Opioid Agonist Treatment: ÒTrading One Substance For Another?Ó
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 ÒjuiceÓ)
b. Occur naturally (i.e. morphine Ð from Greek god of dreams)
c. Used at least 4000 B.C. Ð 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 Ð 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]
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 Ð 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 Ð homicides, suicides, accidents and overdose accounted for ~2/3 [8]
b. Sweden Ð 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 Ð 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 Ð i.e. educational, relapse prevention
3. Urines Ð 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 Ð 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 XÕs 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 Ð opioid dep persons complete 6-12 months of HCV
treatment (same as controls and better than subjects with Òformer drug
addictionÓ) [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 Ð on
methadone less likely to require hospitalization) [27]
3. Pregnant women
a. HIV Ð 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 Ð 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. DonÕt want to go to clinic for daily dosing
2. Misconceptions
a. ÒMethadone dependenceÓ 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. ÒTrading one substance for anotherÓ
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 Ð 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 itÕs not a cure
a. Adjunct to treatment
b. Retains in treatment
c. Helps disengage from drug ÒsubcultureÓ
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 Ð 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 donÕt 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) Ð 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 Ð 50% buprenorphine completed vs.
59% for methadone [35]
ii. 6 weeks Ð 56% bup vs. 90% methadone
[36]
iii. Meta-analysis Ð 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 Ð 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
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