Associate editor: T.C. NapierMedications development: Successes and challenges
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.
Section snippets
Opiate dependence
Opiate dependence is a chronic, relapsing disorder with significant morbidity and mortality. Infectious diseases are often associated with drug use, that is, sharing contaminated needles and other injection equipment and risky sexual behaviors. Of the ∼ 40,000 new HIV infections in the United States each year, almost half are estimated to be associated with injection drug use (Holmberg, 1996). Hepatitis C infection has a high prevalence in injection drug users, primarily opiate injectors (
Medications for opiate dependence: successes
The first medication developed by the MDP was levomethadyl acetate or LAAM. Its efficacy had been established in clinical studies in the 1970s (Ling et al., 1976, Ling et al., 1978). It was approved in 1993 following the results of a large, multicenter safety trial (Fudala et al., 1997). LAAM was confined to the OTP clinic system. It was adopted by less than half of the OTPs. In postmarketing reports, LAAM was shown to increase the QT interval and produce Toursade de Pointes, a polymorphic,
Future challenges for opiate dependence
NIDA will concentrate on the development of nonopiate based treatments for opiate dependence. Naltrexone is approved for the prevention of relapse in formerly opiate-dependent patients. Although naltrexone has been shown to be superior to placebo for prevention of relapse in a criminal justice population (Cornish et al., 1997), the major problem with naltrexone is adherence to therapy. Therefore, NIDA has funded several companies to develop long-acting or depot dosage forms of naltrexone. One
Cocaine dependence
The development of pharmacotherapies for the treatment of cocaine abuse and dependence is a high priority of NIDA's MDP. The incidence and prevalence of cocaine abuse are tracked in the National Survey of Drug Use and Health (NSDUH; SAMHSA, 2003). As this survey does not track incarcerated populations, it is an underestimate of cocaine use in the United States. Nonetheless, a high prevalence of cocaine abuse, over 2.1 million U.S. adults reported using cocaine within the 30 days prior to the
Medications for cocaine dependence: successes
The NIDA MDP has used 2 strategies, a top–down and a bottom–up approach, for the development of medications for cocaine dependence. The top–down strategy has evaluated marketed medications for their ability to reduce or eliminate cocaine abuse. Medications tested for their ability to reduce cocaine use (Table 1) represent an aggregation of funded NIDA medications research studies in this clinical area. Over 60 medications have been tested, with some successes noted (Table 1). Some of the
Medications for cocaine dependence: challenges
There are 4 main challenges in the near future concerning medications for the treatment of cocaine dependence: to conduct confirmatory clinical trials of the medications that have shown preliminary efficacy; to determine which behavioral therapies work best with the effective medications and which patient subpopulations these work for; to assist in disseminating these treatment throughout the treatment system using the Clinical Trials Network and other dissemination mechanisms; and to develop
Methamphetamine dependence
Methamphetamine abuse is now an epidemic of global proportions, and its medical consequences have emerged as a major international public health problem. It is estimated that some 35 million individuals abuse methamphetamine worldwide, second only to cannabis and more than cocaine and heroin combined, yet there has been little research regarding pharmacological treatments for methamphetamine dependence.
The rise in methamphetamine abuse has followed largely on the heels of the cocaine epidemic
Marijuana dependence
As stated previously, marijuana is the most commonly abused illicit drug reported in the National Survey on Drug Use and Health (NSDUH) report of 2002 (SAMHSA, 2003). Of the reported 19.5 million Americans who are illicit drug users, 75% use marijuana. Of this group, 4.8 million had used it 20 or more days in the month prior to the survey and 3.1 million persons are daily users (SAMHSA, 2004).
The incidence of new marijuana use was 2.6 million people in 2001. Marijuana use typically starts in
References (140)
- et al.
Neural systems and cue-induced cocaine craving
Neuropsychopharmacology
(2002) Behavioral therapies for co-occurring substance use and mood disorders
Biol Psychiatry
(2004)- et al.
Effects of the dopamine autoreceptor antagonist (−)-DS121 on the discriminative stimulus properties of d-amphetamine and cocaine
Eur J Pharmacol
(1995) - et al.
Naltrexone pharmacotherapy for opioid dependent federal probationers
J Subst Abuse Treat
(1997) - et al.
A role for nucleus accumbens glutamate transmission in the relapse to cocaine-seeking behavior
Neuroscience
(1999) - et al.
Dissociable effects of antagonism of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell on cocaine-seeking behavior
Neuropsychopharmacology
(2001) - et al.
The neuropsychological basis of addictive behaviour
Brain Res Brain Res Rev
(2001) - et al.
Effects of buprenorphine and naloxone in morphine-stabilized opioid addicts
Drug Alcohol Depend
(1998) - et al.
Involvement of corticotropin-releasing factor receptor subtype 1 in morphine withdrawal regulation of the brain noradrenergic system
Eur J Pharmacol
(2001) - et al.
A controlled trial of impiramine for the treatment of methamphetamine dependence
J Subst Abuse Treat
(1996)
Disulfiram versus placebo for cocaine dependence in buprenorphine-maintained subjects: a preliminary trial
Biol Psychiatry
Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence
Addict Behav
Buprenorphine and naloxone co-administration in opiate-dependent patients stabilized on sublingual buprenorphine
Drug Alcohol Depend
Repeated lofexidine treatment attenuates stress-induced, but not drug cues induced reinstatement of a heroin–cocaine mixture (speedball) seeking in rats
Neuropsychopharmacology
A dopamine partial agonist and antagonist block amphetamine self-administration in a progressive ratio schedule
Pharmacol Biochem Behav
Topiramate-induced neuromodulation of cortico-mesolimbic dopamine function: a new vista for the treatment of comorbid alcohol and nicotine dependence?
Addict Behav
Oral topiramate for treatment of alcohol dependence: a randomised controlled trial
Lancet
Adverse effects of cannabis on health: an update of the literature since 1996
Prog Neuropsychopharmacol Biol Psychiatry
Glutamate systems in cocaine addiction
Curr Opin Pharmacol
A pilot trial of topiramate for the treatment of cocaine dependence
Drug Alcohol Depend
History and current status of opioid maintenance treatments: blending conference session
J Subst Abuse Treat
Injection drug use and crack cocaine smoking: independent and dual risk behaviors for HIV infections
Ann Epidemiol
Treatment of marijuana dependence: a review of the literature
J Subst Abuse Treat
Clinical and pharmacological evaluation of buprenorphine and naloxone combinations: why the 4:1 ratio for treatment?
Drug Alcohol Depend
Buprenorphine and naloxone interactions in methadone maintenance patients
Biol Psychiatry
Abstinence at intake for marijuana dependence treatment predicts response
Drug Alcohol Depend
Relapse in outpatient treatment for marijuana dependence
J Subst Abuse Treat
Sex differences in cocaine-dependent individuals' response to disulfiram treatment
Addict Behav
Bringing buprenorphine–naloxone detoxification to community treatment providers: the NIDA clinical trials network field experience
Am J Addict
Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: findings from the National Comorbidity Survey
Exp Clin Psychopharmacol
Attenuation of cocaine-seeking behaviour by the AMPA/kainate receptor antagonist CNQX in rats
Psychopharmacology (Berl)
Fluoxetine in methamphetamine dependence—a controlled trial: preliminary analysis
Amlodipine treatment of methamphetamine dependence, a controlled outpatient: preliminary analysis
Drug Alcohol Depend
Dependence on tetrahydrocanabinol in rhesus monkeys
J Pharmacol Exp Ther
Impact of self-administered cocaine and cocaine cues on extracellular dopamine in mesolimbic and sensorimotor striatum in rhesus monkeys
J Neurosci
Effect of baclofen on cocaine self-administration in rats reinforced under fixed-ratio 1 and progressive-ratio schedules
Psychopharmacology (Berl)
A potential role for GABA (B) agonists in the treatment of psychostimulant addiction
Alcohol Alcohol
Safety and efficacy of gamma-vinyl GABA (GVG) for treatment of methamphetamine and/or cocaine addiction
Synapse
Marijuana withdrawal among adults seeking treatment for marijuana dependence
Addiction
Adding voucher-based incentives to coping skills and motivational enhancement improves outcomes during treatment for marijuana dependence
J Consult Clin Psychol
Marijuana abstinence effects in marijuana smokers maintained in their home environment
Arch Gen Psychiatry
The time course and significance of cannabis withdrawal
J Abnorm Psychology
Alcoholism in treatment-seeking cocaine abusers: clinical and prognostic significance
J Stud Alcohol
Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram
Addiction
One-year follow-up of disulfiram and psychotherapy for cocaine–alcohol users: sustained effects of treatment
Addiction
Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: a randomized placebo-controlled trial
Arch Gen Psychiatry
Epidemiological estimates of risk in the process of becoming dependent upon cocaine: cocaine hydrochloride powder versus crack cocaine
Psychopharmacology (Berl)
Limbic activation during cue-induced craving for cocaine and for natural rewards
Biol Psychiatry
Depot naltrexone: long-lasting antagonism of the effects of heroin in humans
Psychopharmacology (Berl)
Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction
J Neurosci
Cited by (135)
Oxidation of specific tryptophan residues inhibits high-affinity binding of cocaine and its metabolites to a humanized anticocaine mAb
2022, Journal of Biological ChemistryConfronting the challenge of failed translation in medications development for substance use disorders
2021, Pharmacology Biochemistry and BehaviorCocaine binding to the Fab fragment of a humanized anti-cocaine mAb quantitated by dye absorption and fluorescence spectroscopy
2021, Journal of Immunological MethodsLigand binding to a humanized anti-cocaine mAb measured by dye absorption spectroscopy
2021, Biochemical and Biophysical Research Communications