Date Published: August 15, 2017
Publisher: Public Library of Science
Author(s): Harsha Shanthanna, Ian Gilron, Manikandan Rajarathinam, Rizq AlAmri, Sriganesh Kamath, Lehana Thabane, Philip J. Devereaux, Mohit Bhandari, Alexander C. Tsai
Abstract: Background and objectiveChronic Low Back Pain (CLBP) is very common, with a lifetime prevalence between 51% and 80%. In majority, it is nonspecific in nature and multifactorial in etiology. Pregabalin (PG) and Gabapentin (GB) are gabapentinoids that have demonstrated benefit in neuropathic pain conditions. Despite no clear rationale, they are increasingly used for nonspecific CLBP. They necessitate prolonged use and are associated with adverse effects and increased cost. Recent guidelines from the National Health Service (NHS), England, expressed concerns on their off-label use, in addition to the risk of misuse. We aimed to assess the effectiveness and safety of gabapentinoids in adult CLBP patients.MethodsElectronic databases of MEDLINE, EMBASE, and Cochrane were searched from their inception until December 20th, 2016. We included randomized control trials reporting the use of gabapentinoids for the treatment of CLBP of >3 months duration, in adult patients. Study selection and data extraction was performed independently by paired reviewers. Outcomes were guided by Initiative on Methods, Measurement and Pain Assessment in Clinical Trials guidelines, with pain relief and safety as the primary outcomes. Meta-analyses were performed for outcomes reported in 3 or more studies. Outcomes were reported as mean differences (MDs) or risk ratios (RRs) with their corresponding 95% confidence intervals (CIs), and I2 in percentage representing the percentage variability in effect estimates that could be explained by heterogeneity. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was used to assess the quality of evidence.ResultsOut of 1,385 citations, eight studies were included. Based on the interventions and comparators, studies were analyzed in 3 different groups. GB compared with placebo (3 studies, n = 185) showed minimal improvement of pain (MD = 0.22 units, 95% CI [−0.5 to 0.07] I2 = 0%; GRADE: very low). Three studies compared PG with other types of analgesic medication (n = 332) and showed greater improvement in the other analgesic group (MD = 0.42 units, 95% CI [0.20 to 0.64] I2 = 0; GRADE: very low). Studies using PG as an adjuvant (n = 423) were not pooled due to heterogeneity, but the largest of them showed no benefit of adding PG to tapentadol. There were no deaths or hospitalizations reported. Compared with placebo, the following adverse events were more commonly reported with GB: dizziness-(RR = 1.99, 95% CI [1.17 to 3.37], I2 = 49); fatigue (RR = 1.85, 95% CI [1.12 to 3.05], I2 = 0); difficulties with mentation (RR = 3.34, 95% CI [1.54 to 7.25], I2 = 0); and visual disturbances (RR = 5.72, 95% CI [1.94 to 16.91], I2 = 0). The number needed to harm with 95% CI for dizziness, fatigue, difficulties with mentation, and visual disturbances were 7 (4 to 30), 8 (4 to 44), 6 (4 to 15), and 6 (4 to 13) respectively. The GRADE evidence quality was noted to be very low for dizziness and fatigue, low for difficulties with mentation, and moderate for visual disturbances. Functional and emotional improvements were reported by few studies and showed no significant improvements.Conclusions and relevanceExisting evidence on the use of gabapentinoids in CLBP is limited and demonstrates significant risk of adverse effects without any demonstrated benefit. Given the lack of efficacy, risks, and costs associated, the use of gabapentinoids for CLBP merits caution. There is need for large high-quality trials to more definitively inform this issue.Trial registrationPROSPERO CRD42016034040
Partial Text: Chronic Low Back Pain (CLBP) is very common and is associated with significant patient burden and heath resource expenditure [1–3]. It is largely nonspecific in nature and in up to 85% of patients lacks a clear pathoanatomical diagnosis when present in isolation [1–4]. We have previously highlighted the etiological and treatment considerations for CLBP, along with the limitations within the existing evidence . A large proportion of CLBP patients are treated with routine analgesic medications with unsatisfactory results leading to frequent exploration of second line options including gabapentinoids [6, 7]. In particular, the use of gabapentin (GB) and pregabalin (PG) is made on the rationale of modulating the enhanced neurotransmission at the level of presynaptic receptors of the afferent neurons. Both of these medications primarily act on the α-2 delta-2 subunit of the voltage-dependent calcium channels [8, 9] and can be considered to have very similar pharmacodynamic actions on pain and other symptoms. They are considered to be very effective for neuropathic pain (NP) conditions. Attempts at exploiting their therapeutic potential for other pain conditions have shown mixed results [10, 11]. Use of gabapentinoids for CLBP requires slow titration to therapeutic doses and establishing maintenance on a long-term basis. With prolonged treatment, the potential gain over possible adverse effects and risks could become unclear . There have been concerns over the excessive off-label use of GB, despite there being a clear lack of clinical studies , necessitating advisory guidelines by the National Health Services (NHS), United Kingdom on the risk of the misuse of gabapentinoids . Our primary objectives were to assess the benefits of GB and PG in CLBP in decreasing pain and to examine the risk of adverse effects. Secondarily, we assessed the effects of PG and GB on the Initiative on Methods, Measurement and Pain Assessment in Clinical Trials (IMMPACT) outcomes . The outcomes considered were physical and emotional functioning, participant ratings of global improvement and satisfaction with treatment, and participant disposition. Additionally, we attempted to assess whether the use of gabapentinoids selectively improve pain relief in patients with predominant neuropathic CLBP.
As this is a systematic review, ethics committee approval is not applicable.
Despite the widespread use, our systematic review with meta-analysis found that there are very few RCTs that have attempted to assess the benefit of using GB or PG in patients of CLBP. Use of GB and PG, compared to placebo and active analgesic comparators, respectively, were associated with significant increase in adverse effects without limited evidence for improvement in pain scores or other outcomes. We were unable to examine the pooled effect of using PG as an adjuvant analgesic medication given the limited evidence and heterogeneity of studies. It is reasonable to assume that the clinical benefit would depend upon the primary medication and its potency within each study. The differences within the results of Pota et al.  and Romano et al. , compared to Baron et al.  could be attributed to methodological differences. The study by Baron et al. had a larger sample size along with longer duration of follow up. Hence, the existing evidence does not support the use of gabapentinoids for predominant CLBP, and calls for larger, high quality RCTs to more definitively inform this issue.