patients and the health care system.

• Improved access to naloxone and improved education in New Mexico when they passed HB 370, which requires certain persons to provide opioid overdose education and naloxone to statutorily specified “at risk” citizens in order to prevent opioid overdose deaths. We sent multiple letters of support for this legislation.

These are merely a sampling of the successes that AIPM has worked to achieve on your behalf, and we will continue to be actively engaged with such policies in the future.

What’s more, with access to, and reimbursement for, integrative pain care as our highest policy priority, we will be holding our inaugural Integrative Pain Care Policy Congress October 21-22 in San Diego. This project, led by SPPAN director Amy Goldstein and in partnership with other groups, is bringing together leaders from more than 65 national and state organizations who represent the full scope of licensed and certified health care professionals involved in pain care, along with insurers, HHS agencies, regulators, people with pain, researchers, and policy experts. Collectively, we will agree on a definition of comprehensive, integrative pain care and focus on next steps to promote optimal models to provide this kind of care.

As a member of AIPM’s policy team, I offer my deepest thanks to you, our members, for helping to make what we do possible. Without your support, we would be unable to speak out on behalf of those living with pain and the practitioners who so selflessly care for them.

We look forward to continuing to make policy strides with you into 2018! ❏

Will Abuse-deterrent Formulations Eliminate Opioid Abuse?

By Christine Rhodes, MS

Abuse-deterrent formulations (ADFs) of opioids is one strategy that has been supported by the FDA and other groups to combat the abuse and misuse of opioids. Abuse deterrence is not intended to mean total elimination of abuse potential, but rather provides an additional barrier to abuse that reduces the likelihood that a specific formulation will be used for abuse or diverted for abuse purposes. Because opioid products ultimately must deliver the opioid to the patient, there may always be some abuse of these products. Federal guidance regarding abusedeterrent formulations acknowledges that even when taken orally, full-agonist opioids, which include oxycodone, hydrocodone, and morphine, act on mu receptors in the midbrain to stimulate reward pathways—a process that can precipitate addiction in susceptible people. Abuse-deterrent formulations don’t prevent patients from taking higher doses than prescribed, which is the most common way opioids are misused.

FDA GUIDANCE FOR ADF MANUFACTURE The FDA has issued guidance describing rigorous procedures for the development, evaluation, and labeling of abuse-deterrent formulations. These studies included in vitro preclinical analyses, pharmacokinetic manipulation studies, as well as clinical human abuse potential studies, and are categorized according to the FDA document “Abuse Deterrent Opioids—Evaluation and Labeling: Guidance for Industry” (3).

The FDA Guidance requires data from each of three categories to obtain a complete understanding of the impact of a technology on a product’s abuse potential to obtain ADF labeling. A fourth category includes studies conducted after a drug is approved and in use.

Prescription opioid analgesics are an important treatment option for patients with chronic pain; however, they are now being called the biggest driver of the opioid overdose epidemic.

Opioid abuse is defined as the intentional, non-therapeutic use of a prescription opioid to achieve a desirable psychologic or physiologic effect. Opioid analgesics can be abused simply by taking them at or above the recommended dosage. However, many abusers tamper with the drug product to ingest more of the active drug. For this reason, they generally prefer extended release formulations, which contain greater amounts of the active agent, over short-acting formulations (1).

Tampering could include crushing or grinding the drug for ingestion, smoking, or rectal administration, or dissolving the drug in a solvent such as water or ethanol for injection. Abusers may also take the opioid with alcohol or another drug such as a benzodiazepine. Differences in the routes of abuse vary between drug formulations, duration of abuse, age, sex, and geographic location. However, ingestion remains the most common route of abuse, followed by insufflation (snorting) and injection (2).

• Category 1 studies are laboratory-based in vitro studies of how various types of physical manipulation may extract the active ingredient from the formulation, as well as studies to examine whether the formulation can be readily prepared for specific routes of abuse, including insufflation, IV injection, or smoking. Abusers of prescription extended release opioid formulations are known to tamper with these medications physically in order to increase the release of the active ingredient. This “dose dumping” can also be achieved through the use of chemicals to manipulate prescription opioid formulations.

• Category 2 studies are pharmacokinetic trials that include analysis of active ingredient pharmacokinetics in human subjects following the administration, with and without manipulation, by various routes of abuse. These studies are used to understand the biochemical consequences of formulation manipulation following administration via the examined routes.

• Category 3 studies are clinical trials that include analysis of human abuse potential. These studies utilize patient reported outcomes and feedback to assess the abuse potential of a formulation, according to its desirability or likability. They can be used to understand abuser preference and psychological aspects of the abuse experience and can include endpoints such as drug liking, feeling high, desire to take the drug again, good effects, and bad effects.

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• Category 4 studies are postmarketing studies that assess the impact of an abuse-deterrent formulation on actual abuse.

The first ADF was extended-release oxycodone (OxyContin®).

Originally approved in 1995, the product was often manipulated to defeat its extended-release properties, which caused it to be released more rapidly and increased the risk of serious adverse events including overdose and death. A reformulated version designed to be more difficult to manipulate was approved in April 2010, and in April 2013, the FDA approved updated labeling that indicates the product has physical and chemical properties that are expected to make abuse via injection difficult and reduce abuse via intranasal (snorting) use (4). Because of its reformulation, the number of spontaneous reports of fatalities associated with extended-release oxycodone misuse and abuse decreased (5).

Evidence is accumulating that shows a decline in rates of abuse associated with ADFs; however, studies also show an accompanying increase in abuse of other opioids such as heroin (2). Prescribing abuse-deterrent formulations of opioid analgesics is not mandatory. Thus, it is up to prescribers to choose the most appropriate formulation for an individual patient. The decision can be difficult to make for fear of labeling a patient as an addict or a potential abuser. Several factors have been identified that appear to increase the likelihood of abuse as well as the likelihood of using a riskier route of abuse, and clinicians should consider these factors when prescribing an opioid analgesic in an individual patient (2).

The use of ADFs is controversial. The National Academies of Sciences, Engineering, and Medicine recommend caution and ongoing studies on their optimal role in reducing misuse of prescription opioids (6). ADFs have the potential for benefit, but reliance on them may undermine a successful public health response to the opioid epidemic (6). Data collected from 2009 to 2014 with the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS®) System Web Monitoring Program, an online surveillance system that collects and organizes posts about prescription drugs from social media websites, blogs, and forums, found that users will gravitate to non-ADFs in general and specifically to immediaterelease non-ADF formulations as long as ADFs remain on the market (7). Nevertheless, the introduction of an immediate-release ADF that resists physical methods of abuse, such as crushing or grinding, and extraction in commonly used solvents, is hoped to offer clinicians a new approach for treating patients in pain while fighting against the potential for abuse (8).

Currently, eight extended-release opioids and one immediaterelease opioid have been FDA approved with labeling describing abuse-deterrent properties that are consistent with FDA’s Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling (3) (See Table). A tenth product, Targiniq ER (naloxone hydrochloride; oxycodone hydrochloride) was approved and later discontinued.

Additional ADFs will likely come to market, including an opioid prodrug, which would only become activated following metabolization in the GI tract, in which case abuse by an intranasal or intravenous route would not produce the same effect. Currently under development is NKTR-181, an opioid formulated to enter the central nervous system at a slower rate than typical opioids. Studies have shown that it is safe and well tolerated, and shows a lower potential for abuse in recreational opioid users (9). ❏

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FDA-APPROVED ABUSE-DETERRENT OPIOID FORMULATIONS OxyContin®

(oxycodone hydrochloride)

Embeda®

(morphine sulfate; naltrexone hydrochloride)

Hysingla® ER

(hydrocodone bitartrate)

MorphaBond™ ER

(morphine sulfate)

Xtampza® ER

(oxycodone)

Troxyca® ER

(naltrexone hydrochloride; oxycodone hydrochloride)

Arymo® ER

(morphine sulfate)

Vantrela™ ER

(hydrocodone bitartrate)

RoxyBond™

(oxycodone hydrochloride)

References 1.

2.

3.

4.

5.

6.

7.

8.

9.

Butler ST, Black RA, Cassidy TA, Dailey TM, Budman SH. Abuse risks and routes of administration of different prescription opioid compounds and formulations. Harm Reduct J. 2011;8:29.

Gasior M, Bond M, Malamut R. Routes of abuse of prescription opioid analgesics: a review and assessment of the potential impact of abuse-deterrent formulations. Postgrad Med. 2016;128(1):85-96.

Abuse-Deterrent Opioids - Evaluation and Labeling: Guidance for Industry.

FDA 2015. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm334743.pdf. Accessed September 8, 2017.

U.S. Food and Drug Administration. Timeline of Selected FDA Activities and Significant Events Addressing Opioid Misuse and Abuse. Updated 8/29/17. https:// www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm338566.htm.

Accessed September 11, 2017.

Sessler NE, Downing JM, Kale H, Chilcoat HD, Baumgartner TF, Coplan PM. Reductions in reported deaths following the introduction of extended-release oxycodone (OxyContin) with an abuse-deterrent formulation. Pharmacoepidemiol Drug Saf. 2014;23(12):1238-1246.

National Academies of Sciences, Engineering, and Medicine. 2017. Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use. Washington, DC: The National Academies Press. https://doi.org/10.17226/24781. Accessed September 8, 2017.

Vosburg SK, Haynes C, Besharat A, Green JL. Changes in drug use patterns reported on the web after the introduction of ADF OxyContin: findings from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System Web Monitoring Program. Pharmacoepidemiol Drug Saf. 2017; June 27.

Inspirion Delivery Sciences Receives FDA Approval for RoxyBond™ (oxycodone hydrochloride) tablets CII, the First and Only Immediate Release Opioid Analgesic with Abuse-Deterrent Label Claims [press release]. Basking Ridge, NJ; April 26, 2017.

Webster L, Henningfield J, Buchhalter AR, et al. Human abuse potential of the new opioid analgesic molecule NKTR-181 compared with oxycodone. Pain Med. 2017; Mar 10.

Are ADFs the Answer to Opioid Abuse?

Bob Twillman, PhD, executive director of the AIPM, and Sidney Schnoll, MD, PhD, vice president, pharmaceutical risk management services, Pinney Associates, Inc., recently discussed how abuse-deterrent formulations (ADFs) of opioids could possibly impact the opioid abuse problem.

BT: What are abuse-deterrent formulations (ADFs) designed to do, and what are the mechanisms by which they accomplish it?

SS: ADFs are designed to make it difficult to crush a drug into powder, which could then be insufflated or dissolved and injected. Some ADFs also will gel when put into a liquid, making them hard to inject. Other ADFs contain sequestered opioid antagonists, which will block the effects of the drug if it is manipulated. The ADFs are not abuseproof; they deter abuse by injection and insufflation.

BT: The FDA talks about the need to expand access to ADFs as a means of discouraging abuse. Do you think that focusing on ADFs will discourage abuse and decrease the number of opioid-related deaths?

SS: Opioid abuse is a complex problem, and ADFs are just part of the solution. They can reduce someone’s ability to extract the drug so that it can be taken all at once—what’s called dose-dumping—or retard insufflation or injection, which, in fact, is what they are intended to do. There is evidence that use of products with AD formulations has, in fact, reduced abuse. However, because of the added difficulty in obtaining ADFs, people turn to other products that are cheaper and more readily available, such as heroin and illicit fentanyl.

BT: What is the recent report from the Institute for Clinical and Economic Review (ICER)? What have they found, and why is it a problem?

SS: ICER reviews products for their cost-effectiveness. They recently said they did not believe that the added cost of ADFs was worthwhile, in large part because people switched to illicit opioid products. But, keep in mind that these products were not designed to stop all abuse.

BT: If increasing the preponderance of ADFs on the market causes some people to shift to heroin, is it really good policy to continue to move the market in a direction of more, or perhaps, all, ADFs? Or would we be better off just to forget about ADFs, and let people continue to misuse the prescription products?

SS: That’s a fascinating question. To some extent, letting people abuse a prescription product is potentially safer because they know what they’re getting. It’s a very complex situation, and unfortunately, we have turned people who abuse drugs into criminals, which stigmatizes them. If we stigmatize a disease, it doesn’t get treated the way it should. If somebody shows up in an emergency department with complications due to diabetes, for example, clinicians get them into treatment right away. But if a person shows up with a drug abuse problem, clinicians may try to get them into treatment, but there are waiting lists and the patient must be able to afford it. Also, if a person with diabetes has elevated blood sugar because he went to a party and ate things he shouldn’t in quantities he shouldn’t, he doesn’t get kicked out as a treatment failure.

The treatment may be changed or intensified, and that can happen multiple times. But in drug abuse treatment, if a patient had smuggled drugs into the unit, or had a urine

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test that turned out positive for an illicit drug, often the insurance company would say, “Well, he failed treatment.

We’re not going to pay anymore.” In that case we should have intensified the treatment or changed it to get better results for that person.

We expect ADFs to solve all of these problems, which they’re not going to do. The FDA should only be asking, “Are these drugs reducing abuse by insufflation and injection?” Which they do. That’s all that they can measure.

BT

I have a sense that the FDA is moving in the direction of requiring all opioids to be ADFs, once there is one for each of the opioid molecules. Do you think that’s where they’re headed, and if so, any thoughts about the impact of doing that?

labeling. So, they want to recoup those costs, and when you have a market share that is so low it’s practically unmeasurable, you’ve got to charge more to recoup some of that. The studies that would be needed for a Category 4 label cost many times that for a Category 1 through 3 label.

BT: We talked earlier about one of the consequences of having ADF long-acting formulas on the market is that people have moved to other options, including heroin and fentanyl, but they’ve also moved to the immediaterelease (IR) opioids, the short-acting opioids. Now, we’ve got the first of those with ADF properties ready to come on the market pretty soon. What do you think the impact of that is likely to be?

SS

The ADFs are not abuse-proof; they deter abuse by injection and insufflation.

SS: I do think that’s where they’re headed, but I think they’re in a difficult position. If they keep pushing sponsors to make ADF products, yet don’t give Category 4 (postmarket studies) labeling, why would any company want to invest in creating an ADF, which is very expensive? ADFs constitute less than 2% of opioid prescriptions. The only one of those with a significant market share is OxyContin®. Why would a sponsor want to invest in an ADF if they can’t get sales sufficient to recoup their costs unless the FDA mandates it?

BT: One of the things that we’ve been really concerned about, too, is the cost of these products. All of the data we have indicates that the vast majority of times when these products are abused by means of insufflation or injection, it is not by people for whom they were actually prescribed. But it’s the people for whom they’re prescribed who have to pay the extra cost that’s associated with having an ADF as opposed to a nonADF medication. Is there a solution to that?

SS: A lot of these costs are being dictated by insurance companies, who I think have a big part to play in this problem. Doing exactly what the CDC guideline says costs patients more money for additional office visits and prescription co-pays. Then, the insurance companies place these ADF products in Tier 2 and Tier 3, where the co-pays are $50 or $75, instead of $10 or $15. On the sponsor side, companies are spending millions of dollars to do the studies that the FDA requires to at least get Category 1 through 3

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Well, I think we’re going to see more ADF IR products.

In some sense, ADF IR product is an oxymoron, because an IR product is supposed to work quickly orally. We know that the overwhelming majority of abusers abuse the products orally. Just taking lots more of these products orally potentially leads to an overdose. Also, the overwhelming preponderance of prescription opioid abuse is with IR products, not ER or LA products.

Yet, again, the public narrative is that, “If it wasn’t for OxyContin, we wouldn’t have this problem.”

The president’s opioid commission has suggested implementing treatment on demand and other things that could be very positive. But, on one hand, most “treatment on demand” is paid for by Medicaid, while other parts of the administration say they want to cut Medicaid subsidies.

These are people who are sick and need to be in treatment not in jail, where they don’t get treatment. The public is not aware of what’s going on.

BT: What should clinicians be thinking about when they see a patient and are considering prescribing an opioid?

What kind of assessment should they be doing, and what are some of the considerations about whether or not to prescribe an ADF for a given patient?

SS: I think that they should do, as any clinician should, a good assessment as to the etiology of the pain. They should assess the most appropriate treatment and whether an opioid needs to be involved. They’ve got to look at the patient’s history. Is there a family history of abuse of alcohol or other drugs in the past several generations, not just in the parents? Look at whether the person is a cigarette smoker. I’ve found that people who smoke cigarettes are much more likely to wind up abusing medication.

BT: Given that most of the misuse of these products is not by the people for whom they’re prescribed, to what extent should the assessment include who else might get access to these?

SS: I used to work very closely with my patients to see who else was in the home. If there were young children, it is critical to make sure that the medications are appropriately stored, sometimes under lock and key. Finally, it is important for patients to understand that they should not give their medication to other people. ❏

Opioid Dosing Policy: Pharmacological Considerations Regarding Equianalgesic Dosing

By Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, Mena Raouf, PharmD, and Erica L. Wegrzyn, PharmD

medication is due to its action on the mu opioid receptor; and 2) all patients respond identically to all opioid medications.

One group of opioids with multiple mechanisms of action, often referred to as atypical opioids, illustrates the dangers that can result from erroneously accepting these assumptions.

Using common equianalgesic conversion tables to determine doses of these atypical opioids is fraught with danger, and potentially can result in patients unintentionally being underdosed or over-dosed.

OPIOID AGONISTS THAT SHOULD NOT HAVE MEDD

As the United States grapples with the public health crisis of opioid misuse, abuse, addiction, and overdose deaths, one common response from policymakers and third-party payers has been to suggest (or even mandate) limits on doses of opioid analgesics. In nearly all cases, ranging from the 2015 guideline from the Washington State Agency Medical Directors Group (1) to the 2016 CDC Guideline for Prescribing Opioids for Chronic Pain (2), dose limits are expressed in terms of a morphine equivalent daily dose (MEDD). Recently, third-party payers, including Medicare and Medicaid, have begun limiting coverage for opioid analgesics beyond certain MEDD levels.

Recommended dose limits would be easy to apply if all opioid analgesics had the same potency. Unfortunately, they do not.

Consequently, researchers have carried out studies to determine the relative potency of various opioids in terms of their ability to relieve pain, and have summarized their results in equianalgesic conversion tables that facilitate determining the equipotent dose of any given opioid in comparison to any other given opioid.

Unfortunately, these equianalgesic conversion tables rely on a few assumptions that commonly are ignored by prescribers, dispensers, policymakers, and payers. Among these assumptions are that: 1) all the analgesic effect derived from a given

Mu opioid receptor agonists with additional mechanisms of action above and beyond their traditional opioid agonist activity, otherwise known as atypical opioids, should not be included in MEDD calculations. These include methadone, tramadol, tapentadol, levorphanol, and the less commonly prescribed opioids butorphanol, buprenorphine, nalbuphine, and pentazocine (3-8).

Methadone and levorphanol are synthetic opioids that inhibit norepinephrine (NE) reuptake and block N-methyl-D-aspartate (NMDA) receptors. Both of these actions have inherent analgesic activities (and potential for side effects) apart from their true opioid effects.

Tramadol and tapentadol are opioid receptor agonists of the phenylpropylamine class, and inhibit NE reuptake (4,5).

Additionally, tramadol inhibits reuptake of serotonin. Furthermore, unlike the others listed, tramadol is a prodrug (meaning it has no analgesic activity until after it is metabolized in the body) requiring CYP 2D6 enzyme metabolism to its active form. Tramadol is quite chameleonic compared to most drugs, as it is a partial agonist and has metabolites that create a substantial potential for drug interactions and variable responses due to polymorphism (4).

These medicationsâ&#x20AC;&#x2122; additional pharmacologic properties contribute to their overall analgesic effect independent of mu-receptor activation. For example, tapentadol was found to be 18 times less potent than morphine in binding to a mu-opioid receptor but only two to three times less potent in providing analgesia (9). This is presumably because of its dual analgesic mechanisms of mu-receptor activation and NE reuptake inhibition. Notwithstanding, patients with neuropathic pain components are likely to require lower MEDD when prescribed tapentadol compared to pure mu-receptor agonists because neuropathic pain may respond nicely to various non-opioid antidepressants that specifically work by blocking norepinephrine reuptake alone. Therefore, employing MEDD as a measure of analgesia for these agents is not appropriate.

Partial mu-receptor agonists other than tramadol (e.g., buprenorphine, butorphanol, and pentazocine) exhibit different behavior at the receptor compared to full agonists (10).

Compared to a full agonist, partial agonists do not fit as snugly when bound to the mu receptor. Because of this, they do not provide the same level of analgesia at low-to-moderate doses and, unlike full agonists, their analgesic activity plateaus at a certain dose. At low doses, these partial agonists may provide

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Table 1 Conversion Risks Associated with Commonly Prescribed Atypical Opioids

MECHANISM OF ACTION

BUPRENORPHINE

Partial mu-agonist Kappa antagonist

Full mu-receptor agonist

METHADONE

NMDA inhibitor (weak).

Inhibits reuptake of norepinephrine and serotonin.

Full mu-receptor agonist

TAPENTADOL Inhibits reuptake of norepinephrine.

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RISKS CONVERTING TO TRADITIONAL FULL AGONIST

RISKS CONVERTING FROM TRADITIONAL FULL AGONIST

CYP ENZYMES INVOLVED

OTHER

Buprenorphine has a higher affinity for the mu-receptor compared to traditional opioids.

As buprenorphine undergoes metabolism, risk of overdose due to higher full agonist exposure increases.

Buprenorphine prevents full opioid agonists from binding to mu-receptors, which can cause unanticipated withdrawal symptoms when full agonist is at moderate-to-high dose.

CYP3A4 (major), Moderate risk of drug interactions and genetic variation when converting doses.

Buprenorphineinduced opioid withdrawal is often misinterpreted as intolerance to buprenorphine.

Methadone blood levels linger in the body tissue and blood for several days to weeks.

When methadone is stopped in lieu of a new full agonist opioid, it is synonymous with giving both drugs even though methadone was discontinued. This elevates risk of overdose.

Rapid escalations due to initial poor response as methadone reaches steady state and enters body tissues.

If escalation is done too rapidly (shouldnâ&#x20AC;&#x2122;t be adjusted for 5-7 days), risk of overdose increases. PK of methadone is counter-intuitive; the higher the dose of methadone, the less of a traditional opioid is needed to replace it.

CYP3A4 (major) CYP2B6 (major) CYP2C8 CYP2C19 CYP2C9 CYP2D6 High risk of drug interactions and genetic variation when converting doses.

The higher the dose of methadone, the more potent it becomes.

Low risk. No comparative trials have been powered to assess opioid equivalence when converting tapentadol to morphine or other full agonist opioids.

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Low risk. No comparative trials have been powered to assess opioid equivalence when converting to tapentadol from morphine or other full agonist opioids.

Mostly phase II metabolism with minimal and therapeutically insignificant CYP involvement.

Minimal if any risk of drug interactions and genetic variation when converting doses.

There is an assigned FDA maximum dose of 500 mg per day for ER formulation, and 600 mg per day for IR formulation (after day-1).

similar effects to that of full agonists. As the dose of a full agonist is increased, there is a proportional increase in opioid activity.

However, with partial agonists the activity eventually plateaus where further dose increases will not provide additional analgesic effect, but may cause adverse effects (11). Buprenorphine has a ceiling effect on carbon dioxide accumulation where respiratory depression risk plateaus at higher doses (7). For this reason, it

Using common equianalgesic conversion tables to determine doses of these atypical opioids is fraught with danger, and potentially can result in patients unintentionally being under-dosed or over-dosed.

to be related to methadone’s inhibitory effect on the NMDA receptor, which attenuates tolerance developed as the dose of other opioids is increased. Although counterintuitive, when converting to methadone from another opioid, the higher the dose of that other opioid, the less methadone is needed to replace it. It is critical to understand that these conversions to and from methadone are not bi-directional.

Methadone is lipophilic with a large volume of distribution (Vd) and a long elimination half-life (8-59 hours) subject to high interindividual variability, which can be up to 150 hours in polymorphic outliers (8,12). Methadone relies on phase I metabolism and, therefore, is subject to drug-drug interactions that can increase or decrease its blood concentrations. When a patient is converted to methadone, dose escalations should not occur more frequently than every 5-7 days. Since methadone is lipophilic, it is deposited into fat and other tissues and is slowly released back into the blood. When patients are first started on methadone, their blood methadone levels will continue to gradually rise on the same dose until tissues equilibrate with blood (i.e. steady state is reached).

Rapid dose escalations can cause methadone to accumulate and could result in overdose.

When converting from methadone to another opioid, it is important to remember that methadone’s effects will persist for a few weeks as it continues to be released from the tissues into the blood. If patients switching from methadone to another opioid start the full dose according to equianalgesic mathematical conversion immediately following methadone discontinuation, they can have overlapping exposure to two opioids and potentially overdose. It can generally take up to three weeks for methadone to be fully cleared out of the body after discontinuation.

BUPRENORPHINE should be considered as a first option for patients requiring longterm opioid therapy prior to initiating less expensive and more readily available full agonists such as oxycodone, hydrocodone, and the like. Although many clinicians employ tramadol as their first choice, it presents several risks as outlined above. But also noteworthy is that tramadol’s affinity for mu receptors is 6,000 times lower than that for morphine, which is similar to the extremely weak activity seen with the well-known over-thecounter cough syrup dextromethorphan; therefore, tramadol’s opioid activity cannot account for its analgesic properties.

SPECIAL CONSIDERATIONS WHEN SWITCHING TO OR FROM ATYPICAL OPIOIDS Important considerations impact initial dosing and titration when switching to and from the atypical opioids. Applying MEDD dosing in one-step conversions from these agents to full agonists or vice versa can lead to patient harm. Therefore, conversions need to be done methodically and slowly. Important considerations when converting the most common atypical opioids to or from traditional full agonist opioids are summarized in Table 1.

METHADONE Methadone has a complex pharmacokinetic profile that, if ignored, can lead to increased morbidity and mortality. This should be of no surprise considering methadone contributed to nearly one in three overdoses despite accounting for less than 2% of all prescription sales in 2009 (11). The equianalgesic dose ratio of methadone is non-linear and it becomes more potent as the methadone dose increases (12). This is thought

In addition to its mixed partial agonist/antagonist effects, buprenorphine has strong binding affinity to the mu-receptor with slow dissociation rate from the receptor, which makes it harder for other opioids to displace buprenorphine from the mu-receptor (6). In other words, buprenorphine wraps tightly around the mu-receptor and makes it harder for other opioids to bind to it. Buprenorphine has a long elimination half-life of 24 to 42 hours depending on the formulation. It can generally take up to five to seven days for buprenorphine to be cleared from the body. Therefore, when switching a patient from buprenorphine to another opioid, the patient may require higher dosing in the first few days if buprenorphine was not tapered.

TAPENTADOL There is no mention of MEDD or equianalgesic conversion ratio in the package insert of tapentadol because it has not been studied. In pivotal trials, tapentadol ER (100 - 250 mg bid) demonstrated comparable efficacy to oxycodone CR (25 - 50 mg bid) in moderate to severe osteoarthritis pain, low back pain, and pain related to diabetic peripheral neuropathy (13). These studies were either active or placebo-controlled and, to our knowledge, there are no crossover studies evaluating switching from one opioid to tapentadol or vice versa.

The equianalgesic dose ratios for tapentadol factor in only analgesic potency and not potency in regard to opioid receptor activation. As discussed previously, there is a wide disparity between tapentadol’s affinity and analgesic potency, which is likely due to its additional activity on the descending pain pathway via NE reuptake inhibition. It is important to understand that tapentadol’s MEDD for non-analgesic effects related to opioid receptor activation

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is theoretically less than that stated by equianalgesic doses from clinical trials. Therefore, applying equianalgesic dose conversion when switching a patient from tapentadol to a traditional full agonist opioid such as oxycodone, hydrocodone, or morphine can lead to more opioid activity and potential overdose. Instead, conservative dosing should be exercised when switching patients from tapentadol to another opioid.

HOW TO EMPLOY MEDD IN PRACTICE As not all opioids are created equal with regard to mechanism of action and metabolism, the concept of assigning equivalent dosing conversions is not scientifically reliable. Doing so places patients at increased risk for potentially fatal adverse effects, including but not limited to overdose. Conversely, assigning a maximum daily MEDD ignores the specific needs of patients, placing them at risk for poor outcomes and increased suffering.

While MEDD should not be used as a tool for direct conversion, it can provide a guideline for end dose titration when tapering or switching from one or more opioids to another.

CONCLUSION The use of morphine milligram equivalents to create parameters for patient dosing of opioids is based on an idealistic theory and does not represent the scientific characteristics of each therapy.

Furthermore, it ignores patient-specific parameters that should be considered for individualized therapy. The practice of setting arbitrary milligram dosing cut-offs as suggested by various public health agencies and legally allowed by some states is an attempt to pigeonhole providers into ignoring the patientcentered approach to medicine. Rather than assigning irrational rules based on pseudoscience, public health agencies such as the CDC as well as federal and state governments should be targeting ways to increase knowledge and education regarding opioids to foster safe and efficacious prescribing practices. ❏

This article is the sole work of the authors and stated opinions/assertions do not reflect the opinion of employers or employee affiliates. It was not prepared as part of the author(s) duty as federal employees.

Jeffrey Fudin, PharmD, is president and director, scientific and clinical affairs for Remitigate, LLC, Delmar, New York; adjunct associate professor of pharmacy practice and pain management, Albany College of Pharmacy and Health Sciences, Albany, New York; adjunct associate professor, Western New England University College of Pharmacy, Springfield, Massachusetts; and Clinical Pharmacy Specialist and Director PGY2 pain and palliative care residency (WOC), Stratton VA Medical Center, Albany, New York.

Mena Raouf, PharmD, graduated from Albany College of Pharmacy and Health Sciences in 2016 and completed a PGY-1 residency at the VA Tennessee Valley Healthcare System in Nashville, TN. Dr. Raouf is currently completing PGY-2 residency in pain and palliative care at the Stratton VA Medical Center in Albany, NY.

Erica L. Wegrzyn, PharmD, is a clinical pharmacy specialist in pain management, Stratton VA Medical Center, Albany, New York.

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References 1. Agency Medical Directors’ Group. Interagency Guideline on Prescribing Opioids for Pain. 3rd ed. June 2015. http://www.agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdf.

Accessed September 5, 2017.

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5. Tzchentke TM, Christoph T, Kögel B et al. (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/ norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther. 2007;Oct;323(1):265-276.

6. Lutfy K, Cowan A. Buprenorphine: A Unique Drug with Complex Pharmacology.

Curr Neuropharmacol. 2004;2(4):395-402.

7. Dahan A. Opioid-induced respiratory effects: new data on buprenorphine.

Palliat Med. 2006;20 Suppl 1:s3-8.

8. Inturrisi CE. Pharmacology of methadone and its isomers. Minerva Anestesiol.

2005 Jul-Aug;71(7-8):435-7.

9. Nucynta [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2009.

10. Baumann TJ, Herndon CM, Strickland JM. Pain Management. In: DiPiro JT, Talbert RL, Yee GC, Wells BG, Posey LM. eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed.

New York, NY: McGraw-Hill; 2014:925-942.

11. National Vital Statistics System, 1999-2009; Drug Enforcement Administration Automation of Reports and Consolidated Order Systems (ARCOS), 1999-2010. https://www. deadiversion.usdoj.gov/arcos/. Accessed September 5, 2017.

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Pract Pain Manage. 2012 September;12(8):46-51.

13. Afilalo M, Morlion B. Efficacy of tapentadol ER for managing moderate to severe chronic pain. Pain Physician. 2013 Jan;16(1):27-40.

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