The remaining 4 studies reported no effect of gabapentin on pain or supplemental analgesic use more than 2 months after surgery45,46,49,51 (Table 3). A closer examination of 2 of the negative gabapentin studies46,51 showed that, although there was no difference in the incidence or severity of CPSP after breast cancer surgery at the 3-month and 6-month follow-ups, both studies found that patients who received gabapentin reported less burning pain at these time points. Table 4 shows the odds ratios comparing placebo-treated patients with gabapentin- or pregabalin-treated patients with respect to the outcomes presented in 6 of the 8 gabapentin trials. Among the 6 studies that could be included in meta-analysis, gabapentin caused a moderate-to-large reduction in the development of CPSP (pooled OR 0.52; 95% CI, 0.27 to 0.98; P = 0.04).
Three studies examined the preventive effects of perioperative pregabalin administration on the incidence and intensity of CPSP (Tables 2 and 3).31,34,53 All 3 studies showed significant preventive analgesic effects in that there was a reduced incidence of pain and/or lower analgesic requirements at long-term follow-up, ≥2 months after surgery. Buvanendran et al.31 randomized patients to receive a 300-mg preoperative dose of pregabalin followed by a 14-day twice-a-day (BID) regimen of pregabalin (50 mg to 150 mg) or placebo after total knee arthroplasty.31 The Leeds Assessment of Neuropathic Symptoms and Signs54 was used to diagnose the presence of chronic neuropathic pain at 3 and 6 months after surgery. The results showed that 8.7% and 5.2% of placebo-treated patients experienced chronic neuropathic pain 3 and 6 months after surgery, respectively. In contrast, not a single patient in the pregabalin-treated group was diagnosed with chronic neuropathic pain at either follow-up.31
Pesonen et al. randomly assigned 75 elderly patients (all 75 years or older) to receive either 150 mg of pregabalin before surgery and 75 mg of pregabalin BID for 5 postoperative days or placebo.53 Elderly patients in this study who received pregabalin consumed fewer supplemental analgesics in the acute hospital period and had lower confusion assessment scores on postoperative day 1. The incidence of pain during movement was significantly lower in the pregabalin group 3 months after surgery.53Table 4 presents the odds ratios for the outcomes reported in the 3 pregabalin trials. Within the 2 studies that could be included in the meta-analysis, pregabalin caused a very large reduction in the development of CPSP (pooled OR 0.09; 95% CI, 0.02 to 0.79; P = 0.007).
Six of the 11 trials included a long-term functional outcome measure or disability assessment.31,34,45,47–49 These studies used self-report questionnaires to measure the impact of perioperative gabapentin and pregabalin on daily function in the long-term. The 4 gabapentin trials assessed this outcome by asking the patients, “What impact does pain currently have on your daily activities?”45,47–49
Four of the 6 trials found that perioperative gabapentin/pregabalin administration improved long-term functional outcomes. Two gabapentin trials reported that a single 1200-mg dose of gabapentin was associated with improved daily functioning 1 month after inguinal herniorrhaphy47 and 1 and 3 months after total hysterectomy.48 Two pregabalin trials31,34 used valid and reliable tools to measure postoperative functional disability. Three months after lumbar discectomy the Roland Morris disability score was significantly lower in the patients who received perioperative pregabalin (2.7 ± 2.4) than in those who received placebo (5.6 ± 4.8).34 Using scores from the Knee Osteoarthritis Outcome Score—Physical Function Short-form (KOOS–PS),55 Buvanendran et al.31 reported that patients who were diagnosed with chronic pain at 6 months (all placebo treated) had significantly worse KOOS–PS knee scores (49 ± 16.2) than did pregabalin-treated patients (12.4 ± 5.5). The KOOS–PS knee scores of the pregabalin-treated patients were also significantly better when compared with an age-matched nonchronic pain placebo cohort (25.7 ± 7.2).31
We systematically reviewed the published literature on the development of CPSP (≥2 months after surgery) after perioperative gabapentin or pregabalin administration. Our search yielded 11 trials published between 2002 and 2011. Of the 11 trials published, 8 were perioperative gabapentin trials, 4 of which (i.e., 50%) found that gabapentin decreased the incidence of chronic pain that persisted for more than 2 months after surgery. All pregabalin trials (3 of 3) demonstrated that pregabalin decreased the incidence of CPSP, and 2 of those trials also found an improvement in postsurgical patient function. These findings in individual trials were confirmed by our meta-analysis, which found that gabapentin and pregabalin caused an overall moderate-to-large reduction in CPSP.
The randomized controlled trials included in this systematic review are of moderate to high quality (mean Delphi score = 7.5/9). Fifty percent of the gabapentin trials and 100% of the pregabalin trials demonstrated a preventive effect with respect to the incidence/intensity of chronic postsurgical pain. This is compelling, but early, evidence suggesting that the reduction in CPSP may be linked to the perioperative administration of these medications. However, there are several shortcomings in the literature reviewed.
All 11 trials had small sample sizes and appeared to be underpowered for the secondary outcomes related to the incidence and severity of CPSP. The trial by Burke and Shorten34 is the only one that powered the study, a priori, to detect an effect on chronic postoperative pain 3 months after surgery.34 Importantly, and in contrast to the other 10 studies, Burke and Shorten34 studied the magnitude of the change from preoperative persistent lumbar back pain to CPSP as a function of the drug intervention. The other 10 trials used patients without preexisting pain, and reported the effects of the intervention in relation to the incidence and severity of CPSP without an appropriate power calculation for this endpoint.
Overall, the meta-analysis found very promising pooled effects of gabapentin and pregabalin; the magnitude of these effects, especially with respect to pregabalin given the limited number of studies (OR 0.09), may be clinically implausible. In addition, our analysis found that publication bias might have exaggerated the reported benefits of gabapentin and pregabalin. Consequently, this meta-analysis, while promising, should not be viewed as definitive.
Of the 8 gabapentin trials included in this review, 5 of the studies used single-dose gabapentin 1 to 2 hours before surgery.45,47–50 The 3 trials that used 1200 mg gabapentin before surgery all reported that gabapentin reduced the incidence and severity of chronic pain.47,48,50 The 2 trials that used a single 600-mg gabapentin administration 2 hours before surgery failed to show any reduction in the incidence or severity of CPSP at 3 and 6 months after surgery.45,49 This is limited evidence to suggest that using a high preoperative dose of gabapentin (i.e., 1200 mg) is more effective than using low preoperative doses for the prevention of CPSP. Gabapentin at higher doses in the preoperative period may have a greater effect on blunting the peripheral and central sensitization processes that occur during surgery.
Of the 3 remaining gabapentin studies (all the studies continued gabapentin into the postoperative time period), only 152 demonstrated a significant pain reduction that persisted for 2 or more months after surgery. It has been well documented that the absorption profile of gabapentin in humans is inconsistent due to the active and saturable α-amino acid transport system.56 Thus, the bioavailability of any given dose varies from 35% to 90%.56 Without plasma samples, one cannot confirm therapeutic drug concentrations of gabapentin; no trial identified in this systematic review tested plasma levels to confirm therapeutic levels. The results from this systematic review suggest that pregabalin may have a more promising and effective role in the prevention of CPSP syndromes, given its more reliable absorption profile (≥90% bioavailability of a single dose). Finally, although the results from this review suggest that higher doses of the α-2-δ ligands may produce greater antinociceptive efficacy, higher doses also unreliably increase somnolence and confusion in the clinical setting.57,58 It is not uncommon to have patients who have been given 1200 mg of gabapentin 1 to 2 hours before surgery present in the postoperative care unit completely awake, while others are almost completely somnolent.
The factors involved in the development of CPSP are not well understood. Several observational studies have outlined highly variable rates of CPSP after total knee arthroplasty,59 total hip arthroplasty,59,60 cardiac surgery,61 mastectomy,62 inguinal hernia,63 cholecystectomy,64 and thoracotomy65,66 populations. Future studies need to elaborate on the impact that CPSP syndromes have on patient function. To that end, recommendations have been made for the assessment of core measures and domains in clinical trials focused on chronic pain.67 These recommendations include psychological, emotional, and physical variables in addition to those routinely assessed in perioperative anesthesia trials (i.e., pain incidence and severity, and analgesic consumption). Assessment of additional domains of physical function and the experience of pain during those functional activities may help to identify patient-related factors, which may impact the recovery process after surgery; these factors may also be associated with the development of CPSP.
Multimodal analgesic regimens involve the use of different classes of analgesic drugs to provide superior pain relief at rest and with movement, reduce opioid consumption, and reduce analgesic-related adverse effects.68 Using multimodal perioperative acute pain strategies (i.e., different classes of medications that act on different nociceptive afferent and efferent pathways in the perioperative setting) has become the standard of care for many surgical populations.68 These strategies have demonstrated good acute pain reductions and opioid sparing in the short term.69,70 More data that assess these regimens at preventive endpoints are needed. One study in this review compared a comprehensive multimodal perioperative regimen to placebo and found that patients treated with the multimodal regimen had a decreased incidence and severity of CPSP and used less supplemental analgesics at 3 and 6 months.52 The obvious limitation with this study and other similar studies is the inability to determine to what extent each medication affected the transition to chronic pain.
The field of human pain genetics is in its infancy. One review summarized the rapidly accumulating evidence from animal models of CPSP and studies in human twins, which showed that chronic pain was a complex heritable trait.2 Several studies have recently reported on polymorphisms in certain genes that predispose carriers to transition to pain chronicity.71–73 Burke and Shorten34 attempted to link their findings to known human genetic polymorphisms associated with pain. They did not report significant associations with GCH1 or OPRM1 in the 38 patients followed. However, there were several shortcomings to the genetic data presented, including too few patients, the absence of a detailed description of the assays/methods used with respect to gene mapping, and appropriate input from genetic statisticians. This information is essential for future researchers attempting to replicate and validate positive genetic findings.
The proposed mechanism of action of gabapentin and pregabalin is believed to be the selective inhibitory binding to the α2δ subunit of voltage-dependent calcium channels in activated neurons.74 The binding of gabapentin to the α2δ subunit reduces the expression of voltage-dependent calcium channels.75 A point mutation in the α2δ type 1 subunit (R217A) prevents the binding of gabapentin to the calcium channel.76 The analgesic properties of both gabapentin and pregabalin are greatly reduced in mice expressing this point mutation.77 The mutation also prevents the ability of gabapentin to reduce calcium channel expression.75
Several lines of evidence suggest that this high-affinity site contributes to, but may not fully account for, the analgesic properties of gabapentin. The increased expression of the α2δ subunit that occurs in animal models of hyperalgesia is not a prerequisite for the short-term analgesic actions of gabapentin.78 In addition, a comparison of the antinociceptive properties of gabapentin and stereoisomeric analogues of gabapentin revealed a stereospecific analgesic effect of some but not all of the gabapentin analogues;79 but surprisingly, some of the gabapentin analogues with high affinity for the α2δ subunit did not have antinociceptive properties.
Some evidence suggests that the α2δ subunit also regulates synaptogenesis through mechanisms that are independent of Ca2+ channel function.80 Specifically, the α2δ subunit is a receptor for thrombospondins, proteins that are secreted by astrocytes and promote synapse formation.81 Gabapentin disrupts the interaction between thrombospondins and the α2δ subunit, resulting in decreased synapse formation.80 The disruption of α2δ subunit-mediated synaptogenesis by gabapentin may also contribute to the analgesic effects of gabapentin and pregabalin, particularly for the treatment of chronic pain.
Gabapentin and pregabalin have been proposed to act through a wide variety of mechanisms beyond inhibiting the actions of the α2δ subunit protein. Gabapentin inhibits glutamate release, increases the activity of N-methyl-D-aspartate receptors, inhibits the activity of voltage-gated sodium channels, and enhances the activity of voltage-gated potassium channels.82 Additionally, prolonged exposure to gabapentin can increase the amplitude of a tonic inhibitory GABAergic conductance83 that may regulate pain processes.84 However, it remains to be determined whether these mechanisms contribute to the analgesic effects of gabapentin and pregabalin.
Our systematic review found promising results for gabapentin with respect to the reduction of CPSP. Commonalities among the 4 positive studies should be explored in future trials given that there appears to be emerging basic science data to support its plausibility with respect to the prevention of CPSP. The 3 pregabalin trials included in this systematic review reported even greater promise in preventing the conversion from acute pain to CPSP. The improved absorption profile of pregabalin may be a primary reason for its improved efficacy. The study of the antecedent patient-related factors that may also predict the development of CPSP is important, and future studies should expand current outcome domains. Appropriate measures of psychological and physical functioning should be included, along with measures of chronic pain incidence and severity. Given the limited number of studies identified in our review, the clinical heterogeneity of the trials identified, and the suggestion that a publication bias may be present, future well-designed, appropriately powered studies are needed to clarify whether gabapentin and pregabalin have a perioperative role in the prevention of CPSP.
Hance Clarke is supported by a Canadian Institutes of Health Research PhD Fellowship Award. Hance Clarke and Duminda Wijeysundera are supported by Merit Awards from the Department of Anesthesia at the University of Toronto. Duminda Wijeysundera is supported by a Clinician Scientist Award from the Canadian Institutes of Health Research. Joel Katz is supported by a Canada Research Chair in Health Psychology at York University.
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