Treating the Opiate Epidemic

Thomas Kosten, MD

Jay H. Waggoner Chair and Professor of Psychiatry, Neuroscience, Pharmacology, and ImmunologyBaylor College of MedicineHouston, Texas

Opiates: A Deadly Epidemic

The Associated Press-NORC Center for Public Affairs Research. American Attitudes toward Substance Use in the United States. 2016. www.apnorc.org/projects/Pages/HTML%20Reports/american-attitudes-toward-substance-use-in-the-united-states.aspx. Accessed May 3, 2016. Seelye KQ. Heroin Epidemic Increasingly Seeps Into Public View. The New York Times. March 6, 2016. Muhuri PK, et al. Center for Behavioral Health Statistics and Quality Data Review. August 2013. www.samhsa.gov/data/sites/default/files/DR006/DR006/nonmedical-pain-reliever-use-2013.htm. Accessed May 3, 2016.

• 62% of Americans “said that at least one type of substance use” was a serious problem in their communities,” while 43% said they have a “relative or close friend with substance abuse issues”

• The New York Times reported that 78 people die every day from overdosing on heroin and opiate pain medications, with “many more … revived, brought back from the brink of death –often in full public view” by naloxone. The “visibility of drug users may be partly attributed to the nature of the epidemic, which has grown largely out of dependence on legal [opiates]”, with 4 out of 5 heroin users getting hooked by painkillers first and spreading the epidemic “to white, urban, suburban and rural areas.”

President Obama’s Views on the Opiate Epidemic

President Barack Obama. National Rx Drug Abuse & Heroin Summit: March 28-31, 2016; Atlanta, GA.

• Addiction to painkillers is as great a threat as terrorism. • “Today we are seeing more people killed because of

[opiate] overdose than traffic accidents.” • Opiate deaths, whether caused by pain medicines or

heroin, jumped 372% from 2000 to 2014.• We will require that health insurance policies cover mental

health and substance abuse treatment on par with treatment for physical illness.

• We need a “grassroots approach” to help train physicians while they are still residents in how, when, and why to prescribe opiates and in using buprenorphine for treatment of this addiction.

Case: JB

ED = emergency department; OIF = Operation Iraqi Freedom; OEF = Operation Enduring Freedom; TBI = traumatic brain injury.

• 27-year-old, single Caucasian male OIF/OEF Veteran • Presented at the ED with prescription opiate overdose

after being revived by his wife using an intranasal naloxone kit – Chronic neck pain and headache after moderate TBI while

deployed in Afghanistan about 2 years ago• Admission pain treatment – Chronic Opiate Therapy

• Controlled-release morphine (30 mg, 2 tabs, TID)• Oxycodone/acetaminophen (5 mg/325 mg 1 tab, q 4 hours,

PRN)

• Managing pain and opiate addiction • Assessment for physical therapy • Behavioral interventions• ? Buprenorphine

Chronic Opiates for Pain

• 10-year Epidemic of Abuse• Tolerance and Dependence• Opiate-Induced Hyperalgesia• Addiction• Treatment Options

Epidemic: Prescribing Opiates for Pain

Chen JH, et al. JAMA Intern Med. 2016;176(2):259-261.Case Study: Therapeutic Interchange in Patients Being Treated for Opioid Dependence—Rationale and Real-World Experience. www.ajmc.com/journals/supplement/2016/Case_Study_Therapeutic_Interchange_in_Patients_Being_Treated_for_Opioid_Dependence_Rationale_and_Real_World_Experience. Accessed May 3, 2016.STAT-Harvard TH Chan School of Public Health. American’s Attitudes About Prescription Painkiller Abuse. https://cdn1.sph.harvard.edu/wp-content/uploads/sites/94/2016/03/STAT-Harvard-Poll-Mar-2016-Prescription-Painkillers.pdf. Accessed May 4, 2016. Dowell D, et al. CDC Guideline for Prescribing Opioids for Chronic Pain – United States, 2016. MMWR Recomm Rep. 2016;65:1-49.

• Prescriptions for opiates grew from about 76 million in 1991 to nearly 207 million in 2013

• 15.3 million opiate prescriptions from primary care physicians in 2013 for Medicare patients alone

• 2 million Americans have opiate use disorder based on using prescription painkillers in the past year

• Physicians blamed “for the nation’s epidemic of opiate addiction about as much as public hold individuals responsible for abusing the medications”

• FDA “should forbid the makers of opiates from marketing them to physicians for chronic pain”

• CDC recommends limiting opiates to 3 days of treatment for short-term pain

Past Year Initiates of Specific Illicit Drugs among Persons Aged 12 or Older: 2005

Substance Abuse and Mental Health Services Administration. (2006). Results from the 2005 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NSDUH Series H-30, DHHS Publication No. SMA 06-4194). Rockville, MD. www.dpft.org/resources/NSDUHresults2005.pdf. Accessed May 31, 2016.

AIDS and Current Opiate Use Epidemic

Conrad C, et al. MMWR. 2015;64(16):443-444. www.cdc.gov/mmwr/preview/mmwrhtml/mm6416a4.htm?s_cid=mm6416a4_w. Accessed May 4, 2016.

• Rural Indiana – population 4300• Single case of HIV in 2013• 6 months later – OVER 180 HIV cases

• All from needle sharing as prescription opiate users switched to IV heroin (lower cost and more availability)

Cost of Opiate Dependence

Case Study: Therapeutic Interchange in Patients Being Treated for Opioid Dependence—Rationale and Real-World Experience. www.ajmc.com/journals/supplement/2016/Case_Study_Therapeutic_Interchange_in_Patients_Being_Treated_for_Opioid_Dependence_Rationale_and_Real_World_Experience. Accessed May 3, 2016.

• 78 people dying daily from opiate overdose

• Annual opiate dependence-related costs exceed $55 billion: – $25 billion in direct health care – $26 billion in lost productivity

• Health care costs = Excess medical and prescription costs

• The Coalition Against Insurance Fraud tallied costs for opiate abuse:– $72.5 billion / year – $24.9 billion / year from private

insurers

ED visits due to narcotic pain reliever abuse rose 300% since 1995.

Chronic Opiates: What Price?

• Overdose – Availability of Naloxone• Tolerance and Dependence• Opiate-Induced Hyperalgesia• Addiction• Treatment Options

Progression of Opiate Addiction: Vicodin to Heroin to Fentanyl

Center for Behavioral Health Statistics and Quality. (2015). Behavioral health trends in the United States: Results from the 2014 National Survey on Drug Use and Health (HHS Publication No. SMA 15-4927, NSDUH Series H-50). www.samhsa.gov/data/sites/default/files/NSDUH-FRR1-2014/NSDUH-FRR1-2014.pdf. Accessed May 4, 2016.Seelye KQ. Heroin Epidemic is Yielding to a Deadlier Cousin: Fentanyl. The New York Times. March 25, 2016.

• 2 million Americans have opiate use disorder based on using prescription painkillers in the past year

• 212,000 people aged 12 or older used heroin for the first time within the past 12 months

• 435,000 people used heroin in the past month• Heroin users are shifting over to fentanyl• MORE fentanyl drug seizures and higher mortality:

– Rise from 618 in 2012 to 4585 in 2014– Not detected in urine drug screens (very small doses)

• Much fentanyl is “home made,” not prescribed

Overdose Death Rates from OpiatesMarked Increase from 1999 to 2014 by county

Centers for Disease Control and Prevention. Drug Poison Mortality: United States, 1999–2014. http://blogs.cdc.gov/nchs-data-visualization/drug-poisoning-mortality/. Accessed June 13, 2016.

Naloxone by Non-medical Persons to Prevent Opiate Overdose Deaths

Maxwell S, et al. J Addict Dis. 2006;25(3):89-96.

• Naloxone injection has Intelliject® Prompt System (IPS™) for $100+ has visual and voice instructions for the user to give this injection

• Some states making naloxone available without a prescription

• How to obtain a supply of naloxone: StopOverdose.org

• Fentanyl deaths: fast-acting, less time to give naloxone

• New intranasal naloxone• $37.50; easier and

cheaper

Chronic Opiates: What Price?

• Overdose

• Tolerance and Dependence– Chronic opiates decrease endurance of deep

pain (cold pressor) and its relief by more opiates

• Opiate-Induced Hyperalgesia• Addiction• Treatment Options

Methadone Maintenance Patients: Pain Sensitivity Baseline and 3 Hours after Getting Methadone

Compton P, et al. J Pain Symptom Manage. 2000;20(4):237-245.

Methadone Maintenance Patients: Pain Sensitivity Baseline and 3 Hours after Getting Methadone

Compton P, et al. J Pain Symptom Manage. 2000;20(4):237-245.

Morphine in Methadone Patients

Compton P, et al. J Pain Symptom Manage. 2000;20(4):237-245.

Chronic Opiates: What Price?

• Overdose• Tolerance and Dependence

• Opiate-Induced Hyperalgesia• Addiction• Treatment Options

Chronic Pain and HyperalgesiaCase History: Opiate Abuse?

Angst MS, et al. Anesthesiology. 2006;104(3):570-587.

• 52-year-old male• Fentanyl transdermal system 100 μg, and oxycodone 40

mg 4×/day for the past year for treatment of chronic back pain

• Occasionally takes extra oxycodone when in extremely high pain and takes less when the pain is lower

• In recovery from alcoholism for 20 years and abused no other drugs

Chronic Pain and Hyperalgesia:Case History: Opiate Abuse? (continued)

Angst MS, et al. Anesthesiology. 2006;104(3):570-587.

• He is obese and depressed, taking bupropion SR 300 mg/day

• He has severe pain in the morning, and “getting started” takes him 2 hours of stretches and walks before driving to work

• He now needs pain pills 3 days each week when changing the fentanyl transdermal system

• He is concerned that he is now addicted, since he needs the additional pain pills

Chronic Opiates: What Price?

• Overdose• Tolerance and Dependence• Opiate-Induced Hyperalgesia

• Addiction• Treatment Options

Published Rates of Abuse and/or Addiction in Chronic Pain Populations are ~ 10% (3%–18%)

Adams NJ, et al. J Pain Symptom Manage. 2001;22(3):791-796. Brown RL, et al. J Fam Pract. 1996;43(2):152-160. Fishbain DA, et al. Pain. 1986;26(2):181-197. Fishbain DA, et al. Clin J Pain. 1992;8(2):77-85. Kouyanou K, et al. J Psychosom Res. 1997;43(5):497-504.

• Known risk factors for abuse or addiction in the general population are good predictors for problematic prescription opiate use– History of early substance use– Personal or family history of substance abuse– Comorbid psychiatric disorders

Aberrant Drug-Taking Behaviors

Passik SD, et al. Substance abuse issues in palliative care. In: Berger A, et al (Ed). Principles and Practices of Supportive Oncology. Philadelphia: Lippincott-Raven; 1998.

• Probably more predictive– Selling prescription drugs– Prescription forgery– Stealing or borrowing

another patient’s drugs– Injecting oral formulation– Obtaining prescription drugs

from non-medical sources– Concurrent abuse of related

illicit drugs– Multiple unsanctioned dose

escalations– Recurrent prescription losses

• Probably less predictive– Aggressive complaining

about need for higher doses– Drug hoarding during periods

of reduced symptoms– Requesting specific drugs– Acquisition of similar drugs

from other medical sources– Unsanctioned dose

escalation 1 to 2 ×– Unapproved use of the drug

to treat another symptom– Reporting psychic effects not

intended by the clinician

Most Frequently Reported Aberrant Behaviors

Passik SD, et al. Clin J Pain. 2006;22(2):173-181.

Aberrant Behavior Cancer Patients

(n = 100)AIDS Patients

(n = 73)

Frequency (%) Frequency (%)

Expressed anxiety about symptoms

27 27 37 51

Taken someone else’s pain medicine

11 11 36 50

Aggressively complained to doctor for more drugs

13 13 29 40

Hoarded medications 22 22 28 39

Requested a specific drug 18 18 24 33

Reported Pain Relief

PMI = Pain Management Index.Passik SD, et al. Clin J Pain. 2006;22(2):173-181.

Cancer Patients AIDS Patients

Percent of Pain Relief 76% 37%

Adequate pain relief (PMI)

92 (92%) 49 (67%)

Inadequate pain relief (PMI)

8 (8%) 24 (33%)

The Multiple Etiologies of Aberrant Drug-Taking Attitudes and Behavior

Passik SD, et al. Substance abuse issues in palliative care. In: Berger A, et al (Ed). Principles and Practices of Supportive Oncology. Philadelphia: Lippincott-Raven; 1998.

• Addiction/Abuse• Pseudo-addiction (inadequate analgesia)• Self medication (chemical coping) of psychiatric

problems– Encephalopathy– Personality disorders– Depression and anxiety disorders– Poor coping and medication of situational stressors

• Criminal intent

Preventing Opiate Abuse:Chronic Benign Pain

• Participate in State Prescription Drug Monitoring Program (PDMP)– Before prescribing opiates, check every patient in

PDMP– Easily accessed Web site – takes about 60 seconds (in

Texas)– www.texaspatx.com/Login.aspx

• Collect urine toxicology for prescribed and non-prescribed opiates in any patient suspected of abuse or diversion

• Do not use opiates for > 60 days in benign pain– Headache, low back pain, diabetic neuropathy,

fibromyalgia

The Four “A”s of Pain Treatment Outcomes

Passik SD, et al. Adv Ther. 2000;17(2):70-83.

• Analgesia – modest but meaningful• Activities of Daily Living (psychosocial

functioning) – 80% improved overall is excellent outcome!

• Adverse effects (side effects) – common but tolerable

• Aberrant drug taking (addiction-related outcomes)– Urine toxicology– State Prescription Drug Monitoring Program

Chronic Opiates for Pain – Summary

• New Epidemic of Abuse• Tolerance and Dependence• Opiate-Induced Hyperalgesia• Addiction and Its Prevention

• Treatment Options– Detoxification– Buprenorphine maintenance

Opiate Detoxification

Clonidine and lofexidine are not FDA approved for this indication, and the rapid naltrexone protocol is not FDA approved.

• Needed to reduce tolerance and hyperalgesia• Innovative approaches

– Clonidine or Lofexidine– Clonidine/Naltrexone – rapid– Buprenorphine

Clonidine

Kosten TR, et al. N Engl J Med. 2003;348(18):1786-1795.

• Adrenergic antihypertensive• Non-abusable, oral use• Dose titration, start 0.1 mg TID• Lasts 7 days (except methadone)• Targets autonomic symptoms• Anxiety, diarrhea not well relieved• Side effects – sedation, orthostatic hypotension

Lofexidine vs Clonidine

Stotts AL, et al. Expert Opin Pharmacother. 2009;10(11):1727-1740. Kosten TR, et al. N Engl J Med. 2003;348(18):1786-1795.

• Lofexidine is widely used in Europe for over 20 years• Clinical trials being completed in the United States – as

effective as clonidine, fewer side effects, greater patient acceptance

• Dosing ranges from 2.4 mg to 3.2 mg daily• Treatment strategy very similar to clonidine• Can use rapid detoxification variations with naltrexone

Abruptly Stopping Methadone at 35 mg Daily

Kosten TR, et al. N Engl J Med. 2003;348(18):1786-1795.

With

dra

wa

l

Days Since Last Methadone

Clonidine + naltrexone Clonidine alone

No more methadone

0 5 10 15

Maintenance Opiate Pharmacotherapies

Stotts AL, et al. Expert Opin Pharmacother. 2009;10(11):1727-1740.

• Naltrexone, Methadone, BuprenorphineMECHANISMS– Naltrexone – block μ-opiate receptor, block

euphoria– Methadone – opiate agonist, cross-tolerance @

high dose– Buprenorphine – partial opiate agonist, block

euphoria at high dose

Oral Naltrexone as Treatment for Alcoholor Opiate Use Disorder

Brooks AC, et al. J Clin Psychiatry. 2010;71(10):1371-1378.

• Independent confirmation of efficacy• Approved by FDA • Yet serious limitations exist, primarily centered on oral

naltrexone’s poor pharmacokinetic profile

TherapeuticConsequences

• Suboptimal Efficacy associated with daily nadir in drug plasma levels

• Adverse Events associated with high drug levels

• Adherence Problems compounded by the requirement to take medication daily

All contribute to relapse

Plasma levels from daily dose

Fluctuations each month

Naltrexone’s Poor Pharmacokinetic Profile

Galloway GP, et al. BMC Psychiatry. 2005;5:18.

The Depot Naltrexone Concept

Johnson BA. Expert Opin Pharmacother. 2006;7(8):1065-1073.

Provide sustained naltrexone release following each injection

Dry Powdermicrospheres

+ Diluent

Microsphere suspension

Hypodermic needle

SC or IM

• Avoid daily loss of therapeutic plasma levels, maintaining levels for 30 days

• Eliminate need for daily dosing by patient

• Reduce repetitive high plasma peaks• Eliminate first pass metabolism

Depot Naltrexone Pharmacokinetics

Dunbar JL, et al. Alcohol Clin Exp Res. 2006;30(3):480-490.

Naltrexone mean plasma concentrations over 1 month after 1 depot naltrexone dose

Mean Naltrexone Concentration30

20

Na

ltre

xo

ne

(n

g/m

L)

10

5

0 30

25

15

Increasedand consistent

therapeuticconcentrations

Fluctuating,dose-dependent

plasmaconcentrations

2520151050

Time (Days)

Naltrexone 380 mg IM injectionOral naltrexone 50 mg

Oral vs Depot Naltrexone: Opiates

Brooks AC, et al. J Clin Psychiatry. 2010;71(10):1371-1378.

• Early retention and urine results were compared between patients participating in 2 concurrently run randomized clinical trials of oral (n = 69) and long-acting injectable naltrexone (n = 42). Retention in treatment and opiate use in the first 8 weeks post-detoxification were compared

• Long-acting injectable naltrexone produced significantly better outcome than oral naltrexone on days retained in treatment and proportion of opiate-free urines

• Days retained: depot 42 vs oral 32• Opiate-free urines: depot 0.52 vs oral 0.37

Depot NaltrexoneStudy Design and Outcomes

Krupitsky E, et al. Lancet. 2011;377(9776):1506-1513.

• Randomized, placebo controlled 6-month outpatient clinical trial in 250 opiate addicted patients

• Assigned to depot naltrexone vs placebo after 7 days opiate free while at inpatient setting

• Dose of about 25 mg daily from monthly shot• 6-month outcome

– 1.6 × more abstain completely on depot naltrexone: 36% vs 23%

– Average depot naltrexone patients attain 90% opiate-free weeks vs average placebo patients attain 40% opiate-free weeks

Significant Improvement in Opiate-Free Recovery with Depot Naltrexone

Krupitsky E, et al. Lancet. 2011;377(9776):1506-1513.

• Patients were considered completely abstinent if they were opiate-free from weeks 5 to 24

• Complete abstinence was achieved by 36% of the depot naltrexone-treated group vs 23% of the placebo group

Participants Sustaining Complete Abstinence(ie, 100% Opiate-Free Weeks)

40

30

Pa

tie

nts

(%

)

20

10

0 Naltrexone (n = 126)

Placebo(n = 124)

36%

23% 57%Greater

Abstinence

P = .0002

Adverse Events: Depot Naltrexone

Krupitsky E, et al. Lancet. 2011;377(9776):1506-1513. US Food and Drug Administration. Drugs@FDA. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

Depot Naltrexone Well Tolerated in Opiate-Dependent PatientsDepot Naltrexone

n = 126Placebo n = 124

Alanine aminotransferase increased 13% 6%

Aspartate aminotransferase increased 10% 2%

Gamma-glutamyltransferase increased 7% 3%

Nasopharyngitis 7% 2%

Insomnia 6% 1%

Influenza 5% 4%

Hypertension 5% 3%

Injection site pain 5% 1%

Toothache 4% 2%

Headache 3% 2%

Depot Naltrexone Rare Severe Adverse Events

LFT = liver function test.US Food and Drug Administration. Drugs@FDA. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

• Precipitated withdrawal, if not detoxed• Injection site reactions (mild mostly)

– Sterile abscess from injection into fatty tissue• Eosinophilic pneumonia (rare)• Large increase in LFT (doses > 300 mg daily)

Buprenorphine

Kosten TR, et al. N Engl J Med. 2003;348(18):1786-1795.

• Partial opiate agonist– Low dose withdrawal relief– High dose precipitate withdrawal

• Once daily sublingual dosing• Transition from methadone limited to 40 mg daily• Mild withdrawal during dosage taper• Can combine clonidine/naltrexone for rapid detoxification

Equivalent Opiate Withdrawal Severity

O’Connor PG, et al. JAMA. 1998;279(3):229-234.

Days Since Opiate

0

5 10 15

Morphine

Buprenorphine

Methadone

Buprenorphine with Clonidine/Naltrexone:Rapid Opiate Detoxification to Depot Naltrexone

O’Connor PG, et al. JAMA. 1998;279(3):229-234. Sigmon SC, et al. Am J Drug Alcohol Abuse. 2012;38(3):187-199.

• Induction with buprenorphine 4 to 6 mg sublingual + naltrexone 0.5 mg daily for 3 to 5 days, then stop buprenorphine (Day 0)

• Pre-load with clonidine up to 0.3 mg orally 24 hours after stopping buprenorphine, then give oral naltrexone 3 mg (Day 1)– Naltrexone about 2 to 3 hours after clonidine loading– Continue clonidine at 3 × daily dosing for 5 days (Day 2–6)– Taper clonidine dose at Day 5 and 6 – Stop clonidine at Day 7

• Increase oral naltrexone once daily 6 mg, 12 mg, 25 mg over 3 days (Day 2–4) – Continue oral naltrexone at 25 mg daily (Day 5 and 6)– Consider depot naltrexone (380 mg IM) at Day 7– Last oral naltrexone 25 mg on Day 6

Maintenance Treatment for Addiction

Kosten TR, et al. J Nerv Ment Dis. 1993;181(6):358-364. Kosten TR, et al. Am J Addict. 2004;13 Suppl 1:S1-S7.

• While detoxification may be effective for many patients, some need prolonged stabilization and maintenance on opiates

• Buprenorphine + naloxone is preferred• Buprenorphine + naloxone – pharmacology and clinical

safety• Buprenorphine clinical use – LACK of PROVIDERS !• Buprenorphine vs methadone efficacy – short-term

(months)• Long-term efficacy of maintenance – methadone (years)

Pharmacology of Buprenorphinevs Methadone and Naltrexone

Lutfy K, et al. Curr Neuropharmacol. 2004;2(4):395-402.

• Positive and respiratory depression effects– Full Agonist

(Methadone)

– Partial Agonist (Buprenorphine)

– Antagonist (Naltrexone)

-10 -9 -8 -7 -6 -5 -40

10

20

30

40

50

60

70

80

90

100

Log Dose of opiate

Full Agonist(Methadone)

Partial Agonist(Buprenorphine)

Antagonist (Naltrexone)

Overview of Buprenorphine Safety

Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publication No. (SMA) 04-3939. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004. http://buprenorphine.samhsa.gov/Bup_Guidelines.pdf. Accessed May 4, 2016.Lutfy K, et al. Curr Neuropharmacol. 2004;2(4):395-402.

• Highly safe medication (acute and chronic dosing)• Primary side effects: like other μ-opiate agonists (eg,

nausea, constipation), but may be less severe• No significant disruption in cognitive or psychomotor

performance• No evidence of organ damage with chronic dosing• Possible mild increase in LFTs among patients with hepatitis• Overdose: No reports of respiratory depression in clinical

trials comparing buprenorphine with methadone• Preclinical studies suggest that high doses of buprenorphine

should not produce respiratory depression or other significant problems

Drug Interactions with Buprenorphine

Lutfy K, et al. Curr Neuropharmacol. 2004;2(4):395-402.

• Few clinically significant interactions compared with methadone

• Benzodiazepines or sedating drugs can lead to overdose in combination with buprenorphine

• Medications metabolized by cytochrome P450 3A4 • Methadone also interferes with 2D6 metabolism• Opiate antagonists: few effects• Opiate agonists: mostly blocked

Opiate Abuse + Pain: Buprenorphine

Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publication No. (SMA) 04-3939. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004. http://buprenorphine.samhsa.gov/Bup_Guidelines.pdf. Accessed May 4, 2016.

• Advantages of buprenorphine + naloxone compared to other opiates– Medical safety – overdose prevented– Diversion very unlikely – precipitated withdrawal– Readily discontinued – mild withdrawal– Does not cause hyperalgesia – sustained pain relief– Prevent “doctor shopping” – blocks other opiates– Divided daily dosing for pain – 2 mg SL 4 × daily

Maintenance Using Buprenorphine: Efficacy

Mattick RP, et al. Cochrane Database Syst Rev. 2008;(2):CD002207.Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publication No. (SMA) 04-3939. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004. http://buprenorphine.samhsa.gov/Bup_Guidelines.pdf. Accessed May 4, 2016.

• Numerous outpatient clinical trials comparing efficacy of daily buprenorphine to placebo, and to methadone

• Expect average daily dose will be somewhere between 8/2 and 24/6 mg of buprenorphine/naloxone

• These studies conclude that:– Buprenorphine is more effective than placebo– Buprenorphine is as effective as moderate doses of

methadone (eg, 60 mg/day)

Buprenorphine vs Methadone: Treatment Retention

Johnson RE, et al. JAMA. 1992;267(20):2750-2755.

Pe

rce

nt

Re

tain

ed

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

20% Lo Meth

58% Bup

73% Hi Meth

Study Week

Buprenorphine vs Methadone:Opiate Urine Results

Johnson RE, et al. JAMA. 1992;267(20):2750-2755.

19% Lo Meth

40% Bup39% Hi Meth

All Subjects

Me

an

% N

eg

ati

ve

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Study Week

Methadone or Buprenorphine Efficacy

Stotts AL, et al. Expert Opin Pharmacother. 2009;10(11):1727-1740. Dole VP, et al. JAMA.1965;193:646-650.

• More effective than placebo• Efficacy of the medication is related to the dose • Controlled studies have tested doses as high as 100

mg/day methadone and 16 mg/day buprenorphine• Good treatment retention• Decreased illicit opiate use (urines, self-reports)• Improvements in other areas included employment,

criminal activity, and psychological adjustment (depression)

Methadone Efficacy

Ball JC, et al. The Effectiveness of Methadone Maintenance Treatment. New York, NY: Springer-Verlag; 1991.

Ball and Ross study (1991)• Naturalistic study of methadone treatment (ie, no random

assignment, assessment of treatment in the community)• Examined 388 patients in 6 methadone clinics• IV drug use decreased from 81% to 29% in 4 years• For 105 patients who left treatment, 82% returned to IV

drug use within 1 year

Ball and Ross Study (1991) –IV Drug Use

Mean Time in Treatment: 45 months.Ball JC, et al. The Effectiveness of Methadone Maintenance Treatment. New York, NY: Springer-Verlag; 1991:169.

• Impact of methadone maintenance treatment on intravenous drug use for 388 male methadone patients in 6 programs

0

10

20

30

40

50

60

70

80

90

100

Pre-Admission

Period

1st Year 2nd Year 3rd Year 4th Year

La

st A

dd

icti

on

Pe

rio

d

Ad

mis

sio

n

IV U

se

rs (

%)

In-Treatment*

29%41.7%

63.3%

81%

100%

Ball and Ross Study (1991) – Crime

Ball JC, et al. The Effectiveness of Methadone Maintenance Treatment. New York, NY: Springer-Verlag; 1991:182.

• Reduction in crime by years in methadone maintenance treatment

0

50

100

150

200

250

23.5 Months “Last Addiction Period”

1

Years in Methadone Treatment

Me

an

Cri

me

-Da

ys

(CD

) p

er

Ye

ar

4 Months post Admission

2 3 4 5 6+ over

69.3 CD

28.3 CD21.1 CD

12.4 CD

32.1 CD32.6 CD

14 CD

Pre-Treatment237.5 Crime-Days per year In Outpatient Treatment

71% decline in Crime-Days @ 4 months95% decline in CD @ 3-6 years

Methadone or Buprenorphine Efficacy

D’Onofrio G, et al. JAMA. 2015;313(16):1636-1644.

• Starting buprenorphine treatment even in the ED is highly successful

• However, “methadone or buprenorphine treatment”includes medication PLUS counseling, urine testing, and a certain frequency of visits for success

• Such concurrent nonpharmacologic services markedly enhance outcome

Recognize the key roles of behavioral therapies, self-help programs, physical exercise, supported employment, and other nonpharmacologic interventions for primary and secondary prevention

Behavioral Therapies

• Motivational enhancement therapy – 2 to 4 sessions to engage

• 12-Step facilitation – based on 12-steps of AA, but uses counselor

• Cognitive-behavioral therapy – focus on preventing relapse and keeping patient adherent to treatment including medications

• Contingency management – typically positive contingencies such as pro-social activities, but can be linked to urine toxicology results for medication “take-home” privileges

• Individual- or group-based interventions

Counseling Doubles Efficacy 6-Month Opiate Maintenance Retention and Drug Use

McLellan AT, et al. JAMA. 1993;269(15):1953-1959.

Treatment Retention (%)

Negative Urines > 16 Week (%)

Medication alone 31 0

Medication plus STD counseling

59 28

Medication plus enhanced counseling

81 55

Self-Help, Physical Exercise, Employment

• Self-help, such as AA, has had more limited success for opiate use disorder patients, but has been provided in methadone maintenance program settings

• Physical exercise has been a component of drug-free treatment for many years and may include specific techniques such as yoga

• Employment is a key component of rehabilitation and includes supported employment programs (widely used in Veterans Administration), work release programs in criminal justice settings with naltrexone, and employment placement services

Primary and Secondary Prevention

Educate physicians about appropriate prescribing of opiates

Monitor patients getting opiates for duration, dosage, aberrant behaviors, and prescribing by other providers (PDMP use)

Behavioral and pharmacologic alternatives to opiates for controlling pain

Need More Prescribers – How?

Moran M. Why Aren’t More Physicians Prescribing Buprenorphine? Psychiatric News. March 4, 2016. http://psychnews.psychiatryonline.org/doi/full/10.1176/appi.pn.2016.PP3a2. Accessed May 5, 2016.

• Only 31,862 physicians certified to prescribe buprenorphine and 40% do not prescribe buprenorphine at all

• Address MD fears:– Fear addicted non-patients frequenting their office

practice– Fear of Drug Enforcement Administration (DEA) audit

• Raise patient limits to 150 patients, with prescribers getting 3 hours of addiction-related CME annually

• Permit buprenorphine prescribing by physician assistants and nurse practitioners

Opiate Epidemic and Pain – Summary

• New Epidemic of abuse – adolescents and chronic pain patients getting opiates from Physician prescribing– State Prescription Drug Monitoring Program (Web site)

• Tolerance and Dependence – chronic opiates reduce their efficacy for “deep pain” and induce hyperalgesia

• Addiction – 10% of chronic pain patients, note markers

• Treatment options – detoxification, lofexidine, buprenorphine/naloxone maintenance, even start in EMERGENCY DEPARTMENT

• NEED MORE PROVIDERS FOR BUPRENORPHINE– Currently only 32,000 nationally for 3.5 million patients– Most providers treat 3 to 4 patients, each provider

needs to treat 110 patients – NOT HAPPENING!!

THANK YOU

Participate in State Prescription DrugMonitoring Programwww.texaspatx.com

Obtain DEA “X” number for buprenorphineFROM American Academy of Addiction Psychiatry