1. Office-Based Opioid Therapy: Methadone/Buprenorphine Nexus
Edwin A. Salsitz, M.D., FASAM
Medical Director Office-Based Opioid Therapy
Beth Israel Medical Center, NYC

2. Financial Disclosure Reckitt Benckiser Speaker Honoraria
Pfizer Speaker Honoraria
PriCara Speaker Honoraria
Purdue Pharma Adv.Board Honoraria

3. MEDICATION ASSISTED ADDICTION TREATMENT
“All Treatments Work For Some People/Patients”
“No One Treatment Works for All People/Patients”
Alan I. Leshner, Ph.D
Former Director NIDA

4. OPIATE AGONIST THERAPY
Pharmacology
Addiction
Regulatory
Stigma
Destitution
Political

7. 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

9.   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):
JAMA. 1965;193(8):

10. Exclusion: non-opioid addiction/misuse, severe psychiatric problems

11. Opiate Addiction Treatment Outcome*
Methadone Maintenance – 80%
Naltrexone Maintenance – 20%
“Drug Free” (non-pharmacotherapeutic) 5 – 30%
LAAM Maintenance – 80%
Buprenorphine-Naloxone Maintenance %**
Short-term Detoxification (any mode) – 20% (limited data)
* 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

12. Methadone Synthetic Opioid 1937 Germany T ½ 24—36 hrs. Inherent
Onset of Action 30 min. Peak 3-4 hrs.
R/S(l/d) racemic mixture mu/NMDA antag
CYP3A4, 2D6 Drug/Drug No Active Metab
Renal and biliary excretion
Dosing QD for addiction, Q6H for Pain

13. Functional State (Heroin) Functional State (Methadone)
Impact of Short-Acting Heroin versus Long-Acting Methadone Administered on a Chronic Basis in Humans Study
"High"
Functional State (Heroin)
(overdose)
"Straight"
"Sick" AM PM AM PM AM
Days
"High"
Functional State (Methadone)
"Straight"
"Sick" AM PM AM H PM AM
Days
Dole, Nyswander and Kreek, 1966

15. MesoLimbic Dopaminergic Circuit Pleasure/Reward Center
Acc
VTA
Amphetamine
Cocaine
Opiates
Cannabinoids
Phencyclidine
Ketamine
HIPP
GLU
FCX
AMYG
CRF
GLU
5HT
GABA
OPIOID
OPIOID
ENK
GABA
GABA VP
DYN
5HT
OFT DA
BNST
GABA NE
ABN LC
Opiates
PAG NE
HYPOTHAL
END
LAT-TEG
To dorsal horn
Opiates
Ethanol
Barbiturates
Benzodiazepines
Nicotine
Cannabinoids
5HT
ICSS
Raphé
MesoLimbic Dopaminergic Circuit Pleasure/Reward Center
H2O, Food, Sex, Parenting, Social
RETIC

16. Molecular and Cellular Basis of Addiction
Science 3 October 1997:
Eric J. Nestler,
George K. Aghajanian
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.

17. 39wk
137wk
39 wk
Cerebral phosphorus metabolite abnormalities in opiate-dependent polydrug abusers in methadone maintenance
Psychiatry Research: Neuroimaging Volume 90, Issue 3 , 30 June 1999, Pages
Kaufman,M
Phosphorous MR Spectroscopy
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< vs. control subjects ;†P<0.05 vs. long-term MMT group

18. From these data, we conclude that polydrug abusers in MMT have 31P-MRS results consistent with abnormal brain metabolism and phospholipid balance. The nearly normal metabolite profile in long-term MMT subjects suggests that prolonged MMT may be associated with improved neurochemistry.
Psychiatry Research: Neuroimaging Volume 90, Issue 3 , 30 June 1999, Pages

19. Distribution of Opioid Treatment Programs (OTPs)
2002
SAMHSA/CSAT

20. 581 Male Heroin Addicts Followed for 33yrs
The natural history of narcotics addiction among a male sample (N = 581).
From: Yih-Ing, et. al., A 33-Year Follow-up of Narcotics Addicts. Archives of General Psychiatry, 58: )

23. Medical Maintenance Admission Criteria
At least 4 years in MMTP
Negative urines for last 3 years
Working/School etc.
Adequate income for fees
Recommendation from clinic
Not in military reserves
Stable and safe storage environment

24. Medical Maintenance Procedures
Patient given 28 day supply of methadone, by MD,in disket form, every 4 weeks.
Medication prepared by hospital pharmacy in usual Rx type bottle and label
Routine urine toxicologies
Patient returns before “run out” date
Primary care provided

25. Methadone Maintenance Total duration in years N = 233 patients
4/05
Duration in years

26. Medical Maintenance Total Duration in Years N= 233 patients
4/05
Duration in years

27. Medical Maintenance--Dosage
Average = 75mg./day
Median = 80mg./day
Range = 5mg mg./day
30% Split Dose
04/ N=223

28. Medical Maintenance 1983 - Present
347 =Total Enrolled
Withdrew
22 (6%)
MMTP
41(12%)
Active
184 (53%)
Deaths
59 (17%)
TransferMMTP 7
Cocaine 19
Cause 22 23 14 4 9 1 2
- Tobacco
- Hepatitis C
- Lymphoma
- Medical
- HIV
Old Age
-Homi/Suicide
-Prostate Ca
Leukemia
Buprenorphine 24
Deaths: 1 Tob 1 Hep C
Pain 9
9 liver transplants
8 patients
4 alive
Revised –06/16/09 10

30. Prevalence of HIV-1 (AIDS Virus) Infection in Intravenous Drug Users New York City: Study: Protective Effect of Methadone Maintenance Treatment
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
Kreek , 1984; Des Jarlais et al., 1984; 1989

31. New York Times

32. Dry Mouth Decay, Crave Sugary Drinks, Brushing/Flossing, Caustic Ingredients
Grinding/Clenching Teeth,

33. STIGMA--METHADONE
“My Wife’s Opinion Is That Methadone Maintenance Treatment Is As Close To Evil As You Can Get, Without Killing Someone.”
A “successful” methadone patient quoting his wife’s attitude
toward methadone treatment

34. U.S. Drug Enforcement Administrative Agent Joanne Masur, one of the last government witnesses in the case against Shinderman, took the stand Friday in U.S. District Court in Portland. Masur, whose job is preventing the diversion of prescription drugs to the black market, said she consulted with Shinderman on at least two occasions. But she said she had no bias against him or his clients, although she said she may have referred to them as "dirt bags." "That is a term I use," she said. "But it's not necessarily derogatory."
Portland Press Herald, 7/15/06

35. Crane collapses in busy New York street, killing seven in worst construction accident in recent memory'

36. SUBSTITUTION TREATMENT
SUBSTITUTION TREATMENT ??????? Helpful/Harmful “Substituting one addiction for another”

37. 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.

38. Percent Change in Distribution of Methadone and Three Comparison Drugs, 1998--2002
Percent Change from Baseline Year 1998
This slide illustrates the recent increase in distribution of methadone. MMT programs for addiction and pain therapy are the two uses of methadone. Distribution of methadone through MMT programs remained relatively flat during this period suggesting the increase in distribution was primarily for analgesia.
Center for Substance Abuse Treatment, Methadone-Associated Mortality: Report of a National Assessment, May 8-9, SAMHSA Publication No Rockville, MD: Center for Substance Abuse Treatment, SAMHSA, 2004.

39. 54%
390%

40. Methadone Deaths Not Linked to Misuse of Methadone from Treatment Centers
The consensus report, “Methadone-Associated Mortality, Report of a National Assessment”, concludes that “although the data remain incomplete, National Assessment meeting participants concurred that methadone tablets and/or diskettes distributed through channels other than opioid treatment programs most likely are the central factor in methadone-associated mortality.”
The panel based it conclusion that methadone is coming from other sources on data showing that the greatest growth in methadone distribution in recent years is associated with its use as a prescription analgesic prescribed for pain, primarily in solid tablet or diskette form, and not in the liquid formulations that are the mainstay of opioid treatment programs that treat patients with methadone for abuse of heroin or prescription pain killers.
The experts surmise that current reports of methadone deaths involve one of three scenarios: illicitly obtained methadone used in excessive or repetitive doses in an attempt to achieve euphoric effects; methadone, either licitly or illicitly obtained, used in combination with other prescription medications, such as benzodiazepines (anti-anxiety medications), alcohol or other opioids; or an accumulation of methadone to harmful serum levels in the first few days of treatment for addiction or pain, before tolerance is developed
SAMHSA--2004

41. JAMA 2000:283:

42. Survival Function by Treatment Group
Sees, K. L. et al. JAMA 2000;283:
Copyright restrictions may apply.

43. Proportion of Participants Using Heroin and Mean Days of Heroin Use in Previous 30 Days
Sees, K. L. et al. JAMA 2000;283:
Copyright restrictions may apply.

44. Buprenorphine Maintenance/Withdrawal: Retention20 15
Remaining in treatment (nr) 10
1. This figure shows treatment retention, which was significantly better for the maintenance (buprenorphine) vs. control (withdrawal followed by placebo) group. All placebo patients who dropped out did so following relapse to drug use (as determined by urine testing). In the maintenance group, one patient dropped out of treatment, and four were discharged due to relapse in their drug use.
2. Urine results showed that 74.8% of samples were negative for drugs in the buprenorphine maintenance group over the course of the year. 5
Control
Buprenorphine 50
100
150
200
250
300
350
Treatment duration (days)
(Kakko et al., 2003)

45. Kakko et al, Lancet Feb 22, 2003
Buprenorphine Maintenance/Withdrawal: Mortality
Placebo
Buprenorphine
Cox regression
Dead
4/20 (20%)
0/20 (0%)
2=5.9; p=0.015
1. While not the primary goal of the study, the study noted that four of the patients who underwent a withdrawal (which was inpatient, and lasted six days) had died after one year -- compared to none of the patients in the buprenorphine maintenance group.

46. Transitioning Stable Methadone Maintenance Patients to Buprenorphine Maintenance
Edwin A. Salsitz, M.D., FASAM
Beth Israel Medical Center
New York City 46

47. Why Transition From Methadone?
Office-based availability
Less than monthly visits
Different side effect profile
Possible diminished stigma
Geographic Flexibility

48. 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….”

49. 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. 49

50. Transfer Patients given option to taper methadone to 30-40 mg/day
Standard protocol used
Patients abstained from methadone for hours
First buprenorphine/naloxone dose given when Clinical Opiate Withdrawal Scale (COWS) score indicated withdrawal
Stabilized over following week
Center 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 #SMA Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004. 50

51. 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)

52. Outcomes
25/25 patients successfully stabilized on buprenorphine (100%)
Average buprenorphine dose mg (S.D. 7.6)
Average time on buprenorphine maintenance months (S.D. 16.5)

53. Methadone Dose Compared to Buprenorphine Dose40 35 30 25
Final buprenorphine dose mg/day 20 15 10 5 10 20 30 40 50 60 70 80 90
Baseline methadone dose mg/day
Low-moderate correlation - Spearman rank order coefficient = 0.46, p = 0.02 53

54. Positive Experiences
No stabilized subjects elected to return to methadone
Less frequent office visits
every months, not monthly
several patients moved further away from program
24/25 patients reported feeling “clearer”

55. 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 55

56. 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 56

57. 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

58. Admission EKG QTc~ 600 msec.

60. QTc ~ 440 msec. Off methadone x 1 Week
Bupe started

62. Russia Scorns Methadone for Heroin Addiction Science Times 7-22-08, Michael Schwartz
After the conference in February, which Dr. Mendelevich helped organize, Moscow’s legislature began an inquiry into whether he had engaged in “drug propaganda,” and it called on prosecutors to open a case against him, he said
At the same AIDS conference, Dr. Gennady G. Onishchenko, the country’s chief sanitary doctor, the equivalent of surgeon general, said health officials “are not convinced that this is effective,” and added, “There is little optimism for legalizing methadone therapy in the near future.”
“Scientific arguments, evidence-based data, are not convincing them,” said Evgeny M. Krupitsky, the head of a laboratory that conducts research on drug addiction at St. Petersburg State Pavlov Medical University. Russian methodology regarding opiate addiction “is not evidence-based,” but relies on “subjective opinions of major leaders in this field.

63. DRUG PROBLEM Patients in a program for heroin addiction in Yekaterinburg, Russia, run by a nongovernmental group.

65. MEDICATION ASSISTED ADDICTION TREATMENT
“All Treatments Work For Some People/Patients”
“No One Treatment Works for All People/Patients”
Alan I. Leshner, Ph.D
Former Director NIDA