Medications development: Successes and challenges

Abstract

The National Institute on Drug Abuse has funded a medications program that has concentrated on the development of medications for opiate and cocaine dependence. Levomethadyl acetate (LAAM) and buprenorphine and buprenorphine/naloxone sublingual tablets were developed in conjunction with pharmaceutical partners and approved by the Food and Drug Administration. The remaining challenges for medications development for opiate dependence involves Phase IV studies in special populations, for example, pregnant opiate-dependent patients, and to translate neuroscience-based findings into treatments. Several marketed medications have shown initial efficacy to reduce cocaine use in well-controlled clinical trials. Disulfiram has been shown to reduce cocaine use in several clinical trials, while baclofen, modafinil, naltrexone, ondansetron, tiagabine, and topiramate have shown preliminary efficacy in initial clinical studies. Confirmatory studies of many of these medications is underway. More recently, the NIDA medications program has evaluated medications for their ability to reduce methamphetamine use. To date, no medications tested have shown efficacy to reduce methamphetamine use. Both marketed medications and investigational agents will be tested. Finally, NIDA has begun to test medications for efficacy to reduce cannabis use. Initial studies are underway. Both agonist and antagonist approaches will be evaluated. Additionally, medications will be tested in cannabis-dependent patients for the management of insomnia, withdrawal, and concurrent depression.

Introduction

The National Institute on Drug Abuse funds a broad portfolio of research on drugs of abuse and the causes and treatment of addictive disorders. These disorders exact an enormous toll on society, affected individuals, and their families and communities (see Volkow and Li, this volume). Although the risks of using illicit drugs are well known and publicized, a significant percentage of Americans use illicit drugs and have a substance dependence disorder. A recent epidemiological study reported that 9.3% of the U.S. population (19.4 million people) has a substance abuse disorder, the majority being diagnosed with alcoholism (Grant et al., 2004). The National Survey on Drug Use and Health (NSDUH) report of 2002 reported that 19.5 million Americans over the age of 12 were illicit drug users (used within the past month before the survey). Marijuana use was most common; 55% of marijuana users did not use other drugs. Another 20% of illicit drug users used marijuana in combination with other drugs. Twenty-five percent of the illicit drug users used drugs other than marijuana (Substance Abuse and Mental Health Services Administration [SAMHSA], 2003). Of this group, 2 million were current cocaine users and 166,000 were heroin users. This survey aggregates psychotherapeutic drugs into 1 category, but major classes can be distinguished. Of the 8.8 million people who used illicit drugs other than marijuana, 6.2 million used some type of psychotherapeutic drug. Within this group, 4.4 million used an opiate and 1.2 million used a stimulant for nonmedical purposes.

The initiation of drug use has been tracked in national samples since 1965 and was reported in the 2002 NSDUH. The incidence of new marijuana users peaked in the mid-1970s, with ∼ 3.5 million new users per year. This declined to 1.6 million in 1990 but has varied between 2.5 and 3.0 million new initiates per year since 1995. Cocaine initiation has increased since 1990, with over 1.2 million new users in 2001. Heroin use has increased since the early 1990s. Since 1995, the number of new heroin users has topped 100,000 per year. Moreover, the number of new users of prescription opiate analgesics for nonmedical purposes has increased since 1990. The figure in 2001 was 2.8 million. Although the incidence of dependence varies by drug of abuse, it can be appreciated that the increased incidence of marijuana, cocaine, heroin, and prescription opiate use will, if anything, increase demand for treatment.

Treatment statistics mirror the escalating use of illicit drugs and nonmedical use of prescription medications. In 2002, it was estimated from the NSDUH that 22 million Americans have a substance abuse or dependence disorder (9.4% of the U.S. population). Of this group, it was estimated that 3.5 million sought treatment. Many patients in this sample had multiple drug dependencies. Treatment for individual disorders was as follows: alcohol (2.2 million), marijuana (974,000), cocaine (796,000), prescription opiates (360,00), and heroin (277,000).

In 1989, the U.S. Congress authorized the NIDA Medications Development Program (MDP) to seek pharmacological and biological treatment for opiate and cocaine dependence. In the ensuing years, the MDP has worked independently and in conjunction with the Pharmaceutical Industry to evaluate and develop medications. There have been some successes in developing treatments for these disorders and they will be described below.