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

Drug abuse remains a serious health issue within the UK and throughout the world. In fact, recent reports suggest that the government spends over #15 billion per annum in meeting the social and economic costs of illicit drug use. While some significant progress has been made in recent years, for example with the use of buprenorphine for the treatment of opioid abuse, one of the major difficulties faced is that approximately 70% of treated addicts relapse within the first year following treatment. In this project it is intended to develop a therapeutic agent that could be used to help prevent patients from relapsing. Another significant issue is that most addicts use more than one addictive substance and that deaths from drug misuse more often than not involve a combination of drugs rather than a single compound, or even single compound class. Indeed, the most frequent multiple-drug deaths involve various combinations of opiates/opioids, cocaine, and alcohol. The importance of finding treatment agents, including relapse prevention agents, for these combinations is clear. Fortunately, there is emerging evidence from the clinic that a buprenorphine/naltrexone combination is effective as a relapse prevention agent for opioid abuse, while also decreasing cocaine use in the same individuals. There is also a strong rational, based on preclinical studies, that this combination would reduce alcohol intake in the addict population. A significant problem with developing this as a combination product arises from the fact that buprenorphine and naltrexone need to be administered by different routes. Also buprenorphine would be subject to diversion/abuse if administered separately to the naltrexone and so some mechanism of overcoming the drug delivery problem is required. Both the compounds can be delivered through the skin (transdermally) and so during this pilot project we will determine whether it is possible to develop this method of delivering buprenorphine and naltrexone in a controllable manner and in amounts that provide maximum therapeutic effect while minimising any potential side affects. In order to be able to deliver the required amount of the drugs in a controlled manner, we will use a technique called iontophoresis, in which a mild electric current is used to help deliver the compounds across the skin. This is a technique that is already used in the clinic for the delivery of other drug molecules.

While there has been substantial effort put into the understanding and even treatment of individual drugs of abuse, little work has been directed at the challenge of polydrug abuse. Since most addicts abuse more than one drug, this must be a priority in the coming years. Fortunately, there is emerging evidence from the clinic that a buprenorphine/naltrexone combination is effective as a relapse prevention agent for opioid abuse, while also decreasing cocaine use in the same individuals. There is also a strong rational, based on preclinical studies, that this combination would reduce alcohol intake in the addict population. A significant problem with developing a combination product arises from the fact that buprenorphine and naltrexone need to be administered by different routes (the former is active after sublingual administration, the latter is active after oral administration). In addition buprenorphine would be subject to diversion/abuse if administered separately to the naltrexone and so some mechanism of overcoming the drug delivery problem is required. In this pilot project we will look to develop a method for delivering the combination in a controlled, non-abusable way and confirm the pharmacological profile of the combination product. Specifically, both buprenorphine and naltrexone can be delivered transdermally and we will develop a patch that can deliver the combination at a flux that allows therapeutically relevant concentrations of the compounds, in the correct ratio, to be reached. By using iontophoresis the delivery of the compounds across the skin is significantly increased over passive diffusion and can also be controlled so that dosages can be tailored to the individual. We will determine the pharmacological profile of the patch in rodents and in particular confirmation will be sought that the product displays no opioid reinforcing properties of its own and can act as a relapse prevention agent in a drug reinstatement model.