Developing drugs

Efforts on developing drugs that could possibly cure alcohol dependence have been expanding in the last decade (NIH, 2004). Studies pioneered by Volpicelli et al. (1992) on the efficacy of drug therapy, specifically naltrexone, have led to several other investigations of varied methodological structures. Naltrexone was first introduced into the Australian population in 1999 as a potential treatment for alcohol dependence, albeit when taken in while undergoing still unspecified amount of psychiatric therapy (Latt et al, 2002). Several Australian-based studies have been conducted, and among them is the subject of this appraisal.

Among the proponents is a well-known Australian doctor (Morris, P. L. P. ), and the paper was co-authored by equally well-known and credible people (Hopwood, M. , Gardiner, J. ,Whelan, G. and Drummond, E. ). Whelan (2001), for example, has co-authored a meta-analysis of RCTs on naltrexone. The source of the article is also an internationally renowned journal, Addiction, which has been published since 1884, and has operations centers all around the globe (Addiction, 2008). In terms of credibility of the source and the proponents, this study passes as very satisfactory. However, it may not necessarily be the same case for the study itself.

ABSTRACT The study, ‘Naltrexone for alcohol dependence: a randomized controlled trial’, is what the title implies it is— in the abstract, the main aim of the study was clarified to be an investigation of the efficacy of naltrexone in controlling alcohol dependence. The paper also acknowledges that the study was limited only to men, which means that it has a less diverse set of subjects, recognizing the possibility of differences in results due to innate biological disparity. For one, women in general seem to have a limited tolerance for alcohol, as mentioned in the Scottish Intercollegiate Guidelines Network (2003).

The authors appear to have noted the general requirements of a good RCT, which means that, as mentioned in the abstract, it is double-blind (both patients and immediate supervisors are unaware of the allocation of treatments); the drug to be was tested for efficacy against placebo; the parameters for ascertaining the efficacy was defined and invariable, i. e. the maintenance of abstinence and relapse to drinking; and, all the subjects were well accounted for, as is necessary according to Greenhalgh (1997). The abstract was concise but sufficiently detailed. INTRODUCTION

The introduction provides a kind of brief history of studies on naltrexone as a treatment for alcohol dependence, an account of what previous studies lacked in their methods. However, it would have been better if the introduction section started with a brief description of the condition, hence underscoring the significance of the study, or the need to pursue more knowledge on the drug’s efficacy on alcohol dependence. An example would be to state the fact that alcohol dependence is only one among biochemical effects of alcohol consumption, which basically means habitual, compulsive and long-term drinking (WHO, 2008).

Treatment for it largely targeted the psychology of the patient, limited only to counseling methods, as mentioned by Fuller and Gordis (2001). In addition, highlighting the adverse effects of alcohol as a substance that has complex biochemical effects that in turn have behavioral consequences (Alcohol, 2006), could possibly stress the need for studies such as this. An example would be to state that alcohol consumption is correlated to a large amount of disadvantages and adverse effects on government budgets, like productivity losses through reduced output and alcohol-related diseases, as stated by Settertobulte, Jensen and Hurrelmann (2001).

The authors also did not include the methodological variations of studies, i. e. how the drug is administered (orally or intravenously), as this may have important contribution to the over-all success of the drug therapy, considering that oral administration has the disadvantage of lack of compliance and adverse effects in health such as in the study by Roozen, de Waart and van den Brink (2007).

It would also have been better if the authors even just briefly mentioned the existence of other drugs being tested for an ability to cure alcohol dependence, such as acamprosate (Chick et al, 2000), although in the study by Chick et al (2000) this drug has not similarly shown as much promise as naltrexone. This is in order to strengthen the significance of the study as a contribution to the reproducibility of studies necessary to validate a particular treatment.

Moreover, the parameters for judging whether or not the psychosocial treatments were “more or less intensive” were undefined, which means that these observations are highly subjective (i. e. what are the criteria for saying that a treatment is “more intensive” or “less intensive”? ). Hence, as this is a quantitative study, these observations alone do not qualify as basis for defining the methodology of the study, which was simply “to replicate the findings of original naltrexone treatment studies using a less intense form of psychosocial treatment” (Morris, et al 2001).

METHOD This portion of the paper was very organized in that the authors used headers/titles to distinguish between the different elements of the methodology, allowing us to see that each element (the subject recruitment, the procedure, the study outcome, and the data analysis) was thoroughly thought through. The recruitment of the subjects was done in coordination with authorities from the hospital in question and with due approval of the hospital’s ethics committee and informed consent of the patients.

The inclusion and exclusion criteria were stated and were very specific and thorough, wiping out most if not all possibilities of interference from differences in, i. e. biliburin and alanine aminotransferase levels, and compliance with study visits. However, they were not strict in some specific criteria for inclusion—the recruitment was diverse age-wise (18-65 years old), and the paper did not address the possibility of age as an interfering variable in the study even in the results portion, seeing as the body deteriorates over time and this could possibly lead to correspondingly diverse results.

The procedure was also detailed and reflected a commendable amount of foresight on the part of the authors, seeing as they accounted for the subjects that dropped out and followed them up even after they did so, as the reasons may have a significant impact on the study (i. e. the procedure was obtrusive, etc…). Also, all tests were to be done on all the subjects regardless of treatment allocation, ensuring no biases from exemption to particular procedures. This ensures the uniformity of the subjects at least in those terms or study variables.

However, the authors should have been more specific about the psychosocial treatment being given as the study of Leavitt (2002) was, specifying three kinds of the said therapy: supportive, coping skills, and therapy-as-usual. The kind of adjunctive therapy may have a significant effect on the efficacy of the drug. The statistics used ranged widely also, the authors seemingly discontent with merely measuring confidence intervals. They included tests for variance, which is a measure of the statistical dispersion of results according to Hodgson (2006).

RESULTS In this portion we could see the mean characteristics of all 111 patients included in the study. A table summarizes the demographic descriptions of the patients, their pre-treatment alcohol use patterns and psychiatric co-morbidity status. The authors also mentioned that the subjects were predominantly middle-aged and married, although this does not justify their wide inclusion range age-wise.

developing drugs However, they did focus on some baseline characteristics which had to do with “age of first drink”, drinking patterns and levels of biological substances, i.e. ALT. These baseline characteristics may cover up, although not totally eradicate discrepancies that the age differences could not, as they are products of biological mechanisms (chemical processes occuring with the body) present in all human bodies. And, according to the table, relative to majority of the patient characteristics, the sample is sufficiently all the same. The authors also accounted for all of the subjects that withdrew from the study, down to the reasons for their withdrawal.

The difference between the number of subjects that withdrew from both placebo-treated and naltrexone-treated groups were found to be statistically insignificant, although the withdrawal of the subjects greatly reduced the total number of the population. This great reduction in total sample population should have been somehow augmented since a decreased sample population also decreases the validity of the scientific investigation by decreasing its precision (Buckingham et al, 2008).

They did not present a statistical difference between the before- and after-withdrawal population sizes, which could allow us to determine whether the loss of subjects is significant enough to require action besides merely analyzing as “intention-to-treat”. However, understanding that withdrawal of patients from a study is an uncontrollable variable, the authors included an intention-to-treat analysis that was very much like the analysis of the ‘completers’ or the patients that completed the study duration.

Looking at the intention-to-treat analysis, it has been shown that the naltrexone appeared to not do any good for alcohol dependence, any more than placebo did. The subjects who completed the trial, however, showed more promising results. For this, the authors presented a second table of baseline characteristics for this group and found that they were still at par with the necessity of a homogeneous sample.

Other than these, the proponents also included a safety analysis of the effects of the drug, i.e. their adverse effects on the subjects, which is good. DISCUSSION It is made evident in this portion of the paper that the duration of the study is somewhat insufficient, especially since among their parameters for the efficacy of naltrexone as a treatment is the maintenance of abstinence, which of course requires a lengthy period of observation. The extent to which placebo-treated patients and naltrexone-treated patients abstained from alcohol was said to be equal, or not significantly different.

It is not impossible that no significant results were obtained because the duration for observing the susceptibility to relapse is too short; the authors, however, presented this limitation as a recommendation to further studies to increase the observation period/ period of treatment to about six months, and disguising this discrepancy as due to the fact that the study was a “short-term test of efficacy”. The authors also admitted the earlier mentioned limitation of this study to alcohol-dependent men only.

However, in comparing their results to “large controlled studies”, they have also admitted that their sample size is indeed small, and possibly insufficient for generalization to other patients. Moreover their claim in their summary that naltrexone is an effective treatment among a “wide range of patients” is not necessarily true considering the fact that the study was done only among Australian men who were predominantly middle-aged. This claim is contradictory to the earlier statement that the study does not cover alcohol-dependent women. Nor does the study include young alcohol-drinkers.

Then again, it is understood that the narrower the “linking” characteristics between multiple subjects the better; then again, let us consider the sample size and the duration of the experiment. BIBLIOGRAPHY (2008) Addiction [Internet]. Available from: <http://www. addictionjournal. org/> [Accessed 17 August, 2008] (2006) Alcohol. Microsoft® Encarta® 2007 [CD]. Redmond, WA: Microsoft Corporation. Buckingham, J. , Fisher, B. & Saunders, D. What is sample size? Evidence Based Medicine Toolkit [Internet].

Available from: <http://www. ebm. med. ualberta. ca/Glossary. html#samplesize> [Accessed 17 August 2008] Chick, J. , Howlett, H. , Morgan, M. Y. , & Ritson, B. (2000) United Kingdom Multicentre Acaprosate study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol. Alcohol and Alcoholism, 35 (2), pp. 176-187 (2005) Critical Appraisal for Therapy Articles. University of Oxford [Internet]. Available from <http://www. cebm. net/index. aspx? o=1157> [Accessed 17 August 2008] Fuller, R. & Gordis, E. (2001) Naltrexone treatment for alcohol dependence. New England Journal of Medicine, 345 (24)

December, pp. 1770-1771. Greenhalgh, T (1997). How To Read a Paper: Papers that report drug trials. BMJ. 1997. 315: 480-481 Hodgson, B. (2006) What is Variance?. Connexions [Internet]. Available from <http://cnx. org/content/m13384/latest/Feb 15, 2006 4:52> [Accessed 18 August 2008] Latt, N. Jurd, S. , Houseman, J. & Wutzke, S. (2002) Naltrexone in alcohol dependence: a randomised controlled trial of effectiveness in a standard clinical setting. MJA, 176 (3), June, pp. 530-534. Leavitt, S (2002). Evidence for the efficacy of naltrexone in the treatment of alcohol dependence (alcoholism).

Addiction Treatment Forum: Naltrexone Clinical Update, pp. 1-8. Morris, P. , Hopwood, M. , Whelan, G. , Gardiner, J. & Drummond, E. (2001) Naltrexone for alcohol dependence: a randomized controlled trial. Addiction, 96, pp. 1565-1573. National Institute on Alcohol Abuse and Alcoholism (2004). Alcohol Alert [Internet], 61, pp. 1-6. Available from < http://www. niaaa. nih. gov > [Accessed 17 August 2008] Roozen, H. de Waart, R. & van den Brink, W. (2001). Efficacy and Tolerability of Naltrexone in the Treatment of Alcohol Dependence: Oral versus Injectable Delivery.

European Addiction Research, 13, pp. 201-206. (2003) Scottish Intercollegiate Guidelines Network [Internet]. The management of harmful drinking and alcohol dependence in primary care: a national clinical guideline. Available from <www. sign. ac. uk> [Accessed 17 August 2008] Settertobulte, W. , Jensen, B. & Hurrelmann, K. (2001) Drinking among young Europeans. WHO Regional Office for Europe [Internet] Available from: <http://www. euro. who. int/document/E71921. pdf> [Accessed 18 August 2008] Swift, R. (1999). Drug therapy for alcohol dependence.

New England Journal of Medicine, pp. 1482-1490. Volpicelli, J. R. Alterman, A. I. , Hayadisha, M. and O’Brien, C. P. (1992) Naltrexone in the treatment of alcohol dependence. Archives of General Psychiatry, 49, pp. 876-880. Whelan, G. & Streeton, C. (2001) Naltrexone, a relapse prevention maintenance treatment of alcohol dependence: a meta-analysis of randomized controlled trials. Alcohol and Alcoholism, 36 (6), pp. 544-552 (2008). Alcohol. WHO [Internet]. Available from: <http://www. who. int/substance_abuse/facts/alcohol/en/index. html> [Accessed 18 August 2008]

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