Treatment of heroin-dependent persons with antagonists: current status
The concept of narcotic antagonists
The development of naltrexone
Clinical use of naltrexone
The future of naltrexone
Summary and conclusion
Author: P.F. RENAULT,
Pages: 21 to 29
Creation Date: 1978/01/01
Chief, Clinical-Behavioral Branch, Division of Research, National Institute on Drug Abuse, 5600 Fishers Lane, Rockville, Maryland 20857.
Like many chronic diseases, heroin addiction is a complex condition to treat and a therapist treating heroin dependence must often satisfy non-medical authorities that his treatment will have an impact on "the problem". The "problem" of heroin dependence, however, is not simply an individual behavioural problem but one of cultural, historical, and socio-economic dimensions. Thus, it is not uncommon for the effectiveness of a treatment to be measured more in terms of its impact on crime rate or prevalence of heroin addiction rather than the success in the treatment of afflicted individuals. This complexity has confused therapists and has left the goals of individual treatment poorly defined. Conversely, the lack of definition of treatment goals has encouraged unreasonable expectations of the treatment system and over-simplified conceptualizations of the problem of heroin addiction. In spite of this, effective treatment programmes have been established and a majority of heroin-dependent individuals who come for treatment can expect to be helped.
The ultimate goal of treatment for heroin-dependent persons should be the patient's control over the use of the drug; however, in the case of heroin, society has demanded that control be defined as abstinence. This demand has led Governments to support detoxification programmes, because detoxification is generally applicable, low in cost, and it is the most immediate and direct way of disentangling an individual from heroin. However, government emphasis on detoxification programmes often betrays the over-simplified view that heroin dependence is simply a pharmacologic problem. On the contrary, heroin dependence involves every aspect of an individual and his environment. Individual freedom of choice is undermined by conditioned responses, pressures from peers, the social frustrations which often seem to form the substrate of heroin use, and subtle pharmacologic factors such as the intense craving associated with protracted abstinence.
An often more realistic definition of control over drug use is the elimination of dysfunctional drug use. Dysfunctional drug use has been defined as drug use that results in physical, psychological, economic, legal, and/or social harm or discomfort to the individual drug user or to others affected by that drug user's behaviour. It is the discomfort that drug use causes that brings an individual to treatment, and the elimination of that discomfort should be the most immediate treatment goal. It was this conceptualization of treatment goal that nurtured the development of substitution or maintenance therapy of heroin addiction with methadone. Methadone maintenance effectively returned the control of heroin use to the individual by decreasing craving and eliminating abstinence symptoms. It also promoted functioning in normal society by decreasing the frequency of drug taking, the disruption by drug effects, and the difficulty and costs of obtaining drugs. Although it is clear that methadone or levo-alpha-acetylmethadol (LAAM) maintenance does decrease dysfunctional drug use, it is not applicable to all addicts. Maintenance or stabilization treatment has only been used in chronic addicts where the prospects of total abstinence are poor. However, many narcotic dependent individuals desire total abstinence and find the concept of methadone maintenance unacceptable. Other individuals are currently abstinent but are in danger of relapsing. Among the latter are those recently detoxified from heroin addiction, or those who are being released from prison, or even others who, in spite of prolonged abstinence, have been suddenly tempted to take heroin again by the pressures of emotional turmoil or the ready availability of heroin in their immediate environment. Finally, there are those individuals who have never been dependent on heroin but are using the drug and, therefore, are at risk of becoming dependent. Currently available treatments for such individuals are limited and the pressures on the abstinent addict to relapse are intense. These "abstinent addict" patients are often strongly motivated to seek treatment and relapses often produce guilt and depression, but they are still unable to resist giving in to the intense craving for heroin. They are strongly motivated, but motivation simply is not enough. The recognition of the need to broaden the spectrum of heroin dependence treatment to include these patients has nurtured the development of narcotic antagonist treatment.
Narcotic antagonists are usually defined as chemical compounds which block the effects of opiate drugs. Narcotic antagonists will block the analgesia, the euphoria and all-the physiologic changes such as pupilary constriction produced by agonist opiates. By blocking the effects of agonist opiates, narcotic antagonists also prevent the development of physical dependence and tolerance to opiate drugs.
Opiate drugs exist on a continuum with morphine, heroin and other agonists at one end and antagonists such as naloxone and naltrexone at the other end. There are many well-known drugs which fall between the pure agonists, such as heroin and morphine, and the pure antagonists, such as naloxone and naltrexone. Drugs such as pentacozine, cyclazocine and nalorphine have mixed agonist and antagonist effects. For example, pentazocine, a commonly used analgesic drug, will precipitate the abstinence syndrome in an individual who is physically dependent on heroin. Cyclazocine is a potent antagonist, but the induction period is characterized by agonistic effects of a dysphoric nature. During the induction onto cyclazocine, tolerance builds rapidly to the dysphoria, and not to the antagonistic activity of the drug.
The blockade produced by narcotic antagonists is different from that produced by disulfiram. Disulfiram (Antabuse) is a commonly used drug for the treatment of alcoholism. It exerts its effect not by blocking the effects of alcohol, but by interrupting the metabolism of alcohol at the acetaldehyde stage. The build-up of acetaldehyde produces severe symptoms of nausea, vomiting and hypotension. The knowledge that drinking will produce such symptoms may act as a deterrent to further drinking for some alcoholics. Narcotic antagonists exert their activity by blocking the access of agonists to the opiate receptor sites at the molecular level. Antagonists do not produce symptoms when an agonist is administered. Rather, when opiate receptor sites are occupied by an antagonist, opiate agonists simply have no pharmacologic effect.
Although narcotic antagonists do not produce symptoms when they are used in the treatment of heroin dependence, they will precipitate an abstinence syndrome in individuals who are physically dependent on an opiate drug. By virtue of their greater affinity for the opiate receptors, they will displace opiate agonists from the receptor sites. A heroin addict must be detoxified before he can be treated with a narcotic antagonist. Once completely free of opiate drugs, however, no symptoms will be produced by the administration of a narcotic antagonist.
The theory underlying narcotic antagonist treatment of heroin dependence is based on the concept of extinction. This assumes thas the euphoriant effects of opiate drugs reinforce the self-administration of these drugs. If an ex-addict is given a narcotic antagonist and he takes an agonist drug, he will experience no effect, i.e., no euphoria. This lack of reinforcement will gradually result in the extinction of heroin self-administration  - .
The concept of narcotic antagonist treatment has been criticized on the basis that since these drugs do nothing "positive" for an individual (the only subjective effect is the absence of an effect when an agonist such as heroin is taken) and there are no pharmacologic consequences (such as withdrawal symptoms) for not taking an antagonist; compliance with a treatment programme employing a narcotic antagonist drug will be quite low. Compliance is a problem with medications for most chronic conditions where the medication is given to prevent the progression of the disease rather than to alleviate a symptom which would recur if the medication were not taken.
At least three solutions have been proposed to meet this objection. It has been proposed that naltrexone be administered in a long-acting form. Sustained action preparations lasting up to a month or more could be developed. Another suggestion has been that external coercion be used to force individuals to comply with a narcotic antagonist regimen. For example, individuals released on parole from the criminal justice or civil commitment system could be threatened with reincarceration for lack of compliance. Prisoners in a work release programme could be required to take a narcotic antagonist prior to leaving the prison to work each day. Finally, some have suggested that an antagonist be sought which would have some agonistic euphoriant properties, a mild euphoriant effect which would not be disruptive or lead to dysfunctional drug use but which would act as a reinforcer and encourage compliance.
In the beginning of this decade, the decision was made to encourage the development of a narcotic antagonist to be used in the treatment of heroin dependence. Available compounds included naloxone, cyclazocine and naltrexone. Both naloxone  - and cyclazocine  ,  - were tested in clinical trials. Both of these drugs proved to be excellent antagonists but both had drawbacks. Cyclazocine was limited because of dysphoric side effects during the induction period. Naloxone is a pure antagonist, and thus, it is free of agonist side effects, but lacks potency when administered orally. Finally, naltrexone was selected for development. Nal- trexone is a potent narcotic antagonist. It has a long duration of action, up to three days following one oral dose. It is devoid of agonist activity and thus the induction phase is virtually asymptomatic. Martin et al. found that a 50 mg oral dose of naltrexone will block the subjective effects of 25 mg of morphine for 24 hours and that it will attenuate the development of physical dependence  . O'Brien et al. reported that the blockade produced by a 120-200 mg dose of naltrexone at 48 hours was not absolute, but was sufficient that subjects discontinued self-injection of 1-4 hydromorphone (Dilaudid)  . Resnick et al. reported complete blockade of the agonist effects of 29 mg of intravenous heroin 24 hours after a 50 mg or larger dose of naltrexone, and 48 hours after 120 mg or larger dose  . They also found some individual variability, i.e., one patient required 200 mg (their maximum dose) to achieve 24 hour blockade. Finally, Martin et al. demonstrated that tolerance does not develop to the antagonistic action of naltrexone  .
The drug development process in the United States requires extensive animal toxicity testing followed by phased human clinical trials. Most of the required animal toxicity testing of naltrexone has been completed. Phase I human trials involve the basic pharmacology of the drug in humans such as the work reported by Martin. Phase II involves the testing of the drug in otherwise healthy heroindependent males. Phase II clinical testing of naltrexone was organized into two co-operative studies.
The first co-operative study was a fixed dose, randomly assigned, prospective, double-blind comparison of naltrexone and placebo conducted in five clinics following three protocols. In all, 192 patients participated, 94 were randomly assigned to naltrexone and 98 to placebo. The three protocols were determined by patient characteristics. In one protocol, street addicts were detoxified from heroin and placed on naltrexone or placebo. In the second protocol, individuals were placed on naltrexone or placebo immediately after detoxifying from methadone maintenance and in the third protocol, post-addicts from the criminal justice system were placed on naltrexone or placebo. The other co-operative study involved a loosely-knit group of 12 clinics, who followed a variety of protocols, but used a uniform data collection system. These studies were largely open and uncontrolled. They were intended to gain clinical experience with naltrexone and the data collected was useful primarily as an investigation of the safety of the drug in comparison with the safety results reported in the double-blind study. In all, 1,005 patients participated in this study, 10 of whom were female. Another important difference between the two studies was that dropouts could re-enter the open study. Both co-operative studies have been completed, and the results are available. Both showed naltrexone to be safe. There were no drug-related medical problems in the double-blind study. In the open study, one individual developed idiopathic thrombocytopenic-purpura which may have been the result of sensitivity to naltrexone. Fifty-three of the 1,005 cases were terminated for "medical reasons", none of which were clearly drug-related. (In the double-blind study, five of the 98 placebo medicated patients were terminated for "medical reasons".) No subjects in either study were dropped because of serious deviation in a clinical laboratory determination. In the double-blind study, four laboratory parameters statistically differentiated the naltrexone group from the placebo group. However, none of the differences in haemoglobin, total protein, bilirubin, and urine red blood cells were of a clinically significant magnitude. Only a slight increase in bilirubin was also found in the open study. Again, this was not clinically significant. The naltrexone group did have more side effects. These consisted primarily of gastrointestinal complaints, such as nausea and abdominal pain. There were also more complaints of headache and skin rash. Again, these side effects were of low incidence and the safety data have been judged to support the conclusion that naltrexone has a wide margin of safety for clinical use.
The Phase II clinical trials did show the anticipated poor compliance with naltrexone. And, although retention rate tended to be better and the use of narcotic drugs tended to be less in the naltrexone group compared to the placebo group, these differences, when compared individually, were not statistically significant.
Since the theory behind narcotic antagonist treatment involves extinction and the concept of extinction implies some use of narcotic drugs, a subsample of those individuals who had at least one urine sample positive for morphine and/or methadone was studied. Only 17 of the naltrexone and 18 of the placebo subjects actually tested the blockade by using an opiate agonist (heroin or methadone). But, in this subsample, the naltrexone patients had significantly fewer subsequent urines positive for methadone or morphine and this difference was statistically significant. Also, the pattern between the two groups was different. The pattern in the naltrexone group was to test once or twice with heroin or methadone and then to stop. The use of these drugs in the placebo group was sporadic during the entire course of treatment. Thus, it seems clear that naltrexone can prevent impulsive heroin use in motivated patients from becoming a full-fledged relapse to chronic heroin dependence.
A very interesting finding from the double-blind study deserves a special note. During the course of the study, subjects were administered a craving scale. This was an analogue scale on which subjects rated the amount of craving they felt at the time. Response on this instrument was variable, but the naltrexone patients reported statistically significantly less craving toward the end of their evaluation than did the placebo treated patients.
Naltrexone is administered orally either in liquid or solid (capsule) form. The capsule is preferable, because naltrexone has an extremely bitter taste. However, there is some slight danger of diversion when capsules are used, and the liquid formulation was used in most clinical trials to ensure that subjects actually ingested the administered dose. The frequency of administration is either daily or three times a week. The daily dose is 50 mg and the dosage for a three-times-a-week regimen is 100 mg on Monday and Wednesday and 150 mg on Friday. Both of these regimens had been found to provide an adequate blockade for the heroin used in the United States.
Post-addicts who are not currently physically dependent have generally been inducted onto naltrexone by 10 mg increments until 50 mg daily is reached. Then, they have been converted to a 100-100-150 mg regimen. However, some clinicians feel that an induction period onto naltrexone is unnecessary in the post-addicted patient.
Patients who are currently physically dependent on an opioid drug must first be detoxified before they can be put on naltrexone. The selection of a method of detoxification is up to the individual clinician. Once the patient has been detoxified, it has been customary to administer a small amount of naloxone intravenously to be certain that the patient is no longer physically dependent. Thomas et al. suggest 0.8-1.2 mg intravenously  . If there is no response to this dose of naloxone, induction on a full dose of naltrexone should be without discomfort.
The clinic setting in which naltrexone is administered is critical to the success of the treatment. It should be recognized that naltrexone is not a treatment in itself. It is a pharmacologic adjunct to treatment. The actual treatment consists of the efforts made by the staff to help the individual patient alter his lifestyle so that he can function successfully in normal society apart from the drug-abusing subculture. It is not appropriate in this paper to enter into a lengthy discussion of clinic milieu, psychotherapeutic techniques, and rehabilitative measures that can be employed with heroin-dependent individuals. Suffice it to say that in the United States, the tendency has been to create a supportive and permissive milieu where individuals are strongly encouraged to remain on naltrexone until they have significantly altered their lifestyle.
There are three types of patients for whom naltrexone seems particularly well suited. These are adolescent heroin users, "abstinent" addicts at risk of recidivism, e.g. individuals recently released from prison, and patients recently detoxified from methadone maintenance. Adolescents will have had a relatively short experience with opiate drugs. Many may be experimenters with heroin and not physically dependent. Those who are physically dependent will have been so for only a relatively short period of time. All these individuals are at risk of becoming chronically heroin dependent. Currently, there is no available pharmacologic adjunct to assist in the treatment of adolescent heroin users. Prisoners who have been recently paroled have, presumably, been narcotic free for the duration of their incarceration. However, it is well-known that upon re-entering their old environment, these post-addicts are at risk of becoming readdicted. Often, the sequence of events begins with an impulsive dose of heroin which leads precipitously to the re-establishment of old behavioural patterns and compulsive heroin use. Within the criminal justice system, naltrexone may also make a significant contribution to work release programmes. Naltrexone may make it possible for addicts to participate in such programmes and thereby facilitate their rehabilitation  . Patients recently detoxified from methadone maintenance are also known to be vulnerable to relapse. There is evidence that this vulnerability may have a pharmacologic basis  . In the future, naltrexone may form the basis of a comprehensive after-care programme for methadone maintenance patients which will carry them through this period of pharmacologic vulnerability.
Noticeably absent from this list are freshly detoxified heroin-dependent individuals. The experience in the United States during Phase II clinical testing indicated that the motivation in this group was less than that of other groups tested as measured by their compliance. Admittedly, this may not be true in other treatment situations. The heroin-dependent individuals, who were treated with naltrexone in the Phase II clinical trial, were free to leave at any time, and had no incentive or social constraint to encourage them to remain on naltrexone for sufficient time to participate fully in the clinic's treatment programme.
The problem of compliance is not unique to naltrexone. It is common in all of medecine, but especially with medications administered to asymptomatic individuals who have a latent form of a disease. A convenient analogy is that of antihypertensive medication. It is a human characteristic to forget the pain and the symptoms which led one to treatment, as soon as those symptoms are eliminated by the treatment.
The problem of compliance with naltrexone treatment has led to two basic philosophies underlying the clinical use of naltrexone. Naltrexone has been conceived as a maintenance drug which an individual takes continuously for a year or two or perhaps indefinitely. Naltrexone has also been conceived as a crisis medication to be used by individuals whenever they feel at risk of resuming heroin use. Maintenance on naltrexone appears to be essential for the majority of patients. As a maintenance drug, naltrexone offers protection against the impulsive drug use which can easily lead to the resumption of chronic heroin dependence. On the other hand, when there are few incentives to continue naltrexone use, the problem of compliance often interferes with maintenance. Thus, from a practical point of view, only a minority of patients will use naltrexone as an maintenance drug. Most patients tend to drop out of treatment prematurely, but many return requesting a resumption of naltrexone treatment when they experience themselves relapsing. The problem of compliance has encouraged the free use of clinics and naltrexone for support during crises. However, the recognition of the danger of relapse requires a level of maturity, self reliance, and insight which is not characteristic of most patients .
The immediate future of naltrexone will be the completion of Phase III clinical trials and the eventual marketing of this drug for general use. However, even with the marketing of naltrexone, several important research issues will remain.
We must improve our ability to select patients for naltrexone treatment. This is part of a broader issue which includes all forms of opiate addiction treatment. We are still unable to characterize those individuals who do best with the currently available treatment modalities.
An exciting area of research will be on the effects of naltrexone on the endocrine system. The fact that in the Phase II double-blind study, naltrexone appeared to decrease craving suggests that it may have a "healing" effect on the endocrine system. It may well be that endocrine serve an important function in the regulation of mood and sense of well-being. It also seems possible that prolonged use of heroin may atrophy this system and the subsequent disruption in mood and sense of well-being may be the basis of prolonged craving in addition to the known pharmacologic phenomenon of prolonged abstinence. It would be of the utmost importance if naltrexone proved to be not only a protection against impulsive heroin use, but also directly beneficial by helping to reverse heroin-induced atrophy in the endocrine system.
Along with the development of oral naltrexone, sustained action preparations are also being developed. These are injectables which can be removed if necessary. Their planned duration of action will be approximately one month. However, none has been tested in man as yet. Sustained action preparations have been regarded as a solution to the problem of compliance; but, even monthly injections block narcotic analgesia and therefore must be removable or overridable in the will require patient compliance. Their most serious disadvantage is that they will event of severe pain.
Naltrexone is an important new pharmacologic adjunct to the treatment of heroin dependence. The development of naltrexone has been nurtured in the mature recognition that simple detoxification or simple opiate replacement therapy is not appropriate for every heroin addict. Our current data indicate that naltrexone is safe and effective. Its use may be limited to a minority of addicts, those who are highly motivated and opiate free, because patient compliance has been a major problem with which clinicians using naltrexone have had to contend. Patient compliance is a problem, because there are no immediate consequences to the patient for stopping his naltrexone regimen. Side effects from naltrexone have been minimal and have occurred in a minority of patients. They consist primarily of gastrointestinal symptoms, including nausea and occasionally abdominal pain.
The immediate future of naltrexone will be the completion of clinical testing and the marketing of naltrexone for general use. However, broader research questions also remain. Who are those patients likely to benefit from narcotic antagonist treatment? Is naltrexone the "ideal" antagonist? Naltrexone was chosen for its lack of agonistic properties which were experienced as dysphoric side effects in the case of cyclazocine. But, would an antagonist with some reinforcing euphoric agonistic properties be more acceptable to patients and, therefore, effective in a larger proportion of patients? Does a pure antagonist such as naltrexone have a "healing" action on the disequilibrated endocrine system? What are the effects of naltrexone on protracted abstinence? Is naltrexone best viewed as a maintenance or a crisis drug? Answers to these questions will come as this important technical advance is used more widely by thoughtful clinicians.
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