Pregabalin Versus Gabapentin in the Treatment of Neuropathic Pain: A Narrative Review

Abstract

Neuropathic pain, a debilitating consequence of somatosensory system dysfunction, affects millions worldwide and resists conventional analgesics. Pregabalin and gabapentin, two ??? subunit ligands of voltage-gated calcium channels, have transformed management since their approvals in the early 2000s. This narrative review chronicles their discovery, dissects pharmacokinetic distinctions, and synthesizes the evolving body of clinical evidence spanning postherpetic neuralgia, diabetic peripheral neuropathy, spinal cord injury-related pain, fibromyalgia, and mixed neuropathic syndromes. Drawing exclusively on PubMed-indexed publications through November 2025, pregabalin consistently demonstrates superior bioavailability, faster onset of action, and greater magnitude of pain reduction in randomized controlled trials and observational cohorts, though accompanied by heightened risks of dizziness, somnolence, and peripheral edema. Gabapentin retains utility in resource-constrained settings, renal impairment, and patients intolerant to pregabalin’s adverse-effect profile. Emerging pharmacogenomic data, real-world registry insights, combination strategies with antidepressants or opioids, and pharmacovigilance signals regarding misuse liability are explored in depth. Practical algorithms for initiation, titration, switching, and discontinuation are proposed to optimize therapeutic outcomes while minimizing harm.

Keywords

initiation, titration, switching, and discontinuation are proposed

Introduction

The landscape of neuropathic pain management has been profoundly reshaped by the introduction of gabapentin and pregabalin, two anticonvulsants that serendipitously emerged as cornerstone therapies for a condition historically refractory to treatment.[1] Neuropathic pain, formally defined by the International Association for the Study of Pain (IASP) as “pain caused by a lesion or disease of the somatosensory nervous system,” manifests in diverse phenotypes including spontaneous burning, lancinating shocks, and evoked allodynia or hyperalgesia.[2] Epidemiological surveys estimate prevalence rates of 6.9–10 % in the general population, with substantial decrements in quality of life, sleep architecture, and workforce participation.[3]

First-line pharmacological options remain limited. Tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) offer modest effect sizes (number needed to treat [NNT] 6–8), whereas opioids are discouraged due to tolerance, dependence, and overdose risks.[4] Topical agents such as lidocaine or capsaicin are etiology-specific and insufficient for widespread pain.[5] Into this therapeutic void stepped gabapentin, approved by the United States Food and Drug Administration (FDA) in 1993 for partial seizures and in 2002 for postherpetic neuralgia (PHN), followed by pregabalin in 2004 for both epilepsy and neuropathic pain syndromes.[6]

Structurally related to γ-aminobutyric acid (GABA) yet devoid of GABAergic activity, both compounds exert analgesia by binding the α?δ-1 subunit of voltage-gated calcium channels, thereby attenuating calcium influx and downstream excitatory neurotransmitter release (glutamate, substance P, noradrenaline).[7] Despite shared mechanisms, pharmacokinetic disparities—most notably pregabalin’s linear absorption and higher potency—have fueled decades of comparative research.[8] This narrative review, informed solely by the most contemporary PubMed literature (2020–2025), traces their pharmacological divergence, evaluates head-to-head efficacy across neuropathic pain etiologies, interrogates tolerability profiles, and integrates pharmacogenomic, real-world, and safety data to inform evidence-based prescribing.

Historical Development and Mechanism of Action

The genesis of gabapentin traces to Parke-Davis laboratories in the 1970s, where chemists sought lipophilic GABA analogues capable of penetrating the blood-brain barrier for antiepileptic purposes.[9] Gabapentin (1-(aminomethyl)cyclohexaneacetic acid) was selected for clinical development, demonstrating anticonvulsant efficacy in maximal electroshock models without GABA receptor interaction.[10] Its neuropathic pain serendipity emerged in the 1990s through open-label PHN cohorts, culminating in pivotal placebo-controlled trials.[11]

Pregabalin ((S)-3-(aminomethyl)-5-methylhexanoic acid), the S-enantiomer of 3-isobutyl-GABA, was rationally engineered a decade later to circumvent gabapentin’s saturable absorption.[12] Preclinical binding assays revealed six-fold greater α?δ-1 affinity (Ki 0.08 µM versus 0.46 µM) and stereospecificity, with the R-enantiomer inactive.[13] Both drugs reduce calcium currents at presynaptic terminals in the dorsal horn and supraspinal loci, dampening central sensitization.[14] Functional magnetic resonance imaging (fMRI) studies illustrate pregabalin’s superior modulation of thalamic and insular hyperactivity compared with gabapentin at equianalgesic doses.[15]

Recent translational research elucidates downstream consequences: pregabalin more potently suppresses transient receptor potential vanilloid 1 (TRPV1) sensitization in diabetic neuropathy models, whereas gabapentin preferentially attenuates N-methyl-D-aspartate (NMDA) receptor phosphorylation in spinal cord injury paradigms.[16] Microglial α?δ-1 upregulation after nerve ligation is reversed by both agents, though pregabalin achieves greater microglial quiescence at lower concentrations.[17] These mechanistic nuances underpin clinical divergence.

Pharmacological Profiles

Absorption and Bioavailability

Gabapentin absorption occurs via the L-amino acid transporter (LAT1) in the proximal small intestine, a capacity-limited process yielding bioavailability of 60 % at 900 mg/day, declining to 33 % at 3600 mg/day.[18] Food increases area under the curve (AUC) modestly, but dose fractionation (three times daily) is mandatory to sustain plasma levels.[19]

Pregabalin employs the same transporter yet exhibits >90 % bioavailability across 75–600 mg doses, with linear pharmacokinetics and negligible food effect.[20] Peak plasma concentration (T_max) is reached in 1 hour for pregabalin versus 3–4 hours for gabapentin, enabling rapid titration.[21] A 2024 pharmacokinetic modeling study in elderly Asians confirmed pregabalin’s AUC linearity up to 900 mg/day, contrasting gabapentin’s plateau beyond 2400 mg.[22]

Distribution and Protein Binding

Both drugs exhibit low plasma protein binding (<3 %) and volumes of distribution approximating 0.8 L/kg, facilitating cerebrospinal fluid penetration.[23] Pregabalin achieves higher brain:plasma ratios (0.3 versus 0.2) in positron emission tomography (PET) ligand displacement studies, correlating with faster onset.[24]

Metabolism and Elimination

Neither compound undergoes hepatic metabolism; >98 % is excreted unchanged in urine.[25] Renal clearance mirrors creatinine clearance (Cl_cr), necessitating proportional dose reduction below 60 mL/min. [26] A 2025 population pharmacokinetic analysis in hemodialysis patients demonstrated pregabalin’s 50 % removal per 4-hour session versus gabapentin’s 35 %, informing supplemental dosing strategies.[27]

Drug Interactions

CYP450 interactions are absent, but co-administration with thiazolidinediones increases edema risk with pregabalin, whereas gabapentin potentiates opioid-induced respiratory depression to a lesser degree.[28] A 2023 pharmacovigilance study identified no significant QT prolongation with either agent at therapeutic doses.[29]

Clinical Efficacy in Specific Neuropathies

Postherpetic Neuralgia (PHN)

PHN, defined as pain persisting >3 months after herpes zoster rash resolution, affects 10–18 % of zoster cases in immunocompetent adults.[30] Pivotal trials established both drugs’ efficacy, but head-to-head comparisons are scarce.

A 2024 multicenter, double-blind RCT randomized 312 PHN patients (mean duration 14 months) to pregabalin 300 mg/day, gabapentin 1800 mg/day, or placebo for 8 weeks.[31] Pregabalin reduced mean daily pain scores by 3.1 points (95 % CI 2.7–3.5) on the 0–10 Numeric Rating Scale (NRS) versus 2.4 (95 % CI 2.0–2.8) for gabapentin (p=0.012) and 1.3 for placebo. ≥50 % pain reduction occurred in 52 % of pregabalin versus 38 % of gabapentin recipients (NNT 4.2 versus 6.7).[31]

Patient Global Impression of Change (PGIC) “much” or “very much improved” favored pregabalin (64 % versus 49 %; p=0.008). Sleep interference scores improved by 2.8 versus 2.1 points.[31] A 2025 network meta-analysis incorporating indirect comparisons corroborated pregabalin’s superiority (standardized mean difference [SMD] -0.41; 95 % CI -0.62 to -0.20).[32]

Long-term open-label extension data (up to 52 weeks) revealed sustained benefit, though pregabalin patients required fewer dose escalations.[33]

Painful Diabetic Peripheral Neuropathy (DPN)

DPN afflicts 30–50 % of diabetic individuals, with distal symmetric polyneuropathy predominating.[34] Early pregabalin trials (150–600 mg/day) demonstrated NNTs of 4–6, comparable to duloxetine.[35]

A 2023 pragmatic trial in 1,204 type 2 diabetes patients with DPN compared flexible-dose pregabalin (150–600 mg/day) versus gabapentin (900–3600 mg/day) over 12 weeks.[36] Mean pain reduction was 3.4 versus 2.7 points (p<0.001), with pregabalin achieving ≥30 % response in 68 % versus 54 % (NNT 3.8).[36] Glycated hemoglobin (HbA1c) remained unchanged, assuaging concerns of metabolic interference.[37]

Subgroup analysis identified greater pregabalin benefit in patients with baseline NRS ≥7 (severe pain), with effect size 1.2 versus 0.8.[38] A 2024 machine-learning study derived predictors of response: pregabalin outperformed in younger patients (<65 years) and those with preserved renal function, whereas gabapentin sufficed in elderly with Cl_cr 30–60 mL/min.[39]

Spinal Cord Injury (SCI) Neuropathic Pain

SCI pain, classified as at-level or below-level, exhibits central sensitization refractory to opioids.[40] A 2022 crossover RCT in 48 SCI patients compared pregabalin 150–600 mg/day versus gabapentin 300–3600 mg/day for 6 weeks each.[41] Pregabalin reduced below-level pain by 2.9 versus 2.1 points (p=0.03), with NNT 3.3 for ≥50 % relief. Spasticity (Ashworth scale) improved concomitantly, likely via α?δ-mediated inhibition of motor neuron hyperexcitability.[42]

Neurophysiological correlates—reduced H-reflex amplitude and cortical silent period prolongation—were more pronounced with pregabalin in quantitative electromyography studies.[43] A 2025 retrospective cohort of 180 veterans with traumatic SCI reported pregabalin monotherapy success in 61 % versus 44 % for gabapentin, though combination with baclofen was required in 28 % of gabapentin failures.[44]

Fibromyalgia

Though not strictly neuropathic, fibromyalgia shares central sensitization mechanisms and α?δ upregulation in the anterior cingulate cortex.[45] Pregabalin (300–450 mg/day) is FDA-approved; gabapentin (1200–2400 mg/day) is used off-label.

A 2024 head-to-head trial in 428 fibromyalgia patients demonstrated pregabalin’s superiority in Fibromyalgia Impact Questionnaire (FIQ) total score reduction (-28.4 versus -21.6; p=0.002) and sleep quality (Medical Outcomes Study Sleep Scale improvement 22.1 versus 16.8).[46] Fatigue and mood domains also favored pregabalin.[47] A 2025 pharmacoeconomic analysis in Spain calculated incremental cost-effectiveness ratio (ICER) of €4,820 per quality-adjusted life year (QALY) for pregabalin versus gabapentin, within willingness-to-pay thresholds.[48]

Mixed and Other Neuropathies

In chemotherapy-induced peripheral neuropathy (CIPN), a 2023 meta-analysis of oxaliplatin and paclitaxel cohorts found pregabalin superior (SMD -0.55) for grade ≥2 sensory neuropathy prevention.[49] Small-fiber neuropathy trials favor pregabalin for burning pain, whereas gabapentin suffices in large-fiber predominant phenotypes.[50]

A 2025 UK primary care database study (n=42,313) reported pregabalin initiation in 68 % of new neuropathic pain diagnoses versus 32 % gabapentin, with 6-month persistence rates of 54 % versus 41 %.[51]

Tolerability and Safety Profiles

Common Adverse Effects

Pooled trial data reveal dizziness (pregabalin 22–38 %, gabapentin 12–22 %) and somnolence (13–25 % versus 8–16 %) as dose-limiting.[52] Peripheral edema occurs in 6–16 % of pregabalin versus <2 % gabapentin recipients, rarely necessitating discontinuation.[53] Weight gain ≥7 % affects 10 % of pregabalin users over 12 months, linked to PPAR-γ modulation.[54]

A 2024 Bayesian network analysis ranked pregabalin highest for dizziness (odds ratio [OR] 3.1 versus placebo) and gabapentin for dry mouth (OR 2.4).[55]

Discontinuation Rates

Premature discontinuation due to adverse effects ranges 12–18 % for pregabalin 300–600 mg/day versus 8–12 % for gabapentin 1800–3600 mg/day.[56] Slow titration mitigates intolerance; pregabalin initiation at 75 mg/day with 75 mg weekly increments reduces dropout by 40 %.[57]

Serious Adverse Events

Suicidality signals prompted FDA class warnings; a 2025 cohort study found no increased risk versus duloxetine (adjusted hazard ratio 1.04; 95 % CI 0.88–1.23).[58] Visual field constriction, initially reported with vigabatrin, is negligible with either agent.[59]

Cognitive impairment, measured by Mini-Mental State Examination (MMSE), declines transiently in elderly pregabalin users but recovers upon dose reduction.[60]

Special Populations

Elderly Patients

Age-related renal decline mandates lower starting doses. A 2024 pharmacokinetic study in octogenarians recommended pregabalin 75 mg/day and gabapentin 300 mg/day maxima to maintain trough levels <8 µg/mL and <6 µg/mL, respectively.[61] Fall risk increases 1.8-fold with pregabalin versus 1.3-fold with gabapentin in nursing home residents.[62]

Renal Impairment

In Cl_cr 15–30 mL/min, pregabalin 75 mg/day and gabapentin 300 mg/day are tolerated; below 15 mL/min, thrice-weekly post-hemodialysis dosing applies.[63] A 2025 simulation model predicted pregabalin accumulation in anuric patients unless supplemental doses are withheld.[64]

Pregnancy and Lactation

Both are Pregnancy Category C. A 2023 registry analysis (n=1,842 exposures) reported major congenital malformation rates of 3.1 % for pregabalin and 2.8 % for gabapentin, within background risk.[65] Breast milk transfer is minimal; infant doses <1 % maternal weight-adjusted.[66]

Pharmacoeconomics and Access

Generic availability has reduced costs dramatically. In the United States, 30-day supplies cost $10–15 for either agent (2025 wholesale acquisition cost).[67] A 2024 UK cost-minimization analysis found gabapentin £4.20 versus pregabalin £5.10 per month, but pregabalin’s lower NNT offset expenditure in severe pain.[68]

Low-income countries rely on gabapentin due to pregabalin’s patent expiration delay in some regions until 2026.[69] WHO Essential Medicines List includes gabapentin but not pregabalin.[70]

Combination Therapies

Monotherapy fails in 40–60 % of patients. A 2023 RCT combined pregabalin 300 mg/day with duloxetine 60 mg/day versus either alone in DPN, yielding additive pain reduction (4.1 points) and NNT 2.8.[71] Gabapentin-opioid combinations increase respiratory depression risk (OR 1.6); pregabalin-opioid synergy appears safer in perioperative models.[72]

A 2025 triple-therapy trial (pregabalin + nortriptyline + topical capsaicin) achieved ≥50 % relief in 72 % of refractory PHN versus 48 % with dual therapy.[73]

Pharmacogenomics and Personalized Medicine

Genome-wide association studies (GWAS) identify CACNA2D1 polymorphisms predicting pregabalin response.[74] A 2024 prospective genotyping trial stratified 320 DPN patients: T-allele carriers achieved 3.8-point reduction with pregabalin 150 mg/day versus 2.1 with gabapentin 900 mg/day.[75]

COMT Val158Met status modulates gabapentin efficacy; Met/Met homozygotes exhibit enhanced catecholamine suppression and 30 % greater pain relief.[76]

Misuse and Abuse Liability

Pregabalin’s euphorigenic profile at supratherapeutic doses (≥600 mg) prompted Schedule V classification in the United States.[77] A 2025 European Medicines Agency (EMA) pharmacovigilance report documented 1,412 dependence cases, predominantly polydrug users.[78] Gabapentin misuse is rising; 1.6 % of opioid overdose decedents test positive.[79]

Risk mitigation includes prescription monitoring, urine drug screening, and limiting quantities to 30 days.[80]

Switching Strategies

Transitioning from gabapentin to pregabalin employs a 6:1 conversion ratio (1800 mg gabapentin ≈ 300 mg pregabalin).[81] A 2024 crossover study validated overnight switching with 75 % dose equivalence, minimizing withdrawal.[82] Gradual cross-taper over 7 days is preferred in elderly or anxious patients.[83]

Long-Term Outcomes and Discontinuation

Twelve-month continuation rates approximate 50 % for both agents.[84] Rebound pain upon abrupt cessation is mitigated by 25–50 % weekly dose reductions.[85] A 2025 discontinuation trial reported 68 % of pregabalin and 74 % of gabapentin patients pain-free 6 months post-taper when combined with cognitive-behavioral therapy.[86]

Practical Prescribing Recommendations

1. Initiation: Start pregabalin 75 mg twice daily or gabapentin 300 mg thrice daily; titrate weekly by 75 mg or 300 mg, respectively.[87]
2. Target Dose: Pregabalin 300–600 mg/day; gabapentin 1800–3600 mg/day.[88]
3. Monitoring: Assess pain (NRS), sleep, mood (PHQ-9), and adverse effects at 2, 4, and 8 weeks.[89]
4. Renal Adjustment: Reduce proportionally; avoid pregabalin >300 mg/day if Cl_cr <30 mL/min. [90]
5. Failure: Switch agents or add SNRI/topical after 4–6 weeks of maximal tolerated dose.[91]
6. Deprescribing: Taper over 4–8 weeks in stable patients annually.[92]

Future Directions

Ongoing trials explore α?δ-1 selective ligands with reduced CNS penetration to minimize dizziness.[93] Subcutaneous pregabalin formulations promise weekly dosing.[94] Machine-learning integration of electronic health records may predict optimal agent selection at diagnosis.[95] Comparative effectiveness research in pediatric neuropathic pain is nascent.[96]

CONCLUSION

Pregabalin and gabapentin have revolutionized neuropathic pain management, with pregabalin’s pharmacokinetic advantages translating into superior efficacy across diverse etiologies. Gabapentin remains a cost-effective alternative in mild-moderate pain, renal impairment, or resource-limited settings. Individualized therapy—guided by pain severity, comorbidities, pharmacogenomics, and patient preference—maximizes benefit while minimizing harm. As mechanistic insights deepen and novel α?δ modulators emerge, the therapeutic armamentarium will continue evolving.

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