Systematic Review of the Efficacy and Safety of Gabapentin and Pregabalin for Pain in Children and Adolescents

Oluwaseun Egunsola, PhD; Claire E. Wylie, PhD; Kate M. Chitty, PhD; Nicholas A. Buckley, MD

Disclosures

Anesth Analg. 2019;128(4):811-819. 

In This Article

Discussion

Despite the best efforts of physicians, pain management in children is sometimes suboptimal,[25] and it is imperative to expand the current armamentarium of available analgesics. Children should have the right to access medicines that have been shown to be safe and effective in adults. It is apparent that off-label use occurs in clinical practice following specific studies into off-label prescribing,[26–28] examples of published observational epidemiological studies,[29,30] case series,[31,32] and case reports.[33] Furthermore, dosing recommendations for gabapentin use for neuropathic pain in children and adolescents are available.[34] The extensive supporting evidence in favor of the safety and analgesic efficacy of gabapentin and pregabalin in adults, as summarized in Supplemental Digital Content 5, Table 4, http://links.lww.com/AA/C654, justifies the conduct of randomized controlled trials in children and adolescents. However, this systematic review highlights their sparsity. In total, only 7 relevant randomized controlled trials in children and adolescents were identified: 5 randomized controlled trials in regarding the perioperative use of gabapentin, 1 randomized controlled trial regarding the efficacy of gabapentin on neuropathic pain, and 1 randomized controlled trial regarding the efficacy of pregabalin for fibromyalgia.

Two of the identified clinical trials regarding the efficacy of gabapentin for prophylactic postadenotonsillectomy pain relief were omitted from results and narrative synthesis due to clear evidence of data fabrication.[16,17] A detailed comparison of both trials, published in separate journals in 2011 and 2014 by the same first author, is provided in Supplemental Digital Content 3, Table 2, http://links.lww.com/AA/C652. In brief, the data appear fabricated due to the 2 trials conducted at different times having identical point estimates and standard errors for the age, weight, duration of anesthesia, pethidine consumption, and time to first analgesic for the gabapentin groups and 2 different control groups (paracetamol and dexamethasone, respectively). There are 70+ significant digits in the identical descriptors of these supposedly different trial populations. These concerns were raised with the editors of both journals. On October 7, 2018, the 2014 trial was retracted by one of the journals.[35,36] Concerningly, these trials are being used to inform evidence; in particular, they are both included in a systematic review regarding gabapentin for perioperative analgesia[37] and a meta-analysis regarding the efficacy of gabapentin/pregabalin in improving pain after tonsillectomy.[38] The 2011 paper is also being used to directly inform clinical guidelines.[4] None of these evidence syntheses had expressed concerns over the data integrity; with the 2011 and 2014 papers receiving scores of +2 and +4, respectively, on scale of −2 to +5 in the systematic review,[37] and both considered a low risk of bias in the meta-analysis.[38] It is important that articles that have included these publications for evidence synthesis are correctly interpreted, and current evidence-based practice and clinical guidelines based on these research studies audited to determine whether their conclusions remain robust.

Extrapolation of the results of the retained individual studies also requires caution as each of the studies was considered at risk of methodological shortcomings. Owing to difficulties with patient recruitment, sample sizes were inadequate in some of the studies. Another common limitation was the disparate outcome measures of pain in each of the studies, hence we were unable to pool the results of the included randomized controlled trials for meta-analysis. Young children may have difficulties with the self-reported pain assessment tools utilized because of their limited verbal communication and associative thinking.[39] Uniformity in appropriate measures of pain in children and adolescents in future studies will ensure better evidence synthesis.

This review identified a sparsity of evidence-based data supporting the use of gabapentinoids in children and adolescents. Of the 5 retained studies, the indications for treatment, comparators, and outcome measures for each differed. On the basis of the primary outcome alone, pain scores and postoperative analgesia consumption were the most frequently utilized method of assessment of analgesic efficacy. There was a significant reduction in pain with gabapentin in 2 of the 4 studies utilizing a measure of postoperative analgesia requirements, with evidence for significant reductions in analgesic consumption compared to placebo or active comparators.[18,22] No effect was identified for the primary pain outcome for pregabalin.[21] The secondary outcome measures were highly heterogeneous, and the results were mixed and inconsistent. Furthermore, for the placebo-controlled studies, placebo effect may result in the underestimation of drug effect. Two studies illustrate the possibility of placebo response, with the former generally showing the beneficial effects of gabapentin over placebo and the latter not showing any difference.[18,19] It was not, therefore, considered possible to synthesize any useful evidence from the included studies.

The data regarding the prevalence of adverse effects appeared relatively consistent, with nausea the most common adverse effects of gabapentin[19] and the second most common, following dizziness, for pregabalin.[21] However, only 1 study reported a significantly different proportion of adverse effects between the gabapentinoids and comparator.[22] While the safety of gabapentin as an anticonvulsant has been extensively studied in children,[40,41] the safety of pregabalin among children and adolescents is unknown.[13] The adverse effects frequently associated with gabapentin such as dizziness, somnolence, headache, and weight gain often follow prolonged use during epilepsy treatment.[42] For perioperative analgesia, a single dose, 1–2 hours preoperatively, sometimes with a limited number of additional postoperative doses are required. For neuropathic pain, chronic use of gabapentinoids may be indicated with increased likelihood of chronic adverse effects.

This study complements a recent high-quality systematic review on the use of antiepileptic drugs for chronic noncancer pain in children and adolescents.[8] Each of the 2 included randomized controlled trials from the published review was identified in the current study. The current review provides additional insight into the perioperative effect of gabapentin, which is an emerging indication for gabapentinoids in children and adolescents. Based on records of registered clinical trials, several studies on the analgesic effects of gabapentinoids are currently ongoing (3 studies) or recently completed (6 studies), as such more studies will be available for evidence synthesis in future systematic reviews.[43] Limitations of the current review included usage of only English language articles, introducing bias if relevant studies were reported in other languages, and the decision not to contact primary authors for further information, instead reporting on the available published evidence.

In conclusion, this systematic review found a paucity of data supporting the clinical use of gabapentinoids as prophylactic or treatment options for pain in children and adolescents.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....