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

categories

1. Opiates

                  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 [1]

2. Semisynthetic - produced by modifying opiates

a.       Diacetyl-morphine (Heroin)

b.       Hydromorphone (Dilaudid)

c.       Oxycodone (Percodan)

3. Synthetic

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

                  a. Mu

i. Analgesia

ii. Euphoria

iii. Decreased breathing

iv. Decreased muscle tone

v. Slowed movement in gastrointestinal tract

vi. Reinforcing

                  b. Delta

                                                      i. Decreased breathing

                                                      ii. Euphoria

                                                      iii. Reinforcing                                                    

                  c. Kappa

                                                      i. Analgesia

                                                      ii. Sedation

                                                      iii. Miosis (pupillary constriction)      [1]

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

dependence                

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

a. Tolerance

b. Withdrawal

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                     [3]

D. Epidemiology of opioid use                                                                                     Slide 6

1. Lifetime use

a.       ~ 2/100 10th graders report lifetime heroin use [4]

b.       ~ 20% 10th graders report that heroin is fairly easy to get [4]

c.       ~3.6 million Americans report using heroin in their lifetime [5]

2. Opioid dependence                                                                                          

a.       1:4 people who try have lifetime dependence [6]

b.       About 1:1000 people in US met criteria for heroin dep in past year [5]

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)               [7]

2.       24 yr f/u opioid dependent persons ~20-22% reporting abstinence over

the last 10 yrs of the study [8]

3.       After medical detox alone, rate of relapse is > 90% [9] 

B. Medical risks associated with use                                     

1. Delivery (If IV)                                                                                                Slide 8

a. Abscesses

b. Sepsis

c. Osteomyelitis

d. Thrombophlebitis

e. Endocarditis

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 [10]

g. Human immunodeficiency virus (HIV) (up to 75% of new HIV

infection in IV users; HIV+ ~20% (as high as 60% some

samples) [10,11]      

2. Poor self-care/medical problems. Not use medical services [13]

                  3. Overdose - 1.5% died per year [14]                                                    Slide 10

4. Overall death rate

a.       24 year f/u California ~28% sample deceased – homicides, suicides, accidents and overdose accounted for ~2/3 [8]

b.       Sweden – opioid dep people not in treatment: 63x expected mortality rate - 7.2% died per year of study [15]

C. Active heroin users less employed [8]

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 [13]

2. Dependent persons followed up at 10 years – at time of follow up ~18%

incarcerated [8]

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 [16]

E. Costs to society                                                                                                                    

1. $1.2 billion per year in medical costs

2. $20 billion per year (costs to individual, family and society) [13]

                  F. Natural course summary (briefly summarized III A-E)                        Slide 12

IV. Treatment overview                                                                                                                        Slide 13

                  A. Goals

                  1. Free of the drug forever, if possible

2. Interim goals

a.       Reduce use of heroin

b.       Reduce risk HIV and other med issues

c.       Employed

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

7. Medications

D. Meds – opioid dependence                                                                                         Slide 16

1. Antagonist

                  a. Theory - Block receptors, using offers no high      

b. Naltrexone

                                                                                                                                                   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.                                    [9]

b.       Meds include:

i. Methadone

ii. LAAM

iii. Buprenorphine

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 [17]                                                                                                Slide 19

1. 69% decrease in number of weekly heroin users [18]

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

+ [21]

2. HIV negative patients followed 18 months (seroconversion 3.5% vs.

22% (methadone vs. no treatment) [20]

D. People return to work                                                                                                     Slide 20

1. Full time employment increases 24% [19]

2. Opioid dependent in treatment earn more than twice as much

money from employment than those not in treatment [13]

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, [22]

and double rate of arrests/incarceration [23]

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) [24]

2. On methadone – opioid dep persons complete 6-12 months of HCV

treatment (same as controls and better than subjects with “former drug

addiction”) [25]

                  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) [26]

2. HIV treatment and methadone (hx heroin dep and HIV – on

methadone less likely to require hospitalization) [27]

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 [13]

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 [15]

I. Cost effective                                                                                                                          

1. Costs about $4000 per year (< $13 per day) [29]

2. Cost benefit of 4:1 [29]

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

clinic

c.       Program may be too far away or not available in area

d.       Don’t want to go to clinic for daily dosing

                                    2. Misconceptions

                                                      a. “Methadone dependence” vs physical dependence of methadone

i. Person is physiologically dependent on

methadone. But:

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

daily dosing

                                                      c. Methadone must be taken for life

                                                                                          i. After stable, adjustments made in life – consider

tapering

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,

and crime

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

1. Pharmacology

                  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)                                                                                          [30]

b. 39% LAAM (£100mg MWF) vs 60% retention for methadone;

of non-completers – average number of days in study 72 (LAAM) vs. 122 (methadone)                                               [31]

4.       Similar reduction in heroin use to methadone

a.       No positive urines (collected weekly) for morphine - 55% (LAAM) vs. 46% (methadone)                                          [31]

b. LAAM superior to methadone 50mg but not methadone 100mg                                                                                                                               [30]

5. Concerns about QT prolongation                                                         [32]       

B. Buprenorphine                                                                                                                       Slide 27

1. Pharmacology

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

covered

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 [33])

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) [34]

b. Retention lower

i. 13 weeks – 50% buprenorphine completed vs.

59% for methadone [35]

ii. 6 weeks – 56% bup vs. 90% methadone

[36]

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

[37]

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)                                                             [37]

d. With higher dose or flexible dosing opiate + urines similar to

methadone [35,36]

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                                                                    [35]

ii. Double blind, randomized, 6 week, n=58; urine

collected every week. Opioid-free urines 38%

buprenorphine group vs. 40.5% methadone

                                                                                          [36]

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.

 

36) Petitjean S, Stohler R, Deglon JJ, Livoti S, Waldvogel D, Uehlinger C, Ladewig D. Double-blind randomized trial of buprenorphine and methadone in opiate dependence. Addiction. 2001; 62: 97-104.

 

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.