Nida’s Naltrexone Research Program


The current naltrexone research program sup ported by the National Institute on Drug Abuse can be traced developmentally to its embryonic beginnings in the mid-1960’s. At that time Dr. William Martin and his co-workers at the Addiction Research Center in Lexington, Kentucky initiated a series of studies into the use of narcotic antagonists for the treatment of opioid dependence (). The studies were a practical outgrowth of the theoretical formulations elaborated by Dr. Abraham Wikler over the preceding years (). The results of the studies showed that a narcotic antagonist could be effectively used to block the euphorigenic and dependence-producing properties of opioids in man. Furthermore, this chemotherapeutic agent would produce neither physical dependence nor abuse liability in the treated individual. This was important because previous treatment drugs had the liability of producing their own degree of addiction.

These early clinical studies into the therapeutic use of narcotic antagonists might have faded into textbook obscurity had it not been for a number of concurrent social and political events that were rapidly developing. In the years following the tragedy of President Kennedy’s assassination on November 22, 1963, our nation was quickly pulled into social turmoil at home and military turmoil abroad. By the late 1960’s this multi-determined chaotic national scene had led hundreds of thousands of individuals to seek multiple avenues of relief. Many chose to seek refuge in what was felt to be the blissful escape provided by illicit drugs. This could be viewed sociologically as a massive attempt at self-medication. For many individuals, one dead-end to which these pharmacological avenues led was heroin addiction. Consequently by 1970 the use of heroin both at home and among our military personnel abroad had reached epidemic proportions. Among national authorities, apocalyptic visions of opioid-dependent armed United States soldiers, as well as similarly afflicted anti-war, anti-American anarchists roaming the streets looking for a “fix,” provided necessary impetus to both the Executive and Legislative Branches of the Government to authorize funding for expanded research and treatment of opioid dependence.

On June 17, 1971, President Nixon signed into creation the Special Action Office for Drug Abuse Prevention (SAODAP), to coordinate the various resources of the cederal Government necessary to check the continuing spread of illicit drug abuse. These resources for drug abuse research, prevention, and treatment had been previously scattered across more than fourteen different agencies. In 1972, the Congress passed the Drug Abuse Office and Treatment Act which was signed into Public Law 92-255, Section 224, 86 statement 72 on March 21, 1972. Among the numerous provisions of the Law was a substantial financial support for the expansion of research on “long-lasting, non-addictive. blocking and antagonist drugs or other pharmacological substances for the treatment of heroin addiction.” With these substantial mandates, SAODAP’s first director, Dr. Jerome Jaffe, set the development of a safe and effective narcotic antagonist as one of the highest priorities for this new agency.

Theoretical basis of narcotic antagonist therapy

Pharmacologically, a narcotic antagonist is a substance which has the ability to block the euphorigenic and dependence-producing properties of opioids (). At the present time, it is theorized that this type of drug accomplishes this feat because of its structural similarity to narcotics themselves. Thus, antagonists have the ability to occupy the same presumed opiate receptor sites in the body as the narcotics do, and thereby produce competitive inhibition of narcotics. Different narcotic antagonist drugs also have differential abilities to produce both antagonistic and agonistic action. These differential properties are, of course, important in choosing the proper narcotic antagonist for this type of therapeutic use. It should be noted that a pure narcotic antagonist differs greatly from a drug such as disulfuram (Antabuse) . When alcohol is ingested, by an individual taking the latter medication, a violent physical reaction ensues that can have life-threatening consequences. When heroin is injected in a dose which is blocked by the dose of the former medication being taken by an individual, no physical reaction ensues. Of course, an individual may attempt to overcome the blockade with too great an amount of heroin and fatally overdose himself.

This unique class of antagonist drugs thus formed the basis of a potential treatment modality as outlined by Wikler and Martin. They postulated that operant conditioning plays an important role in initiating and perpetuating heroin use. Initially, the euphorigenic properties of narcotics probably act as strong reinforcers of what was conceptualized as “drug-seeking behavior” in the opioid-dependent individual. Thereafter, tolerance to the narcotic develops and slowly reduces the euphoric effects. In addition to the pursuit of pleasure (the euphoric effects), there is now within the individual a growing awareness of the need to avoid pain (the abstinence syndrome) . Therefore, the avoidance of the discomforting opiate abstinence syndrome also perpetuates the “drug-seeking behavior.” Finally, a hypothesized “conditioned abstinence syndrome” may apparently be precipitated by environmental stimuli that have been associated with opiate dependence in the past. Occasionally after opiate detoxification, dependent individuals have described the onset of withdrawal symptoms by merely coming into contact with their previous environment. This conditioned abstinence syndrome may be characterized by increased reactivity to stimuli, prolonged abnormal autonomic responses, feelings of dysphoria, and often an intense “craving.”

Quite logically, it was theorized, the narcotic antagonist could be used to control these various determinants of drug-seeking behavior. Since the antagonist would block the euphoria and the dependence produced by the opiates, the reinforcement for drug-seeking behavior provided by these two critical determinants of opioid dependence would gradually be attenuated. Furthermore, the antagonist would protect the detoxified individual against the conditioned abstinence syndrome. Thus, with the absence of these reinforcers would come the gradual extinction of the drug-seeking behavior itself.

The protection afforded by the antagonist would then give the needed time to aid the detoxified individual in altering his life’s course. In the context of a close and humane psychotherapeutic milieu, the individual could learn to regain control over his own destiny. That is to say, he could begin to develop greater internal controls and greater independence and begin to extricate himself from the sticky external web of drugs and environmental pressures that had ruled his life until then.

Development of an optimal narcotic antagonist

In light of the above-described socio-political milieu and the enticing theoretical notions concerning the antagonists, we can easily understand why the development of a safe, effective antagonist was of the highest priority for SAODAP in 1971. SAODAP directors also recognized that the selection and development of such an antagonist was of no burning interest to the private pharmaceutical industry. The projected spending of research and development funds and time seemed to outweigh projected returns from what appeared to be a limited market. This projected spending was high because the development of a new drug is a complicated and time-consuming affair.

By law, any new drug must pass through rigorous and controlled testing in several animal species as well as in humans before it can be marketed. The testing is divided into a pre-clinical phase and three clinical phases. In the pre-clinical phase, the gamut of toxicity studies should be carried out on at least two different animal species. Provided the drug proves to have a sufficient margin of safety in these toxicity studies, it may then be introduced into man for the purpose of gathering safety and efficacy data. Phase I of the clinical studies deals with the basic clinical pharmacology of the drug in man. This covers such areas as dosing levels, absorption rates, metabolites, and so on. Phase II represents limited and quite controlled clinical trials intended to demonstrate the safety and relative efficacy of the drug. For reliable results! it is desirable that these studies be carried out within a double-blind placebo design. That is, neither patient nor administering staff know which patients are on the drug and which on a placebo. Phase III then represents both controlled as well as uncontrolled clinical investigation in a much larger group of patients. The successful completion of this phase with a demonstration of drug efficacy is the final step before a New Drug Application (NDA) is submitted to the Food and Drug Administration (FDA). With approval of the NDA, the drug then is eligible for marketing to the general public, Of course, there is a constant financial risk involved in this process, for drug development may be halted at any point, based on unacceptable toxicity or disproven efficacy.

It was with this long and complex procedure ahead that the Federal Government, through the Special Action Office for Drug Abuse Prevention (SAODAP) and the Division of Narcotic Addiction and Drug Abuse (DNADA, NIMH), undertook the development of a safe, effective narcotic antagonist. A research plan was initiated by DNADA in September, 1971 to help organize such an efficient development. In this plan were outlined the necessary pre-clinical research, the procedures for clinical testing, and the cost and personnel estimates. Additionally the optimal characteristics of narcotic antagonists were described. These were as follows:

  1. 1. Ability to antagonize the euphoric high of opiates.
  2. 2. Absent or low-agonistic effects, especially unpleasant ones.
  3. 3. Does not cause physical dependence.
  4. 4. Does not exhibit increasing tolerance to its antagonistic actions.
  5. 5. Absence of serious side effects and toxicity even in chronic use.
  6. 6. Easily administered, i.e., no surgery or painful procedure involved.
  7. 7. Long-lasting or moderate duration of antagonist effects.
  8. 8. Absent or low abuse potential.
  9. 9. Reversible effects in case of medical emergency.
  10. 10. High potency to allow administration of small amounts in a biodegradable vehicle,
  11. 11. Easily available and inexpensive.
  12. 12. Therapeutic efficacy in treatment of narcotic addiction.

By early 1972 there were several antagonists in existence at various stages of development. The purest antagonist was naloxone. It seemed to be a potent antagonist and showed almost no agonist action of its own. Its main drawbacks as a therapeutic agent in opioid dependence were its high cost, the difficulty in synthesizing it, its very poor oral absorption rate, and especially its short duration of action in the body. Naloxone had been approved by the FDA for short-term use in humans as an antidote for opiate overdose. In spite of its drawbacks, naloxone had met with limited success as an adjunct to treatment by several investigators. This seemed encouraging for narcotic antagonist treatment in general.

Concurrently being developed was another promising and potent antagonist called cyclazocine (). This drug demonstrated a longer duration of action of up to 24 hours with 4 milligrams of the substance. However, its drawbacks were also recognized. These consisted of strong agonist properties when administered rapidly to individuals. These properties included quite unpleasant feelings described as dysphoria and psychotomimetic effects. Despite the tolerance that develops to these effects, cyclazocine was not well received by the addict volunteers and soon acquired a bad street reputation. However, it was successful in the treatment of some individuals, and these individuals are still, in fact, being treated with cyclazocine in certain clinics in New York City.

Additionally, three other compounds, designated as M-5050, BC-2605, and EN-1639A, wereinearly animal and human testing at the time. One of these, EN-1639A, seemed to be a potent antagonist and also did not show the dysphoric and unpleasant side effects of cyclazocine (). It had a good duration, in that 50 mg seemed able to block narcotic action for 24 hours. By late 1972, there was a substantial supply available for testing of this drug, which came to be known as naltrexone. By mid-1973 it became evident that this drug fulfilled the criteria of an optimal narcotic antagonist to a greater degree than any of the other available substances ().

Besides the research progress being made, there were also administrative changes occurring within the Government. In 1973, the Division on Narcotic Addiction and Drug Abuse was separated out from NIGH and expanded into the National Institute on Drug Abuse. Thus, from 1973 to 1974, NIDA and SAODAP shared the responsibility for the ongoing development of the narcotic antagonists in general and of naltrexone in particular. By mid-1974, as SAODAP began to phase out of existence, the entire direction and monitoring of the naltrexone research program fell to the Division of Research, NIDA.

Nida-supported naltrexone research

From 1973 to 1974, NIDA supported 26 various grants and contracts in pre-clinical and clinical studies directly related to narcotic antagonists. This support totalled over five million dollars. Approximately seventeen of these grants and contracts dealt with the use of naltrexone in clinical situations, and they fit together into a rather loosely knit naltrexone research program. Five of these research clinics were selected to participate in the double-blind placebo study of naltrexone that was, and still is, being conducted by the National Academy of Science (NAS). It was planned that such a study would satisfy in an elegant manner the Phase II requirements for new drug development and would demonstrate the safety and relative efficacy of naltrexone when compared to placebo. The five NAS clinics in the double-blind studv had a standardized group of three research protocols which they had to follow. The differences in the three protocols derived from the fact that each used a different type of opiate-dependent individual. The Baltimore and New Haven Clinics could use only “post-addicts” in their research. The Detroit and Sepulveda Clinics could use only “methadone maintenance addicts” And the St. Louis Clinic could use only “street addicts.”

By contrast, the remainder of the grants and contracts consisted of a variety of controlled and uncontrolled clinical trials with naltrexone (). Researchers in this group were free to use different protocols, to use different treatment settings, to treat different types of dependent individuals, and to pursue any variety of different research questions. This group of grants and contracts were called the NIDA clinics, for want of a better title. These NIDA clinics were later divided into a group of “open clinical naltrexone studies” and a group of “behavioral naltrexone studies,” in an effort to bring greater order and specificity to the overall naltrexone program. In the former category were classed those studies which tested naltrexone within a variety of clinical contexts, whereas in the latter category were gathered those studies which specifically attempted to test out the original behavioral formulations discussed above.

All of the studies underway by 1974 were conceived by NIDA to represent Phase II testing of naltrexone. That is to say, naltrexone was receiving exposure in limited clinical populations. In Phase II, one of the chief responsibilities of NIDA was providing a watchful eye over the safety aspects of this drug when it was administered to humans. Consequently, a tight monitoring system had to be devised if the limited staff at NIDA was to function properly in detecting any ill effects of the drug. We therefore decided to establish the same kind of monitoring of all the NIDA research clinics that existed for the five clinics in the National Academy of Science’s study. Biometric Research Institute (BRI) of Washington, D.C., was providing the monitoring and statistical capabilities for the NAS study and had developed a number of forms in conjunction with the NAS-CENA committee to carry this out. We therefore arranged for BRI to provide a similar monitoring function for the NIDA clinics. This consisted of gathering information on the monthly laboratory records (NAS-5a), monthly physical and psychiatric summaries (NAS-5b) , weekly symptom check lists (NAS-7), and the daily treatment records (NAS-9 and 9a) from the various open clinical and behavioral NIDA studies. Thus, by early 1975, we were able to gather a large quantity of both safety and efficacy information into the central data bank of Biometric Research Institute and were able to keep constant and close watch over any potentially unpleasant or harm ful effects of the drug.

Up to the present time, we have not seen any dysphoria or other psychic ill effects from naltrexone. The question arose in the past whether naltrexone caused an increase in blood pressure. According to the collective data, there seems to be a small (2-3 millimeters of mercury), but not statistically significant, rise in both systolic and diastolic pressure after initial administration of naltrexone. However, by four to six weeks, there is a return to baseline and in many cases a 2-3 millimeter decrease in both systolic and diastolic pressures (). The only occasional side effect with some subjects seems to be an abdominal and gastrointestinal discomfort. When this was found at the beginning stages of treatment, it was attributed to minor withdrawal symptoms, because opiates were presumably still in the addict’s system. However, these symptoms have been reported later on in treatment as well. Some researchers have found that these symptoms are some-times relieved by antacids or by administering naltrexone to the addict after he has eaten. So it may be that naltrexone acts as a gastric irritant for some addicts.

An intriguing scientific question, however, is: what interaction could naltrexone be having with the endogenously occurring opiatelike compound that has recently been isolated by researchers? Could, in fact, these abdominal symptoms be related to such an interaction? If an individual who is being maintained on naltrexone has a quantity of this endogenous substance secreted into his system and it is, in fact, opioid in nature, is it not possible to assume that some of the same symptomatology might occur as if an external opiate were entering this individual’s system in a sufficient amount to cause such physical effects? This symptomatology might therefore include minor withdrawal symptoms characterized by the abdominal discomfort described.

All of these minor side effects notwithstanding, we have seen no serious lasting side effects directly attributable to the ingestion of naltrexone. This antagonist appears to be a rather safe chemotherapeutic agent for the treatment of opioid dependence.

Naltrexone program – the future

The NIDA naltrexone program currently consists of the NAS-CENA studies, the behavioral naltrexone studies, the open clinical naltrexone studies, and a number of studies at the NAS clinics which are essentially continuation studies of naltrexone safety and efficacy without the double-blind protocol. The NAS-CENA studies, which began intake in mid-1974, are now in the process of gathering follow-up data on the patients who have participated in the study. The double-blind has not yet been officially lifted for the investigators, and the existing data are now being tabulated and analyzed by BRI. These results will be forwarded to NAS-CENA committee which will issue its final report of this particular study by the end of 1976. Approximatelv 190 subjects have taken at least one dose of study medication, about half on placebo, half on naltrexone. The results are not in yet, but it seems that naltrexone was of benefit to a certain percentage of subjects in this study.

Aside from the NAS-CENA study, over 690 individuals have taken at least one dose of naltrexone in the other NIDA-sponsored clinics. This means that the total number of individuals who have at least one-time ingestion of the drug is therefore over 775. From a numbers standpoint, this would seem to be a more than adequate figure for satisfying Phase II requirements for clinical testing. We therefore consider the naltrexone program to be entering into the late stages of Phase II testing and are preparing the data collected to be submitted to the FDA by early 1977.

As this phase of naltrexone development winds down to conclusion before shifting into Phase III, so too does type and method of support provided by NIDA. The program began, as was described above, with an Executive and Legislative mandate for the development of a safe, effective antagonist. This mandate carried with it strong financial support in the form of contract monies. However, as Phase II winds down, so too do these contract funds. We have therefore increasingly encouraged interested researchers to seek grant support for proposed naltrexone research. So far, this seems to be working well, and basic clinical research continues with naltrexone.

As for Phase III of the drug’s development, we are currently exploring the possibility that Endo Laboratories, a pharmaceutical firm and the owner of the patent for naltrexone, will be interested in carrying out that phase of ewanded controlled and uncontrolled clinical investigation. Although naltrexone safety seems to be well supported by the Phase II data, further monitoring of the safety will be carried out during Phase III, as well as the all-important testing of the efficacy claims for this drug.

Naltrexone has proved to be an interesting agent–almost a non-drug drug because of the lack of discernible effects other than its opiate-blocking capacity. This lack of other pharmacologic action may well prove to be one of the most attractive features of the drug. If the sentiment against the dependence-producing properties of other therapeutic modalities such as methadone and LAAM begins to expand, we may well be turning to a therapeutic program which includes naltrexone as a pivotal feature. This “anti-dependence” sentiment is current in two areas of the country, California and Massachusetts. Since these regions often herald what is to come for the rest of the country, we may find a receptive atmosphere for naltrexone as it is being prepared for expanded therapeutic use.

As it has been used to date, therefore, naltrexone seems to be a safe drug and an efficacious one in some addicts. However, further testing of its efficacy needs to be carried out in new and innovative techniques of administration. The question arises of how naltrexone’s efficacy can best be maximized. Should we think of this drug as another long-term maintenance chemotherapy? Or would it be more effective when used in conjunction with short-term crisis-intervention techniques; or in conjunction with various behavioral techniques; or in a contingency manner, so that the addict could ask to be put on naltrexone when he felt the need arise? Furthermore, the pre-clinical research into the use of implantable long-acting preparations continues unabated. These, however, raise-y ethical questions, besides questions concerning the efficacy of this mode of drug delivery. From another angle also, what factors such as attitudinal, environmental, and socio-cultural variables both in the clinic personnel and in the addicts treated are crucial for the effective use of this drug? Finally, are there intrapsychic or personality variables in addicts that make some appropriate for one kind of treatment and others appropriate for another kind of treatment? ().

The papers that follow in this monograph begin to touch on many of these intriguing research questions as well as describing with great clarity and detail many of the research discoveries and conclusions to date dealing with naltrexone as a therapeutic agent. It is our hope that further research will continue to reveal solutions to these questions, and we will be able to place naltrexone therapy most productively into the overall treatment approach to opioid dependence.


Selections from the book: “Narcotic Antagonists: Naltrexone”. Editors: Demetrios Julius, M.D., and Pierre Renault, M.D. Progress report of development, pre-clinical and clinical studies of naltrexone, a new drug for treatment of narcotic addiction. National Institute on Drug Abuse Research Monograph 9. September 1976.