Shoulder pain after laparoscopic procedures is frequent and distressing, with a reported incidence of 31%–80% after laparoscopic cholecystectomy (LC).1,2 Postlaparoscopic shoulder pain (PLSP) is usually mild in intensity and short lived. But, in some cases, it may cause more discomfort to the patient than the pain at the incision sites3 or last up to 7 days or even 5 wk after laparoscopic surgery.4 Although it is not clear whether it is caused by local acidosis5 or distension of the diaphragm,6,7 the resultant irritation or injury of the phrenic nerve at the diaphragm surface during CO2 pneumoperitoneum seems to provoke PLSP.5–8 This study evaluated the efficacy of perioperative pregabalin in preventing and attenuating PLSP after LC.
The study protocol was approved by the hospital ethics committee and written informed consent was obtained from the participating patients. Eighty adult patients (ASA physical status I or II) undergoing elective LC were recruited for this prospective, double-blind, randomized, placebo-controlled study. The patient exclusion criteria disqualified those who were already receiving analgesics or sedatives within 24 h before scheduled surgery, had bile spillage or cholelithiasis with known common bile duct pathology, or were allergic to any of the study medications.
Patients were assigned randomly to two groups of 40 each and received either two 150 mg capsules of pregabalin or matching placebo. All medications were administered orally 1 h before inducing anesthesia and 12 h after the first dose with sips of water. Blinded study medications were dispensed by the hospital pharmacy.
None of the patients received other premedications, and the anesthetic protocol was standardized for all patients. Anesthesia was induced with thiopental sodium 5–7 mg/kg. Orotracheal intubation was facilitated by vecuronium 0.1 mg/kg, and anesthesia was maintained with oxygen, air, and sevoflurane. The same surgical team performed all surgical procedures using the same technical principles for the two groups. Both the patients and surgeons were blinded to group allocation. Intraoperative data recorded included duration of surgery, anesthesia, and pneumoperitoneum, and intraoperative CO2 gas consumption. Patients requiring conversion to laparotomy or insertion of a drain due to undetectable or accidental bile spillage were excluded from the analysis. Pethidine 25 mg was administered IV 10 min before the end of the operation. At the end of surgery, residual neuromuscular paralysis was reversed with neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg. In both groups, staff nurses administered ketorolac 30 mg IV as a rescue analgesic on the patient’s request in the recovery room and ward.
The presence, location (right, left, or both sides), and intensity on a verbal rating scale (VRS; 0 = no pain and 10 = worst imaginable pain) of PLSP were assessed 2, 4, 12, 24, and 48 h postoperatively by a blinded research nurse. Surgical pain (trocar wound and visceral pain) was also assessed using the same pain scale. The times to first rescue analgesia and discharge from the postanesthesia care unit were recorded. Total rescue ketorolac requirement and side effect profiles (postoperative nausea, vomiting, dry mouth, lack of concentration, blurred vision, and oversedation) were recorded at the same timepoints. Oversedation was defined as a score >2 on a 5-point ordinal scale (0, completely awake; 1, awake but drowsy; 2, asleep but responsive to verbal commands; 3, asleep but responsive to tactile stimulus; and 4, asleep and not responsive to any stimulus).
The primary end points were the overall incidence of PLSP and VRS score, which we assumed to be 50% and 2.5 in the placebo group, respectively. To show a two-third reduction in the overall incidence of PLSP and 50% reduction of the VRS score, with a power of 80% and an α value of 0.05, we estimated that approximately 40 patients per group would be required.
Categorical variables were analyzed using Pearson χ2 tests with continuity correction or Fisher’s exact tests when applicable. Continuous variables were analyzed using unpaired two-tailed t-tests. Time to first rescue analgesia was analyzed using Kaplan–Meier survival analysis, with between-group comparisons using the log-rank test. Survival time was defined as the time from the end of operation to the need for first rescue analgesia. In all cases, statistical significance was defined as P <0.05.
Eight patients were screened from the study by our exclusion criteria, and 80 patients were subsequently allocated to two equally-sized groups. Three patients were considered dropouts after the initial randomization and were therefore not subjected to further statistical analysis (two patients underwent conversion to open cholecystectomy and one patient received inappropriate supplemental analgesics). Thus, 77 patients (38 in the placebo group and 39 in the pregabalin group) were included in the final analysis. The demographic and intraoperative data (duration of surgery, anesthesia, and pneumoperitoneum, and total CO2 gas consumption) were similar for both groups.
The overall frequencies of PLSP were similar in both groups. In 44 patients reporting PLSP at any timepoint, right-sided shoulder pain occurred in 33 patients, left-sided pain in three, and bilateral pain in eight. The frequencies of PLSP and VRS pain scores were similar in both groups at each timepoint (Tables 1 and 2).
The VRS pain score for surgical pain, cumulative ketorolac consumption, and proportion of patients not requiring rescue analgesia were no lower in the pregabalin group than in the placebo group throughout the study (Table 2, Fig. 1).
Of the side effects, only the postoperative 2-h incidence of oversedation was significantly higher in the pregabalin group than in the placebo group (Table 3, P < 0.05). The length of postanesthesia care unit stay was similar in both groups (38.7 ± 17.2 min in the placebo group vs 37.4 ± 13.3 min in the pregabalin group).
Pregabalin is widely used to control chronic neuropathic pain under various clinical conditions.9 Although pregabalin has antihyperalgesic effects and reduces peripheral and central sensitization after nerve or tissue injury,9,10 our study failed to find any beneficial effect of this medication on PLSP. The most likely explanation for this lack of efficacy might be that pregabalin has antinociceptive effects mainly in the setting of chronic neural sensitization after nerve or tissue injury, not peripheral nerve injury of acute onset. Another possible explanation is that central sensitization, a process shown to be reduced by pregabalin, may not be a major mechanism in the development of PLSP, as suggested by Huot et al.11 Alternatively, although PLSP is conveyed only via the phrenic nerve, it might not be accompanied by a definite phrenic nerve injury. Pregabalin, like gabapentin, has minimal effects on the normal physiological pain response.9,12
In conclusion, the perioperative administration of two doses of pregabalin 300 mg 12 h apart did not decrease the frequency or severity of PLSP as well as the severity of surgical pain after LC. Rather, it was associated with an increased incidence of undesirable sedation in the early postoperative period.
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© 2009 International Anesthesia Research Society
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