Update on Naltrexone Treatment

2015

Our group in Philadelphia has used naltrexone in the treatment of 201 narcotic addicts in 258 separate treatment episodes as of 1 July 1977. The antagonist treatment program is an important part of our overall multimodality program which includes methadone or propoxyphene maintenance treatment, inpatient detoxification, long-term therapeutic community, family, group, and individual therapies, and a variety of behavioral treatments. Narcotic antagonist treatment, of course, appeals only to those patients who are genuinely interested in becoming drug free. It is not nearly as popular as methadone treatment, but it occupies an important niche — amounting to 5-10 percent of our total patient population at some time in their treatment careers.

Our narcotic antagonist patients are demographically similar to our other patients: mean age 27, 60 percent black, more than 95 percent male, and more than 95 percent veterans of military service. Our methods for detoxification from narcotics and institution of antagonist therapy have been reported elsewhere (2, 4); they are similar to those described by others. We use intravenous naloxone prior to the first naltrexone dose to detect residual physical dependence and thus reduce the incidence of precipitated withdrawal when the first dose of naltrexone is ingested.

Update on Naltrexone Treatment: Results

Our results will be discussed in four categories.

Side Effects and Toxicity of Naltrexone.

Because naltrexone is such an effective antagonist, it will precipitate acute withdrawal reactions in patients who have even small degrees of residual physical dependence on narcotics. Even in addicts detoxified up to a week previously, some degree of cramping and general aches and pains may occur with the first few doses of naltrexone. Patients with a history of peptic ulcer disease may have severe abdominal pain precipitated by naltrexone. We now exclude such subjects from naltrexone treatment.

Other subjective complaints such as dizziness, nausea, insomnia, or weakness may be related to protracted narcotic abstinence symptoms rather than naltrexone effects. They diminish after the first week and gradually disappear over the next several weeks of treatment.

We found no significant and consistent blood pressure changes in our 201. subjects. Inpatient blood pressure recordings tended to be lower than outpatient measures. But outpatient blood pressure prior to and during naltrexone therapy was not significantly changed. In fact, we have identified hypertensive addicts during our screening, treated their hypertension and then successfully placed them on naltrexone with no adverse effects on their anti-hypertension program.

The only serious toxicity occurring in our series was a case of idiopathic thrombocytopenic purpura while on naltrexone which may have been drug-related and a case of allergic dermatitis or drug rash. The relationship to the rash was established by resuming treatment with naltrexone cautiously, and the rash reappeared.

Overall, we found naltrexone to be a safe drug with minimal side effects — the same conclusion reached by Bradford and Kaim ().

Naltrexone Blockading Effects

We evaluated the degree of protection from narcotic effects afforded by naltrexone by conducting hydromorphone and saline self-injections under double blind conditions. Hydromorphone (Dilaudid) is a narcotic whose subjective effects could not be distinguished from heroin by experienced addicts (). A variety of hydromorphone dose levels were used (1-4 mg) equivalent to 7-30 mg heroin, and a variety of dose levels of naltrexone (50-200 mg/70 kg) and a variety of time periods after naltrexone ingestion (2-72 hrs) were used. Our results were quite consistent. Naltrexone reliably attenuated narcotic objective and subjective effects for up to 72 hours. The degree of attenuation was proportional to dose of naltrexone, dose of narcotic, and the time since naltrexone was ingested. Thus, the narcotic effects were less than those produced by a similar dose in that subject prior to naltrexone but reliably more than saline effects. These effects were seen in operant responses, pupillary constriction, and subjective reporting of rush, high, and street value of the injection.

Conditioned Responses Associated With Self-Injection

The availability of patients volunteering to take naltrexone provides an opportunity to study some of the conditioning factors associated with the self-injection ritual. The importance of conditioning in the addiction process was first recognized by Wikler (), and it has been extensively studied in experimental animals. We have described several types of conditioning in human addicts ().

Conditioned abstinence occurs when the addict is exposed to stimuli which, in the past, have consistently been associated with opiate withdrawal and the obtaining of the next dose. Examples are “copping” area, bags of heroin, “cook-up” rituals, and room in which narcotics are usually injected. After repeated pairing, the stimuli are able to elicit drug craving and withdrawal responses (pupillary dilation, cooling of skin, tachycardia) even when the addict is drug free.

The stimuli which elicited withdrawal responses were all pre-injection stimuli. The act of self-injection usually relieved the withdrawal and craving even if the injection actually consisted of saline. Some addicts reported definite pleasure from the self-injection when saline was received in a double-blind design. This has been described clinically as the “needle-freak” phenomenon.

The pleasure received from the injection itself (either saline or narcotic in the presence of naltrexone) extinguished rapidly. After several trials the pleasure turned to dislike and the patients reported that the self-injection caused their craving to be intensified. Thus some of the conditioned effects of self-injection were modified by unreinforced self-injection in the laboratory. This did not have a discernible effect on treatment outcome. Naltrexone patients who had their self-injection responses extinguished had only a slightly better outcome than those who received naltrexone with no self-injections. Still, the changes in injection behavior were dramatic. It may be more clinically effective to begin by desensitizing the patients to environmental stimuli related to drug procurement and then systematically progress in steps to desensitization to the self-injection procedure.

Clinical Outcome

The determination of relative effectiveness of a specific treatment is especially difficult when types of treatment differ radically. In the treatment of narcotic addiction, therapeutic community, methadone or other narcotic maintenance, and narcotic antagonist therapy all appeal to different patients. Thus random assignment of unselected patients to a given treatment is not possible. In our program, all of the above treatment modalities are available, but patients participate in the decision as to which treatment is used. Often they are used sequentially at different stages in a patient’s treatment. The result at followup then might be attributed to several treatments rather than just the last one.

We have interviewed naltrexone patients at one month and six months after stopping naltrexone treatment. Social and vocational functioning, drug use, and urine tests were evaluated. We compared naltrexone patients to patients treated in a maintenance study comparing propoxyphene (a weak opiate) and low dose (up to 36 mg per day) methadone. The only differences at intake were that the naltrexone patients reported more different types of drug abuse in addition to opiate dependence, more alcohol abuse, and more attempts at detoxification.

The results at followup showed that methadone patients remained in treatment longer, but there was no significant difference in treatment duration between propoxyphene maintenance and naltrexone. After termination from study treatment, naltrexone patients were significantly less likely to return to methadone maintenance. Nevertheless, naltrexone patients were more likely to be located for followup at one and six months. Naltrexone patients reported significantly more alcohol use at followup, but this difference was present at intake. Naltrexone patients reported significantly more benefits from treatment and more satisfaction with the program than the two maintenance groups. Significantly more naltrexone patients (40%) were opiate-free at one month, but the difference became nonsignificant six months after stopping treatment. Overall, there were remarkably few differences on any outcome measure. These results will be reported in detail elsewhere ().

Update on Naltrexone Treatment: Summary

To summarize, then, our work with naltrexone in a multi-modality treatment program indicates that it appeals to about 5-10 percent of narcotic addicts — those who consciously want to obtain drug-free status. It does significantly attentuate the effects of narcotics to the extent that they lose their reinforcing properties, and it has minimal side effects. Although we treated a self-selected population, it is noteworthy that about 40 percent of those who remained on naltrexone for more than a week were still opiate free 6 months after cessation of treatment. For some it appeared to be a turning point in their lives. It was the first time in years that they could live in their neighborhood and not be either intoxicated or occupied with the pursuit of narcotics. Our behavioral studies have identified a number of conditioned psychophysiological responses associated with the self-injection ritual. So far, although we have succeeded in extinguishing some of these responses, this has not resulted in an improved clinical outcome. We are currently working on more comprehensive behavioral treatments, but the clinical significance of these conditioned responses is uncertain at present.

Charles P. O’Brien, M.D. Ph.D., Robert Greenstein, M.D., and George E. Woody, M.D.

Selections from the book: “The International Challenge of Drug Abuse”. Robert C. Petersen, Ph.D., editor. A monograph based on papers presented at the World Psychiatric Association 1977 meeting in Honolulu. Emphasis is on emerging patterns of drug use, international aspects of research, and therapeutic issues of particular interest worldwide. National Institute on Drug Abuse Research Monograph 19, 1978.