Reassessing Gabapentinoids for Chronic Neuropathic Pain after Adolescent Idiopathic Scoliosis Surgery—A Systematic Review

Abstract

Background

Gabapentinoids are well known for neuropathic pain management. Pre-emptive use in certain spinal procedures suggests their potential role in reducing post-surgery chronic neuropathic pain. However, its efficacy in adolescent idiopathic scoliosis (AIS) remains uncertain. This review aimed to evaluate the effectiveness of gabapentinoids in reducing neuropathic chronic postsurgical pain (CPSP) at ≥3 months as the primary outcome and on cumulative opioid consumption within the first 72 hours post-surgery as the secondary outcome.

Methods

Major electronic databases, including PubMed, MEDLINE, Embase, Google Scholar, and the Cochrane Library, were screened until February 2025 for RCTs with patients aged ≤21 years who received gabapentin/pregabalin with a follow-up of at least 4 weeks after registering the protocol in PROSPERO (CRD420251112304). Data were synthesized using the Review Manager 5.4 software, employing the generic inverse variance method and random model.

Results

Four RCTs (n = 221) were included. Pre-emptive gabapentinoids showed no significant reduction in chronic neuropathic pain compared with placebo (risk ratio [RR]: 0.90; 95% CI: 0.45–1.78; I² = 0%). Opioid consumption in the first 72 hours was modestly reduced (mean difference [MD]: −0.42; 95% CI: −0.64 to −0.20; I² = 7%). Reported adverse events were generally mild, including sedation, dizziness, and nausea, with no serious respiratory complications. The evidence was very low due to small sample size, heterogeneity in drug type/dose/regimen, and indirectness of long-term pain outcomes.

Conclusion

Pre-emptive gabapentinoids, including gabapentin and pregabalin, do not consistently prevent chronic neuropathic pain in adolescents after posterior spinal fusion and provide only limited short-term opioid-sparing benefit.

Keywords

gabapentinoids - chronic neuropathic pain - adolescent idiopathic scoliosis surgery - posterior spinal fusion

Introduction

Chronic postsurgical pain (CPSP) is a significant clinical challenge following major surgeries, including corrective spinal surgery for adolescent idiopathic scoliosis (AIS). The International Association for the Study of Pain (IASP) defines CPSP as pain that persists for at least 3 months post-surgery, which differs from preoperative pain, and is unrelated to other causes such as malignancy or infection.[1] A subset of this pain can be neuropathic, originating from a lesion or disease of the somatosensory nervous system.[2] Neuropathic pain is generally characterized by symptoms like tingling, numbness, burning, electric-shock-like sensations, allodynia, hyperalgesia, and hypersensitivity to cold or heat stimuli.[3] Epidemiological studies indicate that approximately 10% of individuals over the age of 30 may experience neuropathic pain.[4] [5]

Corrective spinal surgery for scoliosis is a complex orthopedic procedure often accompanied by severe perioperative pain. Although chronic neuropathic pain conditions such as failed back surgery syndrome have been extensively studied in adults,[6] information on the prevalence and risk factors for CPSP in adolescents undergoing scoliosis correction remains scarce. However, data reveal that persistent postsurgical pain is increasingly reported in procedures such as spinal fusion, amputation, mastectomy, thoracotomy, and craniotomy.[7]

Gabapentinoids, including gabapentin and pregabalin, are frequently prescribed for managing neuropathic pain and have been shown to reduce opioid usage in adults undergoing spinal surgery.[8] These medications bind to the α2δ subunit of voltage-gated calcium channels, decreasing neuronal excitability and the release of excitatory neurotransmitters. Pregabalin is approved by the U.S. Food and Drug Administration (FDA) for treating neuropathic pain in adults and as an adjunctive therapy for partial-onset seizures in both adults and pediatric patients (≥1 month old). However, pediatric approvals for neuropathic pain vary by region, and the efficacy and safety of pregabalin for neuropathic pain in children remain uncertain.[9] Recent findings also raise concerns about their perioperative utility, especially in pediatric populations. Earlier studies have shown that pre-emptive pregabalin did not significantly decrease the postoperative pain scores or opioid consumption in children and adolescents undergoing scoliosis surgery, indicating minimal benefits in this demographic.[10]

Moreover, gabapentinoids are increasingly being evaluated for their side effect profile, including sedation, dizziness, and the potential for respiratory depression, particularly when used with opioids.[11] [12] Despite their everyday use in perioperative settings, their role in preventing persistent postoperative neuropathic pain in children and adolescents following scoliosis surgery is yet to be established.

The effectiveness of gabapentinoids for the prevention of persistent neuropathic pain in AIS needs to be thoroughly reevaluated in light of the ongoing controversy and the potential risks related to off-label pediatric use. This systematic review aims to assess the efficacy of perioperative gabapentinoid use (gabapentin or pregabalin) in adolescents undergoing posterior spinal fusion for AIS.[13] The primary objective was to evaluate the risk of developing persistent postsurgical pain during long-term follow-up extending up to 2 years. The secondary objectives included assessing cumulative opioid consumption (e.g., oxycodone or morphine) within the first 72 hours post-surgery and investigating the impact of gabapentinoids on perioperative pain outcomes and adverse events. The included studies administered gabapentinoids in the perioperative period, with dosing initiated preoperatively, ranging from 12 hours to 30 minutes before surgery.

Material and Methods

This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD420251112304).

Search Strategy

A comprehensive literature search was systematically performed using PubMed, MEDLINE, Embase, Google Scholar, the Cochrane Library, and ClinicalTrials.gov up to February 2025, with no restrictions on language or date of publication. The search strategy integrated controlled vocabulary and free-text phrases, including “gabapentinoid” OR “pregabalin” OR “gabapentin” AND “chronic neuropathic pain” OR “perioperative neuropathic pain” OR “complication” AND “adolescent idiopathic scoliosis” OR “AIS” OR “posterior spinal fusion.” Reference lists of all included publications and relevant reviews were also screened to find additional eligible studies. Full database-specific search strategies are provided in [Supplementary Table S1] (available in online version only).

Selection Criteria

We included only randomized controlled trials (RCTs) based on the following criteria:

• Population: Adolescents and young adults (≤21 years) with idiopathic or related spinal deformities with American Society of Anesthesiologists (ASA) physical status I–III who underwent posterior spinal fusion surgery using pedicle screw instrumentation.

• Intervention: Pre-emptive and perioperative administration of gabapentinoids (gabapentin or pregabalin).

• Comparison: Control group without any active intervention for preventing chronic pain.

• Outcome: Incidence of postsurgical pain during long-term follow-up (up to 2 years) and cumulative postoperative opioid consumption (e.g., oxycodone or morphine) within the first 72 hours after surgery.

Case reports, narrative reviews, letters to the editor, cohort studies, studies without an active control group, and articles other than English were excluded.

Data Extraction

Data extraction was performed independently by two investigators from each included study using a preconceived data collection sheet for the following: the first author, publication year, country of origin, the number of patients included, age, and initial 72-hour opioid consumption following surgery, and disagreements were resolved by another investigator.

Risk-of-bias Assessment

Two investigators independently assessed the risk of bias using the RoB 2.0 tool[13]; any disagreements were resolved through discussion with a third investigator.

Quality of the Evidence

Two investigators independently assessed the certainty of evidence for each outcome using the GRADE tool.[14] Any disagreements were resolved through discussion with a third investigator.

Statistical Analysis

Meta-analyses were performed using the Der Simonian-Laird random-effects estimator in RevMan 5.4 and Comprehensive Meta-analysis software (Biostat Inc, Englewood, NJ). This method was chosen given the anticipated clinical heterogeneity in patient populations, gabapentinoid regimens, and outcome measurement timing. Between-study variance (τ²) and 95% prediction intervals were calculated for all outcomes.

Opioid consumption was converted to oral morphine milligram equivalents per kilogram (MME/kg) by using standard conversion ratios. Data were synthesized using mean difference (MD) as all studies presented continuous outcomes in comparable units after conversion.

Trial sequential analyses (TSA) were performed using TSA software (Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigs Hospital, Copenhagen, Denmark) to assess whether the cumulative evidence was sufficient to detect or reject a clinically meaningful reduction in chronic neuropathic pain with gabapentinoids compared with placebo. Type I and II errors were controlled using O'Brien-Fleming α-spending and β-spending functions.

Results

Basic Characteristics

Baseline demographic and clinical characteristics of the included patients are summarized in [Table 1]. This analysis comprised 221 adolescent patients from four RCTs, identified from 159 screened articles ( [Fig. 1] : PRISMA). The gabapentinoid and control groups were comparable at baseline in terms of mean age, sex distribution, ASA physical status, and baseline Cobb angle severity. All patients underwent posterior spinal fusion surgery for AIS and were evaluated for chronic neuropathic pain and postoperative opioid consumption. Of the included studies, two trials (n = 47) evaluated gabapentin and two trials (n = 65) evaluated pregabalin. Gabapentinoids were administered as a single preoperative oral dose in one study (18 patients),[15] while in three other trials,[16] [17] [18] they were given as multiple oral doses (94 patients). All studies reported on pain scores and opioid consumption within the early postoperative period, and two trials also provided data on long-term pain outcomes at 2-year follow-up.

Table 1 Summary of included randomized, double-blind, placebo-controlled trials evaluating perioperative gabapentinoid administration (gabapentin or pregabalin) in adolescents undergoing posterior spinal fusion

Study	Population	Setting	Sex ratio (Male:Female)	Curve severity (Cobb angles)	Co-morbidities	Intervention (Drug & Dose)	Control	Primary Outcome	Secondary Outcomes	Interpretation
Helenius L. et al., 2020 (16)	64 adolescents (31 placebo, 32 pregabalin) aged 10–21 yrs with AIS, Scheuermann kyphosis, or spondylolisthesis	Turku University Hospital, Finland	Not specified	Not mentioned	Not mentioned	Pregabalin 2 mg/kg BID (rounded to next 25 mg; max 150 mg BID). First dose 12 h pre-op, second 2 h pre-anesthesia, continued BID × 5 days post-op.	Matching placebo	vNRS Pain scores: VAS (mean ± SD) pregabalin (N = 25) vs placebo (N = 26): 4h 3.9 ± 1.9 vs 3.4 ± 2.3; 8h 3.1 ± 2.3 vs 3.3 ± 2.2; 12h 2.6 ± 2.0 vs 3.5 ± 2.2; 16h 3.0 ± 2.4 vs 3.4 ± 2.4; 20h 3.4 ± 2.3 vs 3.2 ± 2.5; 24h 3.3 ± 2.6 vs 3.5 ± 2.2; 36h 3.8 ± 2.1 vs 4.3 ± 2.3 (no significant difference, p = 0.196). Pain scores at rest and on movement were comparable between groups (p = 0.196; p = 0.244).	Cumulative Postoperative oxycodone at 48h: pregabalin gp. 1.44 mg/kg (95% CI,1.32 to 1.67 mg/kg) and placebo gp. 1.50 mg/kg (95% CI, 1.39 to 1.79 mg/kg) (p = 0.433); AE - no significant differences between groups.	Pregabalin did not reduce the postoperative opioid consumption or pain scores
Mayell A. et al., 2014 (15)	35 adolescents (17 placebo, 18 gabapentin)aged 10–17 yrs with idiopathic scoliosis undergoing elective corrective spinal surgery; all able to operate a PCA pump	Hospital for Sick Children, Toronto, Canada	Placebo 4 : 13; Gabapentin 2 : 16	Not mentioned	Patients with significant comorbidities were excluded: Unable to cooperate or operate PCA, Unable to rate pain, Known allergy or sensitivity to gabapentin or morphine, History of chronic pain or daily analgesic use, Recent use (within 24 h) of acetaminophen, NSAIDs, or antacids	Gabapentin 600 mg oral, single preoperative dose administered 1 hour before surgery; anesthesia and postoperative analgesia standardized (morphine PCA, acetaminophen q6h)	Matching placebo capsule	NRS Pain scores: no difference at rest or movement; Persistent pain at 6 weeks: 3/16 vs 4/17	Total morphine consumption (mg/kg) within 24 h postoperatively: Gabapentin gp. 1 h, 0.24 ±  0.12 mg/kg; 4 h, 0.44 ±  0.17 mg/kg; 8 h, and 1.29 ±  0.44 mg/kg at 24 h & Placebo gp. 0.121 ± 0.06 mg/kg at 1 h, 0.35 ±  0.16 mg/kg at 4 h, 0.56 ± 0.27 mg/kg at 8 h, and 1.46 ± 0.68 mg/kg at 24 h; AE - no significant differences between groups.	Single-dose gabapentin did not reduce opioid consumption or improve pain control.
Rusy et al., 2010 (17)	59 adolescents (30 placebo, 29 gabapentin) aged 9–18 yrs with idiopathic scoliosis undergoing posterior spinal fusion	Children's Hospital of Wisconsin, Milwaukee, USA	Placebo 7 : 23; Gabapentin 7 : 22	Not mentioned	Obstructive sleep apnea, Severe concomitant disease (neuromuscular scoliosis, neurodegenerative disease), Current opioid or illicit drug use, Pregnancy, Anterior spinal fusion or spinal reoperation, Morbid obesity (BMI ≥ 40), Allergies to morphine, hydromorphone, or gabapentin	Gabapentin pre-op loading 15 mg/kg orally ~30 min before surgery; post-op 5 mg/kg orally TID for 5 days	Matching placebo capsules/ liquid	vNRS Pain scores (mean ± S.D.): significantly lower in recovery room (2.5 ± 2.8 vs 6.0 ± 2.4, P < 0.001) and morning after surgery (3.2 ± 2.6 vs 5.0 ± 2.2, P < 0.05)	Total morphine consumption (mg/kg/h): Gabapentin significantly reduced morphine on day of surgery (0.044 ± 0.017 vs 0.064 ± 0.031, p = 0.003), POD1 (0.046 ± 0.016 vs 0.055 ± 0.017, P = 0.051), POD2 (0.036 ± 0.016 vs 0.047 ± 0.019, P = 0.018); AE - no significant differences between groups.	Gabapentin reduced early morphine use and pain scores up to POD2
Helenius et al., 2021 (18)	64 adolescents and children (31 placebo, 33 pregabalin), aged 10–21 years, undergoing posterior spinal fusion for adolescent idiopathic scoliosis, spondylolisthesis, or Scheuermann kyphosis	Single center, University Hospital, Finland	More females than males	Not mentioned	Patients with other comorbidities were excluded	Pregabalin 2 mg/kg orally, rounded to next 25 mg, given twice daily: preoperative evening and ~2h before induction, then twice daily for 5 days postoperatively (max 150 mg per dose)	Placebo capsules, same schedule	SRS-24 Pain Domain Score (mean): Preoperative: 3.8 (both groups); 2-year follow-up: 4.3 (pregabalin) vs 4.0 (placebo); no significant between-group differences (p = 0.317); back pain VAS improved significantly overall (p = 0.0011).	Cumulative Postoperative oxycodone at 48h: pregabalin gp. 1.44 mg/kg (1.32, 1.67) & Placebo gp. 1.50 mg/kg (1.39, 1.79) placebo (p = 0.433); AE - no significant differences between groups.	Pregabalin did not reduce opioid consumption nor persistent postoperative pain at 2-year follow-up.

Abbreviations: Visual Numeric Rating Scale (vNRS), Numeric Rating Scale (NRS), Scoliosis Research Society-24 (SRS-24) Pain Domain Score, Adverse events (AE), Every 6 hours (q6h), Patient-Controlled Analgesia (PCA), Group (gp), Post-operative day (POD), Twice daily (BID) & Thrice daily (TID).

Fig. 1 PRISMA flow diagram.

The preoperative doses of gabapentinoids varied across studies, including 2 mg/kg, 150 mg, 600 mg, and 15 mg/kg, administered orally. Postoperative opioid analgesia included both oxycodone and morphine, with dosing regimens ranging from 0.12 mg/kg/hour to total cumulative doses of 1.44 mg/kg during the initial postoperative period ([Table 1]).

Adverse events were inconsistently reported among the trials included. Three studies found no significant differences between gabapentinoid and placebo groups in common postoperative adverse effects, including Post operative nausea & vomitting (PONV), pruritus, dizziness, sedation, constipation, and other opioid-related effects.[15] [16] [17] The other did not report any adverse events.[18] None of the trials reported respiratory depression or any other serious adverse events ([Table 1]).

None of the studies has a significant risk of bias ([Fig. 2]).

Fig. 2 Risk of bias assessment of included RCTs.

Meta-analysis

• 1. Chronic Neuropathic Pain: In three studies with 149 pre-emptive gabapentinoids, there was no significant reduction in the risk of developing chronic neuropathic pain compared with placebo in adolescents who underwent corrective scoliosis surgery (risk ratio [RR]: 0.90, 95% confidence interval [CI]: 0.45–1.78; I² = 0%; τ² = 0.00 [95% prediction interval not estimable due to zero heterogeneity) ([Fig. 3A]).

Fig. 3 (A) Forest plot showing the effect of preoperative gabapentinoids on the development of chronic postsurgical neuropathic pain. (B) Trial sequential analysis (TSA) for chronic postsurgical neuropathic pain assuming a 25% relative risk reduction. (C) Forest plot showing the effect of preoperative gabapentinoids on postoperative opioid consumption within 72 hours. Mean difference in cumulative opioid consumption expressed as oral morphine milligram equivalents per kilogram (MME/kg) over 0 to 72 hours postoperatively.

Trial sequential analysis: Using a control event rate of 15.6%, an α of 0.05, a β of 0.20, and a predicted 25% relative risk reduction, the required information size was 329; nonetheless, the available sample remained below this threshold, indicating that the evidence is still inadequate to confirm a clinically significant reduction in chronic neuropathic pain ([Fig. 3B]).

• 2. Postoperative Opioid Consumption: The gabapentinoid administration was associated with a significant reduction in opioid consumption within the first 72 hours postoperatively (mean difference [MD]: −0.42, 95% CI: −0.64 to −0.20; I² = 7%; τ² = 0.01; 95% prediction interval: −0.68 to −0.16) suggesting a short-term opioid-sparing effect ([Fig. 3C]).

Quality of Evidence: The certainty of evidence regarding the impact of preoperative gabapentinoids on reducing chronic neuropathic pain after corrective scoliosis surgery in adolescents was assessed as very low. Although risk of bias and inconsistency were not downgraded, the evidence was downgraded for indirectness due to heterogeneity in gabapentinoid types, dosing (2–15 mg/kg), perioperative regimens, and variations in outcome time windows, and further downgraded for imprecision owing to small sample sizes and broad confidence intervals that included both potential benefit and harm ([Supplementary Table S2], available in online version only).

Publication Bias

Visual inspection of the funnel plot showed no apparent asymmetry ([Fig. 4]). Egger's regression (p = 0.96) and Begg and Mazumdar's rank correlation (p = 1.0) indicate that a publication bias is unlikely. Nevertheless, since only four RCTs were included, the findings should be interpreted with caution, as they are typically recommended for at least 10 studies.

Fig. 4 Funnel plot for visual assessment of potential publication bias.

Discussion

This systematic review found very low-quality evidence regarding the efficacy of preoperative gabapentinoids, particularly gabapentin and pregabalin, in postoperative pain in pediatric patients undergoing spinal fusion surgery for AIS. Gabapentin and pregabalin may differ in their pharmacological characteristics and analgesic effects, as pregabalin exhibits more predictable absorption and higher affinity for the α2δ calcium channel subunit. Pooling both drugs in a meta-analysis could potentially dilute potential drug-specific differences in their efficacy.

The opioid epidemic, which gained momentum in the early 21st century, has urged clinicians and researchers to develop strategies focused on reducing opioid consumption in the management of postoperative pain, especially after orthopedic procedures such as spinal fusion surgery.[19] Multimodal pain management strategies have emerged as a promising approach in this regard, aiming not only to minimize opioid use but also to improve recovery.[20] [21] Although this method is well-documented in adult populations, its efficacy and reliability in pediatric patients remain controversial.

Among the included studies, gabapentinoids showed variable efficacy. Two trials reported an average reduction in postoperative opioid use,[15] [17] while the other two showed no significant difference between gabapentinoid and placebo groups. Helenius et al reported no significant differences in total oxycodone consumption over 48 hours or SRS-24 pain scores during the 2-year follow-up period.[18] Similarly, their earlier study showed similar oxycodone consumption between the pregabalin and placebo groups within the initial 48 hours post-surgery.[16] Mayell et al observed slightly reduced morphine use in the gabapentin group at early time points, yet these differences were not statistically significant.[15] Conversely, Rusy et al found that gabapentin significantly reduced morphine consumption in the recovery room and on the first 2 postoperative days, along with reductions in early postoperative pain scores; however, these improvements were not sustained over time.[17] In summary, while one study reported significant opioid-sparing and analgesic effects with gabapentin, most trials showed no meaningful reduction in opioid consumption or improvement in long-term pain outcomes with perioperative gabapentinoid use in AIS surgery.

Adverse events were inconsistently reported across trials; however, according to the available data, gabapentinoids did not clearly increase or reduce postoperative adverse effects. Nonetheless, all included RCTs were small and underpowered to detect differences in safety outcomes.

Although specific pediatric RCTs have investigated the impact of gabapentinoids on persistent postsurgical pain after spinal fusion, the results are inconsistent and limited by small sample sizes, heterogeneous dosing regimens, and short follow-up durations. Even though the included studies followed patients for up to 2 years, they were not powered to evaluate persistent neuropathic pain. They were limited by variability in drug type, dose, and perioperative regimen. Persistent postsurgical pain is a crucial outcome to consider in pediatric patients, as it may lead to prolonged recovery, reduced functional capacity, psychological distress, and increased risk of long-term opioid usage or misuse.[22]

This review provides a comprehensive synthesis of existing pediatric RCT data on the role of gabapentinoids in preventing chronic postoperative pain. Although one study showed positive short-term analgesic benefit and reduced opioid use, the finding does not support a reliable or strong impact of gabapentinoids in reducing opioid consumption or improving long-term pain outcomes in this group. Moreover, the available data remains limited in scope and size, and current evidence findings do not provide enough support for changes in clinical practice guidelines.

Persistent postoperative pain is a complicated and multifactorial phenomenon. Factors such as preoperative pain, increased perioperative anxiety, increased immediate postoperative pain scores, cumulative in-hospital opioid consumption, and extended surgery time have all been associated with worse long-term pain outcomes.[13] In the studies included, particularly the one by Helenius et al, extended surgical duration was found to be a significant predictor of persistent pain at the 2-year follow-up.[15] These findings underscore the importance of early identification of high-risk patients and the implementation of individualized pain management strategies.

Limitations: The included RCTs are small, and the sample size is limited, which reduces the power to identify significant differences in chronic neuropathic pain outcomes. There is notable variability among studies in terms of gabapentinoid type, dosing regimens, and timing of administration, which could have affected the results. The pooling of gabapentin and pregabalin data assumes comparable efficacy and pharmacodynamics, which may not be valid. There was an absence of standardized pain outcome measures and follow-up periods, complicating comparisons among studies.

In conclusion, although gabapentinoids might provide limited advantages in select cases, existing evidence does not consistently support their standard use in pediatric spinal fusion surgery for AIS to reduce opioid consumption or prevent CPSP. Future large-scale, well-designed randomized controlled trials with long-term follow-up are essential to further elucidate the role of gabapentinoids in managing pediatric pain and to inform evidence-based clinical guidelines.

Conflict of Interest

None declared.

Authors' Contributions

S.S. and P.K.: conceptualization; S.S. and P.K.: methodology; D. and A.K.: literature search and study selection; D., A.K., A.M., and A.S.: data curation; S.S. and A.K.: formal analysis; D. and S.S.: writing—original draft; D., S.S., P.L., and P.K.: writing—review and editing; P.K.: supervision.

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Publication History

Article published online:
28 January 2026