DOV Pharmaceutical Inc has announced positive efficacy and safety results for its Phase II clinical trial investigating its novel, non-narcotic analgesic, bicifadine, in the treatment of moderate to severe post-surgical dental pain. These data indicate that bicifadine is an effective analgesic as compared to placebo, with an efficacy at least equivalent to codeine. It has the advantage of being longer acting and not being a narcotic or having addiction potential.
This Phase II trial was a single dose, double blind, placebo-controlled study conducted in 750 male and female patients between the ages of 16 and 45. Three doses of bicifadine (200, 400, and 600 mg) and one dose of codeine (60 mg) were compared to placebo using as a primary endpoint measure the Summed Pain Relief and Intensity Difference (SPRID) score, a measurement tool that reflects the total analgesia produced over the entire six hour test period.
Bicifadine, in a dose dependent fashion, produced a significant (p<0.002) overall increase in SPRID scores compared to placebo, and codeine did not. Time course analysis revealed that codeine did produce significant pain relief within one hour but not at two hours and thereafter. This short duration of action did not allow codeine to reach significance when analyzed over the entire six hour test period. Both 400mg and 600mg of bicifadine produced significant (p<0.01) time related increases in pain relief with a median latency for onset of significant pain relief within one hour. Maximal analgesic effects of bicifadine occurred in two to three hours and these effects were sustained for the balance of the six hour period. The mean maximal analgesic score for codeine was 2.6 compared to 2.7, 2.9 and 3.3 for 200, 400 and 600 mg of bicifadine, respectively. The scores for 200 and 400 mg bicifadine were comparable to 60 mg codeine, while those for 600 mg of bicifadine were significantly (p<0.01) greater.
Both codeine and bicifadine were safe and relatively well tolerated without producing any serious adverse events. Codeine (60 mg) and the 400 and 600 mg doses of bicifadine produced significantly (p<.05) more adverse events than placebo with the most frequently reported symptoms being nausea and emesis. Some interaction with the surgical procedure may have contributed to these side effects, since more than 13% of the placebo patients also displayed nausea and emesis, effects normally seen with this surgical pain model.
Bicifadine is a chemically distinct molecule with a unique profile of pharmacological activity. It has two primary biochemical actions. It enhances and prolongs the actions of norepinephrine and serotonin by inhibiting the transport proteins that terminate their physiological actions. In addition, it interferes with the ability of glutamate to stimulate calcium entry into neurons. Preclinical and clinical studies indicate that any of these individual actions or a combination may account for the analgesic properties of bicifadine.
Bicifadine is not a narcotic and, in preclinical studies, it has been shown not to act at any opiate receptor. In animal models, bicifadine did not demonstrate abuse, addiction, or dependence potential. Bicifadine development prior to this study included seven Phase I clinical trials, and fourteen Phase II clinical trials, involving over 1,000 patients.