Narcotic antagonists in drug dependence: pilot study showing enhancement of compliance with SYN-10, amino-acid precursors and enkephalinase inhibition therapy

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Abstract

We decided to test the hypothesis that possibly by combining a narcotic antagonist and amino-acid therapy consisting of an enkephalinase inhibitor (d-phenylalanine) and neurotransmitter precursors (l-amino- acids) to promote neuronal dopamine release might enhance compliance in methadone patients rapidly detoxified with the narcotic antagonist Trexan® (Dupont, Delaware). In this regard, Thanos et al. [J. Neurochem. 78 (2001) 1094] and associates found increases in the dopamine D2 receptors (DRD2) via adenoviral vector delivery of the DRD2 gene into the nucleus accumbens, significantly reduced both ethanol preference (43%) and alcohol intake (64%) of ethanol preferring rats, which recovered as the DRD2, returned to baseline levels. This DRD2 overexpression similarly produced significant reductions in ethanol non-preferring rats, in both alcohol preference (16%) and alcohol intake (75%). This work further suggests that high levels of DRD2 may be protective against alcohol abuse [JAMA 263 (1990) 2055; Arch, Gen. Psychiatr. 48 (1991) 648]. The DRD2 A1 allele has also been shown to associate with heroin addicts in a number of studies. In addition, other dopaminergic receptor gene polymorphisms have also associated with opioid dependence. For example, Kotler et al. [Mol. Phychiatr. 3 (1997) 251] showed that the 7 repeat allele of the DRD4 receptor is significantly overpresented in the opioid-dependent cohort and confers a relative risk of 2.46. This has been confirmed by Li et al. [Mol. Psychiatry 2 (1997) 413] for both the 5 and 7 repeat alleles in Han Chinese case control sample of heroin addicts. Similarly Duaux et al. [Mol. Psychiatry 3 (1998) 333] in French Heroin addicts, found a significant association with homozygotes alleles of the DRD3-Bal 1. A study from NIAAA, provided evidence which strongly suggests that DRD2 is a susceptibility gene for substance abusers across multiple populations (2003). Moreover, there are a number of studies utilizing amino-acid and enkephalinase inhibition therapy showing reduction of alcohol, opiate, cocaine and sugar craving behavior in human trials (see Table 1). Over the last decade, a new rapid method to detoxify either methadone or heroin addicts utilizing Trexan® sparked interest in many treatment centers throughout the United States, Canada, as well as many countries on a worldwide basis. In using the combination of Trexan® and amino-acids, results were dramatic in terms of significantly enhancing compliance to continue taking Trexan®. The average number of days of compliance calculated on 1000 patients, without amino-acid therapy, using this rapid detoxification method is only 37 days. In contrast, the 12 subjects tested, receiving both the Trexan® and amino-acid therapy was relapse-free or reported taking the combination for an average of 262 days (p<0.0001). Thus coupling amino-acid therapy and enkephalinase inhibition while blocking the δ-receptors with a pure narcotic antagonist may be quite promising as a novel method to induce rapid detox in chronic methadone patients. This may also have important ramifications in the treatment of both opiate and alcohol-dependent individuals, especially as a relapse prevention tool. It may also be interesting too further test this hypothesis with the sublingual combination of the partial opiate mu receptor agonist buprenorphrine.

Introduction

The purpose of this paper is to review the clinical efficacy of using narcotic antagonism in the treatment of opiate and alcohol dependence. While there is a plethora of evidence for opiate dependence the research on alcohol dependence is more sparse. However, the method called rapid detoxification that relies upon the use of narcotic antagonism both oral and intravenous may be enhanced by amino-acid precursor and enkephalinase inhibition. Thus this paper serves two purposes: (1) a brief review of the literature; (2) pilot clinical evidence showing the synergy between narcotic antagonism and amino-acid and enkephalinase therapy.

It is important to begin by reminding ourselves that we do not fully understand the major effects of alcohol on the brain. There are no easily identified, highly specific “alcohol receptors” [1]. In addition, alcohol exerts an impact on almost all brain chemicals, making it difficult to determine which, if any, are key to the intoxicating or subsequent craving phenomena associated with this drug [2]. To make matters even more complicated, the initial administration of alcohol has different effects on brain chemicals than are seen after repeated administration of this drug, and all these effects are likely to be different at different doses.

Despite these complexities, there are at least three theories about how a drug that affects opiates might have an important impact in the treatment of alcoholism.

First, alcohol, at least indirectly, does affect the brain's natural opiate-like or endorphin system [3]. So, even if the impact is modest, it makes sense that any drug that alters the functioning of the natural brain opiates could alter the effects that alcohol exerts on the brain itself. There are data to indicate that one brain opiate substance; leucine-enkephalin in animals and β-endorphin in humans is decreased in amount in the presence of alcohol [4], [5]. It is theorized that this could be the result of an inhibition of the production of this opiate by alcohol itself [6]. Similarly, another study documented that if opioid peptides are administered to an animal before alcohol is given, that animal is less likely to consume alcohol [7]. Consistent with these observations is an early study showing that animals with prior intake of alcohol are more likely to maintain their abstinence when given morphine [8]. These studies, along with the ill-advised turn of the century practice of administering morphine to alcoholics to attempt to maintain abstinence from alcohol, are consistent with some level of interaction between alcohol and the opiate systems.

A second area of support for the potential interaction between alcohol and the opiate systems occurs through studies of stress. Acute stresses do increase the level of the body's natural opiates. At least theoretically, if stress (either from the environment or from heavy drinking) occurs regularly enough, it is possible that the body becomes used to having higher levels of opiates. Thus, when stress levels decrease (either in the environment or through abstinence) the body might crave the higher levels of endogenous opiates to which it has become accustomed. This discomfort might cause symptoms that make it more likely that the individual will then go back to his or her usual drug of abuse, in this instance alcohol. Consistent with this hypothesis is the observation that animals placed in a high-stress situation are likely to increase their selection of alcoholic beverages, but also that this alcohol-seeking behavior can be blocked by fairly modest doses of analoxone [9], [10].

The third, and perhaps the most attractive, of the theories focuses on the hypothesized brain reward system. A number of investigators feel that most pleasurable experiences, including the acute effects of most drugs, are mediated through the actions of the brain chemical dopamine, especially in a part of the brain called the nucleus accumbens. This area is part of a complex of the brain called the meso-limbic system. Thus, it is possible that the pleasurable effects of alcohol occur, at least in part, through mechanisms that are similar to those that contribute to the pleasurable effects of opiates. If this is true, then a drug that blocks some of the effects of opiates could have a beneficial effect by decreasing the rewarding effects of alcohol, and this elimination of the expected reinforcements might even decrease craving [11], [12], [13].

However, just because a theory makes sense does not mean that it is correct. Nonetheless, there are good reasons to consider whether an opiate antagonist drug might have some beneficial effects in the treatment of alcohol dependence. After 12 years of struggle for approval, the US FDA approved the use of naltrexone/Trexan® for opioid detoxification, then in the mid-90s, the same drug was approved for the treatment of alcoholism under the name Rivera®.

Thus, in this brief review, we focus on the few double-blind trials available. Volpicelli et al. [14] reported on a 12-weeks trial of 50 mg of naltrexone per day in 34 alcohol-dependent outpatient men, comparing results with 36 men treated with placebo. All individuals received the usual treatment for alcohol rehabilitation, and everyone was evaluated weekly. By the end of the 12 weeks, 23% of naltrexone treated patients had relapsed into excessive frequent drinking, compared to 54% of the patients on placebo. These data indicate naltrexone may have been especially helpful for patients who had “slipped” and begun to drink; almost half of them were likely to return to abstinence if they were on naltrexone, while the same is true for only 5% of those treated with placebo. The authors suggested it is possible the naltrexone blocked part of the high or reinforcing effect of alcohol, making it easier for people who had initially returned to drinking do not go on to escalating doses of alcohol. At the same time, the study also reported a possible decrease in craving for alcohol with this narcotic antagonist.

Also, O'Malley et al. [15] reported on 97 alcoholic men and women, 46 of who received 50 mg per day of naltrexone and the remainder placebo over 12 weeks. While the project was complex and other questions were being tested, those on naltrexone demonstrated improved rates of abstinence and lower rates of alcohol intake and problems if they had returned to drinking.

Other more recent studies include both positive and negative reports but the consensus favors the limited use of narcotic antagonism in the treatment of alcoholism [16]. There are over 5000 papers on the subject since the first work of Blum and associates [17] and others in the early 70s, showing the anti-alcohol effect of naloxone in mice and rats (reduction of sleep-time, delay in withdrawal reactions, reduced ethanol intake, and reduction of ethanol-induced dependence).

Positive reports in humans include a number studies that are concerned with abstinence, tolerance, craving behavior in both young and older alcohol-dependent patients [14], [15], [18], [19], [20], [21], [22], [23]. The most up to date and complete reviews of the subject is by Herz from the Department of Neuropharmacology at the Max-Planck Institute for Psychiatry in Germany [24], from Blum and Braverman [16], and from Gonzalez et al. [31].

The use of heroin continues to increase and is estimated that 8 million people in the world (0.14%) abuse opiates. The region with the highest annual prevalence (2%) are South East and South West Asia and based on the National Household Survey, the annual prevalence of heroin use in the United States is 0.3% with a rising trend of heroin use in the last 2 years [24].

New pharmacological treatments for heroin addiction include drugs that reduce withdrawal symptoms and agents that are given during the maintenance phase of treatment. A variety of different types of pharmacological agents (opioid agonists, opioid antagonists and α2-adrenoreceptor agonists) have been extensively studied.

In a review and meta-analysis of randomized controlled studies evaluating the use of naltrexone as a maintenance agent, Kurchmayer et al. [25] found a tendency in favor of naltrexone but concluded that there is not sufficient evidence to evaluate the efficacy of naltrexone treatment for opioid dependence. Shufman et al. [26] in a double-blind, controlled design evaluated the efficacy of naltrexone in reducing opioid positive urine tests during a 12-week trial and found naltrexone to be superior to placebo. Similarly, in a multi-center, randomized controlled trial, Hollister [27], examined 170 opiate-dependent patients at a 9 months follow-up, and found that the group treated with naltrexone had more opiate – free urine tests and reduced attrition rates. Finally, Hulse and Basso [28] evaluated treatment outcome at 6 months for 100 heroin-dependent patients maintained on naltrexone and found that complete abstinence was not characteristic of many of those patients continuing on naltrexone, in spite of its complete blocking of heroin reinforcement. Thus, periodic heroin use during naltrexone maintenance may occur but this periodic use did not prevent successful outcomes for those maintained on naltrexone.

In more recent years, the partial opiate μ-receptor agonist, buprenorphine has been used as opioid substitution therapy for opiate dependence in France since 1996 [29]. It is awaiting approval in the United States as a sublingual combination tablet with naloxone [30].

Additionally, clonidine and lofexidine are α2-receptor agonists and are the most commonly used non-opiate drugs for detoxification from opiates in the US and the UK, respectively. Activation of the presynaptic α2 results in the inhibition of the sympathetic outflow associated with the opiate withdrawal syndrome [31].

The Against Medical Advice (AMA) rate (the rate at which patients or addicts leave treatment before treatment goals are reached) among hardcore addicts even today approaches 90%. The basic concept of a relatively new approach called “rapid detoxification method” is to provide the patient with a pure narcotic antagonist to block the opiate-induced euphoriant effects. Using this approach results in a significantly high recidivism rate due to non-compliance [16]. Once again we believe the non-compliance issue is due to the fact that while the narcotic antagonist blocks the opiate or alcohol-induced euphoria [13], [22], the drug has little effect on craving behavior. To reiterate, Kirchmayer et al. [25] performed a recent systematic review on the efficacy of naltrexone maintenance treatment in opioid dependence and concluded that from the available clinical trials performed up until 2002, there is insufficient evidence to justify the use of naltrexone in the maintenance treatment of opioid addicts.

We decided to test the hypothesis that possibly by combining a narcotic antagonist and amino-acid therapy consisting of an enkephalinase inhibitor (d-phenylalanine) and neurotransmitter precursors (l-amino-acids) to promote neuronal dopamine release might enhance compliance in methadone patients rapidly detoxified with the narcotic antagonist Trexan®. In this regard, Thanos et al. [32] found increases in the dopamine D2 receptors (DRD2) via adenoviral vector delivery of the DRD2 gene into the nucleus accumbens, significantly reduced both ethanol preference (43%) and alcohol intake (64%) of ethanol preferring rats, which recovered as the DRD2, returned to baseline levels. This DRD2 overexpression similarly produced significant reductions in ethanol non-preferring rats, in both alcohol preference (16%) and alcohol intake (75%). This work further suggests that high levels of DRD2 may be protective against alcohol abuse [33], [34]. The DRD2 A1 allele has also been shown to associate with heroin addicts in a number of studies [35]. In addition, other dopaminergic receptor gene polymorphisms have also associated with opioid dependence. For example, Kotler et al. [36] showed that the 7 repeat allele of the DRD4 receptor is significantly overpresented in the opioid-dependent cohort and confers a relative risk if 2.46. This has been confirmed by Li et al. [37] for both the 5 and 7 repeat alleles in Han Chinese case control sample of heroin addicts. Similarly Duaux et al. [38] in French Heroin addicts, found a significant association with homozygotes alleles of the DRD3-Bal 1. Moreover, there are a number of studies utilizing amino-acid and enkephalinase inhibition therapy showing reduction of alcohol, opiate, cocaine and sugar craving behavior in human trials (see Table 1). Over the last decade, a new rapid method to detoxify either methadone or heroin addicts utilizing Trexan® (Dupont, Delaware) sparked interest in many treatment centers throughout the United States, Canada, as well as many countries on a worldwide basis.

In terms of negative reports, we believe a reason for non-compliance resides in the very nature of the pharmacological and physiological basis of the use of narcotic antagonism in treating either opiates or alcohol dependence. Craving behavior is distinct from euphoria and different set of mechanisms are involved. Blocking of euphoria represents the occupancy of a narcotic antagonist, naltrexaone, on δ-opiate receptors. In order to ensure the reduction of craving behavior, however, substances should be employed that either occupy dopamine D2 receptors or cause the preferential pre-synaptic release of dopamine causing reduction of alcohol and opiate craving behavior. We believe based on our own work and others that the preferred therapy should consist of a combination of narcotic antagonists, narcotic agonists and amino-acid precursor and enkephalinase inhibition therapy.

Section snippets

Subjects

We tested our combined therapeutic approach at the J.T. Payte MD, PA Clinic, San Antonio, TX, with 1012 hardcore addicts who had abused euphoriants up to 30 years. Entry into the study included both male and female patients who were considered hardcore addicts as diagnosed using the DSM-IV criteria for heroin/opiate dependence. There were 700 males and 300 females in the 1000 patients in the non-experimental group and 9 males and 3 females in the experimental group. The age range was from 40–70

Results

The results were dramatic in terms of significantly enhancing compliance to continue taking Trexan®. The average number of days of compliance that the J.T. Payte Clinic of San Antonio, Texas, calculated on 1000 of their patients, without amino-acid therapy, using this rapid detoxification method is only 37 ± 7.7 SE days. In contrast, the 12 subjects tested, receiving both the Trexan® and amino-acid therapy was relapse-free or reported taking the combination for an average of 262 + 16.4 SE days (p

Comment

Based on this research we suggest that the addition of the anti-craving formula significantly reduced the craving for opiates (possibly alcohol) and, therefore, seems to be important in assisting those hardcore opiate addicts in preventing relapse – especially in conjunction with the narcotic antagonist Trexan®.

There is even very recent molecular genetic evidence, which supports Blum's original concept of common mechanisms between alcohol and opiates [39]. [3H] Naloxone binding was measured in

Acknowledgements

The authors appreciates the financial support of Path Medical Foundation and The Health Network.

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