In 1989, the National Institute on Drug Abuse (NIDA) established its Medications Development Program. This program has concentrated on developing pharmacotherapies for opiate and cocaine dependence and, more recently, for methamphetamine and cannabis dependence. According to the Office of National Drug Control Policy, there are almost a million long-term opiate users in the United States and there are over 3 million long-term cocaine users in the United States. In a review article Am J Psychiatry 2005; 162:1432–1440)  Frank J. Vocci, Ph.D. Jane Acri, Ph.D. Ahmed Elkashef, M.D. discuss the state of pharmacotherapy treatments for opiates, cocaine, methamphetamine, and cannabis dependence. We summarize their review….

Opiate Treatments:

1. Methadone has been shown to reduce morbidity insofar as it reduces the risk of infectious disease. Methadone maintenance therapy was inversely correlated with the prevalence of HIV. A sevenfold reduction in the incidence of HIV was seen in a methadone-treated group versus an untreated cohort that agreed to be a part of the study but refused treatment.
2. Levomethadyl acetate (LAAM) is the alpha-acetyl congener of methadone. Its principal difference from methadone is its conversion to the active metabolites norLAAM and dinorLAAM . Initial studies were performed in the 1970s with a dosing regimen of three times a week. LAAM was originally thought to be a pro drug, but recent evidence suggests that LAAM has agonist properties. A large phase III safety trial led to its approval by the Food and Drug Administration (FDA) in 1993. Dosing recommendations on the product label suggested that induction doses could range from 20 to 40 mg/day and that maximum thrice-weekly dosing regimens of 30/130/180 mg or 140/140/140 mg were permissible. Alternate-day dosing was also added to the labeling. Postmarketing studies noted that a rapid-induction regimen of 25 to 100 mg/day in 17 days yielded the greatest reduction in illicit opiate use, but a higher side effect profile was encountered. A dose effect of LAAM on illicit opiate use was reported, with the 100/100/140 mg thrice-weekly regimen giving the greatest reduction in opiate use. The FDA issued a “black box” warning for LAAM because of postmarketing surveillance reports of QTc prolongation in ECGs, with several reports of torsades de pointes, a polymorphic life-threatening ventricular arrhythmia.
3. Buprenorphine is a mu opiate partial agonist  that was originally marketed as an analgesic product. Investigators conducting an abuse liability study in human volunteers reported that subcutaneously administered buprenorphine has less subjective effects than morphine, a lesser withdrawal syndrome, and an ability to block the subjective responses of up to 120 mg doses of morphine. Subsequent work established that the sublingual route was preferable to oral dosing because of high firstpass effects. The first outpatient treatment study to our knowledge compared 8 mg of sublingual buprenorphine liquid to 20 and 60 mg doses of orally administered methadone in a randomized, double-blind, double-dummy study. Retention and decreased illicit opiate use in the buprenorphine group were superior to the response seen in the group that was receiving 20 mg/day of methadone. NIDA and Reckitt & Colman (now ReckittBenckiser) received a Cooperative Research and Development Award to develop buprenorphine as a treatment for opiate dependence. Under this agreement, a second study conducted with the liquid formulation was performed in a multisite trial in which opiate-addicted patients were randomly assigned to 1, 4, 8, and 16 mg/day of buprenorphine. The a priori comparison was the effects of 1 mg/day versus 8 mg/day on illicit opiate use, retention, and opiate craving. The 8 mg/day dose group had significant reductions in illicit opiate use, reduced craving, and had better retention.
   
4. Naloxone and buprenorphine subsequent to the study by Ling et al., it was decided to develop a sublingual tablet and to add naloxone, a narcotic antagonist, to one of the formulations. The rationale for adding naloxone was to produce a less abusable, less divertable tablet. The dose ratio of buprenorphine to naloxone was chosen from data gathered in clinical pharmacology studies in opiate-dependent subjects maintained with morphine, methadone, or buprenorphine. In the first study, the subjects maintained on a dosage of 60 mg/day of morphine sulfate were randomly administered one of six medication treatments intravenously in a counterbalanced order: morphine, buprenorphine, buprenorphine/naloxone at 8:1, buprenorphine/naloxone at 4:1, buprenorphine/naloxone at 2:1, and placebo. Subjective measures of positive and negative effects were assessed for the first hour after dosing. The 4:1 ratio was chosen because it produced significant attenuation of buprenorphine’s effects without producing significant withdrawal signs. The 2:1 ratio was aversive because it produced withdrawal on four measures and was the only dose combination that the subjects reported that they would not pay money for. A randomized, double-blind comparison of the effects of tablet formulations of 16 mg/day of buprenorphine at 16/4, buprenorphine/naloxone or placebo, was carried out in a multicenter trial. The placebo-controlled portion of the trial was carried out for a 1-month treatment duration. Subjects in either buprenorphine dose group had reduced opiate use and reduced craving versus the placebo group. Thereafter, all subjects were given open label buprenorphine/naloxone for 11 months. Other subjects participating at new sites were given 1 year of openlabel buprenorphine/naloxone.In October 2002, the FDA approved sublingual buprenorphine tablets and buprenorphine/naloxone tablets for the management of opiate dependence. Buprenorphine was concurrently changed to a Schedule III drug on the U.S. Controlled Substances Act. According to the Drug Abuse Treatment Act of 2000, qualified physicians can prescribe Schedule III, IV, and V opiates for the treatment of opiate dependence, providing that the FDA approves the medications for that purpose.
   

Cocaine and Amphetamine Treatments:
There are no FDA-approved medications for the treatment of cocaine dependence. The NIDA Medications Development  Program has test-marketed medications for their potential efficacy to reduce cocaine use. Several medications have shown efficacy or preliminary evidence of efficacy. These results will be highlighted.

1.  Disulfiram, an inhibitor of sulfhydryl-containing enzymes, is marketed as a treatment for alcohol dependence. Two open-label studies showed reduction in cocaine intake after reductions in alcohol use in disulfiram-medicated patients. Clinical pharmacology studies of the interaction of disulfiram and cocaine have been reported. Responses to intranasal cocaine (1 or 2 mg/kg) were altered in subjects treated with either 250 or 500 mg/day of disulfiram. Subjects receiving disulfiram reported dysphoria, anxiety, and paranoia after cocaine administration. Doses of 250 and 500 mg/day were reported to reduce cocaine use in subjects using cocaine/alcohol. 
2. Naltrexone:  Abstinent, formerly dependent, cocaine-addicted patients showed less relapse when their treatment was combined with a relapse-prevention behavioral therapy but not another behavioral therapy.
3. Baclofen, a γ-aminobutyric acid (GABA) B agonist (60 mg/day), has been reported to reduce the craving for cocaine in a clinical pharmacology setting. Reduction of cocaine use has been reported in baclofen-treated patients in a randomized, placebo-controlled trial. Of interest, the patients with the highest levels of cocaine use during the baseline period benefited the most from this medication.
   

4. Tiagabine, Another GABA-ergic medication,has been reported to reduce cocaine use at a dose of 24 mg/day. A follow-up trial has been completed, and the results will be forthcoming.
   

5. Topiramate (200 mg/day maximum dose) in cocaine-dependent patients with low Cocaine Selective Severity Scale scores. The patients who were abstinent during the 2-week baseline period had less return to cocaine use that those randomly assigned to placebo or the patients who continued to use cocaine during the baseline period.
   

6. Modafinil is another medication of interest. It is a newer stimulant that increases daytime alertness in narcoleptic patients. Preclinical assessment suggests that the stimulatory action is nondopaminergic. Initial assessments of abuse liability in human subjects suggest that the abuse liability is minimal. Moreover, an
   initial report of cases of stimulant abusers treated with modafinil noted that one user described less craving for amphetamines, and another reported decreased craving and less use of cocaine. Clinical laboratory testing of the potential interactive effects of 200 and 400 mg/day doses of modafinil and cocaine in cocaine-experienced subjects was performed.
   

7. Terguride, a partial agonist at D2 receptors, reversed amphetamine withdrawal signs in animals and also reduced amphetamine self-administration under a progressive ratio schedule.  Presently investigational.
   

8. Quinpirole, a full D2 agonist, did not antagonize amphetamine self-administration. These data suggest that these “stabilizer” compounds may have different properties than full agonists or full antagonists. Presently investigational.

9. Aripiprazole, is the first marketed medication with a  mechanism that has been dubbed a dopamine “stabilizer”, which is approved for the treatment of schizophrenia. Its efficacy has been reviewed, and it is believed to have “mixed” actions or different efficacy at different receptor subtypes. Neuroimaging studies have show that clinically relevant doses occupy 95% of the dopamine receptors without producing extrapyramidal side effects (90). Given its characterization as a dopamine system stabilizer, NIDA is interested in evaluating its effects in both cocaine and methamphetamine-dependent patients.
   
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