OpioidAgonist Treatment: ÒTrading One Substance For Another?Ó
JosephSakai, M.D.
Prepared:April2004Slide1
I. Introduction: Theobjectivesof this lecture areto:Slide2
A. Review opioids,and opioid dependence
B. Present thenatural course of opioid dependence
C. Evaluate theefficacy of methadone therapy
D. Discuss otheropioid agonist treatments
II. Opioids and opioid dependence:
A.Define opioids: opioid is a general term made up of3Slide3
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 anSlide4
endogenous opioid systemthat is important in regulating mood, stress and pain
1. Endogenousopioid 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 ofendogenous system
a. May help tobetter understand regulation of pain, stress and
mood andperhaps, the mechanisms underlying substance
dependence
b.Heroin (mu agonist): activation of endogenous opioid receptors ispleasurable and reinforcing - use sometimes escalates
C. When useescalates it can sometimes result in opioid dependence
Definition ofopioid dependence:Slide5
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.Usedespite consequences[3]
D.Epidemiologyof opioid useSlide6
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.Opioiddependence
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 opioiddependence Ð course for patient if untreated
A.Most opioiddependent are likely to relapse afterSlide7
detox withoutrehab
1. 20 yr f/u 100opioid dependent persons after detox: 5 yr f/u
10%stableabstinence; 18 yr f/u 35% stable abstinence (average 8 years)[7]
2.24 yr f/u opioid dependent persons ~20-22% reporting abstinence over
thelast 10 yrs of the study [8]
3.After medical detox alone, rate of relapse is > 90% [9]
B.Medical risksassociated withuse
1.Delivery (IfIV)Slide8
a.Abscesses
b. Sepsis
c. Osteomyelitis
d.Thrombophlebitis
e. Endocarditis
f. Hepatitis C(HCV) ~70% in IV users; up to Slide9
>90% [10,11,12] HCV ~65% after 1 year of needle use; ~85%
after 5 years [10]
g. Humanimmunodeficiency virus (HIV) (up to 75% of new HIV
infection inIV users; HIV+ ~20% (as high as 60% some
samples) [10,11]
2. Poorself-care/medical problems. Not use medical services [13]
3.Overdose - 1.5% died per year [14]Slide10
4. Overall deathrate
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 heroinusers less employed [8]
Hardto keep ajobbecause:
1. Q 6 hoursdosing
2. Much timeneeded recover from use
3. But need moneyto buy drug
D.CrimeSlide11
1.>95% of dependent persons commit crimes [13]
2. Dependentpersons 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 tosociety
1. $1.2 billionper year in medical costs
2. $20 billionper year (costs to individual, family and society) [13]
F.Natural course summary (briefly summarized IIIA-E)Slide12
IV. TreatmentoverviewSlide13
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 focusedon:Slide14
1.Engagingdependent 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.Rehabthrough:Slide15
1.Individualcounseling
2.Group Ð i.e. educational, relapse prevention
3.Urines Ð objective monitoring for relapse
4. Psychosocialtreatments (i.e. contingency management, motivational
interviewing,cognitive behavioral therapy, 12-step facilitation)
5. Sober supportnetwork (i.e. 12-step groups)
6. Vocationalrehabilitation
7. Medications
D.Meds Ð opioiddependenceSlide16
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.AgonistsSlide17
a.Theory - Pre-existing dysphoria or induced receptor dysfunction continue to use. Perhaps opioid dependentpersons need opioids to function.[9]
b.Meds include:
i.Methadone
ii.LAAM
iii.Buprenorphine
V. Methadone agonist therapy
A.MethadoneSlide18
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 onlow dose (about 40mg); many on high dose 60-100mg or higher if necessary
4. Given only inlicensed clinics
B. Reduces heroinuse [17]Slide19
1.69% decrease in number of weekly heroin users [18]
2. Weekly heroinuse down by 52-69% [19,20]
C.Reduces riskforHIV
1. Subjects notin treatment 4 XÕs more likely to seroconvert HIV
+ [21]
2. HIV negativepatients followed 18 months (seroconversion 3.5% vs.
22%(methadone vs. no treatment) [20]
D.People returnto workSlide20
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 lesscrime
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]
anddouble rate of arrests/incarceration [23]
F.Helps retainpeople intreatmentSlide21
1.Double blind placebo controlled 3 year 56% retention vs. 2% for
placebo(placebo group tapered 1mg/d after stabilization) [24]
2. On methadoneÐ 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
withouthx of IDU (even on an intent to treat basis) [26]
2. HIV treatmentand methadone (hx heroin dep and HIV Ð on
methadoneless 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.DecreasesmortalityrateSlide22
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 intreatment [13,14]
4.Sweden 5-8 year follow up- those not in methadone were
about ~7.5times more likely to die [15]
I.Costeffective
1. Costs about$4000 per year (< $13 per day) [29]
2.Cost benefit of 4:1 [29]
J.Barriers to useofmethadone:Slide23
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 isphysiologically dependent on
methadone. But:
ii. Physicaldependence 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.SummarySlide24
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 intreatment
c. Helpsdisengage from drug ÒsubcultureÓ
d.Gives time for rehab
VI. Other opioid agonists (LAAM,and Buprenorphine)
A.LAAM(Levo-alpha-acetyl-methadol)Slide25
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 methadoneSlide26
a. 31% LAAM (80mgMonWedFri) completed 40 weeks of
treatmentvs.42% (methadone 50mg QD) and 52% (methadone 100mg QD)[30]
b. 39% LAAM (100mg MWF) vs 60% retention for methadone;
ofnon-completersÐ 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.LAAMsuperior to methadone 50mg but not methadone 100mg[30]
5.Concernsabout QT prolongation[32]
B.BuprenorphineSlide27
1.Pharmacology
a. Mixed opioidagonist/antagonist (antagonist at high doses)
b. Meanelimination half-life from plasma of 37 hours
c. Good parenteral,fair sublingual, poor oral bioavailability
d. Usual dosage8-32 mg/d; can be given every other day
2.Buprenorphineapproved as office basedtreatmentSlide28
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 aboutinjecting buprenorphine (seen in France [33])
a. Combined withNaloxone (opioid antagonist) in single tablet
b. Naloxone withpoor sublingual absorption but buprenorphine
has fairsublingual absorption.
c.If the tablet is dissolved and injected to get high, because of Naloxone it will precipitate withdrawal
4.Outcomes:Slide29
a. Similarquality of life (to methadone) [34]
b. Retentionlower
i. 13 weeks Ð 50%buprenorphine completed vs.
59% formethadone [35]
ii.6 weeks Ð 56% bup vs. 90% methadone
[36]
iii.Meta-analysis Ð low dose bup (<8mg)
more likely toleave treatment (OR2.72) compared with high dose methadone (>50mg)
iv.High dose bup (8mg) no differencein
retention with high dose methadone
[37]
c. Slightly worseregarding decrease in heroin use (self report and
urinepositive for morphine) [37,38]
i. low dose bup(<8mg) more illicit drug use on
urinetesting(OR 3.39) compared to methadone (>50mg)[37]
d. With higherdose or flexible dosing opiate + urines similar to
methadone [35,36]
i. Double blind Ðdouble dummy, 13 week, n=405;
urinecollectedevery 2 weeks. Morphine free urines similar in bup and methadone at alltimepoints[35]
ii. Double blind,randomized, 6 week, n=58; urine
collectedevery week. Opioid-free urines 38%
buprenorphinegroup vs. 40.5% methadone
[36]
VII.ConclusionsSlide30
A. Withouttreatment opioid dependence is very destructive
B. Methadonemaintenance is effective
1. Offer thisoption 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 agonisttreatments are becoming available
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