Adaptive Approach to Naltrexone Treatment for Alcoholism

Transcription

1 Adaptive Approach to Naltrexone Treatment for Alcoholism David W. Oslin, Kevin G. Lynch, Susan Murphy, Helen M. Pettinati, Kyle M. Kampman, William Dundon, Thomas Ten Have, Peter Gariti, James McKay, Charles P. O Brien Research supported by R01 AA (Oslin), RC1 AA (Lynch), VISN 4 MIRECC (VA)

2 Introduction Alcoholism costs the nation $150 Billion / annum in the US. As such it is the most expensive addictive disorder. Alcoholism leads to increased mortality and morbidity Alcoholism is common with about 7 million Americans afflicted Worldwide alcoholism is the 7 th leading cause of disability

3 Despite a host of options Pharmacotherapy 3

4 How do we use these various treatments? Under what conditions and for which patients will treatment have the greatest impact? How do we adapt / sequence treatments to maximize outcomes?

5 Why Adapt / Sequence? Illness Characteristics Chronic Heterogeneous No universally effective treatment Fluctuating course (acute, maintenance, remission, relapse ) Treatment response is often defined early (if a treatment isn t working do you really stick with it) Patient Characteristics Changing motivation and priorities Changing support systems (health care, social support, etc)

6 Study Goals The aims for this study were to evaluate the best strategies for managing alcohol dependence using naltrexone and Medical Management as the initial treatments The study was divided into two phase in order to test Alternative criteria for defining initial response to naltrexone Alternative maintenance treatments for responders Alternative treatments for nonresponders. We hypothesized that the definition of response would not only lead to different proportions of responders and non responders but would impact the outcomes of subsequent treatment decisions.

7 Treatment Eligibility Inclusion Criteria: at least 18 years of age, meet DSM-IV criteria for alcohol dependence report at least 12 standard drinks per week of drinking or a pattern of binge drinking, obtain at least 2 consecutive days of abstinence prior to the start of medication. Exclusion Criteria: current DSM-IV diagnosis of any psychoactive substance dependence other than alcohol evidence (self-report, UDS) of opioid abuse in the past 30 days Subjects could not be taking psychotropic medications Evidence of current severe psychiatric symptoms or severe medical illnesses Significant hepatocellular injury, elevations of SGPT (ALT) and SGOT (AST) greater than 5 times normal, or elevated bilirubin (of 1.3 or higher).

8 Phase 1 At the start of Phase 1, all patients started on naltrexone combined with psychotherapy (MM). Patients were randomized to one of two definitions of non-response to naltrexone. Stringent Definition : Subjects taking at least 10 days of naltrexone and who have 2 or more heavy drinking days during the first 8 weeks of treatment. Heavy drinking was defined as four or more drinks in a day for women and five or more drinks in a day for men. Lenient Definition: Subjects taking at least 10 days of naltrexone and who have 5 or more heavy drinking days during the first 8 weeks. During Phase 1, subjects were classified as Responders NonResponders Ineligible to continue

9 Phase 2 In second stage: randomize responders to either Usual Care (UC) - follow up every 2 months Telephone Disease Management (TDM), where TDM is UC plus telephone counseling randomize non-responders to one of AUGMENT: NTX/MM plus psychotherapy CBI, SWITCH: PLA/MM + CBI

10 Study Design Randomization Outcome / tailoring variable Randomization Recruitment MM + Nalt Response Stringent Control Nalt +MM Response Lenient Control Response Nonresponse prescription + Telephone Disease Management + Follow-up at 4month prescription + + Follow-up at 4month CBI + MM +Naltrexone CBI + MM +Placebo Up To 8 Weeks. 15 Weeks.

11 Study Sample 302 Subjects Randomized The sample was about 70% White, 86% Male, and 28% were above the age of 55. Stringent Mean (SD) Lenient Mean (SD) Sample Size % Days Drinking 79 (23) 79 (22) % Days Heavy Drinking 67 (31) 68 (29) Drinks Per Drinking Day 10 (5) 11 (7) Years Used Alcohol 26 (12) 27 (11) Years Used Alc to Intox 19 (12) 20 (11)

12 Phase 1 Outcomes Definition NonResponder (%) Responder (%) Dropout 2 day 5 day (33) (17) (44) (69) (11) (13) Days in Phase 1 for non-responders mean SD Stringent Lenient

13 Heavy Drinking behavior in Phase 1 (D2,R) (D5,R) (D2,NR) (D5,NR) % of days where Heavy drinking occurred Small range of heavy drinking days in responders, with three-day difference built in to definition, yields small, but significant difference in rates among responders. Bigger difference, but not significant (p=0.22) in non-responders.

14 Phase 2 drinking Group Week 8 Week 15 % 0 1+ mean (se) % 0 1+ mean (se) UC + TDM (2) (2) UC (2) (2) NTX (4) (3) PLA (4) (4) GEE in responders: Odds ratio of 2.6, (1.3,5.1) in favor of abstinence for UC+TDM versus UC; χ2 (1) = 8, p = 0.01; GEE in non-responders: no significant effects. Some evidence that the 5-day def. was associated with higher abstinence: OR = 1.7, (0.9,3.1), although not significant (p = 0.10);

15 Phase 2 heavy drinking Group Week 8 Week 15 % 0 1+ mean (se) % 0 1+ mean (se) UC + TDM 71 8 (2) (2) UC (3) 62 9 (2) NTX (4) (4) PLA (5) (5) Similar to pattern of effect for drinking GEE in responders/non-responders: No significant effects - all p- values 0.3 rates of abstinence from heavy drinking were 15% higher in TDM then UC for people from 5-day definition (p = 0.08) and about 5% lower for TDM than UC in 2-day condition, with a non-significant interaction: X 2 (1) = 3, p = 0.1.

16 Regime comparisons based on causal contrasts Strategy Threshold Resp NonResp n 1 D2 UC PLA 91 (=27+64) 2 D2 UC NTX 88 (=27+61) 3 D2 TDM PLA 81 (=27+54) 4 D2 TDM NTX 96 (=27+69) 5 D5 UC PLA 85 (=25+60) 6 D5 UC NTX 89 (=25+64) 7 D5 TDM PLA 88 (=25+63) 8 D5 TDM NTX 92 (=25+67)

17 Strategies We focus on a simple, univariate, outcome: number of days of heavy drinking in last seven weeks of second phase. Clinically, after our initial open label treatment, have we achieved in-control drinking by the end of a 15- week rescue or maintenance phase. Poisson regression

18 Regime estimates for ExTend: heavy drinking in final 7 weeks Strategy Threshold Resp NonResp Estimate (se) 1 D2 UC PLA 7.3 (.26) 2 D2 UC NTX 5.9 (.27) 3 D2 TDM PLA 7.3 (.26) 4 D2 TDM NTX 5.8 (.27) 5 D5 UC PLA 4.3 (.32) 6 D5 UC NTX 6.3 (.25) 7 D5 TDM PLA 3.7 (.35) 8 D5 TDM NTX 5.8 (.26) Suggestion that five-day strategies have lower heavy drinking frequency than two-day strategies.

19 Lessons Learned Drop out not improved Initial contrasts may have not distinct enough particularly challenging was to catch people at the time of change Small sample size for non-responders

20 Take Home Messages Phase 1 - more responders with more lax definition. Phase 2 Responders Heavy drinking rates are low intense therapy is not necessary to maintain gains More lenient relapse criteria allows a little more time in phase 1 and has a positive impact on phase 2. TDM improves abstinence rates but not heavy drinking rates While TCM showed only marginal effects, the low cost and easy delivery (telephone) of the intervention suggest the effort may be worth the small effect. Phase 2 non responders a fair number of patients (30-40%) can get better after the change in treatment - unfortunately we cannot say if this is related to CBT continuing naltrexone seemed of no benefit Overall algorithm A little more time (leniency) in phase 1 was good Recovery for non-responders was possible in this study treatment was changed