Placebo-Controlled Monotherapy Trial of Pregabalin in Patients with Fibromyalgia - Dissertation Example

?A 14-week, Randomized, Double-Blinded, Placebo-Controlled Monotherapy Trial of Pregabalin in Patients with Fibromyalgia Fibromyalgia is a chronic pain disorder which has been gaining increasing popularity over the last several years, and deems considerable attention from health care professionals, not only because it has a significant impact on the quality of life and functionality of individuals suffering from it, but also because it incurs significant healthcare related costs (Arnold, et al., 2008). This paper reviews and critically appraises the article “A 14-week, Randomized, Double-Blinded, Placebo-Controlled Monotherapy Trial of Pregabalin in Patients with Fibromyalgia” by Arnold et al. (2008), discusses its main findings and compares them with the existing published literature in this regard, identifies some shortcomings in the existing literature and provides recommendations for future research in this arena. The aforementioned article reports the findings of a randomized, double blinded, placebo controlled monotherapy trial which was conducted with the aim of elucidating the efficacy and the safety profile of the pharmacological agent Pregabalin in patients who were suffering from Fibromyalgia (Arnold, et al., 2008). Moreover, as a co-primary objective, this study also aimed at determining the impact of Pregabalin on other parameters and symptoms of fibromyalgia, in addition to pain, in patients in which a significant improvement in pain was found (Arnold, et al., 2008). The study assessed the outcomes of a group of 750 patients suffering from fibromyalgia (as diagnosed using the American College of Rheumatology criteria for fibromyalgia) who were randomly assigned to two different groups, viz. those who received placebo and those who received Pregabalin in three different doses (i.e. 300 mg/dL, 400 mg/dL and 600 mg/dL) twice a day for a cumulative period of 14 weeks (Arnold, et al., 2008). At the end of the trial, the outcome was assessed using the mean pain scores. For patients in whom a significant improvement in pain scores was observed, additional efficacy assessment using the Patient Global Impression of Change (PGIC) and the Fibromyalgia Impact Questionnaire (FIQ) total score was carried out. The results revealed that there was a significant improvement in all outcome measures, i.e. pain score and the PGIC and FIQ scores, amongst patients who received Pregabalin as compared to those who received the placebo (Arnold, et al., 2008). Moreover, all the three tested doses of Pregabalin were found to be efficacious in improving sleep and were not found to be associated with any major adverse affects. Thus, the study concluded that the use of Pregabalin as a monotherapy for the alleviation of the symptoms of fibromyalgia was both safe and efficacious over a dose range of 300-600mg/dL, over a treatment period of upto 14 weeks (Arnold, et al., 2008). Evaluation of study: In the article “A 14-week, Randomized, Double-Blinded, Placebo-Controlled Monotherapy Trial of Pregabalin in Patients with Fibromyalgia,” the authors have provided sufficient background information regarding the disorder, its prevalence, common manifestations and possible etiological factors, in the introduction section. Moreover, they have also shed light on the mechanism of action of the proposed drug to be used in this study, i.e. Pregabalin. However, with regard to the literature review, in my opinion, the authors have conducted an inadequate literature review and have not reported the findings of the relevant studies. They have just cited a single study and have not explored the topic adequately. Moreover, since the study focuses on monotherapy for fibromyalgia, the authors should have shed some light on the available treatment options for this disorder and whether any treatment regimes which propose the use of a combination of multiple drugs exist. They should have also justified their choice of monotherapy and the pharmacologic agent being used and should have discussed whether this option is the drug of choice for this disorder or not. Although the authors have provided the rationale for conducting this study and have clearly stated how this study differs from the previous studies conducted in this regard, they should have used more studies to identify and highlight the shortcomings of the existing literature and then justify how the present study fills in the gaps left by previous studies. There were two primary objectives of this study, which have been explicitly stated by the authors and are presented in clear terms to facilitate understanding on the part of the readers. However, no research hypotheses have been stated by the authors. For a quantitative study, it is important to state a clear hypothesis so that it can be tested statistically and the analysis can determine the significance of the results obtained (Smith, 2009). The study design chosen by the authors for this study was Randomized, Double-Blinded, Placebo-Controlled Monotherapy Trial. This design is best suited for the study question as the study aimed at elucidating the efficacy and safety of Pregabalin as randomized control trials provide the highest level of evidence and thus are recommended for ascertaining the efficacy and safety profile of a novel drug or intervention (Smith, 2009). The study sample comprised of 750 participants recruited from 84 different research centers located across the United States. The sample size was well above the required sample size per group as estimated via sample size calculation. This is important as an adequate sample size is necessary to ensure that the results have not arisen due to chance and are reliable (EBP Tutorials, 2005). Moreover, all participants were found to have similar baseline characteristics, which help in overcoming any the effect of any possible selection bias. Clear inclusion and exclusion criteria and the method of patient identification have been mentioned by the authors. Moreover, from an ethical perspective, the study was conducted after gaining approval from the Institutional Review Board at each study site and informed consent was taken from each participant at the beginning of the study. The sampling technique used was computer based random sampling, which contributes significantly to the strength of this study as random sampling has been known to provide the strongest degree of evidence (Smith, 2009). In addition, in order to balance the randomization process random permutated blocks were used. It has been stated by the authors that this was a double blinded trial, i.e. both the patients and all the involved research personnel were blinded, and although the authors mention that patients were blinded to the treatment group they were being allocated to by the use of identical encapsulation and similar bottles, the blinding procedure for the research personnel has not been described. The study methodology and protocol has been described by the authors in detail, which facilitates the replication of the same methodology by future researchers. The frequency of outcome assessment, outcome measures and the tools used to assess all outcome variables have described quite clearly and since all the tools used to assess outcomes are pre-validated (Burckhardt, Clark, & Bennett, 1991), the reliability and validity of outcome assessment is ensured. Intent to treat analysis was performed and the results were clearly displayed using tables and graphs where required. Means, standard deviations, P-values and confidence intervals were appropriately used where required. Participant attrition due to dropouts and loss to follow up were clearly accounted for in the form of a flow chart. An important parameter to consider while assessing quantitative studies is the validity of the study findings, which is often compromised due to the presence of bias, which can be of several different types, e.g. selection bias, observer bias, recall bias, etc. In this study, since a random selection method was used, there is minimal possibility of selection bias. Similarly, the use of a diary to record pain scores helped to overcome recall bias. In addition, there were no identifiable confounding factors which may possibly compromise the validity of the study findings. The discussion section of this study adequately discusses all the study findings in light of the existing literature. The significant findings and their implications have been discussed and the authors have also correctly identified the shortcomings and limitations of their study and have suggested possible arenas for further research in this regard. The conclusion is brief and precise and appropriately summarizes the findings of this study in a clear manner. This study was novel in that it assessed a higher number of subjects (i.e. 750), was conducted over a longer time period (i.e. 14 weeks) as compared to previous studies and evaluated the effects of a dose range of the concerned drug, i.e. between 300-600mg/dL of Pregabalin as opposed to testing the impact of a fixed dose of the drug (Arnold, et al., 2008). The results of this trial are generalizable since the sample size is quite large and this is a multicenter trial, so the study population can be considered a true representative of the general population. Comparison to other published information on the topic: The findings of this study are in conjunction with other studies conducted in this regard. Crofford et al. (2005) in their randomized, double-Blind, placebo-controlled trial of 529 patients, conducted over a period of 8 weeks, demonstrated the efficacy of Pregabalin in a dose of 450 mg/dL over placebo in alleviating pain symptoms, improving sleep, fatigue and overall health related quality of life (Crofford, et al., 2005). Another double-blind, placebo-controlled trial to test the durability of effect of Pregabalin for pain associated with fibromyalgia, over a period of six months found that higher doses of Pregabalin (upto 600 mg/dL) were effective in sustained relief of symptoms over a period of 26 weeks (Crafford et al. 2006 cited in Rooks, 2007). These findings are similar to the findings of the study in question which evaluated the efficacy over a dose of range of 300-600mg/dL of Pregabalin. There has been considerable research in order to elucidate the best treatment modality for fibromyalgia. While the guidelines of American Pain Society (APS) (Burckhardt, Goldenberg, Crofford, Gerwin, Gowans, & Kackson, 2005) and the Association of the Scienti?c Medical Societies in Germany (AWMF) (Bernardy, Klose, Uceyler, & Kopp, 2008)recommend the use of multiple treatment modalities as a first line therapy of fibromyalgia, including and not limited to, aerobic exercise, Cognitive behavioral therapy and antidepressents such as amitriptyline, the guidelines issued by the European League Against Rheumatism (EULAR) recommend the use of pharmacologic agents as the first line of treatment. The recommended pharmacological agents include Pregabalin and other agents such as antidepressants and anti-convulsants, e.g. amitriptyline, tramadol, ?uoxetine, duloxetine, milnacipran, moclobemide, pirlindol, tropisetron and pramiprexole (Carville, Arendt-Nielsen, Bliddal, Blotman, Branco, & Buskila, 2008). Thus, it can be concluded from an extensive review of literature that Pregabalin is an effective and safe treatment option for patients with fibromyalgia and can be administered to patients either as monotherapy or as a part of a multicomponent treatment regime. Implications for practice and recommendations for further research: Based on the findings of this study, it can be concluded that Pregabalin is a safe and efficacious drug to be used in patients with fibromyalgia and is not only effective in alleviating pain in such patients but also results in the improvement of other parameters such as sleep. Since fibromyalgia is a disease that significantly impairs the quality of life and functionality of individuals suffering from it, the use of Pregabalin in patients with this disorder in order to relieve their symptoms is advocated and should be adapted in routine clinical practice. Further research in this arena should aim to investigate the long term safety and efficacy profile of Pregabalin for patients suffering from fibromyalgia. Moreover, since this trail focused only on the use of Pregabalin as a monotherapy, future studies should explore the use of Pregabalin as a part of combination therapy regimens and whether such combinations are safe and cost-effective. Another important aspect that needs further research is the comparison of Pregabalin with other available treatment options for fibromyalgia and evaluating that amongst all the available options, which option is the most safe, beneficial in terms of alleviation of symptoms and cost effective. References Arnold, L. M., Russell, I. J., Dir, E. W., Duan, W. R., Young, J. P., Sharma, U., et al. (2008). A 14-week, Randomized, Double-Blinded, Placebo-Controlled Monotherapy Trial of Pregabalin in Patients With Fibromyalgia. The Journal of Pain , 9 (9), 792-805. Bernardy, K., Klose, P., Uceyler, N., & Kopp, I. H. (2008). Methodological fundamentals for the development of the guideline. Schmerz , 244-254. Burckhardt, C., Clark, R., & Bennett, S. (1991). The Fibromyalgia Impact Questionnaire (FIQ): Development and validation. Journal of Rheumatology , 728-733. Burckhardt, C., Goldenberg, D., Crofford, L., Gerwin, R., Gowans, S., & Kackson, e. a. (2005). Guideline for the management of ?bromyalgia syndrome. Pain in adults and children.APS Clinical Practice Guideline Series No. 4. Glenview, IL: American Pain Society. Carville, S., Arendt-Nielsen, S., Bliddal, H., Blotman, F., Branco, J., & Buskila, D. (2008). EULAR evidence-based recommendations for the management of ?bromyalgia syndrome. Annals of Rheumatalogic Diseases , 536-541. Crofford, L. J., Rowbotham, M. C., Mease, P. J., Russell, I. J., Dworkin, R. H., Corbin, A. E., et al. (2005). Pregabalin for the Treatment of Fibromyalgia Syndrome: Pregabalin for the Treatment of Fibromyalgia Syndrome. Arthritis and Rehumatism , 1264–1273. Crofford, L. J., Simpson, S., Young Jr, J. P., et al. (2006). A six-month, double-blind, placebo-controlled, durability of effect study of Pregabalin for pain associated with fibromyalgia. 2006 American College of Rheumatology Meeting; Washington DC. Abstract L44.  EBP Tutorials. (2005, September). Evidence-based practice tutorials - Critical Appraisal Skills. Retrieved April 3, 2011, from http://www.brighton.ac.uk/ncor/tutorials/EBP_Tutorial_intro_Critical_Appraisal_Skills.pdf Rooks, D. S. (2007). Fibromyalgia treatment update. Current Opinion in Rheumatology , 111-117. Smith, T. (2009). Critical appraisal of quantitative and qualitative research literature. The Radiographer , 56 (3), 6–10. Read More