Development of improved B formulations that allow for increased compliance and reduced risk of diversion could be of significant value. A soluble film formulation of B/N is expected to offer advantages over current tablet formulations. Soluble film formulations can have unit dose packaging, improving the ability to track a dose of the medication and providing more child resistant containment of the product. Its quick dissolution can be an advantage to use in settings where monitored dose ingestion needs to be accomplished quickly. Both the 2 and 8 mg soluble films were identical in size and there did not appear to be any difference in dissolution rates between dosages. In addition, higher doses of the medication can be taken relatively easily compared to the tablet form of B.
The results from this clinical trial suggest that these soluble film formulations were clinically effective in suppressing opioid withdrawal. Neither B nor B/N soluble films produced statistically significant differences from each other on the primary or secondary outcomes. Both soluble film formulations were able to attenuate the signs and symptoms of opioid withdrawal. Significant reduction in the overall COWS scores document the ability of the soluble film formulations to attenuate the opioid withdrawal syndrome, as is seen with clinical use of the tablet formulations of B and B/N (13
). These results demonstrate that induction onto B or B/N soluble films was similarly effective.
Like their tablet counterparts, soluble film formulations have the potential to precipitate withdrawal in opioid dependent individuals (9
). In this study, four of the study participants (B = 2; B/N = 2) withdrew after beginning induction onto soluble films due to persistent opioid withdrawal symptoms. However, there was no indication that either of the formulations precipitated withdrawal or worsened existing withdrawal symptoms in any of the study participants, including these four. The presence of withdrawal-alleviating effects and the lack of a difference between the B and B/N groups suggests that neither soluble film formulation is likely to precipitate an opioid withdrawal syndrome when given in a manner consistent with the study protocol. The significant decrease in COWS scores from baseline to post-soluble film shows that both soluble film formulations were effective in treating the symptoms of spontaneous opioid withdrawal observed prior to induction.
Subjects in the study found the use of the soluble films acceptable; while not systematically assessed, there were no spontaneous reports that the films as a delivery system were disliked. The soluble films have a lemon-lime flavor (as do B/N tablets). In a prior study of B/N soluble films in which subjects were asked to rate the flavor, 71% of 160 subjects gave the films a score of 5 or better on a 10-point scale (where 1 was extremely unpleasant, and 10 was extremely pleasant; R.E. Johnson, personal communication, August 15, 2010).
The use of a morphine stabilization phase in this study provided some standardization of the level of physical dependence among participants, although a longer period of stable morphine dosing would have strengthened this aspect of the study design. The use of the naloxone challenge ensured that the lack of B or B/N precipitated withdrawal during the induction phase was not due to a population that was insensitive to the detection of opioid withdrawal. Conversely, the lack of withdrawal from the placebo challenge provided assurance that these were not subjects who were overly sensitive to reporting any opioid withdrawal.
Limitations to the present study should be noted. With respect to the apparent absence of precipitated withdrawal, the present context of abstinence-induced spontaneous withdrawal is perhaps not ideally sensitive for detecting additional precipitated withdrawal. Also, conclusions regarding the withdrawal-suppressing efficacy of B and B/N are based on their rapid reversal of spontaneous withdrawal in the absence of a placebo or a full agonist comparison control condition. A placebo control condition was expected to produce sustained spontaneous withdrawal that increased the risk of study dropout, while an agonist control condition would have replicated prior studies that have already demonstrated B’s efficacy to suppress opioid withdrawal (14
) and would not have addressed the present study question of comparing B versus B/N for suppressing opioid withdrawal. Finally, the present study utilized a fixed dose schedule, and clinical practice generally uses a more flexible dosing procedure that is responsive to patient needs. The protocol did allow for some flexibility with supplemental soluble film doses up to 24mg per day and it is interesting that neither staff nor participants ever requested such.
The study was designed to examine dosing during the induction period. While the concept of gradual induction for opioid treatment is generally well accepted (17
), there is not a well accepted definition of the length or goal of induction onto a medication such as B (or methadone). This study used a two-day period for induction and assumes that the goal of induction is to have the patient successfully transition on to the medication though not necessarily to stop all illicit drug use immediately. Induction should be distinguished from stabilization (which in turn differs from maintenance); stabilization is the period during which a stable dose of medication is determined. This study showed that induction onto B and B/N soluble films could be achieved, and that there was no difference associated with the inclusion of naloxone with B during this critical first period of medication treatment. In summary, this study showed no significant differences in efficacy or tolerability between B and B/N soluble films. Both were effective and safe under the dose induction procedures used here. As with the marketed Suboxone tablets, it is expected that the addition of naloxone to the soluble film formulation will not precipitate withdrawal when taken sublingually as directed. The use of soluble films may have distinct advantages that will facilitate the use of B for the treatment of opioid dependence.