office-based opioid therapy: methadone/buprenorphine nexus edwin a. salsitz, m.d., fasam medical...
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Office-Based Opioid Therapy:Office-Based Opioid Therapy:Methadone/Buprenorphine Methadone/Buprenorphine
NexusNexus
Edwin A. Salsitz, M.D., FASAMEdwin A. Salsitz, M.D., FASAMMedical Director Office-Based Opioid TherapyMedical Director Office-Based Opioid Therapy
Beth Israel Medical Center, NYCBeth Israel Medical Center, NYCesalsitz@chpnet.orgesalsitz@chpnet.org
Financial DisclosureFinancial Disclosure
• Reckitt Benckiser Speaker Reckitt Benckiser Speaker HonorariaHonoraria
• Pfizer Speaker HonorariaPfizer Speaker Honoraria
• PriCara Speaker HonorariaPriCara Speaker Honoraria
• Purdue Pharma Adv.Board Purdue Pharma Adv.Board HonorariaHonoraria
MEDICATION ASSISTEDMEDICATION ASSISTEDADDICTION TREATMENTADDICTION TREATMENT
““AllAll Treatments Work For Treatments Work For Some Some People/Patients”People/Patients”
““No OneNo One Treatment Works for Treatment Works for All All People/Patients” People/Patients”
Alan I. Leshner, Ph.DFormer Director NIDA
OPIATE AGONIST OPIATE AGONIST THERAPYTHERAPY
PharmacologyPharmacology
AddictionAddictionRegulatoryRegulatory
StigmaStigma
DestitutionDestitutionPoliticalPolitical
The Lexington Narcotic Farm
The first facility opened on May 25, 1935, outside Lexington, Ky. The 1,050-acre site included a farm and dairy, working on which was considered therapeutic for patients. With the increased availability of state and local drug abuse treatment programs, the hospital was closed in February 1974.
Drs. Kolb, Himmelsbach, Wikler, Jaffe, Kleber, Vaillant
JAMA. 1965;193(8):646-650 JAMA Classics: Celebrating 125 Years Methadone Maintenance 4 Decades Later Thousands of Lives Saved But Still Controversial Commentary by Herbert D. Kleber, MD JAMA. 2008;300(19):2303-2305
Exclusion: non-opioid addiction/misuse, severe psychiatric problems
Methadone Maintenance 50 – 80%
Naltrexone Maintenance 10 – 20%
“Drug Free” (non-pharmacotherapeutic) 5 – 30%
LAAM Maintenance 50 – 80%
Buprenorphine-Naloxone Maintenance 40-50%**
Short-term Detoxification (any mode) 5 – 20% (limited data)
Opiate Addiction Treatment Opiate Addiction Treatment Outcome*Outcome*
* One year retention in treatment and/or follow-up with significant reduction or elimination of illicit use of opiates
** Maximum effective dose (24mgsl) equal to 60 to 70 mg/d methadone. Data base on 6 month follow-up only.
Kreek, 1996; 2001
MethadoneMethadone
• Synthetic Opioid 1937 GermanySynthetic Opioid 1937 Germany
• T ½ 24—36 hrs. InherentT ½ 24—36 hrs. Inherent
• Onset of Action 30 min. Peak 3-4 hrs.Onset of Action 30 min. Peak 3-4 hrs.
• R/S(l/d) racemic mixture mu/NMDA R/S(l/d) racemic mixture mu/NMDA antagantag
• CYP3A4, 2D6 Drug/Drug No Active CYP3A4, 2D6 Drug/Drug No Active MetabMetab
• Renal and biliary excretionRenal and biliary excretion
• Dosing QD for addiction, Q6H for PainDosing QD for addiction, Q6H for Pain
Impact of Short-Acting Heroin versusLong-Acting Methadone Administered ona Chronic Basis in Humans - 1964 Study
"High"
"Straight"
"Sick"
DaysAM PM AM PM AM
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(Met
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(ove
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"Straight"
"Sick"
DaysAM PM AM PM AM
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(Her
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Dole, Nyswander and Kreek, 1966H
Acc VTA
FCXAMYG
VP
ABN
Raphé
LC
GLU
GABA
ENK OPIOID
GABAGABA
GABA
DYN
5HT
5HT
5HT
NE
HIPP
PAG
RETIC
To dorsal horn
END
DA
GLU
Opiates
ICSS
AmphetamineCocaineOpiatesCannabinoidsPhencyclidineKetamine
OpiatesEthanolBarbituratesBenzodiazepinesNicotineCannabinoids
OPIOID
HYPOTHALLAT-TEG
BNST
NE
CRF
OFT
MesoLimbic Dopaminergic Circuit Pleasure/Reward CenterH2O, Food, Sex, Parenting, Social
Figure 2. Scheme illustrating opiate actions in the locus coeruleus. Opiates acutely inhibit locus coeruleus neurons by increasing the conductance of an inwardly rectifying K+ channel through coupling with subtypes of Gi/o, as well as by decreasing a Na+-dependent inward current through coupling with Gi/o and the consequent inhibition of adenylyl cyclase. Reduced concentrations of cAMP decrease PKA activity and the phosphorylation of the responsible channel or pump. Inhibition of the cAMP pathway also decreases phosphorylation of numerous other proteins and thereby affects many additional processes in the neuron. For example, it reduces the phosphorylation state of CREB, which may initiate some of the longer-term changes in locus coeruleus function. Upward bold arrows summarize effects of chronic morphine administration in the locus coeruleus. Chronic morphine increases concentrations of types I and VIII adenylyl cyclase (AC I and VIII), PKA catalytic (C) and regulatory type II (RII) subunits, and several phosphoproteins, including CREB. These changes contribute to the altered phenotype of the drug-addicted state. For example, the intrinsic excitability of locus coeruleus neurons is increased by enhanced activity of the cAMP pathway and Na+-dependent inward current, which contributes to the tolerance, dependence, and withdrawal exhibited by these neurons. Up-regulation of type VIII adenylyl cyclase is mediated by CREB, whereas up-regulation of type I adenylyl cyclase and of the PKA subunits appears to occur by means of a CREB-independent mechanism not yet identified.
Molecular and Cellular Basis of Addiction
Science 3 October 1997:
Eric J. Nestler, George K. Aghajanian
Fig. 3. Metabolite levels in control subjects (n=16) and in short- (n=7) and long-term (n=8) methadone maintenance treatment (MMT) subgroups. Shown are means±S.D. of percent metabolite measures. Post hoc Scheffé test results: *P<0.05 vs. control subjects; **P<0.01 vs. control subjects;
***P<0.0001 vs. control subjects ;†P<0.05 vs. long-term MMT group
Psychiatry Research: Neuroimaging Volume 90, Issue 3 , 30 June 1999,
Pages 143-152 Kaufman,M
Cerebral phosphorus metabolite abnormalities in opiate-dependent polydrug abusers in methadone maintenance
39 wk39wk137wk
Phosphorous MR Spectroscopy
From these data, we conclude that polydrug From these data, we conclude that polydrug abusers in MMT have 31P-MRS results abusers in MMT have 31P-MRS results consistent with abnormal brain metabolism consistent with abnormal brain metabolism and phospholipid balance. The nearly normal and phospholipid balance. The nearly normal metabolite profile in long-term MMT subjects metabolite profile in long-term MMT subjects suggests that prolonged MMT may be suggests that prolonged MMT may be
associated with improved neurochemistry.associated with improved neurochemistry.
Psychiatry Research: Neuroimaging Volume 90, Issue 3 , 30 June 1999, Pages 143-152
Distribution of Opioid Treatment Programs (OTPs) 2002
SAMHSA/CSAT
581 Male Heroin Addicts Followed for 33yrs
The natural history of narcotics addiction among a male sample (N = 581). From: Yih-Ing, et. al., 2001. A 33-Year Follow-up of Narcotics Addicts. Archives of
General Psychiatry, 58:503-508)
Medical MaintenanceMedical MaintenanceAdmission CriteriaAdmission Criteria
• At least 4 years in MMTPAt least 4 years in MMTP
• Negative urines for last 3 yearsNegative urines for last 3 years
• Working/School etc.Working/School etc.
• Adequate income for feesAdequate income for fees
• Recommendation from clinicRecommendation from clinic
• Not in military reservesNot in military reserves
• Stable and safe storage environmentStable and safe storage environment
Medical MaintenanceMedical MaintenanceProceduresProcedures
• Patient given 28 day supply of methadone, Patient given 28 day supply of methadone, by MD,in disket form, every 4 weeks.by MD,in disket form, every 4 weeks.
• Medication prepared by hospital pharmacy Medication prepared by hospital pharmacy in usual Rx type bottle and labelin usual Rx type bottle and label
• Routine urine toxicologiesRoutine urine toxicologies
• Patient returns before “run out” datePatient returns before “run out” date
• Primary care providedPrimary care provided
Methadone MaintenanceMethadone MaintenanceTotal duration in yearsTotal duration in yearsN = 233 patientsN = 233 patients
0
10
20
30
40
50
60
0-5 6-10 11-15 16-20 21-25 26-30 31-35 36-40
No of patients
Duration in years4/05
Medical MaintenanceMedical MaintenanceTotal Duration in YearsTotal Duration in YearsN= 233 patientsN= 233 patients
0102030405060708090
100
0-5 6-10 11-15 16-20
No. of patients
Duration in years4/05
Medical Maintenance--Medical Maintenance--DosageDosage
• Average = 75mg./dayAverage = 75mg./day
• Median = 80mg./dayMedian = 80mg./day
• Range = 5mg.----200mg./dayRange = 5mg.----200mg./day
• 30% Split Dose30% Split Dose
04/05 N=223
Medical Maintenance1983 - Present
347 =Total Enrolled347 =Total Enrolled
WithdrewWithdrew22 (6%)22 (6%)
MMTPMMTP41(12%)41(12%)
ActiveActive184 (53%)184 (53%)
TransferMMTPTransferMMTP
77CocaineCocaine
1919CauseCause
2222
2323
1414
44
99
44
11
22
11
11
- - TobaccoTobacco
- - Hepatitis CHepatitis C
- Lymphoma- Lymphoma
- Medical- Medical
- HIV- HIV
-Old AgeOld Age
-Homi/Suicide-Homi/Suicide
-Prostate Ca-Prostate Ca
LeukemiaLeukemiaRevised –06/16/09
DeathsDeaths59 (17%)59 (17%)
PainPain99
Buprenorphine 24
Deaths: 1 Tob 1 Hep C 9 liver transplants8 patients4 alive
50 – 60% Untreated, street heroin addicts:Positive for HIV-1 antibody
9% Methadone maintained since<1978(beginning of AIDS epidemic):less than 10% positive for HIV-1 antibody
Prevalence of HIV-1 (AIDS Virus)Infection in Intravenous Drug Users
New York City: 1983 - 1984 Study: Protective Effect of Methadone Maintenance Treatment
Kreek , 1984; Des Jarlais et al., 1984; 1989
New York Times
Dry Mouth Decay, Crave Sugary Drinks, Brushing/Flossing, Caustic IngredientsGrinding/Clenching Teeth,
STIGMA--METHADONESTIGMA--METHADONE
•““My Wife’s Opinion Is That My Wife’s Opinion Is That Methadone Maintenance Methadone Maintenance Treatment Is As Close To Treatment Is As Close To EvilEvil As You Can Get, Without As You Can Get, Without Killing Someone.”Killing Someone.”
A “successful” methadone patient quoting his wife’s attitudetoward methadone treatment
U.S. Drug Enforcement Administrative Agent Joanne U.S. Drug Enforcement Administrative Agent Joanne Masur,Masur, one of the last government witnesses in the one of the last government witnesses in the case against Shinderman, took the stand Friday in case against Shinderman, took the stand Friday in U.S. District Court in Portland.U.S. District Court in Portland.
Masur, whose job is preventing the diversion of Masur, whose job is preventing the diversion of prescription drugs to the black market, said she prescription drugs to the black market, said she consulted with Shinderman on at least two occasions. consulted with Shinderman on at least two occasions. But she said she had no bias against him or his But she said she had no bias against him or his clients, although she said she may have referred to clients, although she said she may have referred to them as them as "dirt bags.""dirt bags."
"That is a term I use," she said. "That is a term I use," she said. "But it's not "But it's not necessarilynecessarily derogatory."derogatory."
Portland Press Herald, 7/15/06
Crane collapses in busy New York street, killing seven in worst construction accident in recent memory'
SUBSTITUTIONSUBSTITUTIONTREATMENTTREATMENT??????????????Helpful/HarmfulHelpful/Harmful“Substituting one “Substituting one addiction for another”addiction for another”
3/19/08
Critics say methadone simply replaces one dependency with another, and some say methadone can be even harder to quit than heroin.
Scottish Conservative Party justice spokesman, Bill Aitken, recently described many of those in methadone programmes in Scotland as “sitting fat, dumb and happy" on the drug.
0%
50%
100%
150%
200%
250%
300%
1999 2000 2001 2002
Methadone Oxycodone Morphine Hydrocodone
Percent Change in Distribution of Percent Change in Distribution of Methadone and Three Comparison Methadone and Three Comparison Drugs, 1998--2002Drugs, 1998--2002
Center for Substance Abuse Treatment, Methadone-Associated Mortality: Report of a National Assessment, May 8-9, 2003. SAMHSA Publication No. 04-3904. Rockville, MD: Center for Substance Abuse Treatment, SAMHSA, 2004.
Per
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Per
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1998
54%
390%
Methadone Deaths Not Linked to Misuse of Methadone Deaths Not Linked to Misuse of Methadone from Treatment Centers Methadone from Treatment Centers
• The consensus report, “Methadone-Associated Mortality, The consensus report, “Methadone-Associated Mortality, Report of a National Assessment”, concludes that “although Report of a National Assessment”, concludes that “although the data remain incomplete, National Assessment meeting the data remain incomplete, National Assessment meeting participants concurred participants concurred that methadone tablets and/or that methadone tablets and/or diskettes distributed through channels diskettes distributed through channels other than opioid other than opioid treatment programstreatment programs most likely are the central factor in most likely are the central factor in methadone-associated mortality.”methadone-associated mortality.”
• The panel based it conclusion that methadone is coming from The panel based it conclusion that methadone is coming from other sources on data showing that the greatest growth in other sources on data showing that the greatest growth in methadone distribution in recent years is associated with its methadone distribution in recent years is associated with its use as a use as a prescription analgesic prescribed for pain,prescription analgesic prescribed for pain, primarily in primarily in solid tablet or diskette form, and not in the liquid formulations solid tablet or diskette form, and not in the liquid formulations that are the mainstay of opioid treatment programs that treat that are the mainstay of opioid treatment programs that treat patients with methadone for abuse of heroin or prescription patients with methadone for abuse of heroin or prescription pain killers. pain killers.
• The experts surmise that current reports of methadone deaths The experts surmise that current reports of methadone deaths involve one of three scenarios: illicitly obtained methadone involve one of three scenarios: illicitly obtained methadone used in excessive or repetitive doses in an attempt to achieve used in excessive or repetitive doses in an attempt to achieve euphoric effects; methadone, either licitly or illicitly obtained, euphoric effects; methadone, either licitly or illicitly obtained, used in combination with other prescription medications, such used in combination with other prescription medications, such as benzodiazepines (anti-anxiety medications), alcohol or other as benzodiazepines (anti-anxiety medications), alcohol or other opioids; or an accumulation of methadone to harmful serum opioids; or an accumulation of methadone to harmful serum levels in the first few days of treatment for addiction or pain, levels in the first few days of treatment for addiction or pain, before tolerance is developed before tolerance is developed SAMHSA--2004
JAMA 2000:283:1303-1310
Copyright restrictions may apply.
Sees, K. L. et al. JAMA 2000;283:1303-1310.
Survival Function by Treatment Group
Copyright restrictions may apply.
Sees, K. L. et al. JAMA 2000;283:1303-1310.
Proportion of Participants Using Heroin and Mean Days of Heroin Use in Previous 30 Days
Treatment duration (days)
Remaining in treatment (nr)
0
5
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15
20
0 50 100 150 200 250 300 350
Control
Buprenorphine
Buprenorphine Maintenance/Withdrawal: Retention
(Kakko et al., 2003)
PlaceboPlacebo BuprenoBuprenorphirphinnee
Cox Cox regressioregressio
nn
DeadDead 4/20 4/20 (20%)(20%) 0/20 (0%)0/20 (0%) 22=5.9; =5.9;
p=0.015p=0.015
Kakko et al, Lancet Feb 22, 2003Buprenorphine Maintenance/Withdrawal: Mortality
Transitioning Stable Methadone Maintenance Patients to
Buprenorphine Maintenance Edwin A. Salsitz, M.D., FASAM
Beth Israel Medical CenterNew York City
Why Transition From Methadone?
• Office-based availability• Less than monthly visits• Different side effect profile• Possible diminished stigma• Geographic Flexibility
Why Not Transition?• May not be as effective for
individual• Fear of destabilization• Transition difficult
– Opioid withdrawal required– May precipitate withdrawal
• Less social and psychological services
• Insurance/cost• Satisfied with methadone• “If it Ain’t Broke….”
Subjects• MMM eligibility requirements
– 4 years in Methadone Maintenance Treatment Program (MMTP)
– 3 years of illicit drug abstinence– No excessive drinking– Employment/Education, etc.– Emotional stability
• 6/03 - 1/08 patients on methadone ≤ 80 mg/day offered transition to buprenorphine
Johnson RE, Chutuape MA, et al. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med. 2000;343:1290–1297.
Transfer
• Patients given option to taper methadone to 30-40 mg/day
• Standard protocol used– Patients abstained from
methadone for 48-72 hours– First buprenorphine/naloxone
dose given when Clinical Opiate Withdrawal Scale (COWS) score indicated withdrawal
• Stabilized over following weekCenter for Substance Abuse Treatment. Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction. Treatment Improvement Protocol Series (TIPS) 40. Department of Health and Human Services Publication #SMA04-3939. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004.
Study Participants• 102 MMM patients offered
buprenorphine• 23 (22.5%) accepted• Two stable MMTP patients referred• 104 patients total-25 (24.0%)
accepted • Reasons for not wanting to switch
– no perceived advantage of switching– concern about efficacy– concern about side effects
(withdrawal)
Outcomes
• 25/25 patients successfully stabilized on buprenorphine (100%)
• Average buprenorphine dose- 10.9 mg (S.D. 7.6)
• Average time on buprenorphine maintenance- 30.3 months (S.D. 16.5)
Methadone Dose Compared to Buprenorphine Dose
Low-moderate correlation - Spearman rank order coefficient = 0.46, p = 0.02
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Positive Experiences
• No stabilized subjects elected to return to methadone
• Less frequent office visits – every 1 - 6 months, not monthly– several patients moved further
away from program
• 24/25 patients reported feeling “clearer”
Unsuccessful Transfers• 5 initially reluctant patients
agreed to attempt conversion • All unsuccessful• Duration of buprenorphine
treatment - 1 dose to 5 days• Returned to methadone without
event• 2 cases - “dysphoria” • 3 cases – no reason listed
Study Strengths
• Subjects– Unique population in research– Findings applicable to stable
methadone maintained patients seeking transfer to Buprenorphine
• Very long follow-up period - absence of negative outcomes
CONCLUSIONS
• Buprenorphine is viable maintenance treatment for stable patients on methadone doses up to 80 mg/day
• Transitioning generally well tolerated
• Buprenorphine efficacious and safe long-term
• Low to moderate association between methadone and buprenorphine doses
Admission EKG QTc~ 600 msec.
QTc ~ 440 msec. Off methadone x 1 WeekBupe started
Russia Scorns Methadone for Heroin Russia Scorns Methadone for Heroin AddictionAddiction Science Times Science Times 7-22-087-22-08,, Michael Schwartz Michael Schwartz
• After the conference in February, which Dr. Mendelevich After the conference in February, which Dr. Mendelevich helped organize, Moscow’s legislature began an inquiry into helped organize, Moscow’s legislature began an inquiry into whether he had engaged in “drug propaganda,” and it whether he had engaged in “drug propaganda,” and it called on prosecutors to open a case against him, he said called on prosecutors to open a case against him, he said
• At the same AIDS conference, Dr. Gennady G. Onishchenko, At the same AIDS conference, Dr. Gennady G. Onishchenko, the country’s chief sanitary doctor, the equivalent of the country’s chief sanitary doctor, the equivalent of surgeon general, said health officials “are not convinced surgeon general, said health officials “are not convinced that this is effective,” and added,that this is effective,” and added, “There is little optimism “There is little optimism for legalizing methadone therapy in the near future.” for legalizing methadone therapy in the near future.”
• ““Scientific arguments, evidence-based data, are not Scientific arguments, evidence-based data, are not convincing them,” said Evgeny M. Krupitsky, the head of a convincing them,” said Evgeny M. Krupitsky, the head of a laboratory that conducts research on drug addiction at St. laboratory that conducts research on drug addiction at St. Petersburg State Pavlov Medical University. Russian Petersburg State Pavlov Medical University. Russian methodology regarding opiate addiction “is not evidence-methodology regarding opiate addiction “is not evidence-based,” but relies on “subjective opinions of major leaders based,” but relies on “subjective opinions of major leaders in this field.in this field.
DRUG PROBLEM Patients in a program for heroin addiction in Yekaterinburg, Russia, run by a nongovernmental group.
MEDICATION ASSISTEDMEDICATION ASSISTEDADDICTION TREATMENTADDICTION TREATMENT
““AllAll Treatments Work For Treatments Work For Some Some People/Patients”People/Patients”
““No OneNo One Treatment Works for Treatment Works for All All People/Patients” People/Patients”
Alan I. Leshner, Ph.DFormer Director NIDA
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