Clinical trials evaluating medications for the treatment of substance abuse disorders usually determine whether the medication facilitates abstinence or prevents relapse, although a third possible effect will be discussed below. A facilitation of abstinence end-point employs an analysis that determines whether abstinence rates are higher in the medication group for a specified portion of the trial. In this issue, Elkashef et al.  report that topiramate was administered for 13 weeks, with a target dose of 200 mg per day. The primary outcome measure of this trial was to determine whether topiramate facilitated abstinence in methamphetamine-dependent participants in weeks 6–12. The primary analysis, using a generalized estimating equations (GEE) model, showed that there was no difference in abstinence rates between the groups (P = 0.13). This lack of a significant finding is often enough to deem a medication as ineffective and abandon further development. However, the secondary analyses and some other trial details give credence to the notion that this medication deserves a second look.
Several features of the trial may have adversely impacted the efficacy analyses. The trial had a 45% dropout rate at week 12, which was higher than anticipated and probably resulted in a loss of power. Further, the majority of topiramate-treated participants took ≤150 mg per day and the compliance from pill counts was, at best, 70%. Thus, the actual amounts taken may have been closer to an average of 100 mg per day. The authors acknowledge that this may have been a barely therapeutic dose, and suggest several methods to improve medication compliance. Inadequate medication compliance was also cited by Anderson et al.  as potentially impacting the determination of the efficacy of modafinil for the treatment of methamphetamine dependence. Moreover, Czobor & Skolnick  emphasize the importance of medication compliance to a successful trial outcome. Clearly, future trials need to pay more attention to medication compliance, possibly including observed dosing at clinic visits.
Secondary measures of methamphetamine use, obtained by self-report and urinalysis, yielded interesting results: reduction in use compared to baseline use, quantitative reduction in methamphetamine urine levels across time and calculation of relapse rates for those subjects with methamphetamine negative urines at baseline. Twenty-six participants, fortuitously split evenly between the two groups, were abstinent at baseline. While there was no difference in relapse rates during weeks 1–6, the topiramate group had significantly fewer relapses during weeks 6–12 (P = 0.02). While the trial was not designed specifically to look at prevention of relapse, this finding suggests that further research should examine this possibility. A similar finding, prevention of relapse in abstinent before randomization cocaine-dependent trial participants treated with topiramate, was reported by Kampman et al. , and strengthens the notion of evaluating topiramate for relapse prevention in methamphetamine-dependent patients who are abstinent at baseline. I concur with Elkashef et al.  that topiramate should be evaluated for relapse prevention in methamphetamine-dependent patients who can achieve a brief period of abstinence. Analysis of methamphetamine in urine relative to baseline revealed that topiramate-treated participants had reduced methamphetamine levels significantly during weeks 1–12 to ≤50% of their baseline values. [The authors suggest that topiramate's effects on methamphetamine pharmacokinetics may underestimate the extent of reduction of use as determined by urinalysis of methamphetamine levels. This supposition could be verified experimentally in a clinical pharmacology study using deuterium-labeled l-methamphetamine  in the presence and absence of topiramate.] Moreover, self-reports of methamphetamine use for the 12-week dosing period as well as for weeks 6–12 corroborated the urinalysis results.
These findings suggest a ‘reduction of use’ indication for topiramate. Reduction of use may be considered a partial response under the facilitation of abstinence indication. Two further conditions would need to be met: (i) the reduction would have to be sustained; and (ii) it would need to be accompanied by sustained improvement in physical or mental health or improved functionality. This premise could be verified experimentally in future trials, with analyses correlating sustained percentage reductions in use in individual trial participants to their sustained improvement in the domains listed above. Exploratory analyses of the data set are recommended from this trial, which attempts to correlate reduction of methamphetamine use with improvements in the Clinical Global Impressions Scale, Self and Observer; the Brief Psychiatric Rating Scale; and the Addiction Severity Index (ASI)-Lite scores. Such analyses would help to determine to what extent reductions in drug use can be correlated with changes in psychosocial domains, and could be hypothesis-generating.
In summary, future investigations of topiramate in this patient population are warranted, and should include higher doses, better measures of medication compliance and a larger sample size to compensate for the high dropout rate. If a sufficient number of participants were enrolled, the relapse prevention and facilitation of abstinence/reduction of use indications could be evaluated in a single trial.