National Institute on Drug Abuse
National Institutes of Health
Naltrexone
An Antagonist Therapy for Heroin Addiction
November 12-13, 1997
SUMMARY
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:
- 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.
- 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.
- 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.
- 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.
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