Preventing early and late postsurgical pain is an important challenge for anesthesiologists and surgeons.1 Therefore, perioperative interventions, and not only surgical procedures, need to be tested in clinical trials. Given the multiplicity of mechanisms involved in postoperative pain, a multimodal analgesia regimen using a combination of opioid, nonopioid analgesics, and regional anesthesia has become the treatment of choice for facilitating the recovery process.2
One of the most promising interventions requiring investigation is the reduction of central sensitization by inhibitors of N-methyl-d-aspartate (NMDA) amino acid receptors (NMDA-R), such as ketamine. Ketamine has been a frequently used general anesthetic and analgesic for the past 3 decades. It has been reported to prevent signs of neuropathic pain in animals3 and postsurgical pain4 with long-term effects.5 The role of ketamine in early postoperative pain seems to be better established than its role in chronic pain.
Another promising drug for postoperative pain management is gabapentin. Gabapentin binds to the α-2 δ subunit of voltage-gated calcium channels, thus preventing the release of nociceptive neurotransmitters including glutamate, substance P, and noradrenaline.6 Evidence suggests that, in addition to being an effective analgesic for patients with neuropathic or chronic pain syndromes, gabapentin also provides effective postoperative analgesia when administered before an operation.7,8 The role of certain neural changes common to both neuropathic and postoperative pain may explain these observations.9,10 Most of these studies have shown early postoperative benefit; thus, the effects on chronic pain need to be further investigated.
The aim of this clinical trial was to test and compare the effects of perioperative ketamine and gabapentin on early and chronic pain after elective hysterectomy.
After obtaining approval of the Institutional Ethics Committee and written informed consent, 60 patients undergoing elective abdominal hysterectomy with salpingo-oophorectomy were enrolled in this prospective, randomized, double-blind study. Patients with indications for leiomyoma, menorrhagia, metrorrhagia, and cervical dysplasia were included, but patients with chronic pelvic pain were excluded from the study. Patients were eligible for enrollment in the study if they were at least 18 yr old, willing to comply with the postoperative follow-up evaluations, within 50% of ideal body weight, had no clinically significant cardiovascular or central nervous system disease, and could operate a patient-controlled analgesia (PCA) device. Exclusion criteria were known allergy to any of the study medications, contraindications to the use of PCA morphine or any of the anesthetic drugs, renal insufficiency, the presence of chronic pain syndrome, epilepsy or history of convulsions, psychiatric problems, previous prescription of gabapentin and analgesic treatment (opiates, tricyclic antidepressants or venlafaxine, pregabalin, clonazepam, carbamazepine, and NMDA-R blockers), or drug abuse.
The patients were randomly assigned to 1 of the 3 treatment groups using a computer-generated table. The control group received oral placebo capsules and bolus plus infusion of saline; the ketamine group received oral placebo capsules and, before incision, 0.3 mg/kg IV bolus and 0.05 mg·kg−1·h−1 infusion of ketamine until the end of surgery11; and the gabapentin group received oral gabapentin 1.2 g (Neurontin™, Pfizer, Goedecke GmbH, Germany)12 and bolus plus infusion of saline. The same label was used for all the infusions for blinding purposes. The initial dose of the study medication was administered 1 h before surgery. All study drugs were prepared by the hospital pharmacy, and an appropriate code number was assigned to each patient.
All patients were premedicated with midazolam, 0.07 mg/kg IM, 45 min before the surgical procedure. On arrival in the operating room, a crystalloid IV infusion was started, and baseline mean arterial blood pressure, heart rate, and peripheral oxygen saturation were obtained using standard monitors. Anesthesia was induced with propofol (2 mg/kg IV) and atracurium (0.5 mg/kg IV) and was initially maintained with sevoflurane 1.5% inspired at a fresh gas flow rate of 2 L/min in combination with nitrous oxide 50% in oxygen. Fentanyl, 2 μg/kg IV, was administered 3–5 min before the surgical incision. The operation was performed via a Pfannenstiel incision by the same surgeon. After endotracheal intubation, all patients’ lungs were mechanically ventilated to maintain the end-expiratory CO2 values between 34 and 36 mm Hg. Morphine, 4 mg IV, was administered immediately before discontinuing sevoflurane and nitrous oxide. At the start of skin closure, residual neuromuscular blockade was antagonized with neostigmine, 1.5 mg IV, and atropine, 0.5 mg IV. Ondansetron, 4 mg IV, was given to all patients.
After tracheal extubation and on awakening from anesthesia, patients were transferred to the postanesthesia care unit (PACU). Assessment of postoperative pain was performed using an 11-point verbal rating scale (VRS), with 0 = no pain and 10 = worst pain imaginable. After arrival in the PACU, patients were connected to a PCA device and postoperative analgesia was provided using 2-mg IV bolus injections of morphine at a lockout interval of 15 min and with a maximum 4-h limit of 24 mg. The incremental bolus dose of morphine was increased to 3 mg if analgesia was inadequate (VRS pain score >5) after the first hour of PCA use. Sedation was assessed using the Aldrete score.13 Assessments of pain, sedation, opioid usage, and side effects were performed at 1-, 4-, 8-, 12-, 16-, 20-, and 24-h intervals after arrival in the PACU by a research assistant blinded to group allocation. The PCA device was discontinued when the patient made no demands for the opioid analgesic in the preceding 4-h interval. Oral analgesia was provided using acetaminophen 500 mg in combination with codeine 30 mg PO q 6—8 h, on demand. The occurrences of postoperative side effects (e.g., nausea and vomiting, constipation, dizziness, drowsiness, peripheral edema, diarrhea, headache, and pruritus) were recorded at follow-up intervals. Assessment of postoperative pain was made both while the patient was resting in bed and during sitting. If the patient experienced sustained nausea or vomiting lasting longer than 5 min, ondansetron (4 mg IV) was administered.
Before the start of the study, patients were instructed to write down the exact time they first passed flatus and experienced their first bowel movement after surgery. In addition, when the research assistant assessed their pain, they were also asked whether they had passed flatus or had a bowel movement. The surgeon auscultated the abdomen for bowel sounds twice daily and documented the presence or absence of bowel sounds in the patient’s chart. The time to resumption of oral dietary intake and unassisted ambulation were also evaluated at regular 2-h intervals during the day by the blinded research assistant. The length of the hospital stay was also recorded.
Patients’ satisfaction with their postoperative pain management was assessed using a 100-point VRS, with 1 = highly dissatisfied to 100 = completely satisfied. All measurements were recorded by a research assistant who was blinded to the study medication. Patients were also contacted by one of the investigators at 1, 3, and 6 mo after discharge to inquire as to when they were able to resume normal activities of daily living (i.e., return to work) and if they had any residual postoperative (incisional) pain. Assessment of postdischarge pain was performed using an 11-point VRS, with 0 = no pain and 10 = worst pain imaginable. Whether pain had an effect on normal activities of daily living was also evaluated.
Initial sample size estimation showed that approximately 18 patients were needed in each group to detect a clinically relevant reduction of the level of pain by 25%, with a power of 0.80 and a level of significance of 5%. Statistical analysis was performed with SPSS for Windows version 11.5 (SPSS, Chicago, IL). According to the distribution of the data, Kruskal-Wallis, Mann-Whitney U-test, 1-way analysis of variance, t-test, and χ2 tests were performed. Mixed effect model by the use of 2-way analysis of variance was used for calculating the effect size. Bonferroni correction was performed to compensate for the possible effects of repeated testing. Data were expressed as mean (sd), number (%), or median (min-max). A P value of <0.05 was accepted as statistically significant.
Sixty consenting patients who fulfilled the entry criteria were enrolled in this study. All patients were able to complete the entire study and their data were included in the final analysis. The 3 groups were comparable with respect to age, body weight, height, ASA physical status, and duration of surgery (Table 1). Mean arterial blood pressure, heart rate, oxygen saturation, and respiratory rate values did not differ among the groups at any of the measured time intervals (data not reported). Sedation scores were also similar among the groups at all the measured time intervals (data not reported).
The VRS pain scores while lying and sitting were significantly lower in the gabapentin group compared with the control group at all measurements for 24 h and in the ketamine group for all measurements in the first 16 h postoperatively (Figs. 1 and 2). However, there were no differences between the ketamine and control groups in VRS pain scores for 24 h. Compared with the control group, the PCA morphine requirement was significantly reduced in the 2 analgesic treatment groups at 8, 12, 16, 20, and 24 h after surgery (Table 2). In addition, total PCA morphine use was decreased by 35% and 42% in the ketamine and gabapentin groups, respectively, compared with the control group (P < 0.001) (Table 2). Return of bowel sounds, passage of flatus, ambulation, and hospitalization times were not significantly different among the 3 groups (Table 3). However, patient satisfaction with pain treatment was significantly improved in the ketamine and gabapentin groups compared with the control group (P < 0.001).
At the 1-, 3-, and 6-mo follow-up, both the incidence of incisional pain and pain scores were found to be significantly lower in the gabapentin group compared with the ketamine and control groups (P < 0.001) (Fig. 3). When patients were questioned concerning the impact of pain on their daily activities, the gabapentin group was significantly less affected compared with the ketamine and control groups, at 1- and 3-mo follow-up. However, there was no significant difference among groups at 6-mo follow-up.
The most common side effects during the postoperative period were nausea and vomiting, and there was no difference in the incidence of side effects among all 3 groups (Table 4).
Perioperative administration of ketamine and the anticonvulsant gabapentin, as part of a multimodal analgesic regimen with PCA morphine, led to improved early pain control, decreased morphine consumption, and less chronic postoperative pain. Furthermore, our data suggest that gabapentin is more beneficial for patients who are at high risk of developing chronic pain.
Ketamine is a well-known general anesthetic and analgesic used after the discovery of the NMDA-R and its link to nociceptive pain transmission and central sensitization. Given its actions as a noncompetitive NMDA-R antagonist, there has been a renewed interest in using ketamine as a potential multimodal analgesic.14 A quantitative systematic review by Nadia and Tramer15 including 53 trials demonstrated a significant decrease in pain scores and morphine consumption postoperatively. Similarly, another systematic review also found ketamine effective in reducing morphine requirements in the first 24 h after surgery.16 However, ketamine is still underutilized probably because of the psychotomimetic adverse effects limiting its widespread use in the perioperative setting. The current study supports that ketamine infusion decreased morphine consumption without increasing the related side effects.
Gabapentin has been very effective for treating neuropathic pain syndromes.17 There are a number of clinical studies regarding the use of gabapentin for the prevention of postoperative pain, and they suggest that gabapentin may also be useful in the perioperative period.12,18,19 A majority of the published placebo-controlled, double-blind, randomized trials have demonstrated postoperative analgesic efficacy with gabapentin, and a small number of the comparative trials suggest that its analgesic and opioid-sparing efficacy are roughly comparable to that of nonsteroidal antiinflammatory drugs and perhaps superior to acetaminophen and tramadol.18,20,21 Our results support the previous studies by demonstrating perioperative analgesic efficacy, which is comparable to ketamine. However, there was no significant benefit with respect to other outcome measures (e.g., bowel sounds, passage of flatus, ambulation, and hospitalization times). Improvement in patient satisfaction with pain treatment was also seen in both the gabapentin and ketamine groups.
Preventive multimodal analgesic techniques using ketamine and gabapentin seem to be promising for the treatment of acute postoperative pain and they may reduce the prevalence of chronic pain after surgery. Postoperative chronic pain development after surgery has been reported after numerous procedures including mastectomy,22 inguinal hernia,23 and hysterectomy.24 Postoperative pain signals have the capacity to initiate prolonged changes in both the peripheral and the central nervous system that lead to the amplification and prolongation of postoperative pain. Peripheral and central sensitization contributes to the postoperative hypersensitivity state that is responsible for a decrease in the pain threshold, both at the site of injury (primary hyperalgesia) and in the surrounding uninjured tissue (secondary hyperalgesia).25 Prolonged central sensitization has the capacity to lead to permanent alterations in the central nervous system, including the death of inhibitory neurons, replacement with new afferent excitatory neurons, and establishment of aberrant excitatory synaptic connections.25 Because of their role in peripheral and central sensitization, both ketamine and gabapentin have sparked interest as part of a preventive multimodal analgesic technique.
Recent studies reported that perioperative ketamine improved early recovery but lacked the effect on chronic postoperative pain.26,27 Although the types of surgery were very different from our current study, we still found similar results. Gabapentin has been successfully used for early postoperative pain and more recent studies have also demonstrated a decrease in chronic pain.28,29 Our current study confirms the results of previous studies that gabapentin decreases early postoperative pain and that it may have an adjuvant role for decreasing chronic postoperative pain. One important factor is that the ketamine dose used in our study seems to be on the lower end of dose ranges used in the literature, which may explain the decreased beneficial effect of ketamine compared with gabapentin.11
A deficiency of the current study design relates to the arbitrarily chosen dosages of the study medications. However, the doses were selected according to the most preferred regimens used in the literature. Another criticism relates to the fact that the study population involved only female patients undergoing lower abdominal surgery. Further comparative studies, with adequate number of (also male) patients encompassing other surgeries in which chronic pain is a potential problem, are clearly needed.
In summary, perioperative administration of gabapentin was found to be similar to ketamine for improving early pain control and for decreasing opioid consumption in the postoperative period after lower abdominal surgery. However, gabapentin provided additional benefit regarding delayed chronic postoperative pain for 6 mo.
1. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet 2006;367:1618–25
2. De Cosmo G, Aceto P, Gualtieri E, Congedo E. Analgesia in thoracic surgery: review. Minerva Anestesiol 2008;75:393–400
3. Burton AW, Lee DH, Saab C, Chung JM. Preemptive intrathecal ketamine injection produces a long lasting decrease in neuropathic pain behaviors in a rat model. Reg Anesth Pain Med 1999;24:208–13
4. Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N
-methyl-d-aspartate (NMDA) receptors in pain: a review. Anesth Analg 2003;97:1108–16
5. De Kock M, Lavand’homme P, Waterloos H. ‘Balanced analgesia’ in the perioperative period: is there a place for ketamine? Pain 2001;92:373–80
6. Qin N, Yagel S, Momplaisir ML, Codd EE, D’Andrea MR. Molecular cloning and characterization of the human voltage-gated calcium channel alpha(2)delta-4 subunit. Mol Pharmacol 2002;62:485–96
7. 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 Anesthesiol Scand 2004;48:1130–6
8. Hurley RW, Cohen SP, Williams KA, Rowlingson AJ, Wu CL. The analgesic effects of perioperative gabapentin on postoperative pain: a meta-analysis. Reg Anesth Pain Med 2006;31:237–47
9. Raja SN, Meyer RA, Campbell JN. Peripheral mechanisms of somatic pain. Anesthesiology 1988;68:571–90
10. Woolf CJ, Chong MS. Preemptive analgesia-treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993;77:362–79
11. Launo C, Bassi C, Spagnolo L, Badano S, Ricci C, Lizzi A, Molinino M. Preemptive ketamine during general anesthesia for postoperative analgesia in patients undergoing laparoscopic cholecystectomy. Minerva Anestesiol 2004;70:727–34
12. Turan A, Karamanlioğlu B, Memiçs D, Usar P, Pamukçu Z, Türe M. The analgesic effects of gabapentin after total abdominal hysterectomy. Anesth Analg 2004;98:1370–3
13. Aldrete JA. The post-anesthesia recovery score revisited. J Clin Anesth 1995;7:89–91
14. Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N
-methyl-d-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain 1991;44:293–9
15. Nadia E, Tramer M. Ketamine and postoperative pain—a quantitative systematic review of randomised trials. Pain 2005; 113:61–70
16. 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
17. Mellegers MA, Furlan AD, Mailis A. Gabapentin for neuropathic pain: systematic review of controlled and uncontrolled literature. Clin J Pain 2001;17:284–95
18. Turan A, White PF, Karamanlioglu B, Memis D, Tasdogan M, Pamukçu Z, Yavuz E. Gabapentin: an alternative to the cyclooxygenase-2 inhibitors for perioperative pain management. Anesth Analg 2006;102:175–81
19. Fassoulaki A, Melemeni A, Stamatakis E, Petropoulos G, Sarantopoulos C. A combination of gabapentin and local anaesthetics attenuates acute and late pain after abdominal hysterectomy. Eur J Anaesthesiol 2007;24:521–8
20. Gilron I, Orr E, Tu D, O’Neill JP, Zamora JE, Bell AC. 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
21. Gilron I. Gabapentin and pregabalin for chronic neuropathic and early postsurgical pain: current evidence and future directions. Curr Opin Anaesthesiol 2007;20:456–72
22. Vilholm OJ, Cold S, Rasmussen L, Sindrup SH. The postmastectomy pain syndrome: an epidemiological study on the prevalence of chronic pain after surgery for breast cancer. Br J Cancer 2008;99:604–10
23. van Hanswijck de Jonge P, Lloyd A, Horsfall L, Tan R, O’Dwyer PJ. The measurement of chronic pain and health-related quality of life following inguinal hernia repair: a review of the literature. Hernia 2008;12:561–9
24. Brandsborg B, Nikolajsen L, Kehlet H, Jensen TS. Chronic pain after hysterectomy. Acta Anaesthesiol Scand 2008;52:327–31
25. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288:1765–9
26. Hayes C, Armstrong-Brown A, Burstal R. Perioperative intravenous ketamine infusion for the prevention of persistent post-amputation pain: a randomized, controlled trial. Anaesth Intensive Care 2004;32:330–8
27. Dualé C, Sibaud F, Guastella V, Vallet L, Gimbert YA, Taheri H, Filaire M, Schoeffler P, Dubray C. Perioperative ketamine does not prevent chronic pain after thoracotomy. Eur J Pain 2008;13:497–505
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. Brogly N, Wattier JM, Andrieu G, Peres D, Robin E, Kipnis E, Arnalsteen L, Thielemans B, Carnaille B, Pattou F, Vallet B, Lebuffe G. Gabapentin attenuates late but not early postoperative pain after thyroidectomy with superficial cervical plexus block. Anesth Analg 2008;107:1720–5