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      Neuropathic pain responds better to increased doses of pregabalin: an in-depth analysis of flexible-dose clinical trials

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          Abstract

          Background

          Pregabalin is an effective treatment option for many patients with neuropathic pain. Higher doses of pregabalin have been shown to be more effective in improving pain outcomes but, in practice, failing to appropriately increase the dose can leave patients under-treated.

          Methods

          This was a pooled analysis of 6 flexible-dose clinical trials of pregabalin in patients with neuropathic pain (diabetic peripheral neuropathy, peripheral herpetic neuralgia, posttraumatic pain, or postsurgical pain). Patients were divided into “dose pathway” groups based on their weekly pregabalin dose from the start of their trial to the first week of their maintenance phase. These were: 150 mg/day only; 150 to 300 mg/day; 150 to 300 to 450 mg/day; 150 to 300 to 450 to 600 mg/day; 150 to 300 to 600 mg/day; 300 to 600 mg/day. Pain outcomes assessed for each group at each new dose were proportion of 30% and 50% responders (≥30% or ≥50% reduction in mean pain score from baseline) and mean change in pain score. Percent change in mean pain score from baseline was assessed using a marginal structural model.

          Results

          Seven hundred and sixty-one patients treated with flexible-dose pregabalin were included in the analysis. For each dose pathway group, there was a notably greater proportion of 30% and 50% responders and change in pain score, at each escalating dose. As assessed by the marginal structural model, higher doses of pregabalin were estimated to result in a significantly greater change in mean pain score at each week. This dose response with flexible-dose pregabalin was consistent with that previously observed with fixed-dose pregabalin.

          Conclusion

          Many patients who do not respond to lower doses of pregabalin will respond with notable improvements in pain outcomes when the dose is escalated. These data should encourage physicians treating patients with neuropathic pain to escalate pregabalin to the dose that delivers optimal analgesia and tolerable side effects.

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          Most cited references 37

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          Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men.

          Standard methods for survival analysis, such as the time-dependent Cox model, may produce biased effect estimates when there exist time-dependent confounders that are themselves affected by previous treatment or exposure. Marginal structural models are a new class of causal models the parameters of which are estimated through inverse-probability-of-treatment weighting; these models allow for appropriate adjustment for confounding. We describe the marginal structural Cox proportional hazards model and use it to estimate the causal effect of zidovudine on the survival of human immunodeficiency virus-positive men participating in the Multicenter AIDS Cohort Study. In this study, CD4 lymphocyte count is both a time-dependent confounder of the causal effect of zidovudine on survival and is affected by past zidovudine treatment. The crude mortality rate ratio (95% confidence interval) for zidovudine was 3.6 (3.0-4.3), which reflects the presence of confounding. After controlling for baseline CD4 count and other baseline covariates using standard methods, the mortality rate ratio decreased to 2.3 (1.9-2.8). Using a marginal structural Cox model to control further for time-dependent confounding due to CD4 count and other time-dependent covariates, the mortality rate ratio was 0.7 (95% conservative confidence interval = 0.6-1.0). We compare marginal structural models with previously proposed causal methods.
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            Treatment of neuropathic pain: an overview of recent guidelines.

            A number of different treatments for neuropathic pain have been studied, but the literature is sizable, rapidly evolving, and lacks important information about practical aspects of patient management. Under the auspices of the International Association for the Study of Pain (IASP) Neuropathic Pain Special Interest Group (NeuPSIG), a consensus process was used to develop evidence-based guidelines for the pharmacologic management of neuropathic pain that take into account clinical efficacy, adverse effects, impact on health-related quality of life, convenience, and costs. On the basis of randomized clinical trials, medications recommended as first-line treatments for neuropathic pain included certain antidepressants (i.e., tricyclic antidepressants and dual reuptake inhibitors of both serotonin and norepinephrine), calcium channel alpha(2)-delta ligands (i.e., gabapentin and pregabalin), and topical lidocaine. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in selected clinical circumstances. Other medications that generally would be used as third-line treatments include certain other antidepressant and antiepileptic medications, topical capsaicin, mexiletine, and N-methyl-d-aspartate receptor antagonists. Two other national and international associations recently published pharmacologic treatment guidelines for neuropathic pain, which are summarized and contrasted with the NeuPSIG recommendations. Recent guidelines for the use of neurostimulation for the treatment of neuropathic pain also are summarized. For all treatments for neuropathic pain, long-term studies, head-to-head comparisons, and studies of treatment combinations are a priority for future research.
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              Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial.

              To evaluate the efficacy and safety of pregabalin in the treatment of postherpetic neuralgia (PHN). The authors conducted a multicenter, parallel-group, double-blind, placebo-controlled, 8-week, randomized clinical trial in PHN, defined as pain for 3 or more months following herpes zoster rash healing. Patients (n = 173) were randomized to treatment with pregabalin or placebo. Patients randomized to pregabalin received either 600 mg/day (creatinine clearance > 60 mL/min) or 300 mg/day (creatinine clearance 30 to 60 mL/min). The primary efficacy measure was the mean of the last seven daily pain ratings. Secondary endpoints included additional pain ratings, sleep interference, quality of life, mood, and patient and clinician ratings of global improvement. Pregabalin-treated patients had greater decreases in pain than patients treated with placebo (endpoint mean scores 3.60 vs 5.29, p = 0.0001). Pain was significantly reduced in the pregabalin-treated patients after the first full day of treatment and throughout the study, and significant improvement on the McGill Pain Questionnaire total, sensory, and affective pain scores was also found. The proportions of patients with >or=30% and >or=50% decreases in mean pain scores were greater in the pregabalin than in the placebo group (63% vs 25% and 50% vs 20%, p = 0.001). Sleep also improved in patients treated with pregabalin compared to placebo (p = 0.0001). Both patients and clinicians were more likely to report global improvement with pregabalin than placebo (p = 0.001). Given the maximal dosage studied, pregabalin had acceptable tolerability compared to placebo despite a greater incidence of side effects, which were generally mild to moderate in intensity. Treatment of PHN with pregabalin is safe, efficacious in relieving pain and sleep interference, and associated with greater global improvement than treatment with placebo.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2017
                26 July 2017
                : 10
                : 1769-1776
                Affiliations
                [1 ]University Department of Anaesthesia, Stobhill Ambulatory Care Hospital, Glasgow
                [2 ]Pfizer Ltd, Tadworth, UK
                [3 ]Pfizer, Groton, CT
                [4 ]Pfizer, New York, NY, USA
                [5 ]Pfizer GEP SLU, Madrid, Spain
                Author notes
                Correspondence: Michael Serpell, University Department of Anaesthesia, Pain Office, 3rd Floor, Stobhill Ambulatory Care Hospital, 133 Balornock Road, Glasgow G21 3UW, UK, Tel +44 141 355 1490, Email mgserpell@ 123456cheerful.com
                Article
                jpr-10-1769
                10.2147/JPR.S129832
                5536312
                © 2017 Serpell et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Anesthesiology & Pain management

                neuropathic pain, pregabalin, dosing

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