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.
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).
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.
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 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.
1. Dolin SJ, Cashman JN. Tolerability of acute postoperative pain management: nausea, vomiting, sedation, pruritis, and urinary retention. Evidence from published data. Br J Anaesth 2005;95:584–91.
2. Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60:1524–34.
3. Rose MA, Kam PC. Gabapentin: pharmacology and its use in pain management. Anaesthesia 2002;57:451–62.
4. Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia 2004;45:13–18.
5. Guay DR. Pregabalin in neuropathic pain: a more “pharmaceutically elegant” gabapentin? Am J Geriatr Pharmacother 2005;3:274–87.
6. Iannetti GD, Zambreanu L, Wise RG, et al. Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans. Proc Natl Acad Sci USA 2005;102:18195–200.
7. Werner MU, Perkins FM, Holte K, et al. Effects of gabapentin in acute inflammatory pain in humans. Reg Anesth Pain Med 2001;26:322–8.
8. Gilron I. Is gabapentin a “broad-spectrum” analgesic? Anesthesiology 2002;97:537–9.
9. Gilron I, Biederman J, Jhamandas K, Hong M. Gabapentin blocks and reverses antinociceptive morphine tolerance in the rat paw-pressure and tail-flick tests. Anesthesiology 2003;98:1288–92.
10. Menigaux C, Adam F, Guignard B, et al. Preoperative gabapentin decreases anxiety and improves early functional recovery from knee surgery. Anesth Analg 2005;100:1394–9.
11. Pollack MH, Matthews J, Scott EL. Gabapentin as a potential treatment for anxiety disorders. Am J Psychiatry 1998;155:992–3.
12. Chouinard G, Beauclair L, Belanger MC. Gabapentin: long-term antianxiety and hypnotic effects in psychiatric patients with comorbid anxiety-related disorders. Can J Psychiatry 1998;43:305.
13. Rickels K, Pollack MH, Feltner DE, et al. Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam. Arch Gen Psychiatry 2005;62:1022–30.
14. Moher D, Cook DJ, Eastwood S, et al. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 1999;354:1896–900.
15. L’Abbé LA, Detsky AS, O’Rourke K. Meta-analysis in clinical research. Ann Intern Med 1987;107:224–33.
16. Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel group randomized trials. BMC Med Res Methodol 2001;1:2.
17. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality or reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12.
18. Smith LA, Oldman AD, McQuay HJ, Moore RA. Teasing apart quality and validity in systematic reviews: an example from acupuncture trials in chronic neck and back pain. Pain 2000;86:119–32.
19. Pandey CK, Navkar DV, Giri PJ, et al. Evaluation of the optimal preemptive dose of gabapentin for postoperative pain relief after lumbar diskectomy: a randomized, double-blind placebo-controlled study. J Neurosurg Anesthesiol 2005;17:65–8.
20. Pandey CK, Singhal V, Kumar M, et al. Gabapentin provides effective postoperative analgesia whether administered pre-emptively or post-incision. Can J Anaesth 2005;52:827–31.
21. Dirks J, Petersen KL, Rowbotham MC, Dahl JB. Gabapentin suppresses cutaneous hyperalgesia following heat-capsaicin sensitization. Anesthesiology 2002;97:102–7.
22. Gregg AK, Francis S, Sharpe P, Rowbotham DJ. Analgesic effect of gabapentin premedication in laparoscopic cholecystectomy: a randomized double-blind placebo-controlled trial [abstract]. Br J Anaesth 2001;87:174P.
23. Leung JM, Sands LP, Rico M, et al. Pilot clinical trial of gabapentin to decrease postoperative delirium in older patients. Neurology 2006;67:1251–3.
24. Al-Mujadi H, A-Refai AR, Katzarov MG, et al. Preemptive gabapentin reduces postoperative pain and opioid demand following thyroid surgery. Can J Anaesth 2006;53:268–73.
25. Dierking G, Duedahl TH, Rasmussen ML, et al. Effects of gabapentin on postoperative morphine consumption and pain after abdominal hysterectomy: a randomized, double-blind trial. Acta Anaesthesiol Scand 2004;48:322–7.
26. Dirks J, Fredensborg BB, Christensen D, et al. A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology 2002;97:560–4.
27. Fassoulaki A, Patris K, Sarantopoulos C, Hogan Q. The analgesic effect of gabapentin and mexiletine after breast surgery for cancer. Anesth Analg 2002;95:985–91.
28. Fassoulaki A, Triga A, Melemeni A, Sarantopoulos C. Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer. Anesth Analg 2005;101:1427–32.
29. Fassoulaki A, Stamatakis E, Petropoulos G, et al. Gabapentin attenuates late but not acute pain after abdominal hysterectomy. Eur J Anaesthesiol 2006;23:136–41.
30. Hill CM, Balkenohl M, Thomas DW, et al. Pregabalin in patients with postoperative dental pain. Eur J Pain 2001;5:119–24.
31. Gilron I, Orr E, Tu D, et al. A placebo-controlled randomized clinical trial of perioperative administration of gabapentin, rofecoxib and their combination for spontaneous and movement-evoked pain after abdominal hysterectomy. Pain 2005;113:191–200.
32. Mikkelsen S, Hilsted KL, Andersen PJ, et al. The effect of gabapentin on post-operative pain following tonsillectomy in adults. Acta Anaesthesiol Scand 2006;50:809–15.
33. Pandey CK, Priye S, Singh S, et al. Preemptive use of gabapentin significantly decreases postoperative pain and rescue analgesic requirements in laparoscopic cholecystectomy. Can J Anaesth 2004;51:358–63.
34. Pandey CK, Sahay S, Gupta D, et al. Preemptive gabapentin decreases postoperative pain after lumbar discoidectomy. Can J Anaesth 2004;51:986–9.
35. Radhakrishnan M, Bithal PK, Chaturvedi A. Effect of preemptive gabapentin on postoperative pain relief and morphine consumption following lumbar laminectomy and discectomy: a randomized, double-blinded, placebo-controlled study. J Neurosurg Anesthesiol 2005;17:125–8.
36. Rorarius MG, Mennander S, Suominen P, et al. Gabapentin for the prevention of postoperative pain after vaginal hysterectomy. Pain 2004;110:175–81.
37. Tuncer S, Bariskaner H, Reisli R, et al. Effect of gabapentin on postoperative pain: a randomized, placebo-controlled clinical study. Pain Clin 2005;17:95–9.
38. Turan A, Karamanlioglu B, Memis D, et al. The analgesic effects of gabapentin after total abdominal hysterectomy. Anesth Analg 2004;98:1370–3.
39. Turan A, Karamanlioglu B, Memis D, et al. Analgesic effects of gabapentin after spinal surgery. Anesthesiology 2004;100:935–8.
40. Turan A, Memis D, Karamanlioglu B, et al. The analgesic effects of gabapentin in monitored anesthesia care for ear-nose-throat surgery. Anesth Analg 2004;99:375–8.
41. Turan A, Kaya G, Karamanlioglu B, et al. Effect of oral gabapentin on postoperative epidural analgesia. Br J Anaesth 2006;96:242–6.
42. Turan A, White PF, Karamanlioglu B, et al. Gabapentin: an alternative to the cyclooxygenase-2 inhibitors for perioperative pain management. Anesth Analg 2006;102:175–81.
43. Dahl JB, Mathiesen O, Moiniche S. “Protective premedication”: an option with gabapentin and related drugs? A review of gabapentin and pregabalin in the treatment of post-operative pain. Acta Anaesthesiol Scand 2004;48:1130–6.
44. Wiffen PJ, McQuay HJ, Edwards JE, Moore RA. Gabapentin for acute and chronic pain. Cochrane Database Syst Rev 2005;20:CD005452.
45. Seib R, Paul J. Preoperative gabapentin for postoperative analgesia: a meta-analysis. Can J Anaesth 2006;53:461–9.
46. Hurley RW, Cohen SP, Williams KA, et al. The analgesic effects of perioperative gabapentin on postoperative pain: A meta-analysis. Reg Anesth Pain Med 2006;31:237–47.
47. Ho KY, Gan TJ, Habib AS. Gabapentin and postoperative pain—a systematic review of randomized controlled trials. Pain 2006;126:91–101.
48. Backonja M, Glanzman RL. Gabapentin dosing neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther 2003;25:81–104.
49. Rosseland LA, Stubhaug A. Gender is a confounding factor in pain trials: women report more pain than men after arthroscopic surgery. Pain 2004;112:248–53.
50. Marret E, Kurdi O, Zufferey P, Bonnet F. Effects of nonsteroidal antiinflammatory drugs on patient-controlled analgesia morphine side effects: meta-analysis of randomized controlled trials. Anesthesiology 2005;102:1249–60.
51. Remy C, Marret E, Bonnet F. Effects of acetaminophen on morphine side-effects and consumption after major surgery: meta-analysis of randomized controlled trials. Br J Anaesth 2005;94:505–13.
52. Bell RF, Dahl JB, Moore RA, Kalso E. Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review [Cochrane review]. Acta Anaesthesiol Scand 2005;49:1405–28.
53. Duedahl TH, Romsing J, Moiniche S, Dahl JB. A qualitative systematic review of peri-operative dextromethorphan in post-operative pain. Acta Anaesthesiol Scand 2006;50:1–13.
54. Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology 2000;93:1123–33.
55. Reuben S, Makari-Judson G, Lurie S. Evaluation of efficacy of the perioperative administration of venlafaxine XR in the prevention of postmastectomy pain syndrome. J Pain Symptom Manage 2004;27:133–9.