The current concept of multimodal postoperative analgesia is mainly based on the combination of opioids, nonsteroidal antiinflammatory drugs (NSAIDs) or paracetamol, small-dose ketamine, and perioperative administration of local anesthetics. The use of opioids may be limited by adverse effects, such as nausea, vomiting, excessive sedation, pruritus, and urinary retention, the incidences of which have been reported to be 25%, 20%, 3%, 15%, and 23%, respectively (1). Interventional techniques such as epidural analgesia are effective but require additional work and carry the potential risk of serious complications. NSAIDs are associated with damage to gastrointestinal mucosa, bleeding, renal toxicity, allergic reactions, and heart failure. Cyclooxygenase-2 selective NSAIDs may have prothrombotic properties, increasing the risk of stroke and myocardial ischemia. Ketamine is psychotogenic. A drug that has analgesic properties, opioid-sparing effects, possibly reduces opioid tolerance, relieves anxiety, and is not associated with the adverse effects typical for the traditional analgesics would be an attractive adjuvant for perioperative analgesia.
Gabapentin was introduced as an antiepileptic drug in 1993. It has been extensively used to treat painful neuropathies in patients with diabetic polyneuropathy, postherpetic neuralgia, and neuropathic pain in general (2). The mechanism of action of gabapentin and its successor, pregabalin is likely mediated by binding to the 21 subunits of the presynaptic voltage-gated calcium channels, which are up-regulated in the dorsal root ganglia and spinal cord after surgical trauma. Gabapentin may produce antinociception by inhibiting calcium influx via these channels, and subsequently inhibiting the release of excitatory neurotransmitters (e.g., substance P, calcitonin gene-related peptide) from the primary afferent nerve fibers in the pain pathway. Bioavailability of gabapentin varies inversely with dose. The peak plasma level is achieved 3 h after ingestion of a single 300 mg capsule. Gabapentin is not metabolized and is eliminated unchanged in the urine with an elimination half-life of 5–9 h. Because of the lack of hepatic metabolism and low protein binding, gabapentin has no known clinically relevant drug interactions (3). However, gabapentin has saturable absorption within the usual dosing. Pregabalin has a more favorable pharmacokinetic profile, including dose-independent absorption (4,5).
Gabapentin has antiallodynic and antihyperalgesic properties with only a minor effect on normal nociception (6). It reduces the hyperexcitability of dorsal horn neurons induced by tissue injury (7,8). Central sensitization of these neurons is important in chronic neuropathic pain, but also occurs after trauma and surgery. Reduction in central sensitization by an antihyperalgesic drug like gabapentin may reduce acute postoperative pain. Gabapentin may also prevent opioid tolerance (9). Both gabapentin and pregabalin have anxiolytic properties (10–13).
In recent years, gabapentin has been introduced as an adjunct in the multimodal approach to managing acute postoperative pain. Initial studies have been encouraging. However, before it can be recommended for routine clinical use more data on efficacy, dosing, adverse effect profile, ideal timing, and duration of treatment to reduce acute postoperative pain and to prevent chronic postoperative pain are needed. The aim of this systematic review was to evaluate the available literature examining the analgesic efficacy, adverse effects, and clinical utility of gabapentinoids in postoperative pain management.
METHODS
This review was performed according to the standards described in “The Quality of Reporting of Meta-analyses” (QUOROM) statement (14).
Literature Search
A systematic search was performed in the following databases: Medline (from 1966), PubMed, and Cochrane Central Register of Controlled Trials (CENTRAL) using the following words: “gabapentin or pregabalin or gabapentinoids or Lyrica or Neurontin” and “postoperative pain.” To identify additional trials, Pfizer Corporation was contacted and reference lists of reports and reviews were checked. Abstracts or unpublished observations were not considered for inclusion. Authors were not contacted for original data. There was no language restriction. The last search was performed in September 2006.
Inclusion and Exclusion Criteria
All randomized, placebo- or active-controlled clinical trials described as double-blind and restricted to humans were included. All studies had a minimum of 10 patients in each study group as recommended by L’Abbé et al. (15). The intervention considered by this review was treatment with gabapentin or pregabalin given orally, in any dose, during the perioperative period.
Data Extraction
The following items were collected on the data extraction form: 1) publication details, 2) patient population, number of patients, age, gender, surgical procedure, 3) description of intervention, 4) design, study duration and follow-up, 5) intra- and postoperative analgesics, 6) outcome measures, 7) analgesic outcome results and 8) withdrawals and adverse effects. This was performed independently by two investigators (E.T, K.H.) and reviewed by the others (E.K, V.K.). Also the sources of funding were checked to determine if the trial was sponsored by the pharmaceutical industry and, if so, whether this was reported, as recommended by the CONSORT statement (16). Study quality (randomization/allocation concealment; details of blinding measures; withdrawals and drop-outs) was evaluated using the three-item (1–5) Oxford Quality Scale (17). Validity was evaluated using the five-item (1–16) Oxford Pain Validity Scale (18). Scorings were performed independently by two reviewers (E.T, K.H.). In case of discrepancy, a third reviewer (E.K.) was consulted and consensus was reached by discussion.
Data Handling and Analysis
The three main outcome measures were pain scores, total analgesic consumption for the first 24 h, and treatment side effects. Quantitative analysis was performed for the opioid consumption on studies in which a single, perioperative dose of gabapentin was given, the duration of the postoperative observation period was at least 24 h, and the opioid consumption data were given as means, with indication of variance. For the statistical analysis, fentanyl and tramadol consumption values were scaled to arbitrary “morphine equivalent” units, using 100:1 and 1:10, respectively, as the conversion factors. The meta-analysis was calculated with the Comprehensive Meta Analysis program, version 2.2.027 (Biostat, Englewood, NJ). Based on high clinical heterogeneity across the studies, including different types of surgery, differences in anesthesia, opioids, and adjunctive analgesics, the random effects model was chosen. The significance level was set at 0.05. Different gabapentin doses (19) and dosing times (20) in a single study were handled as subgroups within the study. The studies were combined using the random effects model assuming a common among-study variance component across subgroups. A possible dose-response on the opioid-sparing effect of a single-dose of gabapentin was analyzed using metaregression (Comprehensive Meta Analysis, version 2.2.027, Biostat) after a single 300–1200 mg preoperative dose of gabapentin 1–2 h before surgery for the first 24 h. Pain intensity difference between the control and gabapentin groups (PIDc-g) was calculated by deducting the pain intensity in the treatment group from the value in the control group at different time points. The number-needed-to-treat was calculated for the reduction of the incidence of nausea, vomiting, and urinary retention caused by gabapentin in comparison to placebo, using the pooled raw data method. The number-needed-to-harm was calculated for the increase of the incidence of sedation and dizziness caused by gabapentin in comparison with placebo during the 24-h follow-up after a single 1200 mg dose of gabapentin administered 1–2 h preoperatively, using the pooled raw data method.
RESULTS
The searches identified 52 possible titles, of which 30 were excluded (Fig. 1). Twenty-six of these were not clinical trials. Two studies examined healthy volunteers (7,21) and one was an abstract (22). In a small pilot study about gabapentin and postoperative delirium, there were only nine patients in the gabapentin group. This study did not meet the inclusion criteria (23). A total of 22 randomized, controlled, double-blind clinical trials of perioperative administration of gabapentin or pregabalin for postoperative pain relief were identified (10,19,20,24–42). All studies are presented in Table 1. A more detailed description of all studies is presented in the Appendix available on the journal’s website (http://anesthesia-analgesia.org). A total of 1909 patients were studied, 786 received gabapentin, and 99 received pregabalin (30). The patients’ ages ranged from 18 to 74 yr. There were 1265 women and 509 men. In three studies gender was not reported. Gabapentin doses ranged from 300 to 1200 mg. In the pregabalin study the dose was 50 or 300 mg. Thirteen of the studies were single-dose trials and nine examined multiple dosing of gabapentin or pregabalin. The duration of the trials varied between 4 h and 10 days. In the only trial in which pregabalin was studied (30), it was administered postoperatively after dental surgery. Pregabalin 300 mg was better than ibuprofen regarding the patients’ satisfaction with pain relief and duration of analgesia. A combination of gabapentin and rofecoxib was given in one treatment arm, which was not included in the present analysis (31).
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Figure 1.:
Flow diagram of the review. RCT = randomized, controlled trials.
Table 1: Randomized, Double-Blind, Controlled Studies of Gabapentin/Pregabalin in Postoperative Pain
Table 1: (continued)
Table 1: (continued)
Table 1: (continued)
Two studies disclosed partial pharmaceutical industry sponsorship (26,30). Pfizer provided the medication in another study (25). Two studies received funding independent from the pharmaceutical industry (10,31) and in the other studies the source of funding was not reported. There were no differences in the positive and negative outcomes between the sponsored and independent studies.
The PIDc-g at rest and on movement during the first 24 h after a single 1200 mg dose of gabapentin administered 1–2 h before surgery are presented in Figure 2. There was wide variation in pain at rest after different types of surgery. Pain on movement after a single preoperative dose of gabapentin was studied in only two trials (24,38). After hysterectomy (38) the PIDc-g was greatest in the early postoperative phase and it decreased after 12 h. The difference was not so clear after thyroidectomy (24), in which pain on movement was measured after swallowing.
Figure 2.:
Pain intensity difference between the control and gabapentin groups (PIDc-g) at rest (panel A) and on movement (panel B) on VAS 0–100 during 24 h observation after a single 1200 mg dose 1–2 h before surgery. Each line represents the difference in the pain intensities between the two groups as a function of time. ACL = anterior cruciate ligament.
Five of 22 studies reported the time to first analgesic request as an outcome (10,27,28,36,40). Two of these studies (10,40) found a difference favoring gabapentin 1200 mg over placebo. A meta-analysis was considered inappropriate because of clinical heterogeneity of the studies.
The opioid-sparing effect during the first 24 h after a single preoperative dose of gabapentin 300–1200 mg, administered 1–2 h before surgery, ranged from 20% to 62%. Figure 3 shows the results of the meta-analysis of the opioid-sparing effect. The combined effect of a single dose of gabapentin on opioid consumption was equivalent to reduction of 30 ± 4 mg of morphine (mean ± 95% CI) consumed during the first 24 h after the surgery. Heterogeneity among the studies was significant (Q = 93, df = 11, P < 0.0001). The dose of gabapentin did not seem to be an important source of the heterogeneity. In metaregression, the gabapentin-induced reduction in the 24-h opioid consumption was not significantly dependent on the gabapentin dose (data not shown).
Figure 3.:
Effect of preoperative gabapentin on postoperative opioid consumption. A meta-analysis was performed for the opioid consumption in studies in which a single preoperative dose of gabapentin was given, the duration of the postoperative observation period was at least 24 h, and opioid consumption data were given as means with indication of variance. For the meta-analysis, fentanyl and tramadol consumption values were converted to arbitrary “morphine equivalent” units, using ratios of 100:1 and 1:10, respectively (for details of the meta-analysis, see the Methods section). For each study and gabapentin dose, the WMD of the opioid consumption with standard error is tabulated. The rectangles indicate the WMD with the 95% CI illustrated with a horizontal line. The vertical lines show the scale for WMD from −8 to 0 (favoring gabapentin) and from 0 to +8 (favoring control treatment). The combined effect (using random effects model) of gabapentin on the opioid consumption (with 95% CI) is indicated with the large rectangle in the bottom line.
Long-term effects were reported in five trials (Table 2). The number of patients ranged from 46 to 103 per study. Administration of gabapentin continued 2–10 days after surgery. Follow-up times varied from 1 to 6 mo. Three studies were of abdominal hysterectomies and two of mastectomies. Four of five studies investigating the long-term effects found a significant difference in acute pain favoring gabapentin in comparison to placebo. Two of these studies found a difference in chronic pain, whereas the other two did not (Table 2). Fassoulaki et al. (27) found more burning pain 1 mo after mastectomy in the placebo group compared with that in the perioperative gabapentin group. In another trial (28) mastectomy patients were treated with perioperative gabapentin, EMLA cream, and intraoperative ropivacaine or placebo. A significant reduction of the total incidence of pain and analgesic consumption in the treatment group compared with placebo group was found at 3 mo after surgery, but the difference disappeared by 6 mo. Fassoulaki et al. (29) also reported less pain in the surgical area and reduced pain intensity with perioperative gabapentin 1 mo after abdominal hysterectomy. In this trial there was no difference in acute pain between the active treatment and placebo groups.
Table 2: Studies on Long-term Effects of Gabapentin (1–3 mo Follow-Up)
Adverse Effects
Five studies provided data on nausea (265 patients), 4 on vomiting (215 patients), 3 on sedation (140 patients), 4 on dizziness (190 patients), and 2 on urinary retention (100 patients) during 20–24 postoperative hours after a single dose of gabapentin 1200 mg administered 1–2 h before surgery. When all data were combined, the numbers-needed-to-treat to prevent nausea, vomiting, or urinary retention were 25, 6, and 7, respectively. The numbers-needed-to-harm for gabapentin to produce excessive sedation or dizziness were 35 and 12, respectively. There were no significant differences in any other adverse effects reported in the original trials.
Anxiolytic Effects
Two trials reported anxiolytic properties of gabapentin. Menigaux et al. (10) measured anxiety on a visual analog scale (VAS) 1–2 h after premedication with gabapentin and found significantly lower preoperative VAS anxiety scores in the gabapentin group compared with placebo. According to Rorarius et al. (36), 15 mg of oxazepam was more effective in relieving preoperative anxiety than 1200 mg of gabapentin.
DISCUSSION
The aim of this systematic review was to assess the analgesic efficacy, adverse effects and clinical value of gabapentin and pregabalin in postoperative pain management. Pain relief was significantly better in the gabapentin groups compared with the control group. The opioid-sparing effect during the first 24 h after a single preoperative dose of gabapentin 300–1200 mg administered 1–2 h before surgery ranged from 20% to 62%. When single gabapentin dose studies were combined, gabapentin treatment reduced opioid consumption by 30 ± 4 mg of morphine equivalents during the first 24 postoperative hours. However, heterogeneity among the studies was significant. Gabapentin also reduced opioid-related adverse effects, such as nausea, vomiting, and urinary retention. Adverse effects related to gabapentin were negligible. Although it is a clinically relevant variable, time to first analgesic request was only reported in few studies.
In the first review of gabapentin and pregabalin in postoperative pain (43), there was a significant reduction in analgesic requirements and pain during the first 24 h in six of seven studies, without major adverse effects. A review of gabapentin in acute and chronic pain (44) concluded that there is no role for gabapentin in the management of acute pain, but the statement was based on one study (26). Seib and Paul (45) reported decreased pain scores and analgesic consumption in the first 24 h after surgery, but could not demonstrate a significant reduction in adverse effects. Hurley et al. (46) showed that perioperative administration of gabapentin decreased both pain intensity scores and opioid consumption for up to 24 h. Gabapentin was associated with a modest increase in sedation, but with no other adverse effects (46). A review of 16 studies by Ho et al. (47) demonstrated that a single preoperative dose of gabapentin (1200 mg or less) reduced pain intensity, opioid consumption, and opioid-related adverse effects such as vomiting and pruritus for the first 24 h postoperatively. After this, six more randomized, controlled trials (RCTs) have been published.
In the trials included in the present analysis pain on movement was measured in only 13 of 22 trials (59%). A significant difference favoring gabapentin was found in 9 of 13 studies. It is possible that gabapentin could be particularly useful in movement-related pain after surgical trauma because of its ability to prevent central neuronal sensitization. It can be speculated that measuring VAS scores on movement would be more informative than measuring them only at rest. The pain intensity and type of surgery seem to be important sources for the clinical heterogeneity across the studies in this review.
The opioid-sparing effect was not related to the gabapentin dose in our meta-analysis. This may be due to the small number of doses and significant clinical heterogeneity among the currently available studies. In one RCT, increasing the dose from 300 mg to 600–1200 mg improved the analgesic and opioid-sparing effect of gabapentin, but there were no significant differences between the effects of the higher doses (19). This could either indicate lack of a dose– response relationship or a ceiling effect. Conversely, experience from treating chronic pain and epilepsy with gabapentin indicates that initiating gabapentin treatment with high doses causes clinically relevant sedation and dizziness during the first days of the treatment (48). It is unclear why these effects have not been reported in the perioperative setting.
There were 1265 women (71%) and 509 men (29%). In three trials, gender was not reported. Nine trials studied only women (hysterectomies or mastectomies). Rosseland and Stubhaug found a striking effect of gender on the intensity of acute pain after knee arthroscopy (49) with women reporting more pain in the early postoperative period. They expressed concern that the gender difference was ignored as a confounding factor in pain trials. In our review, there was only one study in which a gender difference in pain intensity and opioid consumption was reported (33). Pandey et al. studied patients undergoing laparoscopic cholecystectomy, in which men and women were evenly distributed among gabapentin and placebo groups. They found that, in the placebo group, pain intensity at 12–24 h postoperatively was significantly higher in women than in men. Fentanyl requirements were also significantly higher in women. These findings should be considered when interpreting previous RCTs and planning new pain trials.
In recent years, there has been growing interest in adjuvant drugs that have an opioid-sparing effect. NSAIDs have been shown to decrease opioid-related adverse effects, such as postoperative nausea, vomiting, and sedation (50), but they have well-known disadvantages such as gastrointestinal bleeding and renal complications. Paracetamol (acetaminophen), which is considered to be quite safe, also decreases morphine consumption, but it has no effect on the incidence of morphine-related adverse effects after major surgery (51). Ketamine is effective in reducing morphine requirements and postoperative nausea and vomiting, but has adverse effects of its own (52). Dextromethorphan, a weak N-methyl-d-aspartate-antagonist, also has opioid-sparing effects (53). However, the authors of these two reviews emphasize the heterogeneity of their data, and the results should be interpreted with caution. The present review indicates that gabapentin and pregabalin have a clinically significant opioid-sparing effect with less opioid-related adverse effects. The adverse-effect profiles of gabapentin and pregabalin compare favorably with other adjuvant analgesics.
Chronic pain is common after operations such as amputation, inguinal hernia surgery, breast surgery, gallbladder surgery, and lung surgery. For example postthoracotomy pain syndrome may have an incidence of more than 50% (54). In our review, long-term pain was studied in only five trials (27–29,31,42) and all patients were women. Fassoulaki et al. found a significant difference in chronic pain favoring gabapentin in their three trials (27–29), but Gilron et al. (31) and Turan et al. (42) reported no significant benefit to gabapentin in preventing chronic pain. There was wide variation in the number of patients (46–103) and duration of treatment (2–10 days). Only a few studies have explored the effects of other than classical analgesics (opioids, NSAIDs, local anesthetics) on the prevention of chronic postsurgery pain. Reuben et al. treated patients undergoing breast cancer surgery with venlafaxine, an antidepressant that increases the synaptic availability of both serotonin and noradrenalin. The treatment was started preemptively the night before surgery and was continued for up to 2 wk (55). No beneficial effect of venlafaxine was found on either acute postoperative pain or analgesic consumption, but there was a significant reduction in the incidence of postmastectomy pain at 6 mo. The comparable efficacy of various drugs (e.g., venlafaxine versus gabapentin) in the prevention of chronic pain is still unclear. Optimal dosing and duration of administration also need further investigation. It would also be important to determine whether gabapentin could prevent or attenuate postamputation phantom limb pain, postthoracotomy pain syndrome, or other common chronic pain states attributable to surgery.
In conclusion, gabapentin and pregabalin are effective in reducing pain intensity, opioid consumption and opioid-related adverse effects after surgery. Gabapentin and pregabalin have very few adverse effects of their own. Because of the heterogeneous data of these studies, no conclusions about the optimal dose and duration of the treatment can be drawn. The efficacy of gabapentinoids in preventing chronic pain needs to be elucidated in future studies.
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