Safety and Efficacy of Gabapentin for Pain in Pediatric Patients: A Systematic Review Free

A systematic review of the literature was conducted via PubMed query utilizing the indexed medical subject heading terms as follows: [children OR pediatrics OR infants OR neonates] AND [gabapentin], with query limited to English language, human subjects, and publication date range from January 1, 2000, to July 1, 2023.

Case reports, case series, commentaries, opinion articles, review articles, retrospective reviews, and nonclinical articles were excluded. Articles describing patients aged >18 years or including <3 pediatric patients were excluded. Articles not reporting the outcomes of gabapentin for the use in pain management were excluded.

One author (J.W.B.) performed an initial screening of titles and abstracts on the basis of the outlined inclusion/exclusion criteria. Relevant full-text articles were then reviewed by 2 authors independently (J.W.B. and LABORATORY) utilizing the outlined inclusion/exclusion criteria, with any conflicts resolved by a third author (J.M.) to meet consensus. Additionally, bibliographies belonging to included articles were reviewed by 2 reviewers to identify additional studies for inclusion.

Two authors (J.W.B. and LABORATORY) independently extracted the data from the included studies, with disputes resolved by consensus after discussion with a third author (J.M.). Studies were then assessed for their independent risk of bias utilizing the Grading of Recommendations, Assessment, Development, and Evaluations approach to risk of bias (Fig 1).

Given the inherent heterogeneity of study participants and outcomes, statistical analysis of study outcomes was not performed. The original results for each included study were described.

The initial literature search identified 130 studies from the PubMed database. We excluded 1 study as a duplication. We excluded 118 studies because they were not cohort studies, case-control studies, experimental trials, randomized controlled trials (RCTs), or did not study the population of interest. Detailed reasons for exclusion are provided in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram (Fig 2).

A total of 11 studies were included, 9 were RCTs, 1 was a prospective multicenter study, and 1 was an open-label pilot study (Table 1). Ultimately, 195 pediatric patients received gabapentin with varying dosing regimens and durations. Studies were completed in multiple countries between the years 2010 and 2022.

Pain in pediatric patients is multifactorial and difficult to assess and treat.^1–4  Off-label use of medications on the basis of adult safety and efficacy data often occurs in clinical practice within pediatrics, which allow additional multimodal treatment options for these patients. Gabapentin has shown benefits for a variety of pain etiologies in adult patients, thus prompting the review of current studies in pediatric patients to report the used dosing regimens, treatment durations, indications, and outcomes.^16–18  The studies included in this review were divided into 3 major categories to include neuropathic pain, surgical pain, and other (Table 2).

Neuropathic pain is the most predominant form of chronic pain in the pediatric population and accounts for roughly 40% of referrals to pediatric pain clinics in North America.¹⁹  There is a lack of literature on how to treat pediatric neuropathic pain, and current pharmacologic treatment recommendations are extrapolated from adult data. Gabapentin and TCAs are considered first line pharmacologic treatment options for patients with neuropathic pain.²⁰  The following studies describe the use of gabapentin in the treatment of neuropathic pain in pediatric patients.

A 2016 study by Brown et al was the first prospective RCT to compare gabapentin and amitriptyline (a TCA) for the treatment of neuropathic pain or complex regional pain syndrome in 34 pediatric patients aged 8 to 17 years.¹⁹  Patients were called weekly to report pain intensity and sleep disability ratings. Amitriptyline was dosed at 10 mg at bedtime and gabapentin was dosed at 300 mg 3 times per day. Patients in the amitriptyline group received amitriptyline as their evening medication, with placebos as their morning and afternoon medications. The primary outcome was change in pain intensity, evaluated by the Colored Analog Scale (range 0–10). The authors found no statistically significant difference in pain intensity reduction between the 2 groups (P = .62), but found an overall statistically significant decrease in pain intensity in both groups from baseline. Five patients reported adverse effects, with 3 found to be related to the study medications (1 from amitriptyline and 2 from gabapentin). The authors concluded that there were no significant differences between gabapentin and amitriptyline and their effects on pediatric neuropathic pain.

Neuropathic pain is a well-known adverse effect with particular chemotherapy regimens, including vincristine.²¹  Vincristine’s dose-limiting adverse effect, neurotoxicity, can cause sensorimotor neuropathy, such as paresthesia and neurotic pain, and autonomic neuropathy, such as paralytic ileus and abdominal pain. Anghelescu et al evaluated the efficacy of gabapentin for vincristine-related neuropathic pain in children aged 1 to 18 years with acute lymphoblastic leukemia.²²  In a prospective, double-blind, phase-II RCT, 49 patients were given opioids plus either gabapentin or placebo. Patients in the gabapentin arm received gabapentin 20 mg/kg per day divided into 3 daily doses and morphine was used as the opioid in both groups. The primary objectives were opioid dosage and pain scores between the 2 groups. The mean opioid dose taken in morphine milligram equivalents (MME) daily was not statistically significantly between the 2 arms (P = .15). When evaluating pain scores over the previous 24 hours, there was no significant difference between the 2 arms (P = .06). The authors concluded that gabapentin plus an opioid did not demonstrate better analgesic efficacy than placebo plus an opioid. The authors did mention that more literature was published after their study protocol development, suggesting that higher doses and longer durations of gabapentin may show more benefit.

Postoperative pain among pediatric patients is a common occurrence and can vary greatly on the basis of the nature of the surgery and recovery.²³  The source of postoperative pain is likely multifactorial, and many assume may include a neuropathic component. NSAIDs and acetaminophen are often used for surgical type pain; however, they may not always be sufficient alone. Opioids like morphine, tramadol, and oxycodone are also used for postoperative analgesia in pediatric patients.²³  Gabapentin is being explored as an alternative to opioids in pediatric postoperative pain, because it acts on N-methyl-D-aspartate receptors in the central nervous system, effectively blocking further neurotransmitter release and pain signaling.²⁴  With these antagonistic abilities, gabapentin may be useful in supplementing surgical pain in pediatric patients. Multiple studies looking at different dosing regimens of gabapentin for a variety of different pediatric surgeries are discussed.

Neuropathic pain has been described after surgery related to osteosarcoma, the most common malignancy in children and adolescents. Another study by Anghelescu et al evaluated treatment of neuropathic pain after definitive surgery for extremity osteosarcoma.²⁵  This was a prospective, multiinstitutional study utilizing 3 separate neuropathic pain regimens plus opioids. Of the 38 patients included, 26 patients were treated with gabapentin, with 17 receiving gabapentin monotherapy, 5 receiving gabapentin plus amitriptyline, and 4 receiving gabapentin plus amitriptyline and methadone. The study group that received gabapentin had an average age of 13.3 years (minimum 6, maximum 20.2). There was no difference in the intensity or duration of postsurgical neuropathic pain between any of the regimens. Ultimately, gabapentin was used safely to treat neuropathic pain in children and adolescents with limb amputation and limb-sparing procedures alike, but with the majority of the patients receiving gabapentin, efficacy was not able to be defined.

In 2019, Anderson et al evaluated gabapentin as a multimodal pain agent in adolescents after spinal fusion.⁸  This was a prospective double-blind RCT comparing gabapentin to placebo pre- and postoperatively in addition to a standardized pain regimen (scheduled ketorolac with as-needed acetaminophen and opioids). Fifty patients were included, 24 in the gabapentin group and 26 in the placebo group. The primary endpoint was preoperative pain evaluated by the Scoliosis Research Society-22 pain component score and postoperative pain evaluated by the Visual Analog Scale. There was no difference in preoperative pain (P = .91); however, the gabapentin cohort experienced a significant reduction in pain on operation day compared with placebo (P = .02). When averaged over postoperative days 1 to 5, there was no difference in pain scores between the groups (P = .07). Additionally, the gabapentin cohort used significantly less total MME postoperatively than placebo ([3.38 MME ± 1.79 MME] [5.05 MME ± 3.16 MME]) (P = .03)]. There was no difference in adverse events among the 2 groups. This study demonstrates that gabapentin, as a part of a multimodal pain management protocol, can significantly benefit adolescent patients after spinal fusion.

Also in 2019, Tomaszek et al evaluated gabapentin as a multimodal pain agent specifically in pediatric thoracic surgery patients.²⁶  This was a randomized, blinded, placebo-controlled phase intravenous study comparing a standard postoperative pain regimen (epidural ropivacaine, fentanyl, paracetamol, and NSAIDs), plus either gabapentin or placebo. The primary endpoint was pain intensity characterized by the visual numerical rating scale (range 0–10). There was no difference in pain scores among the 2 groups, with the median pain score being <1 for both groups. There was no difference in use of opioid analgesics or adverse effects among the 2 groups. This study did not see a pain reduction or opioid-sparing benefit of gabapentin in pediatric thoracic surgery patients, but the relative low median pain scores across the study population may have blunted the potential benefit.

In their 2014 study, Mayell et al studied the postoperative pain management effects of gabapentin in adolescents receiving scoliosis surgery.²⁷  Participants included adolescents aged 10 to 17 years receiving elective corrective surgery for idiopathic scoliosis. In this randomized, double-blind, placebo-controlled trial, 35 participants were given 1 oral capsule of placebo or 600 mg of gabapentin 1 hour before surgery. Patient-controlled postoperative morphine consumption up to 24 hours was used as a primary endpoint, whereas decreased pain score, nausea and vomiting, persisting pain, and increased patient satisfaction were secondary endpoints. Researchers found no significant differences in primary or secondary outcomes between the placebo and gabapentin groups. This contrasted with other studies referenced, and the authors indicate that this could be because of the complexity of scoliosis surgery and a need for higher doses of gabapentin.

A 2010 study by Rusy et al evaluated the impacts of adding pre- and postoperative gabapentin in pediatric spinal fusion for idiopathic scoliosis.²⁸  This double-blind RCT included 59 total participants between the ages of 9 and 18 years. The test group was given 15 mg/kg of preoperative oral gabapentin and 5 mg/kg of postoperative maintenance gabapentin 3 times per day for 5 days via either oral capsule or liquid. Opioid consumption was the primary outcome of this study, with secondary outcomes including pain score and adverse effects. Researchers found that total patient-controlled morphine consumption was significantly decreased in the gabapentin group, with no difference in opioid-related adverse effects. The authors indicate that more research is needed to optimize the dosing regimen for gabapentin; however, gabapentin can be a useful agent for decreasing postoperative opioid need in pediatric spinal fusion.

In a 2018 study by Wang et al, use of gabapentin was assessed for phantom limb pain (PLP) in pediatric patients undergoing amputation for malignant bone tumors.²⁹  This was a prospective double-blind RCT assessing gabapentin as an adjuvant therapy in this population. Forty-five patients were included in the study (23 in the gabapentin group) with similar mean age and gender (14.3 years gabapentin group versus 13.9 years placebo group, 11 females in each). All patients were given standard cancer-related pain control before amputation, starting 4 days before amputation with opioids plus either placebo or gabapentin at a dose of 300 mg once daily on day 1, 300 mg twice daily on day 2, and 300 mg 3 times daily on day 3 and onward until 30 days postoperation. There was no difference in preoperative pain intensity between the 2 groups, with lower overall rates of postoperative pain intensity (P < .05) and PLP (P = .033) in the gabapentin group. Gabapentin may be used as an adjunctive pain management therapy with opioids to reduce PLP and overall postoperative acute pain intensity in pediatric patients undergoing amputation for malignant bone tumors.

A 2022 study by Gettis et al evaluated the utilization of gabapentin for patients undergoing tonsillectomy/adenoidectomy.³⁰  This was an RCT comparing perioperative gabapentin to placebo in patients aged 3 to 13 years with an American Society of Anesthesiologists physical classification 1 or 2. Fifty-one patients were enrolled and randomized; 2 deemed to be ineligible (gabapentin = 26, placebo = 23) were included with a similar mean age of 6.8 years and 6.6 years, respectively. Patients received 1 dose of gabapentin (15 mg/kg, max dose 600 mg) once or placebo 30 to 60 minutes before transportation to the operating room in conjunction with a standard anesthetic protocol. There were no differences when comparing gabapentin to placebo in the 3 primary outcomes of mean opiate doses (7 MME versus 4.5 MME; P = .7), time to first analgesic (183 minutes versus 145 minutes; P = .4), or combined Faces pain scale and Visual Analog Scale pain scores (4.05 vs 4.09; P = .95). There was a reduction in opiates used in the postanesthesia care unit; however, the authors conclude that multicenter studies are needed to identify optimal timing, dose, and duration of gabapentin as an opiate alternative.

In another 2022 study, Fenikowski et al evaluated gabapentin use for patients with pectus deformities undergoing the Ravitch procedure.³¹  This was a single-center, double-blind, RCT comparing a standard perioperative medication protocol with either gabapentin or placebo. Fifty-six patients were randomized equally to either the gabapentin and placebo groups with similar baseline demographics, including age (14 years versus 15 years; P = .32) and weight (54 kg versus 54 kg; P = .86). Patients received 1 dose of gabapentin (15 mg/kg) 1 hour before surgery, followed by 7.5 mg/kg per dose twice daily for postoperative days 1 to 3. There was a significant reduction using the Numeric Rating Scale in the average pain score on day of surgery (0.3 vs 0.8; P = .049), maximal pain score on day of surgery (3 vs 4; P = .02), and postoperative day 2 (0 vs 0; P = .04) in the gabapentin group compared with placebo. Additionally, there was a significant reduction in the median dose of morphine (21 mg versus 25 mg; P = .03) on postoperative day 1 in the gabapentin group. The authors conclude gabapentin may be beneficial to use as a part of multimodal pain control, with a larger effect in those patients with a higher level of postoperative pain.

The following study describes the safety and efficacy of gabapentin as a multimodal pain agent in pediatric patients for types of pain that do not fit in the previously described categories. This specifically includes dystonic cerebral palsy (CP). Patients with CP commonly have chronic pain, with dystonia having been cited as 1 of the most frequent causes of pain.³²  Gabapentin is commonly used in the management of children with dystonic CP, but there is little evidence to support its use for managing pain in this population.³² 

In a 2021 study by Harvey et al, gabapentin was assessed for managing pain in children with dystonic CP.³²  The study was an open-label pilot to assess the feasibility of future RCTs. The primary outcome was to assess factors which might impact future RCTs and the secondary objective was to assess the effectiveness of gabapentin to reduce pain in children with dystonic CP. There were 13 children included (mean age 10.4 years ± 2.4 years, 9 females). A standard dosing regimen was used for this study starting at gabapentin 100 mg daily and increasing gradually until 300 mg 3 times daily was reached by week 5, with additional dosage increases for patients >30 kg and where the dosage of 30 mg/kg per day was not sufficient to effect change (maximum 50 mg/kg per day). Improvements were seen in pain and comfort in patients with dystonic CP according to the Pediatric Pain Profile; however, there was incomplete data recording, incomplete adherence, and a small sample size impacting the ability to assess pain control with gabapentin. Two children withdrew from the study, with 8 children experiencing adverse effects. Although gabapentin has the potential to manage pain in children with dystonic CP, the effectiveness of gabapentin in this patient population to improve pain and comfort could not be assessed because of these study limitations.

There is limited available literature for gabapentin in multimodal pain relief for pediatric patients. Given the heterogeneity of patient populations and outcome measures evaluated in the included studies, conclusions are hard to draw. Efficacy likely depends significantly on etiology of pain and dose, as well as duration of gabapentin. Despite mixed efficacy results, all studies support that gabapentin is likely safe to use for a variety of pediatric patient populations as a multimodal agent. Further studies to evaluate optimal dosing strategies and patient populations should be conducted.