Secondary Logo

Preoperative Ketamine Improves Postoperative Analgesia After Gynecologic Laparoscopic Surgery

. Kwok, Rebecca F. K, FANZCA*; Lim, Jean, FHKCA*; . Chan, Matthew T.V, FANZCA; Gin, Tony, MD, FRCA, FANZCA; Chiu, Wallace K.Y., FRCA*

doi: 10.1213/01.ANE.0000105911.66089.59
Pain Medicine: Research Report
Free

In this study, we evaluated the preemptive effect of a small dose of ketamine on postoperative wound pain. In a randomized, double-blinded, controlled trial, we compared the analgesic requirement in patients receiving preincision ketamine with ketamine after skin closure or placebo after gynecologic laparoscopic surgery. One-hundred-thirty-five patients were randomly assigned to receive preincision or postoperative ketamine 0.15 mg/kg or saline IV. Anesthetic technique was standardized. Patients were interviewed regularly up to 4 wk after surgery. Pain score, morphine consumption, side effects, and quality of recovery score were recorded. Patients receiving preincision ketamine had a lower pain score in the first 6 h after operation compared with the postoperative (P = 0.001) or placebo groups (P < 0.001). The mean (95% confidence intervals) time to first request for analgesia in the preincision group, 1.8 h (1.4–2.1), was longer than the postoperative group, 1.2 h (0.9–1.5; P < 0.001), or the placebo group, 0.7 h (0.4–0.9; P < 0.001). The mean ± sd morphine consumption in the preincision group, 1.5 ± 2.0 mg, was less than that in the postoperative group, 2.9 ± 3.1 mg (P = 0.04) and the placebo group, 3.4 ± 2.7 mg (P = 0.003). There was no significant difference among groups with respect to hemodynamic variables or side effects. No patient complained of hallucinations or nightmares. We conclude that a small dose of ketamine is not only safe, but it also provides preemptive analgesia in patients undergoing gynecologic laparoscopic surgery.

IMPLICATIONS: In women undergoing laparoscopic gynecologic surgery, a small preoperative dose of ketamine (0.15 mg/kg) produced preemptive analgesia. There were no significant hemodynamic and psychological side effects with this dose.

*Department of Anaesthesia and Intensive Care, Pamela Youde Nethersole Eastern Hospital, Chai Wan; and

†Department of Anaesthesia and Intensive Care, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin

Accepted for publication October 21, 2003.

Address correspondence to Dr. Matthew Chan, Department of Anesthesia and Intensive Care, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong. Address e-mail to mtvchan@cuhk.edu.hk.

Tissue trauma during surgery modifies the central processing pathway for pain perception. These changes decrease stimulus threshold and amplify postoperative pain (1). The induction and maintenance of such central sensitization may be dependent on the activation of N-methyl-d-aspartic acid (NMDA) receptors (2). Therefore, preoperative administration of ketamine, an NMDA-receptor antagonist, should prevent central sensitization and may improve postoperative pain relief. This is termed preemptive analgesia. However, despite the overwhelming success in animal experiments (1,3,4), clinical reports confirming the preemptive analgesic effects of ketamine have not been forthcoming (5–8). Previous studies have concentrated on major surgery, where intense noxious stimuli continue throughout the procedure and may even extend into the postoperative period. It is therefore not surprising that a small bolus of ketamine, given before incision, cannot block the continuous noxious afferent adequately. In this regard, a larger dose of ketamine provides preemptive analgesia in patients undergoing abdominal surgery (9). However, emergence hallucinations and bad dreams have limited the usefulness of large-dose ketamine (10).

Minimally invasive surgery produces less tissue trauma. Conceivably, a smaller dose of ketamine may be sufficient to block perioperative noxious input without additional psychotomimetic side effects. We hypothesized that ketamine produces preemptive analgesia in women undergoing gynecologic laparoscopic surgery. We compared the postoperative analgesic requirement in patients receiving ketamine before skin incision with those receiving it after wound closure or placebo.

Back to Top | Article Outline

Methods

This study was approved by the Clinical Research Ethics Committee, and all patients gave written informed consent. Based on previously reported analgesic requirement in women undergoing laparoscopic gynecologic surgery (11), we calculated that at least 42 patients per group would have 90% power at 5% significance level to detect a 30% reduction in morphine consumption. One-hundred-thirty-five women, ASA physical status I or II, aged between 18 and 65 yr, scheduled for laparoscopic gynecologic surgery entered the study. Patients were excluded if there was a history of psychiatric disorder, chronic pain syndrome, or drug and alcohol abuse. Patients receiving regular opioids or drugs with known analgesic properties in the 24 h before surgery were also excluded. No preanesthetic medication was prescribed, and the patients were fasted from midnight before surgery.

In the operating room, routine monitoring was applied. Patients were randomly assigned, using computer-generated random numbers and concealed opaque envelopes, to one of three treatment groups: (a) preincision group, patients received IV ketamine 0.15 mg/kg (made up to 10 mL with normal saline) immediately before the induction of anesthesia followed by normal saline 10 mL after wound closure; (b) postoperative group, patients received saline before the induction of anesthesia and ketamine 0.15 mg/kg after wound closure; or (c) placebo group, patients received normal saline before the induction of anesthesia and after wound closure. Study drugs were prepared by an anesthesiologist independent of the study and were injected IV over 30 s. Arterial blood pressure and heart rate were recorded noninvasively immediately before and every minute for 10 min after the start of drug administration.

Anesthesia was induced with propofol 2 mg/kg and fentanyl 2 μg/kg IV. Atracurium 0.5 mg/kg was administered to facilitate tracheal intubation. Anesthesia was then maintained with nitrous oxide 70% and isoflurane 0.5%–1.0% in oxygen. The lungs were mechanically ventilated, and the end-tidal carbon dioxide concentration was maintained between 5.0%–5.5%. At the end of surgery, anesthesia was discontinued, and residual neuromuscular blockade was antagonized by neostigmine 40 μg/kg and atropine 20 μg/kg. The trachea was extubated when the patient became fully awake. Anesthetic time was defined from the start of induction to the time when nitrous oxide was discontinued, whereas the duration from skin incision to the last suture was designated as surgical time.

After surgery, all patients were monitored in the postanesthesia care unit for one hour, after which time the patient returned to the ward. Early recovery times included time to tracheal extubation and time to the Aldrete score ≥9 (12). Analgesia was initially provided with IV morphine 1.5 mg and was repeated every 5 min until the patient was comfortable or when the visual analog scale (VAS) pain score was <20 mm. On the ward, patients received IM morphine 0.15 mg/kg every 4 h or 1 to 2 tablets of dologesic (containing paracetamol 325 mg and dextropropoxyphene 32.5 mg) every 6 h as required. Postoperatively, patients were interviewed frequently during the first postoperative day and then daily until hospital discharge. Patients were then contacted again by telephone 7 days and 4 wk after surgery. All interviews were conducted in a standardized fashion by trained nurses who were blinded to the study drug. The severity of pain and sedation was measured at 15-min intervals for the first hour and then at 2, 4, 6, and 24 h after surgery. Severity of pain was graded using a 100-mm VAS printed on a sliderule bar (Astra USA Inc, Westborough, MA). Sedation was scored as 1 = alert, 2 = asleep, alert after arousal, 3 = asleep, drowsy after arousal, 4 = asleep, difficult to rouse, and 5 = unarousable. The incidence of nausea and vomiting was recorded. Patient outcome was assessed by a validated nine-item instrument used to measure the quality of recovery (QoR) score (Figure 1) (13). The first time the patient resumed fluid or solid diets, ambulated without assistance, and returned to normal daily activities was also recorded.

Figure 1.

Figure 1.

All statistical analyses were performed using S-PLUS 6 (Insightful, Seattle, WA). Data were analyzed according to the principle of intention-to-treat. Categorical data were compared among groups using χ2 test, and continuous data were analyzed using the generalized linear model. Multiple comparisons were adjusted by the Sidak procedure. Data that were not normally distributed were compared among groups using a Kruskal-Wallis test. The mean time that the patients first required postoperative analgesia was calculated using the Kaplan-Meier survival analysis and was compared among groups using log-rank test. A P value <0.05 was considered significant.

Back to Top | Article Outline

Results

All patients completed the study. Patient characteristics and operative details did not differ among groups (Table 1). During the first 6 h after surgery, the pain scores were significantly lower in patients receiving ketamine before the induction of anesthesia compared with those in the postoperative (P = 0.001) or placebo groups (P < 0.001). Pain scores in the subsequent period were low and were not different among groups (Fig. 2). The mean time (95% confidence intervals [CI]) to the first request for analgesic was longer in patients in the preincision group, 1.8 h (95% CI, 1.4–2.1), compared with that in patients receiving ketamine after wound closure, 1.1 h (95% CI, 0.9–1.4; P < 0.001), or the placebo group, 0.7 h (95% CI, 0.4–0.9; P < 0.001;Fig. 3). Similarly, the mean ± sd total morphine consumption in the preincision group, 1.5 ± 2.0 mg, was less than that in the postoperative group, 2.9 ± 3.1 mg (P = 0.04), and the placebo group, 3.4 ± 2.7 mg (P = 0.003). Patients receiving ketamine before surgical incision also tended to consume fewer dologesic tablets in the first week, 5.4 ± 4.3, compared with the postincision group, 6.5 ± 2.4, and the placebo group, 6.8 ± 5.4. However, the values are more variable and did not reach statistical significance (P = 0.052).

Table 1

Table 1

Figure 2.

Figure 2.

Figure 3.

Figure 3.

The QoR scores improved gradually over time (Fig. 4). Although patients receiving preincision ketamine tended to rate their recovery better than the other groups, the difference was small, and there was no difference among groups (P = 0.08). Table 2 compares the recovery times in patients receiving preincision ketamine, postoperative ketamine, and the control group. All patients resumed normal daily activity within 3 wk. There was no significant difference among groups.

Figure 4.

Figure 4.

Table 2

Table 2

There was no adverse event during the ketamine injection. Arterial blood pressure and heart rate did not change after drug administration. Sedation scores were similar among groups, and no patient had a score more than 2 over the entire study period. The incidence of postoperative nausea and vomiting was also similar among groups (preincision group, 35%; postoperative group, 32%; placebo group, 33%; P = 0.75). Three patients (one in the postoperative group and two in the placebo group) reported dreaming without explicit recall during surgery. No patients complained of hallucinations or bad dreams in the postoperative period. There were no surgical complications.

Back to Top | Article Outline

Discussion

Our results demonstrate that a small dose of ketamine, given before skin incision, decreases postoperative pain, reduces morphine consumption, and delays patients’ request for analgesia after laparoscopic gynecologic surgery. However, as postoperative analgesia was not improved in patients receiving ketamine after skin closure, these findings suggest that timing of ketamine treatment was critical in its analgesic efficacy. We believe our data confirm the preemptive effect of ketamine analgesia.

The principle of preemptive analgesia is to apply antinociceptive treatment before surgical trauma (14). This should prevent NMDA-receptor activation and remodeling of the central nervous system (1,2). Whereas timing of treatment is an integral part of the concept, the interaction between drug dosage and stimulus intensity must not be overlooked. Thus, an insufficient dose of ketamine or an intense noxious stimulus may initiate NMDA-receptor activation and subsequent hyperalgesia. In rats, even brief painful stimulation produces significant central neuroplasticity (15,16). These experiments highlighted the importance of intraoperative analgesia to prevent postoperative pain. We believe an insufficient afferent block may account for the many studies that have found a lack of evidence for preemptive analgesia (5–8).

In the present report, we chose to study patients undergoing laparoscopic gynecologic surgery because tissue injury is likely to be limited and confined to the intraoperative period; thus, even a small dose of ketamine will be able to block the central sensitization. Interestingly, other reports that have demonstrated an improved analgesia with preincision ketamine have also studied patients undergoing ambulatory (17) or minimally invasive arthroscopic surgery (18). However, these investigations were not designed to evaluate the preemptive effect of ketamine, and a definitive conclusion cannot be drawn. Similarly, in patients undergoing total or distal gastrectomy, the preemptive effect of ketamine was only demonstrated if epidural morphine was also added (19). This study confirms the importance of adequate sensory block in bringing out the preemptive effect of ketamine analgesia.

The intrinsic analgesic properties of ketamine may have reduced the postoperative pain score. The plasma ketamine concentration producing clinical analgesia is in the order of 100–150 ng/mL (20,21). Given that ketamine is rapidly distributed, we have calculated that a bolus injection of ketamine 0.15 mg/kg would provide analgesia for less than 5 minutes. Indeed, the pain scores in patients receiving ketamine after skin incision were not different from the placebo group. Our data indicated that preemptive administration clearly outlasted the duration of ketamine analgesia.

We included a placebo group in the present study to evaluate the influence of anesthetic technique on postoperative pain relief. Large doses of opioids and nitrous oxide administration produce preemptive analgesia (22,23), whereas inhaled anesthetics antagonize this effect (24). The overall results will either exaggerate or obscure the preemptive effect of ketamine analgesia. In the present study, we standardized our anesthetic regime. Therefore, the true preemptive effect of ketamine may be revealed by comparing the analgesic outcome between treatment and placebo groups.

This study also evaluated the preemptive effect of ketamine on rate and QoR. We recorded the early recovery times, time required to return to normal activities, and a patient oriented QoR score (13). Although we did not find statistically significant differences among groups in any of the recovery variables, patients receiving preincision ketamine tended to report better recovery scores in the first 48 h after surgery. Furthermore, these patients also returned to their normal activities 0.5–1 day earlier than the postoperative or control groups. This difference, albeit small, may confer important socioeconomic implications. The present study was not designed to detect a difference in recovery scores among groups. Based on our data, a larger study recruiting 650 patients per group may provide definitive evidence to suggest that preemptive analgesia translates into better recovery profiles.

Large doses of ketamine (>2 mg/kg) are associated with unacceptable psychotomimetic side effects (10). Common complaints include hallucinations, vivid dreams, cognitive decline, and emergence confusion (10). However, side effects are rare with a reduced dose of ketamine ranging from 0.15 to 0.5 mg/kg (10,25,26). In the present study, ketamine 0.15 mg/kg did not change hemodynamic or respiratory variables. Patients were not sedated, and there was no difference in the incidence of postoperative nausea and vomiting among groups.

In conclusion, a small dose of ketamine, given before skin incision, produces preemptive analgesia in women undergoing laparoscopic gynecologic surgery. At this dosage, there were no demonstrable hemodynamic or psychotomimetic side effects.

Back to Top | Article Outline

References

1. Woolf CJ. Evidence for a central component of postinjury pain hypersensitivity. Nature 1983; 306: 686–8.
2. Woolf CJ, Thompson SWN. 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 state. Pain 1991; 44: 293–9.
3. Bennett GJ. Update on the neurophysiology of pain transmission and modulation: focus on the NMDA-receptor. J Pain Symptom Manage 2000; 19: S2–6.
4. Eide PK. Wind-up and the NMDA receptor complex from a clinical perspective. Eur J Pain 2000; 4: 5–15.
5. Heinke W, Grimm D. Preemptive effects caused by co-analgesia with ketamine in gynecological laparotomies? Anaesthesiol Reanim 1999; 24: 60–4.
6. Adam F, Libier M, Oszustowicz T, et al. Preoperative small-dose ketamine has no preemptive analgesic effect in patients undergoing total mastectomy. Anesth Analg 1999; 89: 444–7.
7. Dahl V, Ernoe PE, Steen T, et al. Does ketamine have preemptive effects in women undergoing abdominal hysterectomy procedures? Anesth Analg 2000; 90: 1419–22.
8. Menigaux C, Fletcher D, Dupont X, et al. The benefits of intraoperative small-dose ketamine on postoperative pain after anterior cruciate ligament repair. Anesth Analg 2000; 90: 129–35.
9. Fu ES, Miguel R, Scharf JE. Preemptive ketamine decreases postoperative narcotic requirements in patients undergoing abdominal surgery. Anesth Analg 1997; 84: 1086–90.
10. Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain 1999; 82: 111–25.
11. Yuen PM, Yu KM, Yip SK, et al. A randomized prospective study of laparoscopy and laparotomy in the management of benign ovarian masses. Am J Obstet Gynecol 1997; 177: 109–14.
12. Aldrete JA, Kroulik D. A postanesthetic recovery score. Anesth Analg 1970; 49: 924–34.
13. Myles PS, Hunt JO, Nightingale CE, et al. Development and psychometric testing of a quality of recovery score after general anesthesia and surgery in adults. Anesth Analg 1999; 88: 83–90.
14. Kissin I. Preemptive analgesia: why its effect is not always obvious. Anesthesiology 1996; 84: 1015–9.
15. Seltzer Z, Beilin BZ, Ginzburg R, et al. The role of injury discharge in the induction of neuropathic pain behavior in rats. Pain 1991; 46: 327–36.
16. Vatine JJ, Argov R, Seltzer Z. Brief electrical stimulation of c-fibers in rats produces thermal hyperalgesia lasting weeks. Neurosci Lett 1998; 246: 125–8.
17. Suzuki M, Tsueda K, Lansing PS, et al. Small-dose ketamine enhances morphine-induced analgesia after outpatient surgery. Anesth Analg 1999; 89: 98–103.
18. Menigaux C, Guignard B, Fletcher D, et al. Intraoperative small-dose ketamine enhances analgesia after outpatient knee arthroscopy. Anesth Analg 2001; 93: 606–12.
19. Aida S, Yamakura T, Baba H, et al. Preemptive analgesia by intravenous low-dose ketamine and epidural morphine in gastrectomy: a randomized double-blind study. Anesthesiology 2000; 92: 1624–30.
20. Clements JA, Nimmo WS. Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth 1981; 53: 27–30.
21. Pekoe GM, Smith DJ. The involvement of opiate and monoaminergic neuronal systems in the analgesic effects of ketamine. Pain 1982; 12: 57–73.
22. Dickenson AH. Plasticity: implications for opioid and other pharmacological interventions in specific pain states. Behav Brain Sci 1997; 20: 392–403.
23. Goto T, Marota JJ, Crosby G. Nitrous oxide induces preemptive analgesia in the rat that is antagonized by halothane. Anesthesiology 1994; 80: 409–16.
24. Abram SE, Yaksh TL. Morphine, but not inhalation anesthesia, blocks post-injury facilitation: the role of preemptive suppression of afferent transmission. Anesthesiology 1993; 78: 713–21.
25. 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.
26. Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199–214.
© 2004 International Anesthesia Research Society