Naltrexone - An Antagonist Therapy for Heroin Addiction

United States

Betty Tai, Ph.D.
Jack Blaine, M.D.
NIDA Treatment Workgroup

Introduction

Narcotic antagonist pharmacotherapy of opioid addiction was proposed by Wickler and developed based on the classical behavioral concept of "extinction." The euphoric effects of opioids which reinforce the self-administration behavior are blocked when an individual is being treated with a narcotic antagonist. The repeated lack of reinforcement, as well as the perceived "fuitility" of using the agonist, will gradually result in the extinction of opioid self-administration behavior. Naltrexone is an ideal opioid antagonist treatment medication: It is a pure, potent mu antagonist that can be taken by mouth once daily or every other day, and has minimal side effects. It is neither reinforcing nor addicting and has no potential for abuse or diversion for unprescribed use. However, patient non-compliance in part due to the absence of any agonist effects is a common problem. Therefore, a favorable treatment outcome requires a positive therapeutic relationship, careful monitoring of medication compliance and effective behavioral interventions. Many experienced clinicians believe that naltrexone is most useful for highly motivated recently detoxified patients who desire total abstinence because of external circumstances. Other potential target populations are individuals at the experimenting stage of opioid use, or those who are in early stages of their addiction.

Background

Naltrexone, a derivative of naloxone is an orally active and long acting potent pure narcotic antagonist. Clinical pharmacology studies demonstrated that oral naltrexone at 50, 100 and 150mg effectively blocks the physiological and subjective effects of parenterally administered heroin, hydromorphone or morphine for 24, 48 and 72 hours respectively. Naltrexone is rapidly biotransformed into a less active metabolite. No change was observed in the rate of naltrexone disposition during chronic dosing indicating no metabolic induction. Studies showed the lowest effective plasma naltrexone concentration of 2ng/ml provided an average of 86.5% blockade of 25mg IV heroin effects. Thus, in sustain released therapy for opiate antagonist activity, plasma level of naltrexone should be kept above 2ng/ml. (Veraby, 74)

Initial development of naltrexone as a medication to be marketed for the treatment of heroin addiction was initiated by the Special Action Office for Drug Abuse Prevention (SAODAP) in the early 1980s and completed by NIDA including preclinical toxicology, pharmacokinetics and clinical studies. No organ toxicity, developmental toxicity or carcinogenicity were revealed in the preclinical studies. Naltrexone was approved by the FDA in 1984 on the basis of its pharmacological efficacy as a narcotic antagonist and its safety profile. Although clinical efficacy data in the multi-site placebo controlled clinical trial were inconclusive, naltrexone was superior to placebo in producing less heroin use and more abstinence in those who tested the naltrexone blockade by using heroin at least once. In 1995, Naltrexone was approved by the FDA for the new indication of preventing relapse to alcohol use in formerly dependent alcoholic patients (Vocci).

Naltrexone has been used together with clonidine to shorten detoxification from heroin or methadone from two weeks to only one day. Withdrawal from the opiate is precipitated by naltrexone and resulting symptoms amerolirated by clonidine. The cost saving for this approach are substantial compared to use of methadone tapering (Kosten). More recently, the use of general anesthesia or heavy sedation with medazolam along with naltrexone has further shortened the detoxification to 4-6 hours. This procedure is sought by patients for reasons such as fear of withdrawal discomfort; need to shorten the hospital stay, etc (Kleber).

Barriers for Wider Use of Naltrexone

Naltrexone has very few and minor side effects. It is the treatment of choice in highly motivated patients, especially physicians, nurses, pharmacists and attorneys (O'Brien). However, clinical experience using naltrexone for treating opiate addiction has been replete with data on the poor medication compliance. Ling reported a 6% retention for 60 days and 2% retention for 9 months in 276 methadone maintained patients who expressed some interest in trying naltrexone treatment. Another study with 252 street heroin addicted patients treated with naltrexone had only 5% retention for 60 days and no retention for 9 months. The main reason given for this poor treatment retention and low patient compliance is that naltrexone's lack of agonist activity does not provide any drug reinforcement when taken and produces no negative consequences (withdrawal symptoms) when discontinued.

Others have suggested that patients are reluctant to take naltrexone because of fear of drug related dysphoria or depression. It has been hypothesized that naltrexone may block the effects of endogenous opiate peptides and prevent normal endogenous opioid receptor activity involved in mood modulation producing a subjective state of dysphoria. Animal laboratory data suggest opioid system up regulation associated with chronic naltrexone administration. However, a review of clinical studies using naltrexone treatment for opiate and alcohol dependence showed very limited occurance of naltrexone-related dysphoria and depression. (Miotto,1997)

Some physicians report a reluctance to prescribe naltrexone due to the "black box" warning of liver toxicity in the package insert. The warning was included based on liver enzyme elevations reported with 100-300mg/day doses of naltrexone during studies of naltrexone treatment for obesity. A review of literature and adverse effect reports from the manufacture demonstrated the safety of using 50 mg/day for alcohol or opiate dependent patients (Galloway).

The lack of wider use of naltrexone by physicians may also be partly due to the lack of market promotion by the manufacturer resulting in poor understanding of how and when to use naltrexone. Treatment providers have not been fully informed about naltrexone's unique role in facilitating relapse-prevention in opioid addicted patients. An experienced clinician who has considerable success in naltrexone treatment of heroin addicts suggested that naltrexone should be viewed as an adjunct to a wide range of individualized psychobehavioral treatments which may also include the use of other psychotropic medications for comorbid mental disorders. Patients families or friends should be encouraged to participate in treatment planning and compliance monitoring (Resinick).

Enhancing the Clinical Efficacy

Behavioral therapy, contingency management and a depot formulation have been proposed as approaches to enhance medication compliance and retention. When naltrexone (antagonist) treatment is compared and contrasted with methadone (agonist) treatment, several "obstacles" were identified contributing to naltrexone's poorer clinical effectiveness. Behavioral supports were designed to counteract (alleviate) these shortcomings. For instance, the lack of withdrawal aversion might be counteracted by increasing the consequences for its discontinuation or by increase the rewards for compliance to naltrexone's lack of intrinsic positive reinforcing effects. Counseling should be provided to discuss anticipated side effects (Rounsville).

Adherence to naltrexone may be augmented by contingency management. Study results suggested that reinforcement for naltrexone ingestion increases treatment retention and compliance with naltrexone therapy. Some schedule of reinforcement appear to produce better compliance with overall as well as continuous naltrexone intake (Preston).

The development of a sustained-release depot formulation of naltrexone is ongoing. Current research supports a depot naltrexone which has a sustained release profile of longer than 20days. Further clinical testing is needed to evaluate the acceptability, safety and efficacy (Nuwayser).

Use of Naltrexone in Specific Populations

It has been proposed that Naltrexone treatment should be effective in highly motivated patients. Suggestions have been raised to test the feasibility of applying naltrexone treatment in addicted professionals or in individuals who have entered the criminal justice system.

Physicians Health Programs (PHP) are designed to aid treated individuals to return to their profession. The program serves dual functions: 1) to observe, advise and monitor patient compliance with the treatment and patient abstinence, and 2) to advocate for the recovering physicians' rights with hospital/group, insurance underwriter and State Licensing Boards. The PHPs often combine behavioral modification, appropriate pharmacotherapy, self-help, "tough love," and contingency management, an approach which has produced excellent outcomes. Few opioid addicted physicians participating in PHPs are prescribed naltrexone. However, it does suggest that if naltrexone is to be made acceptable to opioid addicts with contingency management, the "voucher" must be at least as reinforcing as the drug of abuse.(Cohen)

Similarly, the Lawyers Counseling Program(LCP) of the DC Bar protects the lawyer's professional status and assists impaired lawyers seeking treatment and monitors their treatment progress. The services of LCP include assessment, referral, monitoring intervention, etc. Data suggested that 50-75% of the lawyer discipline cases involved addiction. The success rate is very impressive with this program; 100% abstinence for at least two years. These programs may provide an opportunity for the development and utilization of even more effective strategies, such as naltrexone pharmacotherapy for intervention and treatment (Schwartz).

Treating Federal probationers with naltrexone was studied by the Dr. O'Brien's group at University of Pennsylvania. Results suggested that naltrexone treatment reduced the re- incarceration rate by 50% (Cornish).

Recommendations

Proposals made to enhance the effectiveness and expand the use of naltrexone in treating heroin addiction included the following:

1. In order to achieve a opioid free state required to start naltrexone, the detoxification procedure needs to be tailored to assist transition to naltrexone treatment.
2. To improve medication compliance: Develop long acting delivery system, such as depot formulation of naltrexone which lasts for up to 30 days to minimize patient decision making; Coadminister naltrexone with SSRIs or other antidepressant; Add special motivation enhancing behavioral or psychosocial adjuncts.
3. To expand the use of naltrexone in treatment: Use in special patient populations with high external motivation to remain drug free such as impaired professionals, drug-experimenting adolescents, parolees, probationers, work-release participants. etc.
4. To improve the treatment effectiveness of naltrexone: Educate and train treatment practioners the correct and effective way of using naltrexone in treating opioids addicted patients.