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The Prevention of Chronic Postsurgical Pain Using Gabapentin and Pregabalin: A Combined Systematic Review and Meta-Analysis

Clarke, Hance MSc, MD, FRCPC*,†,‡; Bonin, Robert P. PhD§; Orser, Beverley A. MD, PhD, FRCPC†,‡; Englesakis, Marina BA MLIS; Wijeysundera, Duminda N. MD, PhD, FRCPC*,‡,¶,#; Katz, Joel PhD**

doi: 10.1213/ANE.0b013e318249d36e
Analgesia
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SDC

BACKGROUND: Many clinical trials have demonstrated the effectiveness of gabapentin and pregabalin administration in the perioperative period as an adjunct to reduce acute postoperative pain. However, very few clinical trials have examined the use of gabapentin and pregabalin for the prevention of chronic postsurgical pain (CPSP). We (1) systematically reviewed the published literature pertaining to the prevention of CPSP (≥2 months after surgery) after perioperative administration of gabapentin and pregabalin and (2) performed a meta-analysis using studies that report sufficient data. A search of electronic databases (Medline, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, IPA, and CINAHL) for relevant English-language trials to June 2011 was conducted.

METHODS: The following inclusion criteria for identified clinical trials were used for entry into the present systematic review: randomization; double-blind assessments of pain and analgesic use; report of pain using a reliable and valid measure; report of analgesic consumption; and an absence of design flaws, methodological problems or confounders that render interpretation of the results ambiguous. Trials that did not fit the definition of preventive analgesia and did not assess chronic pain at 2 or more months after surgery were excluded.

RESULTS: The database search yielded 474 citations. Eleven studies met the inclusion criteria. Of the 11 trials, 8 studied gabapentin, 4 of which (i.e., 50%) found that perioperative administration of gabapentin decreased the incidence of chronic pain more than 2 months after surgery. The 3 trials that used pregabalin demonstrated a significant reduction in the incidence of CPSP, and 2 of the 3 trials also found an improvement in postsurgical patient function. Eight studies were included in a meta-analysis, 6 of the gabapentin trials demonstrated a moderate-to-large reduction in the development of CPSP (pooled odds ratio [OR] 0.52; 95% confidence interval [CI], 0.27 to 0.98; P = 0.04), and the 2 pregabalin trials found a very large reduction in the development of CPSP (pooled OR 0.09; 95% CI, 0.02 to 0.79; P = 0.007).

CONCLUSIONS: The present review supports the view that perioperative administration of gabapentin and pregabalin are effective in reducing the incidence of CPSP. Better-designed and appropriately powered clinical trials are needed to confirm these early findings.

Published ahead of print March 13, 2012 Supplemental Digital Content is available in the text.

From the *Department of Anesthesia and Pain Management, Toronto General Hospital, Toronto, Ontario, Canada; †Department of Anesthesia, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; ‡Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada; §Centre de Recherche Universite′ Laval Robert-Giffard, Universite′ Laval, Que′bec, Canada; ∥Library and Information Services, University Health Network, Toronto, Ontario, Canada; ¶Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada; #Institute of Health Policy Management and Evaluation, University of Toronto; **Department of Psychology and School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.

Study funding information is listed at the end of the article.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Hance Clarke, MSc, MD, FRCPC, Department of Anesthesia and Pain Management, Toronto General Hospital, 200 Elizabeth Street, Eaton North 3 EB 317, Pain Research Unit, Toronto, ON M5G 2C4, Canada. Address e-mail to hance.clarke@utoronto.ca.

Accepted December 15, 2011

Published ahead of print March 13, 2012

The development of chronic postsurgical pain (CPSP) is an unfortunate consequence of surgery that adversely impacts the patient's quality of life. Efforts to prevent the establishment of CPSP include perioperative administration of a variety of drugs. We systematically reviewed the published literature pertaining to the prevention of CPSP after perioperative interventions using gabapentin and pregabalin. After defining preventive analgesia we present the results of the systematic review and meta-analysis, followed by a discussion of the results, including the limitations of the current literature and future directions for clinical trials. Finally, we provide an overview of recent basic science studies that suggest novel mechanisms that may be responsible for some of the behavioral properties of gabapentin and pregabalin.

The factors that influence the transition from acute postoperative pain to CPSP have yet to be elucidated. CPSP has been defined as pathological pain that persists for longer than 2 months after surgery.1 Several patient-related and surgical factors have been linked to the development of CPSP.2 The most consistent patient factor is the presence and/or intensity of preoperative and postoperative pain.35 Because moderate to severe postoperative pain is a frequent occurrence after surgery,6 novel drugs such as gabapentin and pregabalin in addition to traditional opioids are administered with the aim of providing superior pain relief at rest and with movement, reducing opioid consumption and reducing analgesic-related adverse effects.79 If drugs, such as gabapentin and pregabalin, can prevent the establishment of surgery-induced central sensitization and can decrease postoperative pain,1012 then these drugs, given during the perioperative period, may also play a role in preventing the transition of acute pain to chronic pain.13,14

Neuropathic pain, which is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system,15 has been implicated as a major contributor to the development of CPSP.2,16 Given that both gabapentin and pregabalin are front-line treatments for patients suffering from established chronic neuropathic pain,17,18 it is plausible that these drugs, when used in the perioperative setting, may be of benefit in reducing the incidence and/or intensity of chronic pain.

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PREVENTIVE ANALGESIA

Preventive analgesia has evolved from preemptive analgesia by shifting the focus from blocking solely noxious preoperative stimuli12,1921 to a broader conceptualization involving blocking noxious stimuli across the entire perioperative period.13,14,22 A preventive analgesic effect is demonstrated when postoperative pain and/or analgesic consumption is reduced in relation to an intervention, as long as the effect is observed at a time that exceeds the expected clinical duration of action of the target drug. We have defined a preventive analgesic effect as one that is demonstrated when postoperative pain and/or analgesic use are reduced beyond 5.5 half-lives of the target drug.12,13,22 This requirement ensures that the observed effects are not direct analgesic effects.12,13

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GABAPENTIN (NEURONTIN, PFIZER, INC.) AND PREGABALIN (LYRICA, PFIZER, INC.)

Gabapentin, a structural analog of γ-aminobutyric acid (GABA), was initially used as an anticonvulsant in the late 1980s. Clinically, gabapentin demonstrated poor efficacy as an anticonvulsant.23 The antinociceptive properties of this drug, along with the advantage of producing only mild side effects, made gabapentin an attractive therapeutic option for pain specialists who used other anticonvulsants with significant adverse events (i.e., carbamazepine) for chronic pain conditions.23 By the late 1990s, gabapentin had become a first-line treatment for patients who suffered from chronic neuropathic pain.24,25 In recent years, gabapentin has been used widely as an adjunct for the treatment of acute postsurgical pain. Several meta-analyses have confirmed the efficacy of gabapentin in reducing postoperative opioid use and pain.2628

Pregabalin is structurally similar to gabapentin and was also marketed primarily for epilepsy and neuropathic pain. Pregabalin (S-[+]-3-isobutylgaba) was designed as a lipophilic GABA analog substituted at the 3′ position to facilitate diffusion across the blood–brain barrier.29,30 Pregabalin has also been found to be effective at reducing acute postoperative pain.10,3136

Studies have reported the effects of the gabapentinoids in the prevention of CPSP. We systematically reviewed the published, clinical trials pertaining to the prevention of CPSP (≥2 months after surgery) after perioperative interventions using gabapentin and pregabalin.

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METHODS

Search Strategy

A search strategy was developed using the Medline database and subsequently translated into the remaining databases. The following databases were searched: Medline, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts (IPA, accessed via the OvidSP platform) and Cumulative Index to Nursing & Allied Health Literature (CINAHL, accessed via the EbscoHost platform). The search strategy contained 3 components: pregabalin or gabapentin terms, including generic and trade names, chemical abstract service (CAS) registry numbers, MeSH or Emtree or text words; preemptive, preventive, or perioperative terms, using MeSH or Emtree or text words; and finally, chronic pain terms, using MeSH or Emtree or text words (Appendix 1). These 3 components were combined using the Boolean operator, “AND,” to obtain the intersection of the 3 sets; the results were limited to human subjects and English-language articles. All databases were searched in their entirety to the end of June 2011; however, the Embase database was limited to searches from 2006 to 2011.

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Inclusion Criteria

All clinical trials were evaluated according to the following inclusion criteria for entry into the present review: randomized assignment of patients to treatment groups; double-blind assessments of pain and analgesic use; report of pain using a reliable and valid measure; report of analgesic consumption; and an absence of design flaws, methodological problems, or confounders that render interpretation of the results ambiguous.22 Trials that did not fit the definition of preventive analgesia14 and did not assess chronic pain at 2 or more months after surgery were excluded.

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Data Extraction

Two reviewers (H.C. and J.K.) independently reviewed the abstracts of each reference identified by the above search strategy, independently evaluated each included study for content, and completed a data extraction table that included relevant data. Studies were included if both reviewers agreed that the studies met the inclusion criteria.

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Assessment of the Methodological Quality and Risk of Bias

Two reviewers (H.C. and J.K.) independently assessed the methodological quality of the included trials according to the Delphi criteria list.38 The Delphi list identifies 9 criteria for quality assessment (Table 1).

Table 1

Table 1

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Statistical Analysis

Meta-analysis was used to calculate pooled effects of gabapentin or pregabalin on the development of chronic pain at 3 to 6 months after surgery. For cases in which a study reported the rates of chronic pain development of chronic pain at both 3 and 6 months, we included only 6-month event rates in the statistical analysis. Summary effects were expressed as pooled odds ratios (OR) with associated 95% confidence intervals (CI). Initially, statistical heterogeneity was assessed using the I2 statistic,39,40 which describes the proportion of total variation explained by between-studies variation instead of chance. Higher I2 statistics imply more heterogeneity between studies than would be expected by chance alone. In the presence of low heterogeneity (I2 ≤ 25%), pooled ORs were calculated under the fixed-effects model; otherwise, the random-effects model was used. In addition, a subgroup analysis based on the drug administered was performed, with a statistical test-of-interaction being used to assess for subgroup differences. Finally, funnel plots41 and the test of Harbord et al.42 were used to test for any publication bias.

Statistical significance was defined by a 2-sided P value <0.05, and all analyses were performed using Stata Version 11.2 (StataCorp Inc., College Station, TX). Our review complies with the guidelines set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA).43,44

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RESULTS

Search Results

The database search yielded 474 citations, of which 64 studies were retrieved and examined; 11 studies met the inclusion criteria (Fig. 1).31,34,4553

Figure 1

Figure 1

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Assessment of Methodological Quality

Table 1 summarizes the assessment of methodological quality of the 11 clinical trials. All studies were double-blind, randomized, controlled trials with specified eligibility criteria listed. Outcome assessors were blinded in all studies. Only 1 study reported an intention-to-treat analysis for postoperative outcomes.31

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Study Characteristics

The 11 studies are summarized in Table 2. The studies examined the preventive effects of gabapentin or pregabalin on CPSP (≥2 months after surgery) and were published between October 2002 and June 2011. A total of 930 patients were included in the trials. The sample sizes ranged from n = 30 to n = 240, with a median of n = 50. The surgical populations studied were as follows: breast surgery,46,51,52 total knee arthroplasty,31 total hip arthroplasty,49 cesarean delivery,45 thyroidectomy,50 cardiac surgery,53 lumbar discectomy,34 inguinal herniorraphy,47 and abdominal hysterectomy.48 Eight trials studied the effects of gabapentin,4552 and 3 trials studied the effects of pregabalin31,34,53 on the prevention of pain that persisted for at least 2 months after surgery.

Table 2

Table 2

The clinical heterogeneity is considerable among the 11 trials presented in this systematic review and meta-analysis. The studies using gabapentin varied with respect to the dosing regimen and the perioperative administration. Five of the 8 gabapentin studies administered a single preoperative dose of gabapentin,45,4750 3 studies used a single preoperative dose of 1200 mg,47,48,50 and the 2 other studies used a single 600-mg preoperative dose.45,49 The remaining 3 studies started gabapentin administration before surgery and continued either 1200 mg of gabapentin daily for 8 or 10 days,51,52 or 300 mg for 10 days postoperatively.46 Finally, the pregabalin studies were also variable with respect to the timing and dosing administered. Two studies gave a 300-mg preoperative dose and either continued the drug for 2 more doses (150 mg at 12 hours and 24 hours after surgery)34 or continued a regimen of 50 to 150 mg of pregabalin daily for 2 weeks after surgery.31 The third pregabalin trial gave a single preoperative dose of 150 mg followed by 75 mg of pregabalin twice daily for 5 days after surgery.53

Eight of the included trials31,45,46,4953 reported sufficient data for inclusion in a meta-analysis, the results of which are presented in Figure 2. There was moderate overall statistical heterogeneity (I2 = 36.6%), which was explained in part by the specific drug administered. Specifically, heterogeneity was lower within the subgroups of gabapentin (I2 = 30.5%) and pregabalin studies (I2 = 0%). There was statistical evidence (P = 0.05) of different effects across the 2 subgroups (Fig. 2). Notably, funnel plots of the 8 studies included in the meta-analysis suggest a publication bias (Fig. 3); this raises the possibility that several negative trials of gabapentin or pregabalin have not been published. This possibility of publication bias was supported by formal statistical testing that bordered on significance (P = 0.051).

Figure 2

Figure 2

Figure 3

Figure 3

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Preventive Effects of Gabapentin on CPSP

Of the 8 gabapentin trials, 447,48,50,52 reported that the perioperative use of gabapentin resulted in a lower incidence of pain and/or lower analgesic requirements at long-term follow-up (≥2 months after surgery) (Table 3). Brogly et al.50 administered 1200 mg of gabapentin (n = 25) or placebo (n = 25) 2 hours before total thyroidectomy surgery. Patients also received superficial cervical plexus blocks; a significant difference in opioid consumption or pain scores was not observed during the first 24 hours after surgery.50 Using the neuropathic pain diagnostic questionnaire (DN2) as a diagnostic tool, Brogly et al.50 found that 30% (7 of 24) of patients reported neuropathic pain in the placebo group in comparison with 4% (1 of 23) of gabapentin-treated patients at 6 months after surgery.

Table 3

Table 3

Using a similar design (i.e., 1200 mg gabapentin (n = 30) 1 hour before inguinal herniorrhaphy with spinal anesthesia), Sen et al.47 reported that patients who received gabapentin had less intense pain at 1, 3, and 6 months after surgery. The gabapentin-treated patients reported less interruption with their activities of daily living 1 month postsurgery.47

In another study by Sen et al.,48 40 women were randomly assigned to receive placebo (n = 20) versus intraoperative ketamine until the end of surgery (n = 20) versus 1200 mg gabapentin 1 hour before total abdominal hysterectomy. Patients who received gabapentin had lower pain scores and consumed fewer opioids in the acute postoperative period (24 hours). The incidence of incisional pain and pain intensity at 1, 3, and 6 months after surgery was significantly lower in the gabapentin group than in the ketamine and control groups.48

Finally, Fassoulaki et al.52 found a reduction in pain and analgesic consumption using a multimodal analgesic regimen, which involved 50 women who underwent breast cancer surgery and were randomly assigned to receive 1200 mg gabapentin (for 8 postoperative days) starting the evening before surgery, a eutectic mixture of local anesthetic cream (for 3 postoperative days), and ropivacaine in the wound (at wound closure) (n = 25) and were compared with placebo (n = 25).52 The group that received the multimodal analgesic regimen used significantly less paracetamol and adjunctive pain medications than did controls; they also reported lower pain scores at rest and with movement on early postoperative days. At 3 months after surgery, the patients who were in the multimodal analgesia group reported a significantly lower incidence of chronic pain (82% versus 45%) and used fewer supplemental analgesics (23% versus 0%) than did patients who received only placebo. Six months after surgery, 57% of control patients complained of chronic pain in comparison with 30% in the treatment group; however, this was not a statistically significant finding.

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).

Table 4

Table 4

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Preventive Effects of Pregabalin on CPSP

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

Burke and Shorten34 randomly assigned patients to receive either pregabalin (300 mg at 90 minutes preoperatively and 150 mg at 12 and 24 hours postoperatively) (n = 20) or placebo (n = 20) at corresponding times in a double-blind manner while undergoing lumbar discectomy. The primary outcome measure was a change in the intensity of pain as measured by a visual analog scale from the preoperative assessment to 3-month follow-up. Visual analog scale pain scores were lower at 3 months (37.6 ± 19.6 mm) in treated patients than in controls (25.3 ± 21.9 mm).34

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).

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Functional Outcomes and Disability Assessment

Six of the 11 trials included a long-term functional outcome measure or disability assessment.31,34,45,4749 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?”45,4749

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

The remaining 2 gabapentin trials45,49 reported that a single 600-mg dose of gabapentin did not affect functional outcomes or disability 3 and 6 months after surgery.

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DISCUSSION

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.45,4750 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.7173 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.

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Novel Postulated Mechanisms of Action of Gabapentinoids

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.

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CONCLUSIONS

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.

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STUDY FUNDING

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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DISCLOSURES

Name: Hance Clarke, MSc, MD, FRCPC.

Contribution: This author designed and conducted the research study and wrote the manuscript.

Attestation: Hance Clarke has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Robert P. Bonin, PhD.

Contribution: This author helped to write the manuscript.

Attestation: Robert P. Bonin has approved the final manuscript.

Name: Beverley A. Orser, MD, PhD, FRCPC.

Contribution: This author designed and conducted the research study and wrote the manuscript.

Attestation: Beverley Orser has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Marina Englesakis, BA, MLIS.

Contribution: This author designed and conducted the research study and wrote the manuscript.

Attestation: Marina Englesakis has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Duminda N. Wijeysundera, MD, PhD, FRCPC.

Contribution: This author designed and conducted the research study and wrote the manuscript.

Attestation: Duminda N. Wijeysundera has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Joel Katz, PhD.

Contribution: This author designed and conducted the research study and wrote the manuscript.

Attestation: Joel Katz has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

This manuscript was handled by: Spencer S. Liu, MD.

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    APPENDIX 1

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