Tamea R. Sisco, C.Ad. D.C. Thomas J.D. Chen, Ph.Dl. James T. Payte, M.D. David Hopper, Ph.D. Eric R, Braverman, M.D
The purpose of this paper is to review the clinical efficacy if 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) clinical evidence showing the synergy between narcotic antagonism and amino-acid 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”. 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 (Ticku and Mehta, 1995). 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. 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 beta-endorphin in humans is decreased in amount in the presence of alcohol (Gennazanni et al., 1982). It is theorized that this could be the result of an inhibition of the production of this opiate by alcohol itself. 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 (Ho et al., 1982). 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. 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 naloxone (Ross, Hartmann and Geller 1976)
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 (Meyers and Melclior, 1977).
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 a twelve year battle the US FDA approved the use of naltrexone/Trexan® for opioid detoxification, then in the mid-nineties, the same drug was approved for the treatment of alcoholism under the name Rivera®.
Clinical Trials for Alcoholism
Thus, in this brief review, we focus on the few double-blind trials available. Voipicelli (1992) and colleagues reported on a 12-week trial of 50 milligrams 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 twelve weeks, 23 percent of naltrexone treated patients had relapsed into heavy regular drinking, compared to 54 percent of the patients on placebo. These data indicate naltrexone may have been especially helpful for patients who had “slipped” and begunto drink; almost half of them were likely to return to abstinence if they were on naltrexone, while the same is true for only five percent 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 (Volpicelli et al., 1992).
Also, O’Malley and colleagues (1992) reported on 97 alcoholic men and women, 46 of who received 50mg 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 (consensus report, 1996) The following list is representative of over 5,000 papers on the subject since the first work of associates 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 (Kranzler et al., 1998; King et al., 1997; Mason et al., 1994,Oslin et al., 1997; O’Malley et al., 1996; Volpicelli et al., 1995; O’Malley et al., 1996; Volpicelli et al., 1995; King et al., 1997; and, O’Malley et al., 1992). The most up to date and complete review of the subject is by Herz from the Department of Neuropharmacology at the Max- Planck Institute for Psychiatry in Germany (1997).
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. Craving behavior is distinct from euphoria and different set of mechanism are involved. Blocking of euphoria represents the occupancy of a narcotic antagonist, naloxone, on mu opiate receptors and reducing craving is due to dopamine occupancy on dopamine-D, receptors.
The use of heroin continues to increase and is estimated that eight 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 (Van der Burgh (1999).
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 alpha 2- adrenoreceptor agonists ) have been extensively studied.
Clinical Trials for Opiates
In a review and meta-analysis of randomized controlled studies evaluating the use of naltrexone as a maintenance agent, Kurchmayer et al ( 2001).found a tendency in favor if naltrexone but concluded that there is not sufficient evidence to evaluate the efficacy of naltrexone treatment for opioid dependence. Shufman et al. (1994) in a double-blind, controlled design evaluated the efficacy of naltrexone in reducing opioid positive mine tests during a 12-week trial and found naltrexone to be superior to placebo. Similarly, on a multi-center, randomized controlled trial, Hollister (1978), examined 170 opiate-dependent patients at a 9 month follow-up, and found that the group treated with Naltrexone had more opiate – free urine tests and reduced attrition rates. Finally, Hulse and Basso (1999) 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 mu receptor agonist, buprenorphine has been used as opioid substitution therapy for opiate dependence in France since 1996 (Obadia et. al. 2001) .It is awaiting approval in the United States as a sublingual combination tablet with Naloxone ( Fudala et. al. 1998).
Additionally, Clonidine and lofexidine atreaopha, 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 alpha 2 results in the inhibition of the sympathetic outflow associated with the opiate withdrawal syndrome.( Gonzalez et. al. 2002)
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 percent. 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. At the San Antonio Methadone Clinic according to its director J. T. Payte using this approach results in recidivism rate of over 99 percent due to non-compliance. Once again we believe the noncompliance issue is due to the fact that while the narcotic antagonist blocks the opiate or alcohol induced euphoria (O’Malley et al., 1992 and Volpicelli et al., 1992), the drug has little effect on craving behavior. Moreover, Kirchmayer and associates ( 2002) 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 and neurotransmitter precursors to promote neuronal dopamine release might enhance compliance in methadone patients’ rapidly’ detoxified with the narcotic antagonist Trexan®, In this regard, Thanos et. al. (2001) 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 ofDRD2 may be protective against alcohol abuse ( Blum et. al. 1990, and Nobleet. al. 1991). The DRD2 Al allele has also been shown to associate with heroin addicts in a number of studies O. 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. 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.
We tested our combined therapeutic approach at the San Antonio Methadone Clinic 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 X males and X females in the 1000 patients in the non-experimental group and X males and X females in the experimental group. Each patient signed a consent form and the project received IRB approval from the San Antonio Methadone Clinic and from PATH Medical Foundation IRB which approved future research in this area. ( registration # IRB00002334).
RAPID -DETOX METHODOLOGY
Each patient (n=1000) was pre-evaluated by first receiving an injection of 0.4-0.8 mg. of Narcan and their withdrawal was assessed. If they passed this first test, they were administered an oral dose of 12.5 mg of Trexan® and again evaluated for withdrawal symptoms over a ninety minute period. If the patient passed this test, they were given 50 mg Trexan®. The 1000 patients received the 50 mg. Trexan® daily until the patient relapsed.
For this study twelve patients were selected, those selected received along with Trexan® a combination of amino acids. The number of days without a relapse or self-report of refusal to take either the Trexan® alone or in combination with the amino-acid formula was counted. Each patient (with some degree of failure) was evaluated on a daily basis either via phone or in a face-to-face contact.
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®. Naloxone binding was measured in frontal gray cortex, caudate nucleus, amygdala, hippocampus‘ and cerebella cortex in human alcoholic and non-alcoholic subjects. Binding was found to be higher in alcoholics than in non-alcoholics for all of the brain regions examined. When subjects were grouped by the presence or absence of the DRD2AI allele, [3H] naloxone binding was lower in all brain regions examined of subjects with the A1 allele than in those without this allele, with a significant difference in the caudate nucleus. According to Ritchie and Noble (1996), these findings suggest one of the consequences of chronic alcohol exposure in humans is an enhancement of the brain opioid receptor system. However, the decreased [3H] naloxone binding with the A1 allele may be a compensatory response to their decreased dopaminergic modulation of opiate receptor activity.
Thus coupling amino-acid therapy and enkephalinase inhibition while blocking the delta 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 to further test this hypothesis with the sublingual combination of the partial opiate mu receptor agonist Buprenorphrine.