Presentation Draft
Introduction
Alcohol use disorder (AUD) is a prevalent issue in society that dates back for decades. As such, different studies have been conducted aimed at understanding the issue and providing effective treatment. Although there have been significant efforts in executing research, few drugs are available for the treatment of the disorder. Despite the lack of adequate treatment, there is a vast literature that has investigated various factors that influence the disorder. Indeed, most of the research studies focus on developing literature and results that could help develop an effective treatment. Further, relapsing is a significant concern for individuals who have AUD. As such, researchers are keen on understanding the factors that influence relapse. The interactions between the central nervous system and ethanol intake are also an essential factor identified for research evaluation.
Purpose of the Study
The purpose of the present study was to understand the efficacy of naltrexone in preventing relapse during abstinence. Further, it aimed at determining why treatment efficacy varies between subjects. The study systematically tested the effects of naltrexone at different points during abstinence for both male and female rats.
Definition of Terms
- Alcohol Relapse- Refers to the resumption of alcohol consumption after a period of abstinence.
- Alcohol Dependence –A condition where an individual craves to take drinks containing alcohol and cannot control their consumption.
- Alcohol Withdrawal- Changes in the body that occur when an individual suddenly stops alcohol consumption after long and heavy use.
- Sex/Gender differences- They are the differences in how males and females behave and are affected by alcohol.
- Abstinence- refers to completely avoiding the intake and consumption of alcohol.
- Naltrexone- An approved drug for the treatment of alcoholism.
Background of the Study
Previous research by Dai, Thavundayil & Gianoulakis (2005) indicates that ethanol’s effects on the central nervous system are realized in various ways. Of importance is the alterations that are done to the opioid system. As such, opioid receptors are described as having a high affinity to some classes of endogenous opioids. They are inclusive of β-endorphin, dynorphin, and enkephalins. Further, the study confirms that acute ethanol stimulates the release of the three endogenous opioids, both in rats and humans. Moreover, the research investigated the argument that pituitary β-endorphin responds differently to stress when there is a history of alcoholism. Indeed, the study results indicate that stress significantly increased the concentration of β-endorphin in the different groups of participants. The findings from the research provided a fundamental basis for further investigations. Ultimately, understanding the role that stress play in stimulating the release of β-endorphin is essential.
Similar results for the role stressors in stimulating the release of β-endorphin were presented by Marinelli, Quirion & Gianoulakis (2004). Indeed, the results supported that the brain differently processes stressors with different properties. The researchers concluded that both physical and fear-inducing stressors stimulate β-endorphin in the arcuate nucleus. On the other hand, only the physical stressors were reported to stimulate the release of β-endorphin in the nucleus accumbens. More so, alcohol caused delays in the increase of β-endorphin in the nucleus accumbens but not in the arcuate nucleus. Alcohol can recruit a mechanism that is different from the known stress-related pathways.
According to Volpicelli (1992), naltrexone is an approved medication for the treatment of excessive alcohol disorders. Its approval is based on the efficacy to reduce cravings for the consumption of ethanol. Based on its ability to reduce alcohol consumption cravings, naltrexone can manage cases of relapsing. The study results indicated that only 50% of participants who drank alcohol while receiving treatment relapsed. On the other hand, 95% of the placebo-treated participants relapsed when they took alcohol. As such, naltrexone was determined as being useful in patients who continue to take any form of alcohol during treatment. Therefore, the researchers recommended its use in preventing cases of relapse among individuals who are alcohol-dependent.
Nonetheless, research by Stromberg (2004) presents results that are different from the previous studies. Despite naltrexone being classified as effective in animal models where there was alcohol consumption, Stromberg (2004) states that the efficacy of naltrexone’s clinical use is significantly low. Such is attributed to the fact that ethanol targets various neurotransmitter systems. On the other hand, naltrexone only targets opioid receptors. As such, ethanol can target other systems, reinforcing its effects. In the study, both baclofen and naltrexone were administered. The results indicated a significant reduction in alcohol consumption than when each drug was used independently. Ultimately, the results suggested that using drugs that target different systems is the most effective in preventing relapse cases.
Indeed, the research by Stromberg (2004) confirmed claims that had been presented by Krystal, Cramer, Krol, Kirk & Rosenheck (2001) following their research study. In the latter’s research, there were no significant differences in the number of days to relapse between the placebo group and two naltrexone groups that were used. The results had prompted the researchers to conclude that most patients who receive treatment using naltrexone do not benefit from it. The findings explicitly stated that the use of the medication in males with chronic alcohol dependence was not supported.
The studies that provided results on the low efficacy of naltrexone played a significant role in finding treatment for AUD. This is because researchers began to study other factors that influenced the success of treatment. The factors are inclusive of gender, time of intervention during abstinence, and changes within the opioid system. In turn, most of the studies focused on alcohol drinking patterns. Generally, males are perceived to drink more than their female counterparts. As a result, it was believed that men were at a higher risk of developing AUD as compared to women. Given that there were minimal findings to support the argument, different studies were conducted.
The study by Sabino, Kwak, Rice & Cottone (2012) aimed at testing different drugs and agents that could be utilized in the treatment of AUD. Male Sardinian rats were used in the experiment. Part of the procedure involved dividing the animals into two groups and letting them drink alcohol or water for 24 hours on alternate days. After stabilization of intake, three different medications were used. They included naltrexone, an opioid receptor antagonist, SCH 39166, a dopamine receptor antagonist, and R121919, a CRF1 receptor antagonist. The results of the study indicated that alcohol drinking was reduced, where naltrexone and SCH 39166 were used. The R121919 was identified as ineffective in reducing alcohol consumption. Further, the results showed that of the three medications used, naltrexone was the most effective.
The research on different medications that can be used for the potential treatment of AUD plays a significant role in the overall development of treatment. Indeed, few studies have utilized multiple medications in their experiments. The findings in the study assist in reducing the literature gap. Further, the findings provided a foundation for future investigations and experiments. The study also confirmed that naltrexone has a higher efficacy in treatment than some of the drugs. As such, the determination of the timing to initiate treatment should be considered to improve treatment success.
According to Lindholm, Ploj, Franck & Nylander (2000), repeated administration of ethanol leads to alterations of opioid levels in different brain regions. More so, the alterations could either be short term or long term. In most cases, the alterations occur in the brain regions that are associated with reward and motivation like the nucleus accumbens. The authors measured Dynorphin B (Dyn B) and Met-enkephalinArg(6)Phe(7) (MEAP) endogenous regards. Results indicated that MEAP tissue was decreased in the hippocampus after five days from the last ethanol injection. Further, within the same time, both Dyn B and MEAP concentrations increased within the periaqueductal grey area. Overall, the results from the study confirmed that there are alterations that occur in the brain regions.
The findings of both short-term and long-term alterations of opioid levels in the brain regions after ethanol administration raise questions on humans’ alterations. More so, in cases where individuals are characterized by excessive alcohol consumption. The key interest lies in the influence that the alterations have in response to treatment. Indeed, every individual could have different and unique alterations, which could affect how they respond to medication. Ultimately, researchers should evaluate the significance of influence that the alterations have. In turn, the findings could further assist in making decisions of treatment regarding timing, based on alterations.
The research by Keyes, Grant & Hasin (2008) presented results that ethanol consumption between men and women has changed significantly. Indeed, the findings showed that gender differences regarding alcohol consumption have decreased in younger age cohorts. Similarly, research by Morales, McGinnis & McCool (2015) supported the findings. The latter study examined the effects of chronic intermittent ethanol (CIE) for both males and females. From the results, females were noted to consume higher levels of ethanol than males. Further, the researchers reported that females are less sensitive to ethanol-induced increases as compared to males. This was after both male and female were shortly exposed to CIE. Ultimately, the results have assisted in understanding the influence of gender factors in the vulnerability to AUD.
The background studies and literature provided key findings and results that set the foundation for the current study. Matzeu, Terenius & Martin-Fardon (2018) had noted that relapse after the physical signs of withdrawal had disappeared, is one of the significant factors that hinder medication success. Indeed, there is a lot to study since, despite naltrexone being recommended for AUD treatment, treatment efficacy varies among patients.
Methods and Materials
48 Wistar rats were used for the study, of which 24 were males and 24 females. Their weight ranged between 150 and 175 grams. The rats were housed 2 per cage. Both temperature and humidity were controlled, and there were 12-hour cycles of light and darkness. The rats were housed for a week before the testing began. In turn, it allowed them to adapt to the conditions and food provided. The study’s procedures complied with the guidelines of the National Institute of health guide for care and use of laboratory animals. The Scripps Research Institute’s institutional animal care and use committee also approved the procedures.
The rats were subjected to ethanol self-administration training, a modification of previous studies by Wise (1973) and Simms et al. (2008). During this training, rats were singly housed. By the end of the training, 2 of the rats failed to meet ethanol’s required self-administration. It reduced study animals to 46. Next, the procedure for chronic intermittent ethanol (CIE) vapor exposure was initiated. The behavioral signs of withdrawal were measured during the procedure. After six weeks of CIE exposure, the abstinence phase was initiated. The effects of naltrexone on ethanol self-administration at three abstinence points were measured. The points were acute abstinence, late abstinence, and late abstinence, which occurred in periods of 8 hours, two weeks, and six weeks respectively. Statistical software was utilized to carry out data analysis.
Results
In the last five days of ethanol self-administration, both groups of animals had comparable ethanol intake in 30-minute daily sessions. At the end of CIE exposure, an increase in ethanol intake was reported in ethanol post dependent rats. More so, there were differences between females and males. Nonetheless, inactive lever responses remained unaffected and low for both females and males. There were no differences in blood alcohol levels between males and females in the last three weeks of CIE exposure. Further, blood alcohol levels measured after a self-administration session during CIE exposure were high in ethanol post dependent rats for both females and males. This was after the results were compared with the pre-CIE blood alcohol levels.
For the withdrawal scores in weeks 5 and 6 of CIE vapor exposure, results for measurements taken before the self-administration session was higher in the ethanol post dependent animals compared to those that were ethanol non-dependent and the baseline. The ethanol post dependent females indicated higher withdrawal scores as compared to their male counterparts. The effects of naltrexone on ethanol self-administration varied between the groups during abstinence. In females, naltrexone decreased ethanol intake in both ethanol post-dependent and ethanol non-dependent groups in all the three-time points. For males, ethanol non-dependent animals responded differently to naltrexone compared to the ethanol post-dependent animals across the three-time points. The results showed that naltrexone reduced ethanol intake in the ethanol non-dependent rats in all the abstinence time points. For the ethanol post-dependent male rats, naltrexone reduced ethanol intake only at the post-abstinence point.
After self-administration, the blood alcohol levels following naltrexone treatment were lower in the ethanol non-dependent males than the vehicle-treated animals. In the female groups, blood alcohol levels after self-administration following naltrexone treatment were lower than vehicle-treated animals in all points. For somatic withdrawal sign results, overall effects of dependence, and time abstinence were found during the male and female groups’ withdrawal scoring.
Discussion
The study results supported the use of the CIE exposure model as a valid method to study ethanol dependence. In the study, the overall significant effect of gender on ethanol drinking was noted. Nonetheless, the possible increase in ethanol intake in females was not statistically confirmed. As such, ethanol intake between genders continue to present different results. Such can be attributed to the rat species used in each study and experimental designs adopted.
The results have implications in the research of AUD treatment. First, they support targeting the endogenous opioid system to prevent relapse. Such is even after a period of abstinence. Additionally, the results provide insights that naltrexone treatment varies across gender groups and in different abstinence time points. Generally, this study’s implications point to individual differences that should be considered during the development of drugs for the treatment of AUD.
Overall, the researchers in this study did a remarkable job as research on the efficacy of naltrexone to treat AUD during abstinence had been neglected. The procedures used in the experiment adhered to the established guidelines, which was essential. Further, I do agree with the interpretation of results from the experiment. Despite the experiments being successful, there are limitations to this research. One is that the researchers have not highlighted some of the intervening variables and factors that could have affected their results. Such variables could have been useful during interpretation and confirm validity.
In the future, studies should compare results with other drugs used for the treatment of AUD. Indeed, results from such studies could help make a clinical decision for combining multiple drugs during treatment. One of the drugs is Antabuse, which is identified as the first-choice medicine for alcoholism. Further, it is reported that when it is used in treatment, patients are less likely to relapse as compared to other drugs. As such, there are differences between Antabuse and naltrexone in the treatment of AUD.
Class Discussion Questions
For the class discussion, I developed the following questions:
- Is it translatable on humans?
- How effectively would these medicines be at different ages?
- Should multiple drugs be combined to improve the efficacy of treatment?
References
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