Post-traumatic Peripheral Neuropathic Pain Research Articles

Pregabalin in Patients with Post-Traumatic Peripheral Neuropathic Pain: A Meta-Analysis of Randomized Controlled Trials.

To investigate the safety and efficacy of pregabalin versus placebo in post-traumatic peripheral neuropathic pain (PTNP). PubMed, Cochrane Library, Web of Science, and Google Scholar were searched for relevant evidence up to January 2022. The Cochran tool was used to assess the quality of randomized clinical trials (RCTs). Data analysis was performed using Comprehensive Meta-Analysis software. Three RCTs involving 821 patients were included in the meta-analysis. A significant difference was observed between pregabalin and placebo in terms of the pain score (the standardized mean difference [SMD] = -0.481, 95% CI: -0.75 to 0.20, P=0.04) and sleep interference (MD= -0.481, 95% CI: -0.75 to 0.20, P=0.00). There was also a significant difference between pregabalin and placebo regarding somnolence (risk ratio [RR] = 2.78; 95% CI: 1.64 to 4.71, P=0.00), dizziness (RR=4.13; 95% CI: 2.71 to 6.28, P=0.00), and disturbance in attention (RR: 2.97; 95% CI: 1.02 to 8.65, P=0.04). However, no significant difference was observed between pregabalin and placebo in terms of headache (RR=1.20; 95% CI: 0.70 to 2.06, P=0.50), fatigue (RR=1.42; 95% CI: 0.82 to 2.47, P=0.20), nausea (RR=1.52; 95% CI: 0.88 to 2.62, P=0.13), constipation (RR=1.84; 95% CI: 0.78 to 4.29, P=0.15), and discontinuation (RR=1.52; 95% CI: 0.45 to 5.06, P=0.49). Compared with placebo, pregabalin showed better efficacy in reducing PTNP and improving sleep interference. However, it was associated with higher adverse events. Further RCTs is needed to confirm these findings.

Применение прегабалина для лечения периферической и центральной нейропатической боли у взрослых (научный обзор)

Предпосылки. Прегабалин является габапентиноидом нового поколения с улучшенными фармакологическими свойствами. Нейропатическая боль — актуальная проблема современной медицины, в отдельных случаях трудно поддающаяся лечению. В связи с этим цель настоящего обзора сводится к оценке эффективности прегабалина при лечении периферической и центральной нейропатической боли в клинических исследованиях высокого уровня. Материалы и методы. В настоящий обзор были включены рандомизированные контролируемые исследования (РКИ) с двойным слепым дизайном и их метаанализы. Результаты. В выполненных исследованиях была подтверждена обезболивающая активность прегабалина у пациентов с нейропатической болью: при болевой диабетической нейропатии (9 РКИ), постгерпетической невралгии (4 РКИ), центральной нейропатической боли вследствие повреждения спинного мозга (3 РКИ), посттравматической периферической нейропатической боли, включая хроническую послеоперационную боль (2 РКИ), нейропатической боли при раке (2 РКИ). Требует дальнейшего уточнения эффективность препарата при центральной нейропатической боли вследствие повреждения головного мозга и хронической боли в нижней части спины (в обоих случаях по 2 РКИ с результатами «есть эффект/нет эффекта»). Дополнительно у пациентов с нейропатической болью прегабалин уменьшал нарушение сна, улучшал общее состояние и качество жизни. Кроме того, уменьшалась выраженность аллодинии при постгерпетической невралгии, тревоги при центральной нейропатической боли, снижалась потребность в морфине при нейропатической боли вследствие рака и выраженность обусловленных им запоров, усиливались эффекты нестероидных противовоспалительных средств при хронической боли в нижней части спины. Эффективность прегабалина у пожилых пациентов была сравнима с таковой у более молодых пациентов. Прегабалин назначают в дозе 75 мг/день в 1 прием или в дозе 150 мг/день в 2 приема. Затем дозу постепенно увеличивают до 300–600 мг/день таким образом, чтобы соотношение эффективность/безопасность было оптимальным. Обезболивающий эффект начинает появляться в первую неделю терапии, в зависимости от выбранного дозового режима и тяжести патологии. Побочные эффекты при лечении прегабалином носят легкий и умеренный характер, часто самостоятельно исчезают по ходу лечения. Наиболее частыми побочными эффектами были головокружение (прегабалин — 26,3 %, плацебо — 9 %), сонливость (16,8 и 7 % соответственно) и периферические отеки (8,9 и 0,4 % соответственно). Несмотря на то что частота побочных эффектов для прегабалина превышала таковую для плацебо и в ряде случаев приводила к прекращению приема препарата, авторы исследований сообщают о хорошей переносимости прегабалина. Выводы. Результаты исследований высокого уровня подтверждают эффективность прегабалина в лечении пациентов с периферической и центральной нейропатической болью. Для препарата была характерна хорошая переносимость.

The effect of a topical combination of clonidine and pentoxifylline on post-traumatic neuropathic pain patients: study protocol for a randomized, double-blind placebo-controlled trial

BackgroundFirst-line pharmacotherapy for neuropathic pain entails the use of systemic antidepressants and anticonvulsants. These drugs are not optimally effective and poorly tolerated, especially for older patients with comorbid conditions. Given the high number of such patients, there is a need for a greater repertoire of safer and more effective analgesics. Clonidine and pentoxifylline are vasodilator agents that work synergistically to enhance tissue perfusion and oxygenation. The topical administration of these drugs, individually and in combination, has shown anti-nociceptive properties in rodent models of neuropathic pain. A topically-administered combination of clonidine and pentoxifylline also effectively reduced the intensity of both spontaneous and evoked pain in healthy volunteers with experimentally-induced neuropathic pain. The next step in advancing this formulation to clinical use is the undertaking of a phase II clinical study to assess its efficacy and safety in neuropathic pain patients.Methods/designThis is a study protocol for a randomized, double-blind, placebo-controlled, phase II clinical trial with a cross-over design. It is a single-centered, 5-week study that will enroll a total of 32 patients with post-traumatic peripheral neuropathic pain. Patients will be treated topically with either a combination of clonidine and pentoxifylline or placebo for a period of 2 weeks each, in randomly assigned order across patients, with an intervening washout period of 1 week. The primary outcome measures of the study are the intensity of spontaneous pain recorded daily in a pain diary with a visual analog scale, and the degree of mechanical allodynia evoked by a brush stimulus. The secondary outcome measures of the study include scores of pain relief and change in the area of punctate hyperalgesia. This trial has been prospectively registered with ClinicalTrials.gov on November 1, 2017. ClinicalTrials.gov Identifier: NCT03342950.DiscussionThe analgesic use of topical treatment with clonidine and pentoxifylline in combination has not been investigated in post-traumatic neuropathic pain. This study could generate the first evidence for the efficacy and safety of the formulation in alleviating pain in patients with neuropathic pain. Furthermore, this trial will provide objective grounds for the investigation of other agents that enhance tissue oxygenation in the topical treatment of peripheral neuropathic pain.Trial registrationThis trial has been registered with ClinicalTrials.gov owned by NIH’s US National Library of Medicine.ClinicalTrials.gov NCT03342950. Registered on November 1, 2017 (trial was prospectively registered).Protocol version and identifiersThis is protocol version 5, dated June 2018. McGill University Health Center (MUHC) Reaseach Ethics Board (REB) identification number: TTNP 2018-3906.

Efficacy of pregabalin in post-traumatic peripheral neuropathic pain: a randomized, double-blind, placebo-controlled phase 3 trial

The growing need for symptomatic treatment of post-traumatic neuropathic pain (PTNP) continues to be unmet. Studies evaluating the efficacy of pregabalin for reducing neuropathic pain following trauma and surgery yielded positive results over ≤ 8-week treatment. To assess the efficacy and tolerability of pregabalin over 3 months in patients with PTNP, a randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients with PTNP at 101 centers in 11 countries—the longest, largest such trial. Adults diagnosed with PTNP were randomly assigned (1:1) to 15 weeks of pregabalin (flexibly dosed 150–600 mg/day) or matching placebo. Primary efficacy analysis was by mixed-model repeated measures comparing change from baseline to week 15 in weekly mean pain scores between active and placebo groups. Evaluable patients included 274 in the pregabalin group and 265 in the placebo group. Trauma was surgical in 49.6% of patients, non-surgical in the remainder. The primary efficacy analysis showed no statistically significant difference between pregabalin and placebo groups in the change from baseline to week 15 [mean difference, − 0.22 points (95% confidence interval, 0.54–0.10); p = 0.1823]. However, comparisons for key secondary outcome measures yielded p values < 0.05 favoring pregabalin. Consistent with the known safety profile of pregabalin, the most common adverse events were dizziness and somnolence (14.6 and 9.9% of patients, respectively) with pregabalin (vs 4.2 and 3.4% with placebo). These findings demonstrate the feasibility of conducting a large, phase 3 registration trial in the heterogeneous PTNP study population.ClinicalTrials.gov NCT01701362.

Effect of low frequency transcutaneous magnetic stimulation on sensory and motor transmission.

Peripheral nerve injury diminishes fast conducting large myelinated afferent fibers transmission but enhances smaller pain transmitting fibers firing. This aberrant afferent neuronal behavior contributes to development of chronic post-traumatic peripheral neuropathic pain (PTP-NP). Non-invasive dynamic magnetic flux stimulation has been implicated in treating PTP-NP, a condition currently not adequately addressed by other therapies including transcutaneous electrical nerve stimulation (TENS). The current study assessed the effect of low frequency transcutaneous magnetic stimulation (LFTMS) on peripheral sensory thresholds, nerve conduction properties, and TENS induced fast afferent slowing effect as measured by motor and sensory conduction studies in the ulnar nerve. Results indicated sham LFTMS with TENS (Sham + TENS) significantly (P = 0.02 and 0.007, respectively) reduces sensory conduction velocity (CV) and increases sensory onset latency (OL), and motor peak latency (PL) whereas, real LFTMS with TENS (Real + TENS) reverses effects of TENS on sensory CV and OL, and significantly (P = 0.036) increases the sensory PL. LFTMS alone significantly (P < 0.05) elevates sensory PL and onset-to-peak latency. LFTMS appears to reverse TENS slowing effect on fast conducting fibers and casts a selective peripheral modulatory effect on slow conducting pain afferent fibers.

An investigation of factors contributing to higher levels of placebo response in clinical trials in neuropathic pain: a systematic review and meta-analysis.

In new drug development in neuropathic pain (NeP), randomized, double-blind, placebo-controlled trials (PCTs) with long treatment durations in a parallel-group design are recommended for confirmatory trials. This study was conducted to identify potential factors contributing to elevated placebo response in parallel-group PCTs for oral drugs with at least a 4-week treatment duration. A literature search was conducted through MEDLINE and EMBASE, and was supplemented with data from ClinicalTrials.gov and US/Japanese regulatory approval review information. Using the 30 or 50% responder rate (RR), logistic regression analyses were performed to investigate the relationship between the degree of placebo response and several potential influencing factors. The search identified 71 trials (n=6,126). The estimated 50% RRs (95% confidence intervals) in the placebo group were as follows: peripheral neuropathic pain (P-NeP) 23% (21,26%); central neuropathic pain (C-NeP) 14% (10,19%); postherpetic neuralgia (PHN) 19% (15,24%); painful diabetic peripheral neuropathy (pDPN) 26% (23,29%); posttraumatic peripheral neuropathic pain (PT) 15% (10,20%). From the logistic regression analyses, it was found that there was a significant association between placebo response (50% RR and 30% RR) and NeP classification (P<0.05). Associations between placebo response and several factors were seen in univariate logistic regression analyses of 50% RR. Multivariate analyses showed that age and baseline pain intensity in PHN, and treatment duration, trial design (fixed-dose/flexible-dose) and baseline pain intensity in pDPN, were associated with placebo response, suggesting that a reduced placebo response correlated with increasing age and baseline pain intensity, and a higher placebo response correlated with a longer treatment period and flexible dosing regimen. A similar pattern observed in the analysis of 50% RR was suggested in the analysis of 30% RR, with the exception of treatment duration. In addition, investigations of trials with at least a 12-week treatment duration in pDPN found associations with the number of patients per site, patient enrolment rate, proportion of male patients and baseline pain intensity, suggesting that a higher placebo response correlated with an increasing number of patients per site, and a reduced placebo response correlated with increasing patient enrolment rate and proportion of male patients and baseline pain intensity. The results of this study suggest that NeP condition, trial design, and demographic and baseline characteristics may contribute to elevated placebo response in clinical trials in patients with NeP. In addition, the magnitude of placebo response and the effect of treatment duration are greater in pDPN than in PHN. These facts should be considered when planning and conducting confirmatory trials in NeP.

Transcutaneous Magnetic Stimulation (tMS) in Alleviating Post-Traumatic Peripheral Neuropathic Pain States: A Case Series

Peripheral nerve injury can result in the formation of neuroma/nerve entrapment, a persistent peripheral neuropathic pain state which is often refractory to invasive interventions or medications. Therefore, there is a need in the field of pain management to develop innovative noninvasive therapy in treating post-traumatic peripheral neuropathic pain states. A new intervention, transcutaneous magnetic stimulation (tMS), is derived from the use of transcranial magnetic stimulation in which a rapid discharge of electric current is converted into dynamic magnetic flux for modulating neuronal functions. Low-frequency (0.5 Hz) tMS was developed over the site of neuroma/nerve entrapment in five patients who have failed both steroid injection and conventional pain medications. Four hundred pulses of stimulation were delivered per treatment session. Each patient received three to four sessions of treatment over a period of 2 months. Pre- and post-intervention spontaneous pain levels were assessed with a numerical rating pain scale (NRS). Five patients with post-traumatic neuroma/nerve entrapment pain received the treatment. Average pre and postscores (±standard deviation) on the NRS were 5.00 (±1.41) and 0.80 (±1.10), respectively, with an average pain reduction of 84 (±21.91)% in the NRS after three to four treatments within 2 months. This analgesic effect appeared to be sustainable with repeated treatment delivered at a 6- to 8-week duration. Pretreatment tactile allodynia found in three patients resolved after the initial 2-month treatment sessions. tMS offers a noninvasive treatment option for neuroma-related neuropathic pain conditions. Randomized controlled studies are required in further validating the efficacy of this treatment modality. Additional studies are also needed to assess the underlying electrophysiological mechanisms of the observed analgesic benefit.

Efficient assessment of efficacy in post-traumatic peripheral neuropathic pain patients: pregabalin in a randomized, placebo-controlled, crossover study

Background:Detecting the efficacy of novel analgesic agents in neuropathic pain is challenging. There is a critical need for study designs with the desirable characteristics of assay sensitivity, low placebo response, reliable pain recordings, low cost, short duration of exposure to test drug and placebo, and relevant and recruitable population.Methods:We designed a proof-of-concept, double-blind, randomized, placebo-controlled, crossover study in patients with post-traumatic peripheral neuropathic pain (PTNP) to evaluate whether such a study design had the potential to detect efficacious agents. Pregabalin, known to be efficacious in neuropathic pain, was used as the active analgesic. We also assessed physical activity throughout the study.Results:Twenty-five adults (20–70 years of age) with PTNP for ≥3 months entered a screening week and were then randomized to one of the two following treatment sequences: (1) pregabalin followed by placebo or (2) placebo followed by pregabalin. These 2-week treatment periods were separated by a 2-week washout period. Patients on pregabalin treatment received escalating doses to a final dosage of 300 mg/day (days 5–15). In an attempt to minimize placebo response, patients received placebo treatment during the screening week and the 2-week washout period. Average daily pain scores (primary endpoint) were significantly reduced for pregabalin versus placebo, with a mean treatment difference of −0.81 (95% confidence interval: −1.45 to −0.17; P = 0.015).Conclusion:The efficacy of pregabalin was similar to that identified in a large, parallel group trial in PTNP. Therefore, this efficient crossover study design has potential utility for future proof-of-concept studies in neuropathic pain.

Relationships between changes in pain severity and other patient-reported outcomes: an analysis in patients with posttraumatic peripheral neuropathic pain

BackgroundThe objective of this study is to use the pain numeric rating scale (NRS) to evaluate associations between change in pain severity and changes in sleep, function, and mood assessed via patient-reported outcomes (PROs) in patients with posttraumatic pain.MethodsThis is a secondary analysis of a clinical trial evaluating pregabalin in patients with posttraumatic peripheral neuropathic pain (N = 254). Regression models were used to determine associations between changes in pain (0-10 NRS) as the predictor and scores on the following PRO measures as the outcome: Pain Interference Index; Hospital Anxiety and Depression Scale anxiety and depression subscales; Medical Outcomes Study-Sleep Scale 9-item Sleep Problems Index and Sleep Disturbance subscale; and Daily Sleep Interference Scale (0-10 NRS).ResultsChange in pain severity showed clear, direct relationships with changes in function, anxiety, depression, and sleep PROs, all of which were statistically significant (P <.001). Results from subgroup analyses (≥30% or ≥50% pain responders, pregabalin or placebo treatment, age ≤ 51 years or > 51 years) tended to be consistent with results from the overall sample.ConclusionsOverall, a direct relationship exists between pain and various aspects of patient's well-being and functioning, which can provide a quantitative assessment of how improvements in pain may be expected to relate to other patient outcomes. (http://ClinicalTrials.gov Identifier number NCT00292188; EudraCT #2005-003048-78).

Pregabalin in the treatment of post‐traumatic peripheral neuropathic pain: a randomized double‐blind trial

Pregabalin is effective in the treatment of peripheral and central neuropathic pain. This study evaluated pregabalin in the treatment of post-traumatic peripheral neuropathic pain (including post-surgical). Patients with a pain score >or=4 (0-10 scale) were randomized and treated with either flexible-dose pregabalin 150-600 mg/day (n = 127) or placebo (n = 127) in an 8-week double-blind treatment period preceded by a 2-week placebo run-in. Pregabalin was associated with a significantly greater improvement in the mean end-point pain score vs. placebo; mean treatment difference was -0.62 (95% CI -1.09 to -0.15) (P = 0.01). The average pregabalin dose at end-point was approximately 326 mg/day. Pregabalin was also associated with significant improvements from baseline in pain-related sleep interference, and the Medical Outcomes Study sleep scale sleep problems index and sleep disturbance subscale (all P < 0.001). In the all-patient group (ITT), pregabalin was associated with a statistically significant improvement in the Hospital Anxiety and Depression Scale anxiety subscale (P < 0.05). In total, 29% of patients had moderate/severe baseline anxiety; treatment with pregabalin in this subset did not significantly improve anxiety. More patients reported global improvement at end-point with pregabalin than with placebo (68% vs. 43%; overall P < 0.01). Adverse events led to discontinuation of 20% of patients from pregabalin and 7% from placebo. Mild or moderate dizziness and somnolence were the most common adverse events in the pregabalin group. Flexible-dose pregabalin 150-600 mg/day was effective in relieving neuropathic pain, improving disturbed sleep, improving overall patient status, and was generally well tolerated in patients with post-traumatic peripheral neuropathic pain.

Study—and Experience—Indicate Pregabalin Effective in Post-Traumatic Peripheral Neuropathic Pain

Study—and Experience—Indicate Pregabalin Effective in Post-Traumatic Peripheral Neuropathic Pain

Pregabalin is effective in the treatment of posttraumatic peripheral neuropathic pain

Pregabalin is effective in the treatment of posttraumatic peripheral neuropathic pain