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

Results

Study Selection and Characteristics

The search strategy yielded 4910 publications, of which 464 were deemed potentially eligible and were retrieved in full text for full eligibility assessment (Figure 1). The reasons for exclusion of the 458 full-text articles are summarized in Figure 1, most commonly due to the studies being performed in an adult population. There were a further 45 studies for which the data were aggregated at a higher level and could not be included; 27 analyzed the efficacy of either gabapentin or pregabalin, and a further 18 studied children and adolescents. One further study was identified by screening of the reference lists of identified review articles.

Figure 1.

Flow diagram of the recruitment of studies to a systematic review of the efficacy of gabapentin and pregabalin in children and adolescents. Adapted from Moher et al.14

A total of 7 publications were included in the qualitative synthesis.[16–22] Complete baseline characteristics of the study and population were rarely provided (Table 1). Six of the identified studies investigated the efficacy of gabapentin—5 as prophylactic postsurgical pain relief for either adenotonsillectomy[16,17,22] or scoliosis surgery,[18,19] and 1 for treatment of chronic regional pain syndrome or neuropathic pain.[20] One study investigated the efficacy of pregabalin as a treatment for fibromyalgia.[21] In general, the intervention characteristics for each study were well described (Table 2).

Methodological Assessment

None of the studies were considered to be at an overall low risk of methodological shortcomings (Supplemental Digital Content 2, Figure 1, http://links.lww.com/AA/C651). Four studies (all on gabapentin) were considered to be at an overall unclear risk of methodological shortcomings, while the other 3 (including the pregabalin study[21]) were considered to be at an overall high risk (Figure 2). In general, the highest risk of methodological shortcomings was within the "other sources" category. Within this section, 2 studies on gabapentin[16,20] and the pregabalin study[21] were judged to be at a high risk due to issues regarding inadequate sample sizes, while the Mohamed and Al-Sersy[22] study was judged as unclear due to lack of a sample size methodology and justification. The paper by Amin and Amr[17] was judged as unclear due to concerns regarding the data veracity following comparison of the results presented in the subsequent paper by Amin.[16] As later discussed in further detail in Supplemental Digital Content 3, Table 2, http://links.lww.com/AA/C652, the concerns regarding fabricated data led to exclusion of the results of both papers by Amin[16] and Amin and Amr[17] from the tables and the narrative of this systematic review.

Figure 2.

Methodological quality summary for randomized clinical trials assessing the efficacy of gabapentin or pregabalin for pain in children and adolescents for each methodological quality item for each included study.

The other criteria within methodological assessment were generally well reported, although insufficient detail to judge the risk resulted in an unclear risk being awarded for most categories. This was particularly evident in the blinding of participants, which was unclearly reported for 4 of the gabapentin studies[16,17,19,22] and the pregabalin study,[21] with no specification of the individuals blinded.

Five of the gabapentin studies and the pregabalin study were judged to be at an unclear risk regarding selective reporting due to a lack of study protocol for review or due to the exclusion of intended analyses or inclusion of post hoc analyses. One study was judged to be at low risk regarding selective reporting as they provided sufficient detail to obtain the protocol and no substantial deviations were reported.[18]

Financial support was adequately reported for each of the gabapentin studies and was not considered to impact the results, with the exception of one that did not provide any information regarding funding.[22] The pregabalin study was judged as unclear as they reported funding from Pfizer, and Pfizer employees helped with the writing.[21]

Pain-associated Outcomes

Due to the heterogeneity of the included studies and the variability in the assessment of the pain-associated outcomes, pooling of the outcome data was not attempted, and the results are presented for each individual study (Table 3; Supplemental Digital Content 4, Table 3, http://links.lww.com/AA/C653). Six of the studies identified a primary pain outcome, although each of these was distinct, and one stated that the primary outcome was "morphine consumption," though this was not further defined and 5 different measures of morphine consumption were presented at differing time points. One study did not specify a primary pain outcome, although the sample size calculation was conducted on the basis of postoperative analgesic requirements.[16]

Following exclusion of the 2 papers by Amin[16] and Amin and Amr,[17] on the basis of these "primary outcomes," 2 of the 4 retained gabapentin studies demonstrated a significant reduction in pain: significantly fewer patients requiring nonsteroidal anti-inflammatory intravenous analgesics during the early postoperative period due to complaints of highly significant postoperative pain,[22] and significantly less cumulative morphine consumption through day 2 compared to placebo.[18,22] Two of the studies did not detect an effect of gabapentin: no significant difference in pain intensity decrease measured on a Colored Analog Scale compared to amitriptyline,[20] and no significant difference in total morphine consumption 24 hours postoperatively compared to placebo.[19] The pregabalin study[21] found no significant difference for the primary outcome measure of mean change in pain score based on a numeric rating scale compared to placebo.

Of the 5 retained studies, the number of secondary pain-associated outcomes varied from 0 to 35 (median 13)—commonly repeated measures of pain assessment at varying time points. One study reported a significant reduction in pain for the gabapentin-treated group for 4 of its 15 secondary outcome measures, with no significant difference in total morphine consumption on day 1, 3, 4, or 5 postoperatively, and no significant difference in the pain score other than for the postoperative period (postanesthesia recovery unit) and the morning immediately after surgery.[18] Two studies reported no efficacy of gabapentin for any of their respective 4 and 24 secondary outcome measures.[19,20] The pregabalin study[21] reported a significant reduction in pain for the pregabalin-treated group for 11 of 15 weeks assessment change in pain score and for both the patient and parent global impression of change, as well as an improvement for 2 of 15 weeks assessment change in sleep quality score. However, no significant differences were found in the other 4 of 15 weeks assessment of change in pain score (week 1, 2, 5, or 13), the other 13 of 15 weeks assessment change in mean sleep quality score (weeks 1–7, week 9 or week 11–15), the 30% or 50% pain responders or the mean fibromyalgia impact questionnaire score.

Adverse Effects

Adverse effect outcomes from the gabapentin or pregabalin were reported by 4 of the 5 retained studies, with differing definitions and level of detail (Table 4). One study reported on the adverse effects of the morphine used as an outcome, but not any adverse effects related to the interventions.[18] Nausea was the most commonly reported individual adverse event, often reported in combination with vomiting, occurring in between 17% and 26% of patients.

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