JC2011-12 Buprenorphine maintenance versus placebo or methadone mainte

JOURNAL CLUB 12/01/11: 

JOURNAL CLUB 12/01/11 By Yenny VanderWaerden , MD

Behavioral Science and Addiction Medicine: 

Behavioral Science and Addiction Medicine Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence ( Review)

The Case: 

The Case A 37 year old man was transferred to the emergency department at HGH after being found unresponsive by bystanders. His pulse rate was 30 beats/min with prolonged QT. Patient currently is in a methadone maintenance program. The question is: Should this patient be on methadone?

INTRODUCTION : 

INTRODUCTION Heroin dependence Chronic relapsing condition Affects more than 1 million persons in the US

INTRODUCTION : 

INTRODUCTION Risk of heroin dependence includes: fatal overdoses infections ( endocarditis, HIV, Hep C virus) social disintegration violence and crime associated burden on communities including medical & public health criminal-justice cost public disorder and crime against property

BACKGROUND : 

BACKGROUND Methadone is very difficult to use and very toxic in overdose Buprenorphine has been reported as an alternative to methadone for maintenance treatment of opioid dependence

METHADONE : 

METHADONE Standard opioid-substitution treatment Methadone is a full agonist at µ receptors Down side of methadone: P otential to produce and or maintain dependence on opioids Experience withdrawal if a daily dose is missed Very toxic in overdose Detoxification is prolonged and difficult Overdose: respiratory depression or sedation Other limitations of use : Daily dosing, clinic visits

BUPRENORPHINE : 

BUPRENORPHINE Synthetic opioid Used for management of acute pain Causes morphine like subjective effects and produces cross tolerance to other opioids It is partial agonist at opioid receptors sites This feature appears to make buprenorphine safer in overdoses (especially when combined with naloxone ) Easier withdrawal phase Longer duration of action

OBJECTIVE : 

OBJECTIVE To evaluate the effects of buprenorphine maintenance against placebo and methadone maintenance in retaining patients in treatment and in suppressing illicit drug use.

DESCRIPTION OF THE STUDY: 

DESCRIPTION OF THE STUDY Meta-analysis of all published studies evaluating buprenorphine vs. methadone (and vs. placebo). Twenty four studies met the inclusion criteria; half of the studies were from North America and the other half included Europe, the Middle East and Australia

DESCRIPTION OF THE STUDY: 

DESCRIPTION OF THE STUDY Majority of participants were male and tended to be approximately 30 years old Interventions ranged from 2 weeks to 52 weeks Of the 24 studies which met the inclusion criteria (4,497 participants), all were randomized clinical trials and all but 6 were double blind.

POPULATION: 

POPULATION Individuals dependent on heroin or other opioids No distinction was made between those using heroin and those in methadone treatment Pregnant women were not included

SOURCES : 

SOURCES Various Electronic sources such as Cochrane Drugs and Alcohol Review Group Register, Medline etc. Additional research Library of Congress databases Authors were asked about any other published or unpublished relevant RCT’s

Multiple Dose Comparisons (Fixed Dosing Approach): 

Multiple Dose Comparisons (Fixed Dosing Approach) Dose Ranges Buprenorphine with Methodone Buprenorphine Placebo Comparator Low 20 - 35 mg 2 - 6 mg 0-1 vs 2-5 mg Medium 50 - 80 mg 7 - 15 mg 0-1 vs 6-12 mg High 120 mg (or more) 16 mg 0-1 vs 16 mg

Five Primary Outcome Measures: 

Five Primary Outcome Measures 1 . Retention in Treatment for Opioid Dependence Measured by the number of participants still in treatment by the end of the study 2. Use of opioids Measured through urinalysis and self reported 3. Other substance abuse Measured through urinalysis 4. Criminal activity (Self Reported) 5. Mortality

RESULTS: 

RESULTS Buprenorphine was statistically significantly superior to placebo medication in retention of patients in treatment low doses (RR=1.50; 95% CI: 1.19 - 1.88 ) medium (RR=1.74; 95% CI: 1.06 - 2.87 ) high doses (RR=1.74; 95% CI: 1.02 - 2.96 ) However , only medium and high dose of buprenorphine suppressed heroin use significantly above placebo.

Results (Abbreviated): 

Results (Abbreviated) Primary Outcome Relative Risk (buprenorphine vs. methadone) Retention in Treatment 0.83 (0.72-0.95) Use of Opioids Nonsignificant Other Substance Misuse Nonsignificant Criminal Activity Nonsignificant Mortality Nonsignificant

Results: 

Results More patients taking buprenorphine drop out of treatment than patients taking methadone. There are no real differences in the other primary outcomes.

Discussion Questions: 

Discussion Questions Should we prescribe buprenorphine at Highland? Why do you think buprenorphine is inferior to methadone in retaining people in treatment?

Author’s Conclusions: 

Author’s Conclusions “Methadone is statistically significantly better able to retain patients than buprenorphine in flexible dosing approaches, the difference being slight in favor of methadone.” “ Buprenorphine maintenance should be supported as a maintenance treatment, where higher doses of methadone cannot be administered or methadone is not tolerated.” “Given buprenorphine’s different pharmacological properties, it may have advantages in some settings and under some policies where its relative safety and alternate day administration are useful clinically compared to methadone.”

My Conclusions: 

My Conclusions Patients, as in the above example, who have an intolerance to methadone should be considered for high doses of buprenorphine Remaining question relates to the success rate of permanent separation from opioid dependence