Transdermal delivery of a buprenorphine/naltrexone combination for the treatment of polydrug abuse

Abstract

This thesis investigated a buprenorphine (BUP) and naltrexone (NTX) combination therapy for the prevention of relapse to heroin and cocaine. Delivery of the combination by transdermal iontophoresis was also explored. In the first half of the thesis, experiments were carried out using Sprague Dawley rats; an assay of analgesia (the tail withdrawal assay) and a behavioural assay (conditioned place preference; CPP) were employed. It was found that 1.0 mg/kg of NTX (but not 0.3 mg/kg NTX) blocked the analgesic and rewarding properties of 0.3 mg/kg BUP. Interestingly, 0.3 mg/kg BUP with 3.0 mg/kg NTX, but not the same dose of NTX alone, was aversive. Using a CPP-extinction-reinstatement method, it was shown that the combination (0.3 mg/kg BUP and 1.0 mg/kg NTX), administered 10 minutes before a priming dose, prevented reinstatement of both morphine- and cocaine-seeking. In the second half of the thesis, iontophoresis (0.3 or 0.4 mA/cm2) was used to transport BUP and NTX across the skin; experiments were carried out using excised pig skin in side-bi-side glass cells. NTX transport was efficient and consistent with the standard mechanisms (electrorepulsion and electroosmosis) of iontophoresis. BUP was less efficiently delivered and accumulated in the skin; the size of the BUP skin depot increased with pH and with the concentration of BUP in the donor solution. BUP’s presence in the skin reduced convective solvent flow (indicated by a neutral marker) which had a negative impact on its flux, and also on that of NTX. The BUP/NTX combination has real potential as a relapse prevention therapy, and it is particularly exciting that it seems to be efficacious against cocaine, as treatments for cocaine dependence are desperately needed. Delivery of a therapeutically relevant amount of the combination by transdermal iontophoresis is achievable, but careful investigation is required to understand the atypical behaviour of BUP.