Improving Treatment for Illicit Drug Abuse

By Arline Kaplan ©2002 (All Rights Reserved)

The babies are premature and underweight. Many endure severe abdominal pain, diarrhea, sweating and jitteriness. A few have seizures and die. They are heroin babies, and they are part of the $11.9 billion in health care costs and $109.9 billion in societal costs attributable to drug abuse each year (Rice et al., 1995, Harwood et al., 1992, as cited in Robert Wood Johnson Foundation, 2001).

To help the nation’s estimated 13.6 million illicit drug users, including pregnant women addicted to heroin, cocaine and other drugs, the National Institute on Drug Abuse (NIDA) is funding studies on possible pharmacological and behavioral treatments

According to Frank Vocci, Ph.D., director of NIDA’s division of treatment research and development, the institute funds 85% of the world’s treatment research

In the treatment process, therapeutic medications serve several functions. They can make withdrawal easier, reduce drug craving, alter the effects of drugs of abuse (should they be ingested) and help retain patients in treatment.

“Our primary focus is on developing medications for stimulant addiction, and secondarily, opiate addiction,” said Vocci.

Researchers supported by NIDA have published clinical trials that show disulfiram (Antabuse), a medication used to treat alcohol addiction, has a positive effect on reducing cocaine use in both individuals who co-abuse alcohol and those who do not (Carroll, 1998 and George et al., 2000 as cited in Mathias, 2001). Additionally, Vocci said several studies are funding right now and others are being planned, with most of the research being conducted at Yale University Medical School in New Haven, Conn., and at the University of Pennsylvania in Philadelphia.

The clinical pharmacology studies suggest that disulfiram makes cocaine less likeable and more aversive, Vocci said. In the absence of cocaine, disulfiram may increase dopamine levels sufficiently to reduce the drive to use cocaine. When disulfiram is used with cocaine, disulfiram makes cocaine effects so unpleasant that users are deterred from further use (Mathias, 2001). Other studies are underway examining whether disulfiram reduces cocaine abuse in opiate-addicted patients being treated with buprenorphine (Buprenex) (Mathias, 2001).

Naltrexone (ReVia), an opioid antagonist that blocks the subjective effects of opioids, has an effect to reduce relapse to cocaine, Vocci said. There are also studies from the University of Pennsylvania on propranolol (Inderal, Pronol) and amantadine (Symmetrel, Symadine) that are showing an effect on individuals who exhibit a severe cocaine withdrawal syndrome. .

“Propranolol is a beta blocker, so it blocks the effects of adrenaline,” said Kyle Kampman, M.D., assistant professor of psychiatry at University of Pennsylvania, and medical director of University of Pennsylvania Treatment Research Center. “Cocaine-dependent patients are extremely sensitive to the effects of adrenaline, and they often have panic attacks during cocaine withdrawal. What propranolol can do is block the effects of adrenaline, such that when these patients are exposed to things that remind them of cocaine, and the cocaine craving begins, they have less of an autonomic response; they don’t get the sweaty, shaky, heart-racing, anxious feelings that they usually get. Hopefully, that will be make the craving easier to resist, and they will be able to stay clean.”

Propranolol also may help by diminishing the memory of prior cocaine use. Kampman, along with other investigators from the University of Pennsylvania and the Department of Veterans Affairs Medical Center in Philadelphia, evaluated the efficacy of propranolol in the treatment of cocaine dependency (Kampman et al., 2001). The eight-week, double-blind, placebo-controlled trial involving 108 people dependent on cocaine. The primary outcome measure was quantitative urinary levels of benzoylecgonine, a cocaine metabolite. Secondary outcome measures included treatment retention, Addiction Severity Index results, cocaine craving, mood and anxiety symptoms, cocaine withdrawal symptoms and adverse effects. Propranolol-treated subjects had lower cocaine withdrawal symptoms severity. But in the group as a whole, propranolol did not appear to be superior to placebo in keeping people in treatment or preventing them from using cocaine.

Propranolol, however, did help patients experiencing severe cocaine withdrawal.

“Now, we knew from our previous research on cocaine withdrawal that patients who have severe cocaine withdrawal symptoms when they enter treatment are different than other cocaine addicts, [because] they tend to do much worse in treatment. They tend to drop out earlier and have a more difficult time to getting clean,” Kampman said. “We thought that propranolol would work more effectively in patients who entered treatment with more severe withdrawal symptoms, so we went back to the data and looked specifically at people who entered treatment with more severe withdrawal symptoms, and we found, in fact, the propranolol did improve treatment retention in these people and it also reduced the amount of cocaine they used.”

Kampman and his group are also looking at using propranolol and amantadine together. It is thought that cocaine withdrawal may be associated with changes in the mesocorticolimbic dopamine system (Volkow et al., 1991, as cited in Kampman et al., 1999). As an indirect dopamine agonist, amantadine may be able to stimulate the release of dopamine and relieve some of the cocaine withdrawal symptoms. Previous trials have yielded mixed results, he said.

So Kampman and colleagues decided to conduct a double-blind, placebo-controlled trial to study propranolol and amantadine alone and in combination on patients with severe cocaine withdrawal symptoms.

“Because of their different mechanisms of actions, we felt they may be twice as effective together,” he said.

Treating Opiate Abusers

For heroin and other opiate abusers, methadone has been the primary pharmacological treatment since the 1960s. An estimated 115,000 heroin abusers are enrolled in methadone treatment programs in 40 states, according to data from the College on Problems of Drug Dependence, an independent organization promoting scientific research on drug abuse problems. Yet, it is estimated that fewer than one in five heroin users receive methadone treatment for their addiction.

To identify new treatments, NIDA is supporting studies on several other medications, including naltrexone, buprenorphine and the combination of buprenorphine/naloxone,

Buprenorphine, a partial opiate agonist, is being used in treating opiate addiction. A recent study by Schottenfeld and others at Yale University found that buprenorphine taken three times per week is as effective as daily doses in treating heroin addiction. That finding may facilitate the movement of treatment beyond traditional narcotic treatment programs into new treatment settings, such as primary care clinics (Zickler, 2001).

The primary use of the buprenorphine/naloxone combination would be for detoxifying opiate-dependent patients. Vocci said a pharmacokinetics study requested by the Food and Drug Administration has been completed. With that data and additional data from the drug manufacturers, he said the FDA might approve the combination drug some time next year. Additionally, Vocci said the FDA is expected to review and approve a New Drug Application for buprenorphine alone.

NIDA is also funding research on three formulations of naltrexone, including a depot formulation; as well as a double-blind, placebo-controlled, multisite trial of lofexidine (Britannia Pharmaceuticals, Ltd.). Lofexidine is a clonidine-like compound that has been shown in European studies to have an effect in opiate detoxification.

Other medications being evaluated by NIDA include a corticotropin-releasing factor (CRF) antagonist; Bioproject’s BP-897, a dopamine D₃ receptor agonist, that may reduce drug craving and vulnerability to relapse elicited by drug-associated environmental stimuli; and Abbott Laboratories’ adrogoglide (DAS-431), a dopamine D₁ agonist that may reduce cocaine craving and other cocaine-induced subjective effects.

Behavioral and Psychosocial Treatments

Behavioral and psychosocial treatments are cornerstones in helping drug abusers achieve and sustain abstinence.

“We initially thought that medications and behavioral therapies would be complimentary in some sort of additive fashion, that is, they would address different issues in the individual,” Vocci said. “Now, we are starting to see that they are interactive…there may be behavioral therapies that will enhance a medication effect …and there may be medications that may enhance a certain part of the behavioral therapies. So we are on the verge of new era where the treatment context and the way the treatment is delivered may be extremely important in terms of both how the drug is administered and also how the behavioral therapy is administered.”

Several approaches are being studied by NIDA, including cognitive behavioral therapy (CBT), motivational interviewing, motivational enhancement therapy, contingency management, community reinforcement therapy and relapse prevention.

A number of clinicians and researchers in the field use CBT, particularly for cocaine abusers, Vocci said. Many are also using community reinforcement therapy (combines couples counseling, recreational therapy and tangible incentives to help motivate abstinence) and relapse prevention (teaches patients to recognize high-risk situations for drug use and implement coping strategies).

Motivational interviewing has a potent effect in terms of getting people to initiate treatment, according to Vocci. It is where you actually enriching the number of individuals who apply for treatment, For example, a child welfare worker may determine a family needs a substance abuse evaluation because the mother may be having problems with drugs. In the interview process, the mother moves from denying or equivocating about a drug abuse problem to considering treatment options.

“It is a way of empathizing with the individual about what the issues are and getting them to do something that is beneficial for them,” Vocci said.

Motivational enhancement therapy, which involves individual counseling, works toward helping clients resolve their ambivalence about engaging in treatment and stopping drug use. The therapy involves strengthening motivation and building a plan for change in behaviors, developing coping strategies for high-risk situations and assessing changes.

Currently, a NIDA-sponsored multisite study is investigating whether three individual sessions of motivation enhancement therapy/motivational interviewing can improve treatment engagement and outcome in patients seeking treatment for substance abuse. The principal investigator is Kathleen Carroll, Ph.D., at the Veterans Affairs Connecticut Healthcare System.

Contingency management involves frequent monitoring of target behaviors, positive reinforcers when the target behavior occurs and removal of the reinforcers when the target behavior does not occur (Petry et al., 2001). Nancy Petry, Ph.D., at the University of Connecticut Health Center, conducted a study of chronic substance abusers where if individuals remained abstinent for a week, they were eligible to stick their hands in a fishbowl and usually win a prize—the prizes ranged in value from $1 to $100. Most of the prizes were $1 value, but it really had a robust effect, Vocci said.

“We’ve also looked at contingency management and cognitive behavioral therapy for cocaine- and methamphetamine-dependent patients,” said Vocci. “Contingency management gives you better retention and lower rates of stimulant use while in effect, but cognitive behavioral therapy produces comparable long-term outcomes.”

At the University of Vermont, Alan Budney, Ph.D., and colleagues found that if you layer contingency management on top of other existing therapies you are going to increase the number of individuals who will become abstinent, Vocci said. In that study, 60 people seeking outpatient treatment for marijuana dependence were randomly assigned to one of three groups, motivational enhancement; motivational enhancement plus behavioral coping skills therapy, or motivational enhancement plus coping skills plus voucher-based incentives. Over the 14-week study, 40% of the patients in the incentives group achieved at least seven weeks of continuous abstinence from marijuana, compared with 5% in each of the other groups (Budney et al., 2000).

An interesting twist on the contingency management, according to Vocci, is the therapeutic workplace study conducted by Ken Silverman, Ph.D., from Johns Hopkins University School of Medicine (Silverman et al., 2001). In that study, patients were paid to work, but they had to provide drug-free urine samples to gain daily access to the workplace. In Phase 1 of the study, each participant’s “job” was to work in a job skills training program where they were paid in vouchers exchangeable for goods and services. Results showed that Phase 1 effectively promoted long-term abstinence from heroin and cocaine in poor, chronically unemployed pregnant and postpartum women. In Phase 2, successful participants were hired as regular employees of real income-producing businesses. They still had to provide drug-free urine samples to maintain access to the workplace each day, but they earned regular paychecks instead of vouchers.

There have also been some things done in contingency management in terms of methadone maintained pregnant women, Vocci said. For example, Hendree Jones, Ph.D., and colleagues examined the effectiveness of short-term contingency management for eliminating cocaine use and increasing full-day treatment attendance with pregnant methadone-maintained women randomly assigned to either an escalating voucher incentive schedule (n =44) or non-incentive (n = 36) condition. Full-day treatment attendance and urine toxicologies for cocaine and heroin were assessed for 14 days. The escalating voucher incentive schedule significantly increased the treatment attendance and drug abstinence compared to the non-incentive schedule (Jones et al., 2001).

Jones is research director for the Center for Addiction and Pregnancy (CAP) at Johns Hopkins Bayview Medical Center and associate professor in the department of psychiatry and behavioral science at Johns Hopkins.

“We have primarily focused on behavioral interventions for treating pregnant drug-dependent women. The drug that we most commonly see is heroin, so the studies we do have focused on methadone-maintained pregnant women. We know when they come in and are dependent on heroin, they are using a variety of other drugs—cocaine, alcohol, benzodiazepines. Methadone is very good for reducing illicit opiate use, but it doesn’t do much for cocaine, benzodiazepines, alcohol, marijuana and other drugs of abuse,” Jones said in an interview. “So our incentive studies, rather than taking a punitive approach, are taking a positive approach. We are reinforcing them for staying away drugs, and the way that we verify they are staying away from drugs is through urine samples.”

One ongoing trial Jones and colleagues are conducting involves 135 women who are eight weeks or more into their pregnancy and receiving methadone-maintenance. The objective is to have the women stay free of drugs other than methadone..

“We have two schedules we are looking at. One is an escalating schedule, …the first drug-free urine that they get is worth $7.50 in voucher value, the next one is worth $8.50, $9.50 and so on. As long as they are providing consecutive drug-free urine, [the amount] increases each time by a dollar, up to $42.50. Women who have been clean for 12 weeks can earn $42.50 times three (Monday, Wednesday, Friday). They can earn a lot of money, so we pay their rent or phone bills or even buy nursery sets for them,” Jones said.

However, if a woman misses a urine test or gives a drug-positive urine, she receives nothing, and then when she gives a clean urine after the lapse, the payment schedule is reset to the $7.50 level.

The other schedule involves a constant level of payment, so the first time a woman gets a drug-negative urine, she gets $25 in vouchers, enabling her to earn $75 per week, but if she relapses or doesn’t show up, that’s considered a drug-positive urine, then she wouldn’t get anything, but the next time she gives a drug-free urine, she gets $25 again.

The study is going really well, said Jones.

“We have had women who have come in their eighth week of pregnancy and maintained abstinence all the way through their pregnancy,” she said. “We have longer durations of abstinence for consistent periods of time in the women receiving the escalating schedule versus the constant schedule.”

Jones and colleagues are also conducting a study of pregnant women not receiving methadone maintenance. She explained that addicted women come to the Center for Addiction and Pregnancy’s inpatient unit. They stay for about seven days to get the drugs out of their system and become stabilized. And even though they are offered comprehensive outpatient treatment for the duration of their pregnancy and up to six weeks postpartum, they tend not enter outpatient treatment. Jones and colleagues are conducting a study using a decreasing schedule of payments in vouchers for each full day of outpatient treatment attended and an increasing schedule of payments for each drug-free urine provided.

The concept is that the women are first paid in vouchers for something they can more easily achieve, attending a full-day of outpatient treatment.

“Hopefully, the more treatment contact they have, the more likely they will be able to attain some abstinence, and they we can start our escalating schedule of paying for drug-free urine,” Jones said.

Among the other studies being conducted at CAP is one involving partners of the addicted mothers.

“It is a common belief…that these women are very promiscuous and tend to not have stable relationships, but that is truly a misconception. Actually, when you ask them about their relationships, 80% of the women coming into CAP say they have a stable relationship. …Of the 80% of women who say that, half of them report having partners that use drugs,” Jones said.

From previous studies, Jones knew that women with drug-using partners tended to stay in treatment only half as long as women whose partners were not using drugs. So, she and colleagues initiated a pilot project to get the drug-using partners into treatment as well. The six-month study involved the male partners of 10 pregnant women.

“We just completed a pilot project and we know that from our preliminary data, we got all of the male partners into treatment. Most of them are in methadone maintenance; a few of them are in inpatient detox. And we were able to bring them into our aftercare setting,” Jones said. “They have all maintained a period of abstinence (shortest one was two weeks and the longest was five months)…. I thought it would be pulling teeth to get these guys into treatment, and in fact it wasn’t at all. They wanted treatment.”

References

Budney et al. (2000), Adding voucher-based incentives to coping skills: a motivational enhancement improved outcomes during treatment for marijuana dependence. Journal of Consulting and Clinical Psychology 68:1051-1061.

Carroll KM, Ball SA, Nich C et al. (2001), Targeting behavioral therapies to enhance naltrexone treatment of opioid dependence. Arch Gen Psychiatry 58:755-761.

Jones H, Haug N, Silverman K et al. (2001), The effectiveness of incentives in enhancing treatment attendance and drug abstinence in methadone-maintained pregnant women. Drug Alcohol Depend 61(3):297-306.

Kampman KM, Volpicelli JR, Alterman AI et al. (1999), Amantadine reduces cocaine use in cocaine dependent patients with severe cocaine withdrawal symptoms. Presented at the College on Problems of Drug Dependence Annual Meeting. Acapulco, Mexico, June.

Kampman KM, Volpicelli JR, Mulvaney F et al., (2001), Effectiveness of propranolol for cocaine dependence treatment may depend on cocaine withdrawal symptom severity. Drug Alcohol Depend 63(1):69-78.

Mathias R (2001), Alcohol-treatment medication may help reduce cocaine abuse among heroin treatment patients. NIDA Notes 16(1):6-7.

Petry NM, Petrakis I, Trevisan L et al., (2001), Contingency management interventions: from research to practice. Am J Psychiatry 158(5):694-702.

Robert Wood Johnson Foundation (2001), Substance Abuse. The Nation’s Number One Health Problem. Key Indicators for Policy Update. Princeton, NJ: Robert Wood Johnson Foundation.

Schmitz JM, Stotts AL, Rhoades HM, Grabowski J (2001), Naltrexone and relapse prevention treatment for cocaine-dependent patients. Addic Behav 26:167-180.

Silverman K, Wong CJ, Svikis D et al. (2001), The therapeutic workplace: a promising treatment for heroin and cocaine addiction among the chronically unemployed. In proceedings of 2001 ONDCP International Technology symposium: Counterdrug Research and Development: Technologies for the Next Decade.

Zickler P (2001), Buprenorphine taken three times per week is as effective as daily doses in treating heroin addiction. NIDA Notes 16(4):6-7.

(PT0202)

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