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.
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.
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.
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).
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.
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.
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.
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© 2004 International Anesthesia Research Society
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