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Pregabalin Treatment for Peripheral Neuropathic Pain

A Review of Safety Data from Randomized Controlled Trials Conducted in Japan and in the West

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Abstract

Two well-studied conditions of peripheral neuropathic pain are postherpetic neuralgia (PHN) and painful diabetic peripheral neuropathy (DPN). Several pregabalin trials for peripheral neuropathic pain have been conducted in the West, but limited data are available for Japan. As ethnicity may influence health risks, differences may be evident in safety data from pregabalin trials in Japan and in the West.

The objectives of this review were to compare large pooled safety data from randomized controlled trials evaluating pregabalin for the treatment of PHN or DPN in the West with data from two (one PHN, N = 371; one DPN, N = 314) similar trials in Japan. Longer-term safety data from Japanese open-label extension studies were also reviewed in these neuropathic pain populations. Published and unpublished Pfizer-supported pregabalin trials were identified and sourced from internal Pfizer records.

A PubMed search to check for inclusiveness was conducted on 2 November 2011 using the following criteria: ‘diabetic peripheral neuropathy’ OR ‘postherpetic neuralgia’ OR ‘neuropathic pain’ AND ‘pregabalin’, with limits set for clinical and randomized controlled trials published in English. Five PHN trials (N= 1250) and nine DPN trials (N = 2554) were identified as suitable for inclusion based on methodological comparability. Descriptive safety data from the original trials were reviewed and the most commonly reported adverse events (AEs; dizziness, somnolence, peripheral oedema and weight gain) were identified to be of primary interest. The majority of AEs were of mild to moderate severity in Japanese and Western populations. The most commonly reported AE data (all-causality) with pregabalin (regardless of dose) in Japan (dizziness: PHN = 31.1%; DPN = 24.6%, and somnolence: PHN = 28.6%; DPN = 25.7%) were compared with pooled data from the Western trials (dizziness: PHN = 24.9%; DPN = 23.0%, and somnolence: PHN=15.1%; DPN=13.4%). Further assessment of these pooled AE (all-causality) data showed that dizziness and somnolence appeared early in the course of pregabalin treatment, but resolved before the end of the treatment in the majority of PHN and DPN patients (maximum duration of trials was 13 weeks).

The slightly higher incidence of dizziness and somnolence in the two Japanese trials than that seen in the Western trials may reflect an increased exposure to pregabalin per fixed dose due to the lower mean bodyweight of the Japanese versus Western populations (on a mg/kg basis). However, of the participants who experienced these AEs (all-causality), the proportion who withdrew from the trials in Japan (dizziness: PHN = 23.5%; DPN = 18.2%, and somnolence: PHN = 10.3%; DPN = 10.9%) were comparable with the proportion who withdrew from trials in the West (dizziness: PHN= 16.0%; DPN = 29.3%, and somnolence: PHN = 19.4%; DPN = 34.2%). In Japan, 12.5% (PHN) and 15.1% (DPN) of patients experienced peripheral oedema as an AE (all-causality) compared with 8.8% (PHN) and 10.3% (DPN) in the West. Weight gain as an AE (all-causality) was experienced in 11.7% (PHN) and 13.4% (DPN) of patients in Japan compared with 3.8% (PHN) and 7.0% (DPN) in the West, but stabilized with continued treatment. Despite the lower mean bodyweight in Japanese versus Western patients, the PHN and DPN patients in Japan had stable blood glucose and HbA1c levels throughout the trials.

The results of this review indicate safety outcomes in pregabalin trials are comparable between patients in Japan and those in the West. While managing peripheral neuropathic pain with pregabalin treatment, all patients should be observed closely for the incidence of dizziness and somnolence, especially at the beginning of treatment. These patients should also be monitored for evidence of peripheral oedema and weight gain during stable treatment, regardless of the source of neuropathic pain.

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Acknowledgements

The studies included within this pooled analysis were all sponsored and funded by Pfizer Inc. All authors contributed to the writing, reviewing, preparation and interpretation of the data, and approval of the manuscript. They were also involved in the decision to submit the paper for publication. Setsuro Ogawa has received consultancy fees or lecture fees from Janssen, Hisamitsu, Pfizer, Nippon Shinyaku and Showa Yakuhin Kakou. Jo Satoh has received research funding, lecture fees and consultancy fees from Astellas, Banyu, Daiichi-Sankyo, Dainippon-Sumitomo, Eli Lilly, Novo Nordisk, Ono, Pfizer, Sanofi-Aventis and Takeda. Akio Arakawa, Tamotsu Yoshiyama and Makoto Suzuki are employees of Pfizer. Medical writing support was provided by Brenda Meyer, PhD, of UBC Scientific Solutions and funded by Pfizer Inc.

The Medical Dictionary for Regulatory Activities (MedDRA®) trademark is owned by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) on behalf of the International Conference on Harmonisation.

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Authors and Affiliations

  1. Department of Anesthesiology, Nihon University School of Medicine/Surugadai Nihon University Hospital, Tokyo, Japan

    Setsuro Ogawa (Professor)

  2. Division of Diabetes and Metabolism, Department of Internal Medicine, Iwate Medical University School of Medicine, Iwate, Japan

    Jo Satoh

  3. Pfizer Japan Inc., Tokyo, Japan

    Akio Arakawa, Tamotsu Yoshiyama & Makoto Suzuki

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  1. Setsuro Ogawa
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  2. Jo Satoh
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  4. Tamotsu Yoshiyama
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  5. Makoto Suzuki
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Correspondence to Setsuro Ogawa.

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Ogawa, S., Satoh, J., Arakawa, A. et al. Pregabalin Treatment for Peripheral Neuropathic Pain. Drug Saf 35, 793–806 (2012). https://doi.org/10.1007/BF03261976

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