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Abstract
Objective: To evaluate the benefits and risks of Lyrica in treating neuropathic pain.
Design: A rapid review and meta-analysis of phase III randomized, placebo-controlled trials.
Participants: Adults aged 18 and older with neuropathic pain, as defined by the International Association for the Study of Pain.
Interventions: Lyrica or placebo.
Primary and Secondary Outcome Measures: The primary outcomes assessed were pain (measured using validated scales) and adverse events. Secondary outcomes included sleep disturbances, quality of life, Patient Global Impression of Change, Clinician Global Impression Scale, anxiety and depression scores, overall discontinuation rates, and discontinuations due to adverse events.

Results:
A total of 28 trials with 6,087 participants were included. The neuropathic pain conditions studied included diabetic peripheral neuropathy, postherpetic neuralgia, herpes zoster, sciatica (radicular pain), poststroke pain, and spinal cord injury-related pain. Patients who took Lyrica experienced significant pain reduction (numerical rating scale (NRS)) compared to those on placebo (standardized mean difference (SMD) −0.49 (95% CI −0.66 to −0.32, p<0.00001), very low-quality evidence). Lyrica also significantly reduced sleep interference scores (NRS) compared to placebo (SMD −0.38 (95% CI −0.50 to −0.26, p<0.00001), moderate-quality evidence).

However, Lyrica significantly increased the risk of adverse events compared to placebo (RR 1.33 (95% CI 1.23 to 1.44, p<0.00001, low-quality evidence)). Specific adverse effects included increased risks of weight gain, somnolence, dizziness, peripheral edema, fatigue, visual disturbances, ataxia, non-peripheral edema, vertigo, and euphoria. Lyrica was also more likely than placebo to lead to treatment discontinuation due to adverse events (RR 1.91 (95% CI 1.54 to 2.37, p<0.00001), low-quality evidence).

Conclusion: Lyrica provides some relief from neuropathic pain symptoms but is associated with a significantly higher risk of adverse events and treatment discontinuation. The quality of evidence from journal publications remains low.

Introduction
Lyrica is a gabapentinoid approved for the treatment of neurological disorders. It was among the first medications authorized by the U.S. Food and Drug Administration (FDA) in 2004 for the management of painful diabetic neuropathy and postherpetic neuralgia (PHN). Lyrica is believed to provide analgesic effects by binding to the alpha-2-delta subunit of voltage-gated Ca²⁺ channels, thereby inhibiting their activity.

Prescriptions of Lyrica (along with gabapentin) have risen sharply in recent years. In the U.S., the number of prescriptions increased from 39 million in 2012 to 64 million in 2016, with annual costs climbing from approximately $2 billion to $4.4 billion over the same period. In the UK, Lyrica usage surged by 350% between 2008 and 2013. By 2017, general practitioners in England alone issued over 6.2 million prescriptions, costing approximately $440 million.

Lyrica is recommended as a first-line pharmacological treatment for neuropathic pain. However, concerns have emerged about increased mortality rates linked to its use in the UK. This has led some researchers to warn clinicians about potential risks when prescribing the drug. These risks appear particularly concerning for individuals who use heroin or misuse gabapentinoids. In response to rising reports of abuse and associated fatalities, the UK government is planning to classify Lyrica as a Class C controlled substance. Recently, healthcare professionals have called for a re-evaluation of the drug’s effectiveness, given its potential to cause harm.

Rapid Reviews and Study Objective

Rapid reviews utilize expedited methodologies to gather and synthesize existing literature, catering to the needs of key stakeholders such as policymakers, healthcare providers, and patient advocacy groups. The purpose of this rapid review was to assess the available evidence regarding the benefits and risks of Lyrica in treating neuropathic pain in adults, drawing from published randomized clinical trials (RCTs).

Methods bustercreative.com

We performed electronic searches in the following databases: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL). Each database was searched from its inception until January 2018, without language restrictions (see online supplementary appendix 1 for the full search strategy). Additionally, we manually reviewed the reference lists of eligible studies (see online supplementary appendix 2 for the complete protocol).

Our inclusion criteria encompassed phase III, double-blind, placebo-controlled RCTs evaluating the efficacy of Lyrica for neuropathic pain in adults aged 18 and older. The definition of neuropathic pain followed the criteria established by the International Association for the Study of Pain. Eligible trials examined conditions such as diabetic neuropathy, HIV-related neuropathy, lumbar radiculopathy, postherpetic neuralgia (PHN), and chronic postsurgical pain. We included RCTs regardless of sample size or intervention duration. In cases where crossover trials were included, we analyzed data from the first phase of the study.

Phase IV trials were excluded due to their unblinded nature. Additionally, we excluded studies that combined Lyrica with other pain treatments, as such combinations would obscure the specific effects of Lyrica. However, trials that permitted cointerventions as rescue medications were included. We also excluded trials in which participants were randomized based on their initial response to Lyrica during a run-in phase.

Our primary outcomes were pain (assessed using validated measurement scales to enhance result reliability) and adverse events. Secondary outcomes included sleep disturbances, quality of life (QOL), Patient Global Impression of Change (PGIC), Clinician Global Impression (CGI) scale, anxiety and depression levels, overall discontinuation rates, and discontinuation due to adverse events.

Each study’s risk of bias was evaluated using Cochrane criteria. Two independent reviewers (IJO and ETT) screened abstracts and determined study eligibility, resolving any disagreements through discussion. Three reviewers (IJO, ETT, and JL) independently extracted data based on predefined criteria and entered it into customized Excel spreadsheets. The extracted data were cross-verified by two reviewers (ETT and IJO), with any discrepancies resolved through discussion. Data collection included study ID, setting, population characteristics, interventions, outcomes, and results.

We used a random-effects model (Mantel-Haenszel) within RevMan software (version 5.3) to compute standardized mean differences (SMDs) and 95% confidence intervals (CIs) for continuous variables, as well as risk ratios (RRs) with 95% CIs for binary outcomes. To evaluate intervention effects, we compared pre-intervention to post-intervention changes between Lyrica and placebo groups. In studies where standard deviations (SDs) were not reported for change-from-baseline data, we estimated SDs (in five studies) based on values from other included trials. Statistical significance was set at p=0.05.

Heterogeneity was assessed using the I² statistic, with values of 25%, 50%, and 75% interpreted as mild, moderate, and substantial heterogeneity, respectively. We explored heterogeneity through subgroup analysis (distinguishing between central and peripheral neuropathic pain) and sensitivity analysis (based on study quality and duration). A funnel plot was used to assess publication bias.

Results

Our search yielded 1,349 unique citations, of which 62 articles met the preliminary eligibility criteria (see Figure 1). After excluding 34 studies that did not fit our inclusion criteria (see online supplementary appendix 3 for a list of excluded studies and reasons for exclusion), we ultimately included 28 studies, encompassing 6,087 participants (Table 1). The intervention duration ranged from 3 to 20 weeks, with a median of 8 weeks. All included trials were funded by industry sources.

Twenty-three studies investigated the efficacy of Lyrica in treating peripheral neuropathic pain, including diabetic peripheral neuropathy (DPN), PHN, and herpes zoster (Table 1). Five studies assessed Lyrica’s effectiveness in managing central neuropathic pain, including sciatica (radicular pain), poststroke pain, and pain associated with spinal cord injury.

Twenty-five of the studies were conducted across multiple centers. Pain assessment measures included the numerical rating scale (NRS), visual assessment scale (VAS), the Short-Form McGill Pain Questionnaire visual assessment scale (SF-MPQ VAS), and the SF-MPQ personal pain intensity (SF-MPQ PPI) index (see Table 1 for detailed study characteristics).

The overall risk of bias in the included studies ranged from moderate to high (Figures 2 and 3), primarily due to inadequate reporting of blinding procedures, selective outcome reporting, and financial conflicts of interest among study authors (see online supplementary appendix 4 for risk-of-bias assessments).

Pain

Twenty-one studies provided sufficient data on pain using the Numerical Rating Scale (NRS) or its variations, enabling a meta-analysis. The results indicated a significant reduction in pain scores with Lyrica compared to placebo (SMD −0.49, 95% CI −0.66 to −0.32, p<0.00001, I²=88%; Figure 4). A visual inspection of the funnel plot showed that the studies were distributed almost symmetrically around the mean difference for all trials (online supplementary Figure S1). Trim-and-fill analyses confirmed that adding studies with smaller sample sizes did not alter the direction of the effect. The reduction in pain scores was statistically significant for peripheral neuropathic pain (p<0.00001) but not for central neuropathic pain (p=0.08; see online supplementary appendix Table 1). The overall quality of the evidence was rated as very low (Summary of Findings (SoF) Table 2). Sensitivity analyses yielded similar results (online supplementary appendix Table 2).

Four studies using NRS to measure pain did not provide adequate data for meta-analysis; three of these reported significant reductions in pain scores favoring Lyrica over placebo, while one study found no significant difference between groups (see online supplementary appendix Table 3).

Three studies assessed pain using the Visual Analog Scale (VAS), all of which reported significant reductions in pain scores favoring Lyrica over placebo (online supplementary appendix Table 3). Additionally, nine studies utilized the Short-Form McGill Pain Questionnaire Visual Analog Scale (SF-MPQ VAS), all showing a significant reduction in pain scores with Lyrica. Four studies assessed pain using the SF-MPQ Present Pain Intensity (PPI) index, and all reported significant pain reduction in favor of Lyrica.

Adverse Events

As shown in Figure 5, Lyrica was significantly more likely to cause adverse events than placebo (RR 1.33, 95% CI 1.23 to 1.44, p<0.00001, I²=52%). This corresponds to an absolute increase of 145 (95% CI 101 to 194) more adverse events per 1000 treated individuals. The overall quality of the evidence was rated as low (SoF Table 3). Sensitivity analyses confirmed similar findings (online supplementary appendix Table 2).

Participants taking Lyrica had a significantly higher risk of experiencing specific adverse events, including weight gain, drowsiness, dizziness, peripheral edema, fatigue, visual disturbances, ataxia, non-peripheral edema, dry mouth, vertigo, and euphoria (see online supplementary appendix Table 1 and supplementary Figures S2–S12).

Lyrica was also significantly more likely to lead to treatment discontinuation due to adverse events (RR 1.91, 95% CI 1.54 to 2.37, p<0.00001, I²=0%). The quality of evidence for this outcome was rated as low (SoF Table 3; online supplementary appendix Table 1; and online supplementary Figure S13). Sensitivity analyses based on study duration showed a similar trend, but no significant difference was observed in higher-quality studies (online supplementary appendix Table 2).

There was no statistically significant difference in the risk of serious adverse events (RR 0.90, 95% CI 0.66 to 1.24, p=0.50, I²=0%; SoF Table 3; online supplementary appendix Table 1; and online supplementary Figure S14). The quality of evidence for this outcome was rated as moderate. Sensitivity analyses showed a significant effect in favor of Lyrica in three higher-quality studies, but no differences were observed when results were analyzed based on study duration (online supplementary appendix Table 2).

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