NIDA-supported researchers from Harvard Medical School-McLean Hospital, in Belmont, Massachusetts, discovered that a combination of the drugs buprenorphine and indatraline reduced the self-administration of "speedball" by monkeys. Speedball is a cocaine-heroin mixture that is taken by some injecting drug users and may increase the adverse consequences of drug abuse, such as greater severity of psychiatric disorders, higher incidence of failure in drug abuse treatment, and increased risk of contracting HIV infection.

Speedball abuse presents special challenges for drug abuse treatment. Cocaine and heroin exert different effects on the brain, and little is known scientifically about how the two drugs interact. Current medications for heroin abuse, such as methadone, are only moderately effective in reducing speedball abuse and at present there are no effective medications for cocaine abuse. Combinations of medications that target the effects of either cocaine or heroin have shown promise in reducing speedball self-administration in preclinical studies.

"Clinical experience has shown that the most effective medications currently available to treat drug abuse have two distinguishing characteristics," said co-investigator Dr. Nancy K. Mello. "First, these medications produce behavioral effects that are similar to the abused drug and minimize or prevent withdrawal symptoms. Second, these medications have a slow onset and long duration of action, resulting in a lower potential for abuse than rapid-onset, short-acting drugs such as heroin or cocaine. Indatraline, a dopamine reuptake inhibitor, and buprenorphine, an opioid mixed agonist-antagonist, each meet both of these criteria. Both drugs have a long duration of action; buprenorphine produces behavioral and physiological effects similar to heroin; indatraline is an experimental drug that produces cocaine-like effects."

Indatraline-Buprenorphine Combination Reduces Self-Injection of Speedball by Monkeys

Before treatment with a combination of indatraline and buprenorphine, monkeys injected speedball an average of 66 to 78 times per day. After treatment, speedball self-administration was reduced and the decreases were sustained throughout 10 days of treatment. After 5 days of treatment with the highest dose of the combined medications, speedball self-administration decreased to between zero and five injections per day.

Dr. Mello and Dr. S. Stevens Negus compared the effects of chronic treatment with indatraline and buprenorphine separately and in combination on speedball self-administration by rhesus monkeys. Five monkeys previously trained to self-administer cocaine were given access to speedball combinations (3:1 ratios of cocaine to heroin), which they began to self-administer more than 70 times a day.

Over four 10-day periods, the monkeys were treated daily with saline, with indatraline or buprenorphine alone, and with the indatraline-buprenorphine combination in three increasing concentrations. Saline and the lowest concentration of the combined medications had little effect on speedball self-administration; the highest doses of the combined medications significantly decreased the number of times the monkeys self-administered speedball.

By the fifth day of treatment with a combination of indatraline and buprenorphine, speedball injections decreased by more than 90 percent, to fewer than five injections per day in four of the five monkeys studied. The same doses of indatraline or buprenorphine alone did not significantly reduce speedball self-administration.

"The combination of indatraline and buprenorphine not only reduced speedball self-administration, but these effects were sustained across the 10-day treatment period and over a range of doses," says Dr. Mello. "These findings underline the importance of exploring medication combinations as a novel approach for treatment of polydrug abuse."

"Although this study used an animal model, the results are intriguing and suggestive of potential clinical efficacy," said Dr. Jane Acri of NIDA's Division of Treatment Research and Development. "There is evidence that buprenorphine can reduce opiate use in humans, but the data supporting the use of compounds such as indatraline for reducing cocaine use by humans are more limited. The selection of a combination mechanism strategy is reasonable; further study is needed to determine the effectiveness of these compounds in the treatment of speedball abuse in humans."

Sources

Mello, N.K., and Negus, S.S. Effects of flupenthixol and quadazocine on self-administration of speedball combinations of cocaine and heroin by rhesus monkeys. Neuropsychopharmacology 21:575-588, 1999.

Mello, N.K., and Negus, S.S. Effects of indatraline and buprenorphine on self-administration of speedball combinations of cocaine and heroin by rhesus monkeys. Neuropsychopharmacology 25(1):104-117, 2001.

Volume 17, Number 3 (October 2002)