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Referencias: dolor neuropático asociado a neuropatía diabética periférica dolorosa

Argoff CE, Cole E. Diabetic peripheral neuropathic pain: clinical and quality-of-life issues. Mayo Clin Proc. 2006;81(suppl 4):S3-S11.

Diabetic peripheral neuropathy (DPN) Is estimated to be present In 50% of people living with diabetes mellitus (DM). Comorbldities of DM, such as macrovascular and microvascular changes, also Interact with DPN and affect Its course. In patients with DM, DPN Is the leading cause of foot ulcers, which In turn are a major cause of amputation In the United States. Although most patients with DPN do not have pain, approximately 11% of patients with DPN have chronic, painful symptoms that diminish quality of life, disrupt sleep, and can lead to depression. Despite the number of patients affected by DPN pain, little consensus exists about the pathophysiology, best diagnostic tools, and primary treatment choices. This article reviews the current knowledge about and presents recommendations for diagnostic assessment of DPN pain based on a review of the literature.

Attal N, Cruccu G, Baron R, et al. EFNS guidelines on pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;13(11):1113-1123.

Background and objectives: This second European Federation of Neurological Societies Task Force aimed at updating the existing evidence about the pharmacological treatment of neuropathic pain since 2005. Methods: Studies were identified using the Cochrane Database and Medline. Trials were classified according to the aetiological condition. All class I and II randomized controlled trials (RCTs) were assessed; lower class studies were considered only in conditions that had no top-level studies. Treatments administered using repeated or single administrations were considered, provided they are feasible in an outpatient setting.
Results: Most large RCTs included patients with diabetic polyneuropathies and postherpetic neuralgia, while an increasing number of smaller studies explored other conditions. Drugs generally have similar efficacy in various conditions, except in trigeminal neuralgia, chronic radiculopathy and HIV neuropathy, with level A evidence in support of tricyclic antidepressants (TCA), pregabalin, gabapentin, tramadol and opioids (in various conditions), duloxetine, venlafaxine, topical lidocaine and capsaicin patches (in restricted conditions). Combination therapy appears useful for TCAgabapentin and gabapentin-opioids (level A).
Conclusions: There are still too few large-scale comparative studies. For future trials, we recommend to assess comorbidities, quality of life, symptoms and signs with standardized tools and attempt to better define responder profiles to specific drug treatments.

Bohlega S, Alsaadi T, Amir A, et al. Guidelines for the pharmacological treatment of peripheral neuropathic pain: expert panel recommendations for the Middle East region. J Int Med Res. 2010;38(2):295-317.

Neuropathic pain (NeP) has been the focus of extensive basic and clinical research over the past 20 years. This has led to an increased understanding of underlying pathophysiological mechanisms and the development of new therapeutic agents, as well as a clearer definition of the role of established medications. To date there are no published treatment guidelines for NeP in the Middle East. A multidisciplinary panel of Middle East and international experts met to review critically and reach a consensus on how best to apply evidencebased guidelines for the treatment of NeP (mainly peripheral NeP) in the Middle East. The expert panel recommended pregabalin, gabapentin and secondary amine tricyclic antidepressants (nortriptyline and desipramine) as first-line treatments for peripheral NeP. Serotonin–norepinephrine reuptake inhibitor antidepressants, tramadol and controlled-release opioid analgesics were recommended as second-line treatments. There is a need to increase diagnostic awareness of NeP, use validated screening questionnaires and undertake more treatment research in the Middle East region.

Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain. 2005;114:29-36.

TFew studies have directly compared the clinical features of neuropathic and non-neuropathic pains. For this purpose, the French Neuropathic Pain Group developed a clinician-administered questionnaire named DN4 consisting of both sensory descriptors and signs related to bedside sensory examination. This questionnaire was used in a prospective study of 160 patients presenting with pain associated with a definite neurological or somatic lesion. The most common aetiologies of nervous lesions (n=89) were traumatic nerve injury, post-herpetic neuralgia and post stroke pain. Non-neurological lesions (n=71) were represented by osteoarthritis, inflammatory arthropathies and mechanical low back pain. Each patient was seen independently by two experts in order to confirm the diagnosis of neuropathic or nonneuropathic pain. The prevalence of pain descriptors and sensory dysfunctions were systematically compared in the two groups of patients. The analysis of the psychometric properties of the DN4 questionnaire included: face validity, inter-rater reliability, factor analysis and logistic regression to identify the discriminant properties of items or combinations of items for the diagnosis of neuropathic pain. We found that a relatively small number of items are sufficient to discriminate neuropathic pain. The 10-item questionnaire developed in the present study constitutes a new diagnostic instrument, which might be helpful both in clinical research and daily practice.

Bril V, England J. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76(20):1758-1765.

Objective: To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN).
Methods: We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: “What is the efficacy of a given treatment (pharmacologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?”
Results and Recommendations: Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL.

Davies M, Williams R. The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care. 2006;29(7):1518-1522.

OBJECTIVE— To determine the prevalence of painful diabetic peripheral neuropathy (PDPN) in a population-based sample and to estimate its severity and impact.
RESEARCH DESIGN AND METHODS— A cross-sectional descriptive study consisting of two phases: phase 1, a postal survey to patients with type 2 diabetes (an initial screening questionnaire including one question about pain); phase 2, neurological history and examination using the Toronto Clinical Scoring System. Subjects with PDPN or mixed (PDPN and nonneuropathic) pain completed the Neuropathic Pain Scale and Neuroqol to assess severity and nature of the pain and impact on quality of life. Those without PDPN completed the Neuroqol only.
RESULTS— In phase 1, there was a 92.7% response (n _ 326), with 208 (63.8%) subjects reporting pain. In phase 2, 269 (82.5%) subjects attended and 51 (19.0%) were found to have PDPN: 99 (36.8%) nonneuropathic pain, 20 (7.4%) mixed pain, and 99 (36.8%) no pain (PDPN prevalence 26.4%). Of those with PDPN, 80% stated that their pain was moderate or severe. Those affected had poorer quality of life than those with no pain (difference in mean scores 3.6 [95% CI 2.5– 4.6%]) compared with those with nonneuropathic pain (1.7 [0.4 –2.9%]). Both pain and neuropathy score were independently associated with quality of life, and subjects with PDPN had significantly higher neuropathy scores.

Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: An overview and literature update. Mayo Clin Proc. 2010;85(3 suppl):S3-S14.

The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain recently sponsored the development of evidence-based guidelines for the pharmacological treatment of neuropathic pain. Tricyclic antidepressants, dual reuptake Inhibitors of serotonin and norepinephrine, calcium channel α2- ligands (ie, gabapentin and pregabalin), and topical lidocaine were recommended as first-line treatment options on the basis of the results of randomized clinical trials. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in certain clinical circumstances. Results of several recent clinical trials have become available since the development of these guidelines. These studies have examined botulinum toxin, high-concentration capsaicin patch, lacosamide, selective serotonin reuptake inhibitors, and combination therapies in various neuropathic pain conditions. The increasing number of negative clinical trials of pharmacological treatments for neuropathic pain and ambiguities in the interpretation of these negative trials must also be considered in developing treatment guidelines. The objectives of the current article are to review the Neuropathic Pain Special Interest Group guidelines for the pharmacological management of neuropathic pain and to provide a brief overview of these recent studies.

Freeman R, Durso-DeCruz E. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy. Diabetes Care. 2008;31(7):1448-1454.

OBJECTIVE— To evaluate the efficacy, safety, and tolerability of pregabalin across the effective dosing range, to determine differences in the efficacy of three times daily (TID) versus twice daily (BID) dosage schedules, and to use time-to-event analysis to determine the time to onset of a sustained therapeutic effect using data from seven trials of pregabalin in painful diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS— Data were pooled across seven doubleblind, randomized, placebo-controlled trials using pregabalin to treat painful DPN with dosages of 150, 300, and 600 mg/day administered TID or BID. Only one trial included all three of these dosages, and TID dosing was used in four. All studies shared fundamental selection criteria, and treatment durations ranged from 5 to 13 weeks.
RESULTS— Pooled analysis showed that pregabalin significantly reduced pain and painrelated sleep interference associated with DPN (150, 300, and 600 mg/day administered TID vs. placebo, all P ≤ 0.007). Only the 600 mg/day dosage showed efficacy when administered BID (P ≤ 0.001). Pain and sleep interference reductions associated with pregabalin appear to be positively correlated with dosage; the greatest effect was observed in patients treated with 600 mg/day. Kaplan-Meier analysis revealed that the median time to onset of a sustained (≥30% at end point) 1-point improvement was 4 days in patients treated with pregabalin at 600 mg/day, 5 days in patients treated with pregabalin at 300 mg/day, 13 days in patients treated with pregabalin at 150 mg/day, and 60 days in patients receiving placebo. The most common treatment-emergent adverse events were dizziness, somnolence, and peripheral edema.

Gautam V. Shrikhande • J ames F. McKinsey, Diabetes and Peripheral Vascular Disease, Diagnosis and Management, ISBN 978-1-62703-157-8 ISBN 978-1-62703-158-5 (eBook), DOI 10.1007/978-1-62703-158-5

Pregabalin is a commonly used therapy currently recommended as first-line treatment for a number of neuropathic pain (NeP) conditions. Since licensure, a number of clinical trials of pregabalin in different NeP conditions have been completed from which additional data on safety and tolerability can be drawn. In this analysis, patient-level data from 31 randomized clinical trials of pregabalin in peripheral NeP sponsored by Pfizer were pooled and assessed for incidence of adverse events (AEs). Incidence by age, disease condition, and race, together with risk differences and time to onset and resolution of AEs, was assessed. In total, 7,510 patients were included: 4,884 on pregabalin (representing 805 patient-years treatment) and 2,626 on placebo. Pregabalin vs. placebo risk analysis identified 9 AEs with a risk difference, for which the lower limit of the 95% confidence interval (CI) was > 1%: dizziness (risk difference [95% CI]: (17.0 [15.4 to 18.6]), somnolence (10.8 [9.5 to 12.1]), peripheral edema (5.4 [4.3 to 6.4]), weight increase (4.7 [3.9 to 5.5]), dry mouth (2.9 [2.1 to 3.8]), constipation (2.3 [1.5 to 3.2]), blurred vision (2.2 [1.6 to 2.9]), balance disorder (2.0 [1.5 to 2.5]), and euphoric mood (1.6 [1.2 to 2.0]). The most common AEs, dizziness and somnolence, typically emerged within the first 1 to 2 weeks of treatment and resolved 1 to 2 weeks later, without resulting in cessation of treatment. The data from this review provide information, indicating which AEs may be expected in patients treated with pregabalin, and suggest that careful dose titration to the highest tolerable dose is the most appropriate approach in clinical practice.

Gore M, Brandengurg NA. Pain severity in diabetic peripheral neuropathy is associated with patient functioning, symptom levels of anxiety and depression, and sleep. J Pain Symptom Manag. 2005;30(4):374-385.

The prevalence of peripheral arterial disease (PAD) among American adults is estimated at 4% . Among the elderly, the prevalence exceeds 20%, affecting over four million individuals, and accounting for over $20 billion in annual healthcare costs. Its most advanced form, critical limb ischemia (CLI), is a highly morbid condition with 1-year mortality and major amputation rates estimated at 20% and 35%,respectively. The frequent coexistence of diabetes mellitus (DM) and PAD is readily apparent to healthcare providers involved in the care of patients with either condition. The co-prevalence of these conditions is not simply an association due to shared risk factors; DM plays a fundamental role in the pathophysiology of PAD. The relationship between diabetes and vasculopathy is complex, and despite a signi fi cant research effort in molecular, animal, and translational models, the details of this relationship have yet to be completely elucidated. At present, the end result of peripheral ischemia is thought to result from the interplay between hemodynamic, neurohumoral, and metabolic factors, culminating in endothelial dysfunction. This, in turn, leads to medial smooth muscle cell dysfunction, platelet hyperactivity, and impaired fi brinolysis coupled with hypercoagulability . Fundamental concerns remain unanswered. An example is the phenomenon that the regression in microvascular disease following strict blood glucose control is not observed in the larger vessels encountered by .the vascular specialist

Gore M, Brandengurg NA. Pain severity in diabetic peripheral neuropathy is associated with patient functioning, symptom levels of anxiety and depression, and sleep. J Pain Symptom Manag. 2005;30(4):374-385.

Our goal was to evaluate pain severity, pain-related interference with function, sleep impairment, symptom levels of anxiety and depression, and quality of life among patients with painful diabetic peripheral neuropathy (DPN). Participants in a burden of illness survey (n = 255) completed the modified Brief Pain Inventory-DPN (BPI-DPN), MOS Sleep Scale, Hospital Anxiety and Depression Scale (HADS), Short Form Health Survey-12v2 (SF-12v2), and the EuroQoL (EQ-5D). Patients were 61 ± 12.8 years old (51.4% female), had diabetes for 12 ± 10.3 years and painful DPN for 6.4 ± 6.4 years. Average and Worst Pain scores (BPI-DPN, 0--10 scales) were 5.0 ± 2.5 and 5.6 ± 2.8. Pain substantially interfered (≥4 on 0--10 scales) with walking ability, normal work, sleep, enjoyment of life, mood, and general activity. Moderate to severe symptom levels of anxiety and depression (HADS-A and HADS-D scores ≥11 on 0--21 scales) occurred in 35% and 28% of patients, respectively. Patients reported greater sleep problems compared with the general U.S. population and significant impairment in both physical and mental functioning (SF-12v2) compared with subjects with diabetes. The mean EQ-5D utility score was 0.5 ± 0.3. Greater pain levels in DPN (mild to moderate to severe) corresponded with higher symptom levels of anxiety and depression, more sleep problems, and lower utility ratings and physical and mental functioning, (all Ps < 0.01). Painful DPN is associated with decrements in many aspects of patients’ lives: physical and emotional functioning, affective symptoms, and sleep problems. The negative impact is higher in patients with greater pain severity.


Griene B, Bouajina E, Haddad M, et al. Pharmacological treatment of peripheral neuropathic pain: Expert panel recommendations for the French-speaking Maghrebian region. Douleur et Analgésic. 2011;24(2):112-120.

Peripheral neuropathic pain (NeP) has been a major theme of basic and clinical research over the past 20 years. Extensive research has led to an increased knowledge of underlying pathophysiological mechanisms, the development of new therapeutic agents, and the publication of treatment guidelines. Nonetheless, a significant gap in the treatment guideline literature appears to be the exclusive focus on recommendations for managing NeP patients in North America and Europe. To date there are no guidelines for NeP in the French-speaking North-African countries (Algeria, Tunisia, Morocco), while these countries display several specificities in terms of aetiologies of NeP and comorbidities. A multidisciplinary panel of experts met to reach a consensus on how best to apply evidence-based guidelines for the treatment of NeP in this region of the world. From the so far published guidelines, they propose recommendations for the pharmacological management of NeP in their countries.

Hoffman DL, Sadosky A. Cross-national burden of painful diabetic peripheral neuropathy in Asia, Latin America, and Middle East. Pain Pract. 2009;9(1):35-42.

The burden of painful diabetic peripheral neuropathy (DPN) is a common complication of diabetes. This study expanded on the human burden of painful DPN by quantifying functional and health status impairments among international patients from a randomized, double-blind, placebo-controlled trial of painful DPN. Evaluated outcomes measures included: Brief Pain Inventory-Short Form (mBPI-sf), EuroQOL 5D, Hospital Anxiety and Depression Scale, and Medical Outcomes Study Sleep Scale. Outcomes were stratified by pain severity using cut-points: 0 to 10 numeric rating scale (NRS) for average pain (0 to 3: none/mild, 4 to 6: moderate, 7 to 10: severe). Study sample is: 401 patients (163 in Asia, 110 in Latin America and 128 in the Middle East), mostly female (61%) (± standard deviation, SD), age of 57 ± 10 years. Participants reported at least moderate levels of pain severity (mean [1 SD] scores on a 0 to 10NRS for average pain of 5.9 ± 1.8 for Asia, 6.7 ± 1.6 for Latin America, and 6.6 ± 1.7 for the Middle East). Mean (± SD) values on the mBPI-sf Pain Interference Index were 4.7 ± 2.3 for Asia, 5.6 ± 2.1 for Latin America, and 5.5 ± 2.3 for the Middle East. Patients in all 3 regions reported difficulties with functioning, sleep, and overall health status, which increased with higher pain severity levels. Patients in Asia had substantial impairments; however, they reported less serious problems than the other regions. These data are consistent with painful DPN being a burdensome condition worldwide: people with poorly managed neuropathic pain report a substantial burden of disease.

Hartsfield Cynthia L,. Korner Eli J, Pharm.D, Painful Diabetic Peripheral Neuropathy in a Managed Care Setting: Patient Identification, Prevalence Estimates, and Pharmacy Utilization Patterns, POPULATION HEALTH MANAGEMENT Volume 11, Number 6, 2008

The objectives of this study were to validate an algorithm for identifying patients with painful diabetic peripheral neuropathy (pDPN) and demonstrate its practical applications. Using the Kaiser Permanente Colorado Diabetes Registry, an algorithm was developed with selected ICD-9 diagnosis codes combined with automated pharmacy data for medications prescribed for pDPN symptoms. Medical records were reviewed to confirm pDPN presence and to inform algorithm refinement. Prevalence was estimated with a numerator of members with diabetes who had inclusion but no exclusion codes in 2003 (Method 1) and with a numerator of diabetes patients with inclusion codes between 1998 and 2003 who had no subsequent exclusion codes and who remained members in 2003 (Method 2); the denominator was all members with diabetes in 2003. Medication utilization was compared between patients with and without pDPN. A total of 19,577 members with diabetes were identified; 2612 met initial inclusion criteria. Medical record review (n =298) demonstrated sensitivity of 94%, specificity of 55%, and positive predictive value (PPV) of 64%. Inclusion criteria were modified and pharmacy data eliminated. The revised algorithm identified 1754 additional patients meeting inclusion criteria. Medical record review (n=190) demonstrated sensitivity of 99%, specificity of 49%, and PPV of 79%. Using the validated algorithm, pDPN prevalence was 113 (Method 1) and 208 (Method 2) per 1000 persons with diabetes. Significant differences were observed in medication prescriptions between patients with and without pDPN. Estimated pDPN prevalence among persons with diabetes was 11%–21% and pDPN patients had greater utilization of selected medications than those without pDPN. Identifying patients with pDPN is a fundamental step for improving disease management and understanding the economic impact of pDPN. (Population Health Management 2008;11:317–328).

Lesser H, Sharma U. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology. 2004;63(11):2104-2110.

Objective: Pregabalin, an alpha2-delta ligand with analgesic, anxiolytic, and anticonvulsant activity, has beenevaluated for treatment of neuropathic pain. The authors assessed the efficacy and tolerability of pregabalin (75, 300, 600 mg/day) vs placebo in patients with diabetic peripheral neuropathy (DPN). Methods: Patients with a 1- to 5-year history of DPN and average weekly pain score of ≥4 on an 11-point numeric pain-rating scale were enrolled in a 5-week, doubleblind, multicenter, placebo-controlled study. Patients (n= 338) were randomized to receive one of three doses of pregabalin or placebo TID. Pregabalin 600 mg/day was titrated over 6 days; lower doses were initiated on day 1. Results: Patients in the 300- and 600-mg/day pregabalin groups showed improvements in endpoint mean pain score (primary efficacy measure) vs placebo (p=0.0001). Improvements were also seen in weekly pain score, sleep interference score, patient global impression of change, clinical global impression of change, SF-McGill Pain Questionnaire, and multiple domains of the SF-36 Health Survey. Improvements in pain and sleep were seen as early as week 1 and were sustained throughout the 5 weeks. Responders (patients with ≥50% reduction in pain compared to baseline) were 46% (300 mg/day), 48% (600 mg/day), and 18% (placebo). Pregabalin was well tolerated with a low discontinuation rate. The most common adverse events were dizziness and somnolence. Conclusions: In patients with diabetic peripheral neuropathy, pregabalin demonstrated early and sustained improvement in pain and a beneficial effect on sleep, which were confirmed by positive patient global impression. Pregabalin was well tolerated at all doses.

Moulin DE, Clark AJ, Gilron I, et al. Pharmacological management of chronic neuropathic pain – consensus statement and guidelines from the Canadian Pain Society. J Can Pain Soc. 2007;12(1):13-21.

Neuropathic pain (NeP), generated by disorders of the peripheral and central nervous system, can be particularly severe and disabling. Prevalence estimates indicate that 2% to 3% of the population in the developed world suffer from NeP, which suggests that up to one million Canadians have this disabling condition. Evidence-based guidelines for the pharmacological management of NeP are therefore urgently needed. Randomized, controlled trials, systematic reviews and existing guidelines focusing on the pharmacological management of NeP were evaluated at a consensus meeting. Medications are recommended in the guidelines if their analgesic efficacy was supported by at least one methodologically sound, randomized, controlled trial showing significant benefit relative to placebo or another relevant control group. Recommendations for treatment are based on degree of evidence of analgesic efficacy, safety, ease of use and cost-effectiveness. Analgesic agents recommended for first-line treatments are certain antidepressants (tricyclics) and anticonvulsants (gabapentin and pregabalin). Second-line treatments recommended are serotonin noradrenaline reuptake inhibitors and topical lidocaine. Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain. Recommended fourth-line treatments include cannabinoids, methadone and anticonvulsants with lesser evidence of efficacy, such as lamotrigine, topiramate and valproic acid. Treatment must be individualized for each patient based on efficacy, side-effect profile and drug accessibility, including cost. Further studies are required to examine head-to-head comparisons among analgesics, combinations of analgesics, long-term outcomes, and treatment of pediatric and central NeP.

Rosenstock J, Tuchman M. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain. 2004;110:628-638.

A randomized, double-blind, placebo-controlled, parallel-group, multicenter, 8-week trial (with subsequent open-label phase) evaluated the effectiveness of pregabalin in alleviating pain associated with diabetic peripheral neuropathy (DPN). For enrollment, patients must have had at baseline: 1- to 5-year history of DPN pain; pain score ≥40 mm (Short-Form McGill Pain Questionnaire [SF-MPQ] visual analogue scale); average daily pain score of ≥4 (11-point numerical pain rating scale [0 = no pain, 10 = worst possible pain]). One hundred forty-six (146) patients were randomized to receive placebo (n=70) or pregabalin 300 mg/day (n=76): Primary efficacy measure was endpoint mean pain score from daily patient diaries (11-point numerical pain rating scale). Secondary measures included SF-MPQ scores; sleep interference scores; Patient and Clinical Global Impression of Change (PGIC and CGIC); Short Form-36 (SF-36) Health Survey scores; and Profile of Mood States (POMS) scores. Safety assessment included incidence and intensity of adverse events, physical and neurological examinations, and laboratory evaluations. Pregabalin produced significant improvements versus placebo for mean pain scores (P<0.0001); mean sleep interference scores (P<0.0001); total SF-MPQ score (P<0.01); SF-36 Bodily Pain subscale (P<0.03); PGIC (P=0.001); and Total Mood Disturbance and Tension–Anxiety components of POMS (P<0.03): Pain relief and improved sleep began during week 1 and remained significant throughout the study (P<0.01). Pregabalin was well tolerated despite a greater incidence of dizziness and somnolence than placebo. Most adverse events were mild to moderate and did not result in withdrawal. Pregabalin was safe and effective in decreasing pain associated with DPN, and also improved mood, sleep disturbance, and quality of life.

Satoh J, Yagihashi S. Efficacy and safety evaluation of pregabalin treatment over 52 weeks in patients with diabetic neuropathic pain extended after a double-blind placebo-controlled trial. J Diabetes Invest. 2011;6:457-463.

Aims/Introduction: Diabetic peripheral neuropathy (DPN) is often associated with pain, and thus a new treatment option is anticipated. We recently showed the efficacy of pregabalin in a randomized, double-blind, placebo-controlled, 14-week trial in Japanese patients with painful DPN. In the present study, we evaluated the long-term efficacy and safety of pregabalin for the relief of painful DPN. Materials and Methods: A total of 123 patients were enrolled in a 52-week open-label study, from among those who participated in the preceding double-blind trial. The subjects received pregabalin 150–600 mg/day. Pain intensity was measured using the short-form McGill pain questionnaire (SF-MPQ: total score, visual analog scale and present pain intensity).
Results: The efficacy parameter SF-MPQ showed a decrease over the treatment period. The changes in visual analog scale and present pain intensity at the final evaluation were -25.4 mm and -0.7, respectively, suggesting an analgesic effect of pregabalin. Commonly reported adverse events were somnolence, weight gain, dizziness and peripheral edema, but most of them were mild to moderate in intensity. No new concerns about safety as a result of long-term administration of pregabalin were identified.
Conclusions: The findings from this trial suggest that long-term treatment with pregabalin is beneficial for pain relief in patients with DPN.

Sharma U, Griesing T. Time to onset of neuropathic pain reduction: a retrospective analysis of data from nine controlled trials of pregabalin for painful diabetic peripheral neuropathy and postherpetic neuralgia. Am J Ther. 2010 Nov-Dec;17(6):577-585.

These retrospective analyses of daily lnean pain scores from nine placebo-conrrolled trials of pregabalin at 150, 300, or 600 mg/day (pregabalin, n=1205; placebo, n=772) examined time to significant reduction of pain during the first 2 weeks of treatment of painful diabetic peripheral neuropathy and postherpetic neuralgia. Time to onset of reduction in pain·····defined as the first day for which patients treated with pregabalin had significant reductions (P < 0.05) in mean pain score compared with the placebo group for that day and the subsequent day-····was calculated for all treatment groups demonstrating statistically significant reduction in pain at trial end point. The time to a 1-point or greater improvement in mean pain score was measured for each patient who was a responder at end point (30% or greater improvenlent in mean pain score). In seven of the nine trials (representing 11 of 14 pregabalin arrns), significant reduction in pain was achieved at end point. The time to onset for reduction in pain was treatment Day 1 or 2 in nine of these successful treatment arms. Individual responder analysis confirmed that responders in the pregabalin groups reported a 1-point or greater pain reduction earlier than responders in placebo groups (P < 0.0001). However this analysis is not a direct estimate of the likelihood that an individual patient would experience noticeable pain relief by the end of the second day. Overall, for patients who will respond to pregabalin, statistically significant and sustained reduction of pain associated with diabetic peripheral neuropathy and posttherapeutic neuralgia occurs early, usually by the end of 2 days of pregabalin treatment.

Toelle TR, Varvara R. Pregabalin in neuropathic pain related to DPN, cancer and back pain: analysis of a 6-week observational study. Open Pain J. 2012;5:1-11.

Abstract: Background: Neuropathic pain is associated with many conditions. Pregabalin has demonstrated efficacy in randomized, controlled trials (RCTs) in peripheral and central neuropathic pain. Observational studies complement findings from RCTs by enabling an agent to be studied in real-world patients and circumstances.
Methods: Patients with neuropathic pain were treated with pregabalin 150-600 mg/day in this 6 week observational study. Analyses of subsets of patients with painful diabetic peripheral neuropathy (DPN; n=4633), back pain with a neuropathic component (n=3800), and cancer-related neuropathic pain (n=345) were undertaken.
Results: The mean pregabalin doses ranged from 219 to 250 mg/day across the disease groups. Mean baseline pain scores (6.4 to 7.0 across the three disease states) indicated patients had moderate to severe pain. Pregabalin was associated with a rapid and significant reduction in pain from week 1 to endpoint in all groups. Over 80% in each of the groups had a ≥30% pain reduction in their pain at 6 weeks, and over two-thirds had a ≥50% reduction. Pain-related sleep interference decreased rapidly and significantly. Most patients (87%) were either very satisfied or satisfied with the action of pregabalin. General well-being improved significantly over the 6 weeks. Pregabalin was generally well tolerated; the most common adverse event overall was dizziness (1.4%). Few patients (≤6.1%/group) discontinued due to adverse events.
Conclusions: In neuropathic pain patients in day-to-day practice, pregabalin was associated with notable reductions in pain and sleep interference. The benefits of pregabalin were reflected in the high level of patient satisfaction and improvement in general well-being.

Xochilcal-Morales M, Castro EM, Guajardo-Rosas J, et al. A prospective, open-label, multicentre study of pregabalin in the treatment of neuropathic pain in Latin America. Int J Clin Pract. 2010;64(9):1301-1309.

Aims: The objective of this study was to evaluate the safety and efficacy of pregabalin at flexible doses of 150–600 mg ⁄ day in Latin American patients with neuropathic pain. Methods: A prospective, multicentre, open-label, non-comparative study included patients age ≥18 years diagnosed with neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, chemotherapy-induced peripheral neuropathic pain (PNP), or human immunodeficiency virus-related PNP. Eligible patients (N = 121) had a score of ≥40 mm on the visual analogue scale and a daily pain rating scale (DPRS) score of ≥4 throughout screening. Patients received flexible-dose pregabalin (150–600 mg ⁄ day) for 12 weeks, which included a 4-week dose-adjustment phase. The primary efficacy measure was change from baseline to end of treatment ⁄ last observation carried forward (EOT ⁄ LOCF) in weekly mean pain score on the DPRS. Secondary efficacy measures included pain, anxiety, sleep interference, treatment satisfaction and Patient and Clinician Global Impression of Change. Results: Pregabalin significantly reduced the weekly mean pain score on DPRS from baseline to EOT ⁄ LOCF [–3.8 (95% CI: )4.2 to )3.3); p < 0.0001]. Reductions from baseline to EOT ⁄ LOCF were observed for all secondary efficacy outcomes (p < 0.0001). Pain and sleep interference were significantly improved compared with baseline across all weeks of the study, as early as 1 week after initiation of pregabalin (p < 0.0001). The most common adverse events (AEs) were somnolence, dizziness, weight gain and peripheral oedema. Nine (7.4%) patients discontinued the study because of AEs and 25 (20.7%) temporarily stopped or reduced their pregabalin dose because of AEs. Conclusions: Flexible-dose pregabalin (150–600 mg ⁄ day) significantly reduced pain and anxiety and improved sleep and was generally well tolerated in Latin American patients with neuropathic pain..




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