Opioid Agonist Treatment: “Trading One Substance For Another?”
Joseph Sakai, M.D.
Prepared: April 2004 Slide 1
I. Introduction: The objectives of this lecture are to: Slide 2
A. Review opioids, and opioid dependence
B. Present the natural course of opioid dependence
C. Evaluate the efficacy of methadone therapy
D. Discuss other opioid agonist treatments
II. Opioids and opioid dependence:
A. Define opioids: opioid is a general term made up of 3 Slide 3
a. Derived from opium (Greek meaning “juice”)
b. Occur naturally (i.e. morphine – from Greek god of dreams)
c. Used at least 4000 B.C. – Sumerians 
2. Semisynthetic - produced by modifying opiates
a. Diacetyl-morphine (Heroin)
b. Hydromorphone (Dilaudid)
c. Oxycodone (Percodan)
a. Propoxyphene (Darvon)
b. Meperidine (Demerol) [1,2]
B. Endogenous opioid system: within the brain there is an Slide 4
endogenous opioid system that is important in regulating mood, stress and pain
1. Endogenous opioid receptors
iii. Decreased breathing
iv. Decreased muscle tone
v. Slowed movement in gastrointestinal tract
i. Decreased breathing
iii. Miosis (pupillary constriction) 
2. Endorphins: three types of endogenous opioid agonists – each bind
preferentially at specific receptors:
a. Beta-endorphins (mu and delta receptors)
b. Enkephalins (delta receptors)
c. Dynorphins (kappa receptors)
3. Importance of endogenous system
a. May help to better understand regulation of pain, stress and
mood and perhaps, the mechanisms underlying substance
b. Heroin (mu agonist): activation of endogenous opioid receptors is pleasurable and reinforcing - use sometimes escalates
C. When use escalates it can sometimes result in opioid dependence
Definition of opioid dependence: Slide 5
1. 3 of 7 criteria in same 12 months
2. Criteria - physiological
3. 5 criteria - loss of control of use
a. Use more than intended
b. Unable to cut down
c. Increased time spent using
d. Giving up other activities
e. Use despite consequences 
D. Epidemiology of opioid use Slide 6
1. Lifetime use
a. ~ 2/100 10th graders report lifetime heroin use 
b. ~ 20% 10th graders report that heroin is fairly easy to get 
2. Opioid dependence
a. 1:4 people who try have lifetime dependence 
b. About 1:1000 people in US met criteria for heroin dep in past year 
III. The natural course of opioid dependence – course for patient if untreated
A. Most opioid dependent are likely to relapse after Slide 7
detox without rehab
1. 20 yr f/u 100 opioid dependent persons after detox: 5 yr f/u
10% stable abstinence; 18 yr f/u 35% stable abstinence (average 8 years) 
2. 24 yr f/u opioid dependent persons ~20-22% reporting abstinence over
the last 10 yrs of the study 
3. After medical detox alone, rate of relapse is > 90% 
B. Medical risks associated with use
1. Delivery (If IV) Slide 8
f. Hepatitis C (HCV) ~70% in IV users; up to Slide 9
>90% [10,11,12] HCV ~65% after 1 year of needle use; ~85%
after 5 years 
g. Human immunodeficiency virus (HIV) (up to 75% of new HIV
infection in IV users; HIV+ ~20% (as high as 60% some
2. Poor self-care/medical problems. Not use medical services 
3. Overdose - 1.5% died per year  Slide 10
4. Overall death rate
a. 24 year f/u California ~28% sample deceased – homicides, suicides, accidents and overdose accounted for ~2/3 
b. Sweden – opioid dep people not in treatment: 63x expected mortality rate - 7.2% died per year of study 
C. Active heroin users less employed 
Hard to keep a job because:
1. Q 6 hours dosing
2. Much time needed recover from use
3. But need money to buy drug
D. Crime Slide 11
1. >95% of dependent persons commit crimes 
2. Dependent persons followed up at 10 years – at time of follow up ~18%
3. Among 573 opioid dep persons over 12 month period
a. 6,000 robberies, assaults
b. 6,700 burglaries
c. 900 stolen vehicles
d. 25,000 instances shoplifting
e. 46,000 instances larceny/fraud 
E. Costs to society
1. $1.2 billion per year in medical costs
2. $20 billion per year (costs to individual, family and society) 
F. Natural course summary (briefly summarized III A-E) Slide 12
IV. Treatment overview Slide 13
1. Free of the drug forever, if possible
2. Interim goals
a. Reduce use of heroin
b. Reduce risk HIV and other med issues
d. Reduce crime
e. Engage in treatment (so could provide other services)
f. Be cost effective
B. Rehab focused on: Slide 14
1. Engaging dependent persons in treatment
2. Supporting abstinence
3. Preventing or reduce the extent of relapse
4. Building life management skills
5. Learning to cope with anxiety and stress.
C. Rehab through: Slide 15
1. Individual counseling
2. Group – i.e. educational, relapse prevention
3. Urines – objective monitoring for relapse
4. Psychosocial treatments (i.e. contingency management, motivational
interviewing, cognitive behavioral therapy, 12-step facilitation)
5. Sober support network (i.e. 12-step groups)
6. Vocational rehabilitation
D. Meds – opioid dependence Slide 16
a. Theory - Block receptors, using offers no high
i. Pure opioid antagonist
ii. Well absorbed orally
iii. 50 mg/day by mouth (can be 100mg QOD)
iv. Effective x 24 hours
v. Retention poor relative to methadone
2. Agonists Slide 17
a. Theory - Pre-existing dysphoria or induced receptor dysfunction ® continue to use. Perhaps opioid dependent persons need opioids to function. 
b. Meds include:
V. Methadone agonist therapy
A. Methadone Slide 18
1. Mu opioid agonist
2. Half life 22-48 hours with repeated administration
3. Usual dosage: start 20mg (1st day max dose 40mg); some are
maintained on low dose (about 40mg); many on high dose 60-100mg or higher if necessary
4. Given only in licensed clinics
B. Reduces heroin use  Slide 19
1. 69% decrease in number of weekly heroin users 
2. Weekly heroin use down by 52-69% [19,20]
C. Reduces risk for HIV
1. Subjects not in treatment 4 X’s more likely to seroconvert HIV
2. HIV negative patients followed 18 months (seroconversion 3.5% vs.
22% (methadone vs. no treatment) 
D. People return to work Slide 20
1. Full time employment increases 24% 
2. Opioid dependent in treatment earn more than twice as much
money from employment than those not in treatment 
E. Leads to less crime
1. Criminal activity decrease 52% while in treatment (methadone) [18,19]
2. Methadone program closure led to increased antisocial behavior among
those unable/unwilling to go to new methadone program, 
and double rate of arrests/incarceration 
F. Helps retain people in treatment Slide 21
1. Double blind placebo controlled 3 year 56% retention vs. 2% for
placebo (placebo group tapered 1mg/d after stabilization) 
2. On methadone – opioid dep persons complete 6-12 months of HCV
treatment (same as controls and better than subjects with “former drug
G. Methadone (↑ retention) → better health outcomes:
1. On methadone - respond to HCV treatment similar to patients
without hx of IDU (even on an intent to treat basis) 
2. HIV treatment and methadone (hx heroin dep and HIV – on
methadone less likely to require hospitalization) 
3. Pregnant women
a. HIV – more likely to get zidovudine treatment (reduces by two-
thirds the transmission of HIV to fetus)
b. Methadone during pregnancy - associated with decreased
obstetrical and fetal complications 
H. Decreases mortality rate Slide 22
1. Before methadone death rates for opioid dependence ~ 21/1000
2. After methadone drops to ~ 13/1000
3. Opioid dependent in methadone about 25-30% of death rate of those
not in treatment [13,14]
4. Sweden 5-8 year follow up- those not in methadone were
about ~7.5 times more likely to die 
I. Cost effective
1. Costs about $4000 per year (< $13 per day) 
2. Cost benefit of 4:1 
J. Barriers to use of methadone: Slide 23
1. Federal regulations
a. Out of medical mainstream – some doctors not know who/when
to refer or where programs are
b. Dependent persons may not want stigma of going to specialized
c. Program may be too far away or not available in area
d. Don’t want to go to clinic for daily dosing
a. “Methadone dependence” vs physical dependence of methadone
i. Person is physiologically dependent on
ii. Physical dependence alone not define substance
dependence, need loss of control and use despite consequences
iii. Methadone dispensed in controlled way
b. “Trading one substance for another”
i. Heroin and methadone very different
ii. Multiple daily doses and withdrawal vs. single
c. Methadone must be taken for life
i. After stable, adjustments made in life – consider
ii. May be used long term safely
K. Summary Slide 24
1. Opioid dep persons: ↑ risk of HIV/HCV, death, commit crime
2. Methadone: ↓ risk for HIV, ↑ HCV treatment retention, ↓ mortality rate,
3. But it’s not a cure
a. Adjunct to treatment
b. Retains in treatment
c. Helps disengage from drug “subculture”
d. Gives time for rehab
VI. Other opioid agonists (LAAM, and Buprenorphine)
A. LAAM (Levo-alpha-acetyl-methadol) Slide 25
a. Long acting synthetic mu opioid agonist
b. Well absorbed orally
c. Effect lasts for up to 72 hours
d. Dosed at ~20-100mg three times per week
2. Given only in licensed clinics
3. Retention in treatment slightly lower than methadone Slide 26
a. 31% LAAM (80mg MonWedFri) completed 40 weeks of
treatment vs. 42% (methadone 50mg QD) and 52% (methadone 100mg QD) 
b. 39% LAAM (£100mg MWF) vs 60% retention for methadone;
of non-completers – average number of days in study 72 (LAAM) vs. 122 (methadone) 
4. Similar reduction in heroin use to methadone
a. No positive urines (collected weekly) for morphine - 55% (LAAM) vs. 46% (methadone) 
b. LAAM superior to methadone 50mg but not methadone 100mg 
5. Concerns about QT prolongation 
B. Buprenorphine Slide 27
a. Mixed opioid agonist/antagonist (antagonist at high doses)
b. Mean elimination half-life from plasma of 37 hours
c. Good parenteral, fair sublingual, poor oral bioavailability
d. Usual dosage 8-32 mg/d; can be given every other day
2. Buprenorphine approved as office based treatment Slide 28
a. Increased access vs. methadone
i. ~20% of 800,000 heroin dependent people
ii. Some states don’t have methadone
iii. Highly regulated treatment programs (initial
dose, frequency of take outs)
iv. For methadone - specialized clinics required and
are often far away
b. Any physician can be trained to prescribe
c. Partial agonist (ceiling to effect) – safer in overdose
3. Concern about injecting buprenorphine (seen in France )
a. Combined with Naloxone (opioid antagonist) in single tablet
b. Naloxone with poor sublingual absorption but buprenorphine
has fair sublingual absorption.
c. If the tablet is dissolved and injected to get high, because of Naloxone it will precipitate withdrawal
4. Outcomes: Slide 29
a. Similar quality of life (to methadone) 
b. Retention lower
i. 13 weeks – 50% buprenorphine completed vs.
59% for methadone 
ii. 6 weeks – 56% bup vs. 90% methadone
iii. Meta-analysis – low dose bup (<8mg)
more likely to leave treatment (OR2.72) compared with high dose methadone (>50mg)
iv. High dose bup (³8mg) no difference in
retention with high dose methadone
c. Slightly worse regarding decrease in heroin use (self report and
urine positive for morphine) [37,38]
i. low dose bup (<8mg) more illicit drug use on
urine testing (OR 3.39) compared to methadone (>50mg) 
d. With higher dose or flexible dosing opiate + urines similar to
i. Double blind – double dummy, 13 week, n=405;
urine collected every 2 weeks. Morphine free urines similar in bup and methadone at all time points 
ii. Double blind, randomized, 6 week, n=58; urine
collected every week. Opioid-free urines 38%
buprenorphine group vs. 40.5% methadone
VII. Conclusions Slide 30
A. Without treatment opioid dependence is very destructive
B. Methadone maintenance is effective
1. Offer this option to your patients
2. Find out where the methadone clinics are in your community
3. Learn how to make a referral to the clinic
C. Other agonist treatments are becoming available
1) Schuckit MA. Drug and Alcohol Abuse: A clinical Guide to Diagnosis and Treatment, 5th ed. New York: Kluwer Academic/Plenum Publishers, 2000.
2) Jaffe JH, Jaffe AB. Neurobiology of Opiates/Opioids. In Galanter M, Kleber HD (Ed.) Textbook of Substance Abuse Treatment. Washington, DC: American Psychiatric Press, Inc., 1999.
3) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994.
4) Johnston LD, O’Malley PM, Bachman JG: Monitoring the future national results on adolescent drug use: overview of key findings, 2002. Bethesda, MD, National Institute on Drug Abuse, 2003.
5) Office of Applied Studies. (2003). Results from the 2002 National Survey on Drug Use and Health: Summary of National Finding (DHHS Publication No. SMA 03-3836, NHSDS Series H-22). Rockville, MD: Substance Abuse and Mental Health Services Administration.
6) Anthony JC, Warner LA, Kessler RC. Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the national comorbidity survey. Exp Clin Psychopharmacol. 1994; 2: 244-268.
7) Vaillant GE. A 20-year follow-up of New York narcotic addicts. Arch Gen Psychiatry. 1973; 29: 237-241.
8) Hser Y, Anglin D, Powers K. A 24-year follow up of California narcotics addicts. Arch Gen Psychiatry. 1993; 50: 577-584.
9) Dole VP. Implications of methadone maintenance for theories of narcotic addiction. JAMA. 1988; 25: 3025-3029.
10) Garfein RS, Vlahov D, Galai N, Moherty MC, Nelson KE. Viral infections in short-term injection drug users: the prevalence of the hepatitis C, hepatitis B, human immunodeficiency, and human T-lymphocyte viruses. Am J Publ Health. 1996; 86: 655-661.
11) Krambeer LL, McKnelly WV, Gabrielli WF, Penick EC. Methadone therapy for opioid dependence. American Family Physician. 2001; 63: 2404-2410.
12) Diamantis I, Bassetti S, Erb P, et al. High prevalence and coinfection rate of hepatitis G and C infections in intravenous drug addicts. Journal of Hepatology. 1997; 26: 794-797.
13) National Consensus Development Panel on Effective Medical Treatment of Opiate Addiction. Effective medical treatment of opiate addiction. JAMA. 1998; 280:1936-1943.
14) Caplehorn JR, Dalton MSYN, Haldar F, et al. Methadone maintenance and addicts’ risk of fatal heroin overdose. Substance Use and Misuse. 1996; 31: 177-196.
15) Gronbladh L, Ohlund LS, Gunne LM. Mortality in heroin addiction: impact of methadone treatment. Acta Pyschiatr Scand. 1990; 82: 223-227.
16) Nurco DN, Ball JC, Shaffer JW, et al. The criminality of narcotic addicts. Journal of Nervous and Mental Disorders. 1985; 173: 94-102.
17) Dole VP, Nyswander M. A medical treatment for diacetylmorphine (heroin) addiction. JAMA. 1965; 193: 646-650.
18) Hubbard RL, Craddock, SG, Flynn, PM, Anderson, J, Etheridge, RM, Overview of 1-year follow-up outcomes in drug abuse treatment outcome study (DATOS), Psychology of Addictive Behaviors, 11, pp 261-278, 1997.
19) Office of National Drug Control Policy, “Consultation document on methadone/LAAM” Washington DC, p.5, September 29, 1998.
20) Metzger DS, Woody GE, McLellan T, O’Brien CP, Druley P, Navaline H, DePhilippis D, Stolley P, Abrutyn E. Human immunodeficiency virus seroconversion among intravenous drug users in- and out-of-treatment: an 18-month prospective follow-up. J Acquir Immune Defic Syndr. 1993; 6: 1049-1056.
21) Stoller KB, Bigelow GE. Regulatory, cost and policy issues. In Strain EC, Stitzer ML (Ed.) Methadone Treatment for Opioid Dependence. Baltimore, MD: The John’s Hopkins University Press, 1999.
22) Anglin MD, Speckart GR, Booth MW, Ryan TM. Consequences and costs of shutting off methadone. Addictive Behaviors. 1989; 14: 307-326.
23) McGlothlin WH, Anglin MD. Shutting off methadone. Arch Gen Psychiatry. 1981; 39: 885-892.
24) Newman RG, Whitehill WB. Double-blind comparison of methadone and placebo maintenance treatments of narcotic addicts in Hong Kong. Lancet. 1979; 2: 485-488.
25) Schaefer M, Schmidt F, Folwaczny C, Lorenz R, Martin G, Schindlbeck N, Heldwein W, Soyka M, Grunze H, Koenig A, Loeschke K. Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups. Hepatology. 2003; 37: 443-451.
26) Sylvestre DL. Treating hepatitis C in methadone maintenance patients: an interim analysis. Drug Alcohol Depend. 2002; 67: 117-123.
27) Stanclif S. Methadone maintenance. American Family Physician. 2001; 63: 2335.
28) Stoller KB, Bigelow GE. Regulation, cost, and policy issues. In Strain EC, Stitzer ML (Ed.) Methadone Treatment for Opioid Dependence. Baltimore, MD: The John’s Hopkins University Press, 1999.
29) Office of National Drug Control Policy, “Methadone” Washington DC, April 2000.
30) Ling W, Charuvastra C, Kaim SC, Klett J. Methadyl acetate and methadone as maintenance treatments for heroin addicts. Arch Gen Psychiatry. 1976; 33: 709-720.
31) Ling W, Klett J, Gillis RD. A cooperative clinical study of methadyl acetate. Arch Gen Psychiatry. 1978; 35: 345-353.
32) Ritter AJ, Lintzeris N, Clark N, Kutin JJ, Bammer G, Panjari M. A randomized trial comparing levo-alpha acetylmethadol with methadone maintenance for patients in primary care settings in Australia. Addiction. 2003; 98: 1605-1613.
33) Guichard A, Lert F, Calderon C, Gaigi H., Maguet O, Soletti J, Brodeur JM, Richard L, Benigeri M, Zunzunegui MV. Illicit drug use and injection practices among drug users on methadone and buprenorphine maintenance treatment in France. Addiction. 2003; 98: 1585-1597.
34) Giacomuzzi SM, Riemer Y, Ertl M, Kemmler G, Rossler H, Hinterhuber H, Kurz M. Buprenorphine versus methadone maintenance treatment in an ambulant setting: a health-related quality of life assessment. Addiction. 2003; 98: 693-702.
35) Mattick RP, Ali R, White JM, O’Brien S, Wolk S, Danz C. Buprenorphine versus methadone maintenance therapy: a randomized double-blind trial with 405 opioid dependent patients. Addiction. 2003; 98: 441-452.
37) Farre M, Mas A, Torrens M, Moreno V, Cami J. Retention rate and illicit opioid use during methadone maintenance interventions: a meta-analysis. Drug Alcohol Depend. 2002; 65: 283-290.
38) Barnett PG, Rodgers JH, Bloch DA. A meta-analysis comparing buprenorphine to methadone for treatment of opiate dependence. Addiction. 2001; 96: 683-690.