INTRODUCTION

 

Due to the chemical complexity of the human organism it is difficult to imagine that any one chemical agent would produce a single pharmacological effect. The "magic bullet" theory, envisioned by Paul Erlich around the turn of the_century, postulated that after drug administration the drug is absorbed, transported by the blood to its site of action, performs the desired pharmacological action without effecting other cells or organs and then excreted. It was soon discovered that such selective chemicals were nonexistent. After searching for decades, scientists had to be satisfied by finding chemicals with the minimal number and least severe side effects. Interestingly, naltrexone seems to be close to the description of the "magic bullet."

 

Addiction to narcotics occurs after the chronic interaction of the opiate receptors in the brain with the exogenous opioids such as heroin, morphine, or methadone. What happens if the opiates cannot interact with the receptors because they are already occupied by another ligand which has no opioid activity? The answer is: nothing, absolutely nothing, and this is the most desired pharmacological effect of naltrexone. In most ex-addicts naltrexone has no readily observable effects. A way to confirm the presence of naltrexone is by the injection of heroin. This procedure is called a "heroin challenge." If a sufficient amount of naltrexone is present in the individual, all the heroin related effects are blocked. By having a greater affinity for the opiate receptor than heroin, naltrexone is able to interfere with the heroin-opiate receptor interaction and consequently prevent the development or continuation of narcotic addiction. If this is true, we have a perfect drug which could end heroin addiction once and for all. If naltrexone is such a perfect drug, why isn't there more enthusiasm about its development for general use? In this overview of the pharmacodynamics and medical application of naltrexone I will also examine the possible reasons for the relatively low profile of naltrexone.

 

HISTORY

 

Martin was the first to suggest using antagonists as a protective measure for ex-opiate addicts to remain abstinent (Martin, 1966). Various compounds were tested for this purpose. Naloxone, the N-allyl congener of naltrexone, is a pure narcotic antagonist with a short time/action. When tested as an opiate blocker, gram quantities were needed to provide 24 hr protection against heroin effects. Not only were the large doses of naloxone uncomfortable for the patients but the large amount needed for continued therapy was very expensive. Another compound, a partial agonist-antagonist, cyclazocine was also tested for the same purpose. This drug at very low doses had a desirable, long duration of narcotic blockade. But in many subjects it caused psychotomimetic reactions especially during induction, which was unacceptable for most subjects (Verebey, 1975).

The synthesis of naltrexone was one of those rare projects in which a logical line of thought was followed resulting exactly in the desired product. Blumberg et al (1965) thought of the possible transplantation of the cyclazocine N-substitution, the cyclopropyl-methyl group, onto the nitrogen of naloxone replacing the ally] group (Fig. 1). The resulting molecule, named naltrexone, had all the desired characteristics. It was like naloxone—a pure narcotic antagonist. In addition, it was partly like cyclazocine, having a long time/action but without the psychotomimetic effects. Once the initial animal studies indicated that naltrexone was not toxic, clinical trials began in 1973. The pharmacodynamic profile of naltrexone in humans was studied in collaboration with Drs. Volavka, Resnick, and Washton of the New York Medical College, and with the collaboration of Drs. Mulct and Kogan in our laboratory (1976).

 

DISPOSITION OF NALTREXONE

 

The major metabolite of naltrexone in humans is 6f3-naltrexol, isolated by Cone (1973). A minor metabolite, 2-hydroxy-3-methoxy-643-naltrexol (HMN) was isolated in my laboratory (1975, Fig. 2). The rapid peaking of 60-naltrexol only an hour after oral administration of naltrexone indicated that a major portion of the drug is biotransformed during its first pass through the liver, converting 75 to 80 percent of the dose to less active metabolites (Fig. 3). The opiate antagonist activity of 613-naltrexol varies in different species and methods from 1/50th to 1/12th that of naltrexone (Verebey, 1975). Preliminary studies of HMN using the opiate receptor binding assay, prepared from rat synaptosomes, indicated that HMN binding was typically antagonist-like, but its affinity was approximately 1,000 times less than that of naltrexone (Hiller, 1979). Thus the preliminary animal data indicate that among the three compounds naltrexone is the most potent antagonist followed by 60-naltrexol and the weakest is HMN. However, these relative activities have not been studied in humans.

 

To determine the major contribution to the narcotic antagonistic effects of naltrexone based not only on potency but also on abundance, the relative concentrations of the three bases were determined in urine, plasma, red blood cells (RBC), and saliva (Verebey, 1980). The patients received 400 mg naltrexone daily, and urine samples were collected 12 hr after the last dose. The relative percentages in urine were 76.6 percent 60-naltrexol, 14.4 percent HMN, and 9.0 percent naltrexone for the 12-hr spot sample (Table 1). In plasma, collected at the same time as the urine, the relative concentrations were similar: 73.5 percent 6/3-naltrexol, 23.1 percent HMN, and 3.4 percent naltrexone (Table 2). It is interesting that no significant amount of 6Pnaltrexol was present in RBC and no significant amount of HMN was present in saliva. Even though 613-naltrexol is less potent than naltrexone, quantitatively it is important and seems to significantly contribute to the narcotic antagonistic activity of the parent compound. HMN, based on the in vitro potency data, appears to be least important.

These observations indicate that individuals who metabolize naltrexone at a slower rate would have longer narcotic antagonism than fast metabolizers. This phenomenon was confirmed by determining the correlation coefficient between individual half-life (t 1/2) values of naltrexone and the responses to heroin challenges 72-hr after the dose in four subjects (Verebey, 1976). The figure indicates that the subject with the longest t 1/2 or slowest metabolizer correlated with the least response to heroin or had the best opiate blockade (Fig. 4).

 

Another aspect of metabolism which is of concern therapeutically is the possible self-induction of the metabolic rate from an acute dose to chronic drug administration. The relative abundance of 6/i-naltrexol and naltrexone was determined in 24-hr urines after acute and chronic administration of naltrexone in four subjects (Table 3). No changes in the ratio (3.31 vs 3.29) indicated no self-induction of naltrexone biotransformation (Verebey, 1976). This is a desirable feature for any drug intended for chronic use because the initial dose remains affective during the whole course of the treatment.

 

 

Another indication of the simplicity of naltrexone use in a clinical setting is the rapid achievement of plasma steady state-equilibrium (Fig. 5). The figure shows that by the second daily dose, the 24-hr blood levels of naltrexone and 6f3-naltrexol are stabilized (Verebey, 1976). For this reason it is not necessary to start at low doses and slowly build up to the therapeutic dose as is often necessary with other drugs.

 

 

Naltrexone was also studied in schizophrenic patients for its possible use as an antipsychotic drug (Verebey, 1979; Fig. 6). Initial studies failed to indicate promise for that application. However, the rising dose-efficacy study design allowed doses to rise as high as 800 mg/day which are the highest doses ever given to humans. At that dose the average 24-hr plasma level of naltrexone, HMN, and 60-naltrexol were 9.2, 123, and 331 ng/ml, respectively. There were no signs of toxicity in any of the subjects. Two weeks after the discontinuation of naltrexone the plasma was free of naltrexone and its metabolites indicating very efficient clearance of the drug after chronic administration of large doses (Verebey, 1979).

HEROIN CHALLENGES: THE TIME COURSE OF NARCOTIC BLOCKADE

 

The opiate receptor blocking activity of naltrexone was studied by challenging it with 25 mg intravenous heroin injections and observing two objective and four subjective responses (Verebey, 1976). A modified version of the Addiction Research Center Inventory was used (Table 4). Opiate symptoms and signs were evaluated separately. The absolute heroin effects were investigated by asking for the ten commonly reported opiate symptoms. The greater number of true responses indicated more complete heroin effects. The relative response was a comparison of the current heroin episode with past heroin experiences. Liking scores represent a state of euphoria which is influenced by the subject's environment. It was scored on a 0 to 4 scale. Another test was devised based on the subject's estimation of how much he would pay for the injection he just received, based on the street value of heroin. The opioid signs constitute measurements and notations of the subject's physiological state (objective) and the behavioral state (subjective) reported by the observers.

Control heroin related responses were assessed in the absence of naltrexone (Fig. 7). These values were considered 100 percent. During naltrexone treatment using 100 mg daily doses, the narcotic antagonism of naltrexone was challenged by 25 mg heroin injections 24, 48, and 72 hours after the last naltrexone dose. The heroin challenges were at least 10 days apart in the same patient to eliminate the possibility of tolerance development. Observing all test parameters at 24-hr, almost no response was elicited by 25 mg intravenous heroin.

 

However, by 48 and 72-hr after naltrexone some heroin related effects were observed. The overall average responding to heroin were 4.0 percent at 24, 13.5 percent at 48, and 53.4 percent at 72-hr, compared to the 100 percent response in the absence of naltrexone. The subjective heroin related responses were blocked somewhat better and lasted longer. The average subjective responses were 1.2 percent, 8.2 percent, and 42.8 percent for 24, 48, and 72-hr respectively (Verebey, 1976).

 

It should be emphasized that 25 mg intravenous heroin is a sizable dose, not readily available for most addicts routinely. Thus, the observed length and magnitude of the narcotic blockade seem very effective for most practical preventive measures.

 

Twenty-four hours after naltrexone the narcotic antagonism was still close to complete yet the blood level of naltrexone is already very low (2.4 ng/ml). The terminal phase plasma level decline is 2.4 to 2.0 to 1.8 ng/ml at 24, 48, and 72-hrs after the last naltrexone dose. This translates into a 98-hr terminal t 1/2 indicating that at 2.4 ng/ml or above complete narcotic antagonism can be maintained (Verebey, 1976).

 

CHOOSE THE RIGHT PATIENT FOR THE RIGHT DRUG

 

Based on the experience gained while studying the clinical pharmacology of naltrexone, I formed some opinions in trying to understand the relatively low level of interest in this pharmacologically perfect drug.

 

Most importantly, when naltrexone first appeared as a treatment modality, it was visualized by most people as a replacement of methadone maintenance. Obviously, expectations of euphoria from a drug which is void of opiate effects have disappointed many early volunteers. Comparing naltrexone with methadone and expecting equivalent effects was a mistake. Expectations should be clarified in the future, explaining the differences between the two treatment modalities. It should be very clear in the minds of the staff as well as the clients that the two modalities are very different. Methadone has a role in maintaining the opiate dependent state while naltrexone has a role to maintain an opiate abstinent state.

 

Because of the great difference in the pharmacological effects of methadone and naltrexone, it is important to typify individuals suited for naltrexone therapy and identify types who are most likely to fail because of their biological constitution and/or their environmental circumstances.

Figure 8 indicates an abrupt failure point for naltrexone use right below subject A. These are subjects who indicate a biological need for opiates in order to function normally. Before the discovery of the endorphins this reasoning would have been considered highly speculative. In fact, it still has not been proven experimentally that endorphin deficiency or endorphin release problems causes behavioral disturbances which respond to exogenous opioids. The hypothesis that such individuals exist originates from observations made on thousands of methadone maintenance patients during the past decade. The biological need for opioids is observed especially during attempted detoxification. A certain percentage of the addict population when administered less than 15 mg of methadone exhibit acute psychosis, which is readily reversible by the administration of larger doses of methadone. Naltrexone blocks all opiate effects; thus a biologically opiate dependent subject would most likely fail the naltrexone treatment modality regardless of the external support mechanisms provided.

Most of the addict population, however, is not biologically dependent on exogenous opioids. This is indicated by the lack of major difficulty during slow-rate detoxification from methadone. These individuals belong to group B. Their success with naltrexone therapy requires important supports. The external support mechanisms are essential at least initially. They consist of psychological and social counselings and a strong family interest in the subject's fate. Family support is exemplified by a mother, a spouse, or other family members ascertaining that naltrexone is taken regularly. As long as naltrexone is taken the subject is in no danger of readdiction. The role of the counselors is to teach the ex-addict gratifications such as self-reliance and self-improvement, so that he'll be able to function without the crutch of opioids. The external support mechanisms and services are important for the successful clinical use of naltrexone. The total feeling of satisfaction provided by the opioids is given up by the ex-addict, and it is very hard to replace it with the harshness of reality which they must face while taking naltrexone.

 

The few subjects who fit under the "D" heading have very strong self-motivation. They are good candidates for naltrexone therapy. Some of these subjects can be successfully abstinent from opioids even without naltrexone, but it is good to know that during severe temptations even if opiates are tried, readdiction is virtually impossible.

 

In conclusion, naltrexone provides nearly 100 percent blockade against 25 mg intravenous heroin for 48-hr after 100 mg oral doses of naltrexone. The absence of pharmacologic and metabolic tolerance during chronic treatment provides carefree clinical use of naltrexone. Plasma level monitoring can provide reliable estimation of the degree of opiate antagonism. The drug has a high margin of safety and should be effective for the rehabilitation of well motivated narcotic addicts. When adequate psychological and social counseling is provided this rehabilitation modality should be very successful.

 

ACKNOWLEDGEMENTS

 

Supported by the National Institute on Drug Abuse grant No. DA-01737.

 

The author thanks Mr. Dennis Jukofsky for proofreading, Mr. Jed Shaw for illustrations and Ms. Reynita Lane for typing the manuscript.

 

REFERENCES

 

Blumberg H, Pachter IJ and Matossian Z: US Patent 3, 332, 950 (July 25, 1976)

Cone EJ: Human metabolite of naltrexone (N-cyclopropylmethylnoroxymorphone) with a novel C-6 isomorphine configuration. Tetrahedron Lett 23:2607-2610, 1973 Hiller J and Simon E: New York University Medical School, Personal Communication,

1979

Martin WR, Gorodetzky CW and McClane TK: An experimental study in the treatment

of narcotic addicts with cyclazocine. Clin Pharmacol Ther 7:455-465, 1966 Verebey K and Mule SJ: Naltrexone pharmacology, pharmacokinetics and metabolism:

Current status. Am J Drug Alcohol Abuse 2:357-363, 1975

Verebey K and Mule SJ: Naltrexone and 6g-naltrexol plasma levels in schizophrenic patients after large doses of cal'rexone. Res Commun Psycho!, Psychiatry & Behavior 4:311-317, 1979

Verebey K, Chedekel MA, Mule SJ and Rosenthal D: Isolation and identification of a new metabolite of naltrexone in human blood and urine. Res Commun Chem Pathol Pharmacol 12:67-84, 1975

Verebey K, DePace A, Jukofsky D, Volavka JV and Mule SJ: Quantitative determination of 2-hydroxy-3-methoxy-60-naltrexol (HMN), naltrexone, and 6/3-naltrexol in human plasma, red blood cells, saliva and urine by gas liquid chromatography. J Analytical Toxicol 4:33-37, 1980

Verebey K, Volavka J, Mule SJ and Resnick RB: Naltrexone: Disposition, metabolism and effects after acute and chronic dosing. Clin Pharmacol Ther 20:315-328, 1976