CARING FOR PATIENTS

WITH

CHRONIC PAIN

Responsible Opioid Prescribing to ACHIEVE INDIVIDUALIZED FUNCTIONAL GOALS

November 21, 2014 Dearborn, Michigan

Educational Partner:

CARING FOR PATIENTS WITH CHRONIC PAIN Responsible Opioid Prescribing to ACHIEVE INDIVIDUALIZED FUNCTIONAL GOALS FACULTY

Michael J. Brennan, MD Interactive Professor The Pain Center of Fairfield Fairfield, Connecticut Senior Attending Physician Department of Medicine Bridgeport Hospital Bridgeport, Connecticut

Jeffrey A. Gudin, MD Director Pain Management and Wellness Center Englewood Hospital and Medical Center Englewood, New Jersey

Bill H. McCarberg, MD Adjunct Assistant Clinical Professor University of California, San Diego School of Medicine Founder, Chronic Pain Management Program Kaiser Permanente San Diego Family Practitioner Neighborhood Health San Diego, California

EDUCATIONAL OBJECTIVES After completing this activity, the participant should be better able to: • Discuss the neurobiologic mechanisms that underlie chronic pain and associated functional disability • Assess biopsychosocial factors that contribute to chronic pain via patient histories, clinical interviews, and physical exams • Tailor multimodal opioid-based therapy for patients with chronic pain based on analgesia, functional responses, adverse events, and stratified risk of aberrant behaviors • Employ opioid prescribing principles for patient monitoring and documentation to comply with medical standards of care, government agencies, and risk evaluation and mitigation strategies • Educate patients about the safe and appropriate use of prescription opioid analgesics, including common side effects, drug-drug interactions, and the critical need to adhere to the therapeutic plan

CLINICAL RESOURCE CENTER Access the program syllabus and additional resources by scanning the image on the left. If you do not have a QR Code Reader on your mobile device, visit getscanlife.com for a free download.

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Education Partner

FACULTY FINANCIAL DISCLOSURE STATEMENTS

CONFLICT OF INTEREST RESOLUTION STATEMENT

As a continuing medical education provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of pmiCME to require any individual in a position to influence educational content to disclose the existence of any financial interest or other personal relationship with the manufacturer(s) of any commercial product(s).

When individuals in a position to control content have reported financial relationships with one or more commercial interests, as listed previously, pmiCME works with them to resolve such conflicts to ensure that the content presented is free of commercial bias. The content of this presentation was vetted by the following mechanisms and modified as required to meet this standard:

The presenting faculty reported the following: Michael J. Brennan, MD, is a member of the Advisory Boards for Insys Therapeutics Inc., Mallinckrodt Pharmaceuticals, Purdue Pharma L.P., Teva Pharmaceuticals Industries Ltd., and Zogenix, Inc. Jeffrey A. Gudin, MD, is a member of the Speakers’ Bureau for Depomed, Inc., Iroko Pharmaceuticals, Purdue Pharma, LP, Salix Pharmaceuticals, and Xenoport; he is also a consultant for Alere, Insys Therapeutics Inc., Nektar, Pfizer, Inc., Teva Pharmaceutical Industries Ltd., and Zogenix, Inc. Bill H. McCarberg, MD, is a member of the Advisory Boards for AstraZeneca Pharmaceuticals LP, Collegium Pharmaceutical, Inc., Depomed, Inc., Inspirion Pharmaceuticals, LLC, Iroko Pharmaceuticals, LLC, Janssen Pharmaceuticals, Inc., Kaléo, Inc., Mallinckrodt Pharmaceuticals, Millennium Laboratories, LLC, Pfizer Inc., Salix Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc., and Zogenix, Inc.; he is also a stockholder of BioSpecifics Technologies Corp, Galena Biopharma, Inc., Johnson & Johnson, Nektar Therapeutics, and Protein Design Labs, Inc.

EDUCATION PARTNER FINANCIAL DISCLOSURE STATEMENTS

• Content peer review by external topic expert • Content validation by external topic expert and internal pmiCME clinical editorial staff

OFF-LABEL/INVESTIGATIONAL DISCLOSURES In accordance with pmiCME policy, faculty members have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

ACCREDITATION STATEMENT  pmiCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

DESIGNATION STATEMENT  pmiCME designates this educational activity for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The content collaborators at Integritas Communications have reported the following:

ACKNOWLEDGMENT OF COMMERCIAL SUPPORT

Jim Kappler, PhD, has nothing to disclose.

This activity is supported by an educational grant from Teva CNS and Endo Pharmaceuticals.

pmiCME Clinical Staff and University of Wisconsin School of Medicine and Tufts Health Care Institute Expert Reviewer Financial Disclosure As a continuing medical education provider accredited by the ACCME, it is the policy of pmiCME to require any individual in a position to influence educational content to disclose the existence of any financial interest or other personal relationship with the manufacturer(s) of any commercial product(s). pmiCME clinical staff and University of Wisconsin School of Medicine and Tufts Health Care Institute expert content reviewers have provided financial disclosure and have no conflicts of interest to resolve for each of the sessions related to this activity. pmiCME Medical Advisory Board Financial Disclosure George Mejicano, MD, has nothing to disclose. Victor Diaz, MD, has nothing to disclose. Stephen Goldfinger, MD, has nothing to disclose. Michael Bloch, MD, is a member of the Speakers Bureaus for AstraZeneca Pharmaceuticals LP, Novartis Pharmaceuticals Corporation, Pfizer Inc., and sanofi-aventis US; he also receives research support from AstraZeneca Pharmaceuticals LP and Novartis Pharmaceuticals Corporation. Zorba Paster, MD, is a member of the Speakers Bureaus for Pfizer Inc. and Endo Pharmaceuticals Inc.; he also receives research support from Pfizer Inc., TAP Pharmaceutical Products Inc., Aventis, and Endo Pharmaceuticals Inc.

CE CERTIFICATE PROCESS 1. Please locate the evaluation form for this activity. 2. Put your name and badge number on page 1 of the form. 3. Designate the type of credit you seek and sign. Please do not fill out more than one certification statement. 4. Please be sure to fill out the amount of credit you are claiming within the certification statement and complete the evaluation section on side 2 of this form. 5. Before you leave the activity, please hand in your evaluation form to a Pri-Med staff member at the registration table. Time-stamped evaluation forms will be accepted by mail if postmarked within five (5) business days of the activity’s completion. Unfortunately, we cannot accept evaluation forms by fax. 6. Within 4 weeks following the program, certificates will be posted online to Pri-Med Member Account holders at www.pri-med.com (log in to your account and visit the CME Tracker to print out a copy of your certificate). 7. If you have questions about, or corrections to, your certificate after you have downloaded it, please call: 1-877-4PRIMED.

Presenter Disclosure Information

SESSION 3

The following relationships exist related to this presentation:

10:45am – 12pm Caring for Patients With Chronic Pain: Responsible Opioid Prescribing to Achieve Individualized Functional Goals SPEAKERS Michael Brennan, MD Jeffrey Gudin, MD Bill McCarberg, MD

► Michael J. Brennan, MD, is a member of the Advisory Boards for Insys Therapeutics Inc., Mallinckrodt Pharmaceuticals, Purdue Pharma L.P., Teva Pharmaceuticals Industries Ltd., and Zogenix, Inc. ► Jeffrey A. Gudin, MD, is a member of the Speakers’ Bureau for Depomed, Inc., Iroko Pharmaceuticals, Purdue Pharma, LP, Salix Pharmaceuticals, and Xenoport; he is also a consultant for Alere, Insys Therapeutics Inc., Nektar, Pfizer, Inc., Teva Pharmaceutical Industries Ltd., and Zogenix, Inc. ► Bill H. McCarberg, MD, is a member of the Advisory Boards for AstraZeneca Pharmaceuticals LP, Collegium Pharmaceutical, Inc., Depomed, Inc., Inspirion Pharmaceuticals, LLC, Iroko Pharmaceuticals, LLC, Janssen Pharmaceuticals, Inc., Kaléo, Inc., Mallinckrodt Pharmaceuticals, Millennium Laboratories, LLC, Pfizer Inc., Salix Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc., and Zogenix, Inc.; he is also a stockholder of BioSpecifics Technologies Corp, Galena Biopharma, Inc., Johnson & Johnson, Nektar Therapeutics, and Protein Design Labs, Inc.

Medications Discussed in Program

Presenter Disclosure Information Off-Label/Investigational Discussion ►In accordance with pmiCME policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

• Medication classes – Opioids – Nonsteroidal anti-inflammatory drugs – Serotonin-norepinephrine reuptake inhibitors – Selective serotonin reuptake inhibitors – α2δ ligands – Tricyclic antidepressants – Topical agents – Benzodiazepines – Barbiturates

• Specific medications – Acetaminophen – Oxycodone – Morphine – Fentanyl – Methadone – Tramadol – Tapentadol – Gabapentin – Duloxetine – Insulin glargine – Metformin – Desipramine – Fluoxetine – Paroxetine – Sertraline – Dexamethasone – Dextromethorphan – Venlafaxine – Carbamazepine – Phenobarbital – Phenytoin – Erythromycin – Modafinil

Michael J. Brennan, MD

CARING FOR PATIENTS WITH

CHRONIC PAIN

Responsible Opioid Prescribing to Achieve Individualized Functional Goals

Director, Pain Center of Fairfield Fairfield, Connecticut Senior Attending Physician Department of Medicine, Physical Medicine, and Rehabilitation Bridgeport Hospital Bridgeport, Connecticut Associate Director, Chronic Pain and Recovery Center Silver Hill Hospital New Canaan, Connecticut

Jeffrey A. Gudin, MD

Clinical Instructor, Anesthesiology Mount Sinai University School of Medicine Director, Pain Management and Palliative Care Englewood Hospital and Medical Center Englewood, New Jersey

Bill H. McCarberg, MD

Adjunct Assistant Clinical Professor University of California, San Diego School of Medicine Founder, Chronic Pain Management Program Kaiser Permanente San Diego Family Practitioner Neighborhood Health San Diego, California

Educational Objectives • Discuss the neurobiologic mechanisms that underlie chronic pain and associated functional disability • Assess biopsychosocial factors that contribute to chronic pain via patient histories, clinical interviews, and physical exams • Tailor multimodal opioid-based therapy for patients with chronic pain based on analgesia, functional responses, adverse events, and stratified risk of aberrant behaviors • Employ opioid prescribing principles for patient monitoring and documentation to comply with medical standards of care, government agencies, and risk evaluation and mitigation strategies • Educate patients about the safe and appropriate use of prescription opioid analgesics, including common side effects, drug-drug interactions, and the critical need to adhere to the therapeutic plan

Scientific Insights Into Opioid Pharmacology

Scientific Insights Into OPIOID

Key Points

• Endogenous opioid peptides modulate painrelated signaling all along the nociceptive neuraxis • Opioid peptide ligands bind μ-, κ-, and ∆-opioid receptors throughout the CNS as well as the gastrointestinal tract • Analgesic and nonanalgesic effects of opioids vary between patients and in individual patients

PHARMACOLOGY Michael J. Brennan, MD

Medical Director, Pain Center of Fairfield Fairfield, Connecticut Senior Attending Physician Department of Medicine, Physical Medicine, and Rehabilitation Bridgeport Hospital Bridgeport, Connecticut Associate Director, Chronic Pain and Recovery Center Silver Hill Hospital New Canaan, Connecticut

– Drug selection and titration should be individualized • • • •

Pain levels Functional compromise Adverse events Risks of aberrant medication use

CNS, central nervous system. Fine PG, Portenoy RK. A Clinical Guide to Opioid Analgesia. 2nd ed. New York, NY: Vendome Group, LLC; 2007.

Rising Rates of Chronic Pain

US Therapeutic Opioid Use

• 100 million US adults currently affected by chronic pain • Prevalence predicted to increase with aging population Grams/100,000 People

65+ years old 45-64 years old 18-44 years old

80,000 70,000

Arthritis Prevalence (1000x)a

15,000

60,000 50,000 40,000 30,000 20,000

Oxycodone

12,000 9,000

Hydrocodone 6,000

Morphine 3,000

10,000 0 2005

2010

2015

Year

2020

2025

2030

Methadone

0 1997

1998

1999

2000

prevalence of doctor-diagnosed arthritis in the US by age. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press; 2011; Hootman JM, Helmick CG. Arthritis Rheum. 22006;54(1):226-229.

Admitted Patients Aged ≥12 years old, %

Cocaine

Marijuana

2004

2005

Sources of Nonmedically Used Pain Relievers

Treatment for Substance Abuse Opiates

2003

Based on data from the US Drug Enforcement Administration. Manchikanti L, Singh A. Pain Physician. 2008;11(suppl 2):S63-S88.

Primary Substance of Abuse at Admission Alcohol

2002

Year

aProjected

50

2001

Methamphetamine/ amphetamines

40

Friend or Relative for Free Bought from Friend or Relative Took from Friend or Relative

3.8%

30

Prescription from 1 Doctor Drug Dealer or Other Stranger Other a

15.1%

4.8%

20 10

53.0%

10.6%

0 2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

Year

Admissions for opioids other than heroin rose from 2% in 2002 to 10% in 2012 SAMSHA. Treatment Episode Data Set (TEDS): 2002-2012. National Admissions to Substance Abuse Treatment Services. BHSIS Series S-71; HHS Publication No. (SMA) 14-4850. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2014.

12.7%

Source of most recent pain reliever used nonmedically in the past 12 months among persons ≥12 years old. aOther includes got prescriptions from >1 doctor; wrote a fake prescription; bought on Internet; stole from a health facility; and got in some other way. Office of Applied Studies, Substance Abuse and Mental Health Services Administration. NSDUH Report: How Young Adults Obtain Prescription Pain Relievers for Nonmedical Use. Rockville, MD: 39;2006.

2006

Drug-Related Overdose Deaths

Opioid-Related Overdose Deaths

Number of Deaths

Data from the National Vital Statistics System Mortality File

16,000

Any opioid analgesica

14,000

Specific drug(s) other than opioid analgesic

Risks of Respiratory Depression

Only nonspecified drug(s)b

12,000

Increase in Total Opioid Prescriptions

10,000

Coadministration of CNS Depressants

Increased Methadone Prescribing

8,000

Comorbid Conditions

6,000

(Sleep Apnea, Other Sleep Disorders, Morbid Obesity, Pulmonary or Cardiac Disease/Dysfunction)

4,000 2,000

Failure to Adhere

(Overuse, Altered Routes of Administration)

0 1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

Year aOpioid analgesics include natural and semi-synthetic opioid analgesics (eg, morphine, hydrocodone, and oxycodone) and synthetic opioid analgesics (eg, methadone and fentanyl). bSome deaths for which drug was poorly specified or unspecified may have involved opioid analgesics. Warner M, et al. Drug Poisoning Deaths in the United States, 1980-2008. NCHS Data Brief No. 81: 2011.

Salvador

Patient Background • 56-year-old stock broker – Divorced and lives alone – Son and teenaged grandson visit weekly

• BMI, 30.9 kg/m2 • Smokes 1 pack of cigarettes daily • 5-year history of T2DM (current A1c, 6.9%) – Adherent to exercise and dietary recommendations – Metformin 1000 mg twice daily – Insulin glargine 10 units at bedtime

Multidimensional Pain Assessment for Improved Outcomes Patient Report of Pain

• Developed pain in both feet 2 years ago – Duloxetine was ineffective – Currently taking gabapentin ER 600 mg twice daily – Average pain, 7/10 • Causing him to frequently miss work

• Family history – Father is an alcoholic – Brother died of a cocaine overdose 10 years ago

Comprehensive Pain Assessment

Assess Outcomes • Pain relief • Progress to treatment goals • Side effects

Monitor Treatment Adherence

Intolerable side effects and/or failure to meet treatment goals

Document, Assess, and Plan

• • • •

Assess PQRST Physical exam Detailed medical history Clarify pathophysiology (treat the treatable) • Determine effects on QoL, function, psychosocial status

Evaluate Treatment Goals Develop Treatment Plan:

You consider adding an opioid to his pain management regimen A1c, glycated hemoglobin; BMI, body mass index; ER, extended-release; T2DM, type 2 diabetes.

Mechanism-Based Diagnosis in Low Back Pain Musculoskeletal Pain • Pain localized to area of injury (with/without somatic referral) • Proportionate anatomic/mechanical relationship with aggravating and palliative factors • Lack of burning pain, dysesthesias, antalgic postures/movements

• Pain referred in a dermatomal or cutaneous distribution • Provoked pain with mechanical tests that move, load, or compress neural tissue • History of nerve injury

• Disproportionate, nonmechanical pain from nonspecific aggravating and palliative factors • Pain disproportionate to injury/pathology • Diffuse tenderness on palpation • Strong association with maladaptive psychosocial factors

Nociceptive

Neuropathic

Central Sensitization

Smart KM, et al. Clin J Pain. 2011;27:655-663.

Fine PG, Portenoy RK. A Clinical Guide to Opioid Analgesia. 2nd ed. New York, NY: Vendome Group, LLC; 2007; Manchikanti L, Singh A. Pain Physician. 2008;11(suppl 2):S63-S88; Webster LR, et al. Pain Med. 2011;12(suppl 2):S26-S35.

Review With Patient PQRST, palliative or precipitating factors, quality of pain, region of radiation of pain, severity, temporal nature of pain; QoL, quality of life. Brunton S. J Fam Pract. 2004;53(suppl 10):S3-S10; National Pharmaceutical Council, Joint Commission on Accreditation of Healthcare Organizations. Pain: Current Understanding of Assessment, Management, and Treatments. 2001; Slaughter A, et al. Am J Nurs. 2002;102(5):75-77.

Opioid Therapy Patient Selection

• Opioids effective for nociceptive, inflammatory, and neuropathic pain • Standard of care for pain associated with cancer or advanced illness • Evidence of efficacy lacking in chronic pain syndromes with strong psychosocial components (eg, fibromyalgia)

APS/AAPM Guideline Recommendation Consider a COT trial if chronic pain is moderate or severe, pain adversely affects function or quality of life, and potential benefits outweigh or are likely to outweigh potential harms 1.Do other treatments have more favorable risk-benefit ratios than opioids? 2.Are there relatively high risks related to opioid pharmacology? 3.Are there concerns about responsible medication use over time? AAPM, American Academy of Pain Medicine; APS, American Pain Society; COT, chronic opioid therapy. Chou R, et al. J Pain. 2009;10(2):113-130; Fine PG, Portenoy RK. A Clinical Guide to Opioid Analgesia. New York, NY: Vendome Group; 2007.

Risk Stratification for Chronic Opioid Therapy

Promoting Responsible Medication Use • Universal Precautions in pain management • Assess for risk factors related to abuse, addiction, and diversion Personal history of substance abuse

Salvador

Risk Stratification With the ORT Mark each box that applies

Female Male

1. Family history of substance abuse – Alcohol – Illegal drugs – Prescription drugs

1 2 4

3 3 4

3 4 5

3 4 5

3. Age (mark box if between 16-45 years)

1

1

4. History of preadolescent sexual abuse

3

0

2 1

2 1

2. Personal history of substance abuse

Family history of substance abuse

Psychiatric pathology

– Alcohol – Illegal drugs – Prescription drugs

5. Psychological disease

• Consider office-based screening tools (eg, ORT, SOAPP-R) • Structure monitoring based on ongoing risk stratification ORT, Opioid Risk Tool; SOAPP-R, Screener and Opioid Assessment for Patients with Pain-Revised. Boscarino JA, et al. J Addict Dis. 2011;30(3):185-194; Butler SF, et al. J Addict Med. 2009;3(2):66-73; Chou R, et al. J Pain. 2009;10(2):113-130; Gourlay DL, et al. Pain Med. 2005;6(2):107-112; Turk DC, et al. Clin J Pain. 2008;24(6):497-508; Webster LR, Webster RM. Pain Med. 2005;6(6):432-442.

Opioid Treatment Agreements

Outlining Responsibilities and Treatment Goals

– ADD, OCD, bipolar, schizophrenia – Depression

Scoring 0-3 Low risk 4-7 Moderate risk ≥8 High risk

Total ORT score 6 (moderate risk)

Does his positive smoking status change your risk stratification? ADD, attention-deficit disorder; OCD, obsessive-compulsive disorder. Webster LR, Webster RM. Pain Med. 2005;6(6):432-442.

Patient Education

Opioid Storage and Disposal Storage

4. I will not seek opioid medications from another physician. Regular follow-up care is required and only my provider will prescribe these medications for me at scheduled appointments.

– Explain why proper storage is important – Discuss storage plans (eg, safe) – Address issue again at next office visit

Disposal 9. I agree to periodic unscheduled drug screens. 11. I understand that if I fail to meet these requirements, my medications may be discontinued.

– Provide prescribing information or patient handouts – Consider community take-back programs for drug disposal – Some medications (eg, opioids) should be flushed down the sink or toilet when they are no longer needed and cannot be returned to a drug take-back program • Medications recommended for flushing are on FDA Web site

The Management of Opioid Therapy for Chronic Pain Working Group. VA/DOD Clinical Practice Guideline for Management of Opioid Therapy for Chronic Pain. Washington, DC: Department of Veterans Affairs, Department of Defense; 2010.

Prescription Monitoring Programs in the United States Operational

US FDA. Disposal of Unused Medicines: What You Should Know. Available at http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/EnsuringSafeUseofMedicine/ SafeDisposalofMedicines/ucm186187.htm. Accessed July 25, 2014.

Urine Drug Testing

Why Should You Drug Test? • Monitor prescription drug and other substance use – Positive for prescribed drug(s) of interest – Negative for illicit drugs and other prescribed drugs

• Objectively analyze adherence to therapeutic plan • Help diagnose substance misuse, abuse, and addiction • Identify patients who may be diverting medications • Meet expectations of medical boards and regulatory agencies The District of Columbia program is not yet operational. Data from the National Alliance for Model State Drug Laws as of June 2014; http://www.namsdl.org/library/8DB6720C-91EE-8472-E365F7818C02C8B5/. Accessed August 15, 2014.

Heit HA, Gourlay DL. J Pain Symptom Manage. 2004;27(3):260-267.

Interpretation of Test Results • Examine results together with other clinical information – – – – –

Past substance abuse Other risk factors and aberrant drug-related behaviors Current pain control Psychosocial stressors All prescription and OTC drugs used by the patient

Considerations for Opioid Selection and Titration • Previous responses to opioids • Comorbid conditions that effect opioid metabolism – eg, poor liver or renal function

• Short-acting versus long-acting opioids • Other medications and substances used by the patient, including daily opioid doses FDA Definition of Opioid-Tolerant Patients Patients taking a minimum of the following for ≥1 week

• Consider metabolic pathways and all potential metabolites • Understand testing methods

Oral morphine, 60 mg daily Transdermal fentanyl, 25 µg/h Oral oxycodone, 30 mg daily Oral hydromorphone, 8 mg daily Oxymorphone, 25 mg daily Equianalgesic daily dose of another opioid

– Verify immunoassay with GC/MS or LC/MS GC, gas chromatography; LC, liquid chromatography; MS, mass spectrometry; OTC, over-the-counter. Wolff K, et al. Addiction. 1999;94(9):1279-1298.

Fine PG, Portenoy RK. A Clinical Guide to Opioid Analgesia. 2nd ed. New York, NY: Vendome Group, LLC; 2007.

Examples of Drug-Drug Interactions Potential Interaction With Opioidsa CNS and respiratory depression

Doses >200 mg oral morphine equivalents/day should prompt re-evaluation and increased monitoring APS/AAPM Opioid Guidelines for Chronic Noncancer Pain

• Alcohol, Barbiturates, Benzodiazepines

Cytochrome P450 inhibitors (increased opioid effectsa)

Cytochrome P450 inducers (decreased opioid effectsa) Serotonin toxicitya (tramadol, tapentadol)

Examples of Potentially Problematic Drugs or Drug Classes

Dosing and Monitoring

• CYP2D6: Desipramine; Fluoxetine, Paroxetine,

Sertraline

• CYP3A: Dexamethasone, Dextromethorphan,

If doses >200 mg/day oral morphine equivalents provide no further improvement in function, consider consultation rather than further increasing the dose

Fluoxetine, Sertraline, Venlafaxine

Department of Veterans Affairs, Department of Defense Guidelines

• CYP2D6: Carbamazepine, Phenobarbital,

Phenytoin • CYP3A4: Carbamazepine, Dexamethasone, Erythromycin, Modafinil, Phenobarbital, Phenytoin

Do not exceed 120 mg of oral morphine equivalents/day without either demonstrated improvements in function and pain or first obtaining a consultation with pain management expert. Washington State Medical Directors Guideline on Opioid Dosing

• SNRIs, SSRIs, TCAs

aEffects

are not universal for all opioids but depend on specific mechanisms of action and/or metabolic pathways. SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin–norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant. Fine PG, Portenoy RK. A Clinical Guide to Opioid Analgesia. Vendrome Group: New York, NY; 2007.

AAPM, American Academy of Pain Medicine; APS, American Pain Society. Chou R, et al. J Pain. 2009;10(2):113-130; The Management of Opioid Therapy for Chronic Pain Working Group. VA/DOD Clinical Practice Guideline for Management of Opioid Therapy for Chronic Pain. Washington, DC: Department of Veterans Affairs, Department of Defense; 2010; Washington State Agency Medical Directors’ Group. Interagency Guideline on Opioid Dosing for Chronic Non-cancer Pain: An Educational Aid to Improve Care and Safety with Opioid Treatment. Olympia, WA: Washington State Department of Labor and Industries; 2010.

Evaluating and Labeling Abuse-Deterrent Formulations

Abuse-Deterrent Opioid Formulations

Draft FDA Guidance

1. Physical and/or chemical barriers to abuse – eg, data on crushing and drug extraction

2. Pharmacokinetic data with reference products

Formulation Physical Barriers

– eg, data on clinical serum concentrations and effects of food or alcohol

3. Demonstration of reduced abuse potential – eg, clinical studies comparing subjective effects of whole/tampered test product with whole/tampered reference product

Agonist/ Antagonist

Delivery

Active Drug

Technology

FDA Approval

Oxycodone ER

Fused polymer creating plastic-like coating

2010

Oxycodone IR

Assumes gel-like consistency with tampering, and causes local irritation symptoms

2012

Morphine ER/ naltrexone

Morphine pellets with sequestered naltrexone that may be released with tampering

2009 (recalled for quality concerns) Anticipated available again in 2015

Buprenorphine/ naloxone

Naloxone becomes active if used parenterally, but not sublingually

Yes, 2003

Hydromorphone OROS

Difficult to crush or extract for injection

Yes, 2010

4. Demonstration of reduced abuse – eg, postmarketing data on product use and misuse US FDA. Draft guidance released January 2013. See: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM334743.pdf.

IR, immediate-release; OROS, osmotic controlled release oral delivery system. Jamison RN, et al. Pain Res Treat. 2011;2011:941808; Moorman-Li R, et al. P T. 2012;37(7):412-418; Schaeffer T. J Med Toxicol. 2012;8(4):400-407.

Examples of Abuse-Deterrent Formulations in Development

Abuse-Deterrent Hydrocodone ER Subjective Drug Liking Strong 100 Liking

Abuse-Deterrent Mechanism

Description

Hydrocodone ER (CEP-33237)

OraGuard Technology

Resists physical manipulation, and certain chemical and multistep chemical extraction techniques

Oxycodone HCl/ Acetaminophen

Aversion Technology

Difficult to extract oxycodone for injection Causes burning or irritation if snorted

Oxycodone

DETERx Technology

Drug on beads in a tamper-resistant matrix Oxycodone not released even if crushed

NKTR-181 (μ opioid)

Small molecule delivery

Enters CNS at reduced rate compared with traditional opioid medication

Hydromorphone

Bio-MD/MPAR Technology

Hydromorphone released only when the medication is exposed to specific physiologic conditions

50

Strong Disliking

2

4

6

8

Definitely 100 So

12 Placebo Crushed MSN 30 mg Crushed MS 30 mg

50 Definitely Not

2

4

6

8

45

Time Postdose, Hours

35

20

Postperiod (Abuse-Deterrent Oxycodone ER Only)

52.7

50 40

35.7 25.4

30

15.9

20

6.4

10 0

Oral

Snort

a

15 10

Other Opioidsc

5

Hydrocodone

Other Oxycodone

Oxycodone ER

0 Q3, 2010

Q4, 2010

Q1, 2011

Q2, 2011

Q3, 2011

Q4, 2011

Q1, 2012

Quarter

Effects of Abuse-Deterrent Oxycodone ER Reduced Reports of Fatal Overdose

4.2

Smoke

Inject

N=140,496 individuals examined in US substance abuse treatment centers assessed using the Addiction Severity Index Multimedia Version. aPercentages do not add up to 100% because some respondents reported multiple routes of administration. ROA, route of administration. Butler SF, et al. J Pain. 2013;14(4):351-358.

Number of Cases Per Quarter

Reported Abuse via Various ROAs, % of Respondentsa

Preperiod (Original Oxycodone ER Only)

54.5

b

N=2,566 patients with opioid dependence (DSM IV definition) whose primary drug of abuse was a prescription opioid. aP