Clinic-based methadone vs.

officebased buprenorphine: A costeffectiveness analysis

Jordan King, PharmD Candidate

Objectives
Discuss current approaches for opioid dependence Review pharmacology of buprenorphine and methadone Examine the Markov model used Review inputs used in the model and how they were determined Evaluate results of the cost-effectiveness analysis Discuss conclusions and weaknesses of model

Step 3: Mod. - Severe Pain

WHO Pain Ladder

Step 2: Mild - Mod. Pain Mild - mod. potency opioids +/- non-opioids +/- adjuvant Step 1: Mild Pain hydrocodone/APAP oxycodone/APAP codeine

Mod. - severe potency opioids +/- non-opioids +/- adjuvant morphine fentanyl methadone oxymorphone hydromorphone

Non-opioids +/- adjuvant

APAP ASA NSAIDs tramadol

Azevedo So Leo Ferreira K, Kimura M, Jacobsen Teixeira M. The WHO analgesic ladder for cancer pain control, twenty years of use. How much pain relief does one get from using it? Support Care Cancer. 2006 Nov;14(11):1086-93. Epub 2006 Jun 8

Opioid Dependence vs. Addiction

Addiction Dependence State of adaption Withdrawal syndrome produced by: abrupt cessation rapid dose reduction decreasing blood level of drug administration of antagonist

Chronicity Compulsive use Impaired control Craving Compulsive use Continued use despite harm

DSM-IV TR Criteria Substance Dependence

Gold Standard Must have > 3 at any time in last 12 months
Tolerance Withdrawal Substance in larger amounts over longer time than intended Desire or unsuccessful attempts to limit or control use Time spent to obtain, use, or recover from substance Effect on activities due to substance use Continued use despite knowing should not use
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000.

Management of opioid dependence

1. Opioid substitution with methadone or buprenorphine
Followed by gradual taper Appropriate for dependence >1 year

2. Abrupt opioid discontinuation with the use of clonidine 3. Clonidine naltrexone detoxification
American Psychiatric Association. Practice guidelines for the treatment of patients with substance use disorders, 2nd edition. 2006. Available at: http://www.psych.org. Accessed November 05, 2013.

Methadone
Used for opioid dependence since the 1960s May only be dispensed in a certified Opioid Treatment Program Full mu-receptor agonist NMDA antagonist (mediates opioid tolerance) Highly variable pharmacokinetics
t1/2 = 8-59 hours (longer than analgesic effects) Drug accumulation/over-dose

Buprenorphine
Available for office-based treatment in the U.S. since 2000 High affinity and low intrinsic activity at the mureceptor
Dissociates other opioids May precipitate withdrawal

t1/2 = 24-60 hours

Buprenorphine/naloxone
Deter abuse of medication

Study Rationale
Higher direct annual healthcare costs among opioid abusers vs non-abusers ($15,884 vs $1,830) Lower costs in first 6 months of patients receiving any medication for opioid dependence treatment, than no medication ($10,192 vs $14,353) Buprenorphine was shown to have lower total direct healthcare costs during first 6 months than methadone ($10,049 vs $16,752) Many insurance plans do not pay for methadone or will limit duration of treatment
White AG, Birnbaum HG, Mareva M, et al. Direct costs of opioid abuse in an insured population in the United States. J Manag Care Pharm, 2005. 11(6);469-79. Baser O, Chalk M, Fiellin DA, et al. Cost and utilization outcomes of opioid-dependent treatments. Am J Manag Care, 2011. 17Suppl8: p.S235-48.

Objective of the study

Compare the cost-effectiveness of flexible dose clinic-based methadone maintenance therapy (MMT) to office-based buprenorphine maintenance therapy (BMT) in the United States

Study Design
Constructed a Markov model
Third-party payer perspective One year time horizon One week cycle length Cohort analysis performed

Inputs derived from literature

Primary Outcome
Retention in treatment Provider cost of treatment Incremental cost-effectiveness ratio (ICER)
Cost of Treatment / patients retained in treatment at one year

Baseline Cohort
Age > 18 Opioid dependent No history of treatment in last 30 days Clinically stable

Markov Model Transition States

Literature Search
PubMed Search terms: Methadone[Mesh], Buprenorphine[Mesh], "Opioid-Related Disorders"[Mesh], maintenance, dependence

Variations of above terms

Literature Search
Inclusion Criteria Head to head comparisons of MMT and BMT Flexible dosing regimens Patients entering opioid maintenance therapy Outcomes include retention in treatment and percentage of opioid negative drug screens Examined pregnant or breastfeeding patients Exclusion Criteria < six weeks in duration

Included patients <18 y/o

Used medications for indications other than dependence maintenance

Allowed patients to change medication during observation

Baseline probability of non-retention in treatment

Converted clinical trial retention in treatment data to weekly drop-out probabilities
1. 2. 3. Probability of dropping out at t1 weeks during trial (p1) p1 = drop-outs/N Convert probability to rate (r) r = -(1/t1)*ln(1-p1) Convert rate to 1-week (t2=1) probability (p2) p2 = 1-e^(-rt2)

One-week probabilities were pooled across all studies to obtain a weighted average

Probability of opioid negative urine screen

Percentages of overall opioid negative screens during clinical trials Probabilities were pooled across all studies to obtain a weighted average

Risk of non-retention with continued illicit opioid use

No data reported in clinical trials
used expert opinion
Methadone Clinics Contacted Methadone Range of Clinics Who Estimates Provided Opinion 4 0-50% Base-Case Value

25% (+/-12.5%)

Costs
Cost of Treatment (Reported in 2010 US$) Reference Design/Duration Data Source 2005 VHA, DSS Drug MMT N 2828 Cost per Week $118 VHA Funding

Barnett (2009) HC 12 Months *Schackman et al. (2012) CEA 24 Months

2001-2006 Primary Care Physician Office

BMT

741

$115

Robert Wood Johnson Foundation; National Institute on Drug Abuse

Note. HC = Historic Cohort; CEA = Cost-Effectiveness Analysis; VHA, DSS = Veterans Health Administration Decision Support System
*Data was derived from a prospective cohort analysis by Fiellin et al. ()

Barnett PG. Comparison of costs and utilization among buprenorphine and methadone patients. Addiction. 2009 Jun;104(6):982-92. Schackman BR, Leff JA, Polsky D, et al. Cost-effectiveness of long-term outpatient buprenorphine-naloxone treatment for opioid dependence in primary care. J Gen Intern Med. 2012 Jun;27(6):669-76.

Sensitivity Analysis (SA)

One-way sensitivity analysis was performed for all variables
Probability of non-retention: Low-high reported in clinical trials

Probability of opioid-negative urine drug screen: Low-high reported in clinical trials Second analysis using an estimated regression curve Increased risk of non-retention from positive UDS: Low-high estimates from expert opinion Cost per week of treatment: +/- 25% base-cost

Secondary SA altering negative-opioid rates over time

0.6

Week

MMT

BMT

0.5

0.275

0.311
0.4 Methadone

0.367

0.417
0.3 Buprenorphine Log. (Methadone) 0.2 Log. (Buprenorphine) y = 0.0859ln(x) + 0.2327 y = 0.0742ln(x) + 0.2202

0.41

0.44

12

0.433

0.42
0.1

15

0.437

0.426
0 0 5 10 15 20

18

0.377

0.513

Model Inputs
Parameters used in cost-effectiveness model Parameter Base-case Range in SA Low High Secondary SA Baseline probability of non-retention in treatment MMT BMT Probability of opioid negative UDS MMT BMT 0.423 0.415 0.47 0.55 0.76 0.65 0.0742*ln(x)+0.2202 0.0859*ln(x)+0.2327 0.027 0.042 0.014 0.031 0.04 0.055

Increased risk of non-retention from positive UDS MMT BMT Direct cost per week in treatment MMT BMT
drug screen, SA = sensitivity analysis x = week in treatment

0.25 0.25

0 0

0.5 0.5

118 115

88.5 81

147.5 135

Note. MMT = methadone maintenance therapy; BMT = buprenorphine maintenance therapy; UDS = Urine

Results
Incremental cost-effectiveness ratio Retention in treatment at one year Incremental Incremental cost retention ICER (cost/additional retention at one year)

Treatment
Base-case Methadone Buprenorphine
2010 United States dollars

Total cost

$3,155 $2,251

0.227 0.098

$904

0.13

$6,964

Cost per week of MMT

Probability of nonadherence on MMT

Cost per week of BMT

Probability of nonadherence on BMT

Probability of a negative UDS on MMT

Incremental risk of non-adherence by UDS results

Proability of negative UDS on BMT 0 2000 4000 6000 6964 8000 10000 12000 14000 16000

Incremental cost-effectiveness ratio

Secondary SA Results

Incremental cost-effectiveness ratio Treatment Secondary Sensitivity Analysis Methadone Buprenorphine $3,136 $2,247 0.227 0.098 $889 0.13 $7,003 Total cost Retention in Incremental cost Incremental treatment ICER (cost/additional week in treatment)

Note. In the secondary sensitivity analysis the probability of having a opioid negative UDS was varied over time to more closely approximate the date seen in the clinical trials. ICER = Incremental cost-effectiveness ratio, UDS = Urine drug screen. 2010 United States dollars

Discussion
MMT is associated with higher costs and higher retention
Costs due to increased time in treatment

Costs for both treatments are similar Other studies have found both options effective at reducing overall healthcare costs Insurance plans may cover BMT, but likely not MMT

Strengths
Model based off of randomized controlled trials Flexible dosing regimens were used in trials
Both medications more effective for retention at flexible dosing

Varied rates of negative UDS over time to more closely reflect real world Retention in treatment at one year is a significant endpoint and one that has not been studied in a CEA
WHO guidelines recommend this time frame as the minimum duration of treatment Retention >1 year is associated with improved longterm outcomes

Limitations
Single outcome measure retention in treatment
Drug treatment is complex; many potential confounders
Social support, socioeconomic status, accessibility to treatment facility, patient perception of medication, injectable vs non-injectable abuse history

Did not capture re-entrance into treatment post-dropout Retention is a surrogate marker for other outcomes
Mortality, reduced healthcare utilization, reduced crime, decreased comorbidity (ie, HIV/AIDS, Hepatitis)

Limitations
Costs
Studies examined two different populations
VHA vs private primary-care office BMT costs were based off provider costs and medication costs
Not true payer perspective

Limitation
Expert opinion used to determine risk of dropout with continued illicit opioid abuse
Almost no effect on model

Next Steps
Probabilistic sensitivity analysis Submit manuscript for publication Present results at ASHP midyear

Conclusions
Methadone is more costly, but also more effective at maintaining patients in treatment Cost differences between the two drugs are minimal when used in these settings

Conclusions
Medication decision should be individualized
Insurance Patient perception/desire Access to treatment program Previous failed attempts

Managed care organizations should cover both medications indefinitely Further research should include changes in total healthcare utilization and costs

QUESTIONS??