Extended Abstract
P. W. H. Peng
Abstract
Abstract Background. The objective of this study was to examine the effects of low-dose pregabalin on the analgesic efficacy, side- effects, and recovery profile in patients undergoing laparoscopic cholecystectomy. Methods. One hundred and sixty-two patients aged 18 – 65 yr, of ASA physical status I – III, undergoing elective outpatient laparoscopic cholecystectomy were recruited and randomized in this prospective, placebo-controlled, double-blind study to receive one of the following study medications orally: pregabalin 50 mg, pregabalin 75 mg, or placebo, 1 h before surgery and then every 12 h after operation for a total of three doses. Postoperative numeric pain scores, analgesic consumption, recovery score (QoR-40), and side-effects (opioid-related symptom distress scale) were assessed in the early postoperative period (every 15 min during the first hour, at 90, 120 min, 6, and 12 h) and at days 1, 2, and 7. Data were analysed using an intention-to-treat method. Results. Compared with the placebo group, the pain scores were lower in the pregabalin 75 mg group in the first 90 min after surgery (P,0.05). Pregabalin 50 mg resulted in pain reduction at 30 and 45 min (P,0.05) relative to placebo. The analgesic consumption, side-effects, and recovery scores were similar among the three groups. Conclusions. Perioperative administration of pregabalin 75 mg provided limited analgesic benefit in the postoperative period. An updated meta-analysis confirms this finding (see Supplementary material). Keywords: anaesthesia; cholecystectomy; general surgery; pain, postoperative; pregabalin; premedication Gabapentinoids are anti-convulsants with membrane stabilizing and anti-nociceptive effects. These drugs bind to the presynaptic a2 –d subunit voltage-dependent calcium channel.1 2 The anti-nociceptive effect is believed to be related to the reduction of the Ca2+ influx at presynaptic terminals in hyperexcited neurones, which may lead to the reduction of the release of several excit-atory neurotransmitters, including glutamate, norepi-nephrine, substance P, and calcitonin gene- related peptide.3 4 Thus, gabapentinoids appear to reduce the hyperexcitability of dorsal horn neurones that is induced by tissue damage The analgesic effect of gabapentin has been well estab-lished in various surgical populations and was described in multiple systematic reviews.5 – 9 Compared with gabapentin, pregabalin has a more favourable pharmacokinetic profile with better, faster, and more predictable absorption. It is rapidly and extensively absorbed after oral dosing, with maximal plasma concentration at 1 h after single or mul-tiple doses. The oral bioavailability is 90% and is indepen-dent of dose.1 3 These properties offer some advantages over gabapentin as a perioperative medication. Pregabalin has recently been investigated for perioperative use, but the results are inconsistent.10 – 18 Four out of nine peri-operative trials were negative10 13 14 16 and only two trials showed a reduction in both analgesic consumption and pain scores.17 18 Two other trials demonstrated a reduction in the analgesic consumption at the expense of an increase in pregabalin-related side- effects.12 15 The doses of pregabalin used in the aforementioned studies ranged from 75 to 300 mg. The hypothesis of this study was that multiple low doses of pregabalin would provide superior analgesic effects with minimal pregabalin-related side-effects in the first 24 h after day surgery. The objective of the study was to examine the effects of pregabalin in low doses, 50 and 75 mg, on the analgesic efficacy, side-effects, and recovery profile in patients undergoing outpatient laparoscopic cholecystectomy. Methods This double-blind, randomized, controlled study was designed to recruit patients aged between 18 and 65, of ASA physical status I – III, undergoing laparoscopic chole-cystectomy. After Institutional Ethic Review Board approval and written consent, patients were randomized to receive one of the study medications orally: pregabalin 50 mg, pregabalin 75 mg, or placebo, 1 h before surgery and then every 12 h after operation for a total of three doses. This study was registered with www.controlled-trial .com (ISRCTN01000893). Patients were excluded from recruitment if they required urgent or emergent cholecystectomy, or analgesics in 24 h before surgery (except the premedication as per protocol); had a body mass index more than 40, a clinical diagnosis of acute pancreatitis or a history of allergy or contraindica-tion to gabapentin or pregabalin, non-steroidal anti-inflammatory agents, codeine or acetaminophen, or serious organ disease or dysfunction, severe psychiatric disease, or drug addiction; or were pregnant or could not communicate in English. The study medications were prepared in capsules of identical colour and appearance and were packaged by the hospital pharmacy according to a computer-generated randomization list. On the day of surgery, patients received standard premedications as per our institution protocol: naprosynw 500 mg and acetaminophen 1000 mg 1 h before surgery in the preadmission unit. The study medi-cation was given to the patient together with the premedica-tions. The anaesthetist responsible for the operating theatre list, the patient, the surgeon, nurses, and the research assist-ant were blinded to the randomization. Before surgery, patients were instructed to rate their pain using a numeric verbal rating score (NRS) on a scale of 10 (0, no pain; and 10, worst imaginable pain). Patients received standardized general anaesthesia. Induction of general anaesthesia was achieved with i.v. pro-pofol 1 – 2 mg kg21 and fentanyl 2 – 5 mg kg21, followed by rocuronium 0.8 – 1 mg kg21 to facilitate orotracheal intuba-tion with a cuff tube. Balanced anaesthesia was maintained using nitrous oxide and desflurane at end-tidal concentration 3 – 6% in oxygen, and i.v. fentanyl. The amount of the induc-tion agent and volatile agent were titrated by the attending anaesthetist and recorded. All patients were given a single i.v. dose of prophylactic antiemetic, granisetron 1 mg, at the end of operation. The surgeon administered local anaes-thetic (bupivacaine 0.25% with epinephrine 1 in 200 000 to a volume of 30 ml) around the gall bladder bed and the lapara- scopy port sites (10 ml of the same solution). Neuromuscular block was antagonized with neostigmine 70 mg kg21 and gly- copyrrolate 0.05 mg kg21 i.v. On completion of surgery, patients were transferred to the post-anaesthesia care unit (PACU) where their pain scores (NRS) were measured on arrival and every 30 min until dis- charge from the PACU. Pain was assessed at rest and on active movement (or coughing). When patients requested analgesia, a fentanyl bolus at an increment of 25 – 50 mg was titrated according to patient’s comfort with the standard protocol in the PACU every 5 – 10 min. Dimenhydrinate 25 – 50 mg i.v. was given as a rescue antiemetic if needed. Patients were discharged to the day surgery unit (DSU) when the Aldrete19 score was ≥9. In the DSU, patients received combi-nation tablets of acetaminophen 325 mg with codeine 30 mg when NRS was .3 or on request. Eligibility for discharge from DSU was based on the post-anaesthesia discharge score which was recorded every 15 min.20 Patients took their pregabalin medication or oral placebo 12 and 24 h after the first dose regardless of the level of pain they were experiencing. Patients who experienced insuf-ficient pain relief were allowed to take supplementary com-bination tablets of acetaminophen 325 mg and codeine 30 mg 1 – 2 tablets orally every 4 – 6 h as needed (maximum of 12 tablets per day). Patients were instructed to complete a diary to record the pain score, adverse events experienced, satisfaction, amount of nalgesics taken, sleep quality, the opioid-related symptom distress scale (SDS), and the 40-item recovery score (QoR-40). They were followed up on the first, second, and seventh day after operation by telephone to determine the completion of the diary. The patients mailed the ques-tionnaire package back after completion. The opioid-related SDS is a validated instrument record-ing 12 opioid-related symptoms for the assessment of patient postoperative recovery functional status and side-effects.21 This questionnaire measures the interference of pain (frequency, severity, and bothersomeness) with various daily activities by using a categorical scale (Appen-dix). Clinically meaningful events (CME) were defined based on the level of patient response to each symptom in the three measured dimensions: frequency, severity, and both-ersomeness.22 For each study symptom, a patient with a response of ‘frequently’ to ‘almost constantly’ for the frequency dimension, ‘moderate’ to ‘very severe’ for the severity dimension, or ‘quite a bit’ to ‘very much bothered’ for the bothersomeness dimension was considered to have a CME. Postoperative quality of functional recovery was assessed by a well-validated QoR-40, which measured five dimensions of recovery: physical comfort (12 items), emotional state (nine items), physical independence (five items), psychologi-cal support (seven items), and pain (seven items).23 Each item was rated on a five-point Likert scale. The QoR-40 has a possible score of 40 (extremely poor quality of recovery) to 200 (excellent quality of recovery). It was specifically designed to measure a patient’s health status after surgery and anaesthesia and has been proposed as a measure of outcome in clinical trials.24 The patient’s sleep quality was recorded with the Likert scale: a rating scale measuring sleep quality on a scale of 0 – 10, where 0, poor sleep, and 10, best sleep. Pain scores are presented as a median and inter-quartile range. All other data are presented as mean and standard devi-ation. P. W. H. Peng University of Toronto, Canada, E-mail: philip.peng@uhn.on.ca P-values of ,0.05 were considered significant. Pain scores were analysed with the Kruskal–Wallis test. If there was a significant difference among the groups, individual groups were compared in a pairwise manner using a Mann– Whitney U- test. Patient data, analgesic consumption, side-effects, and recovery scores were analysed with analysis of var-iance. If there was a significant difference among the groups, post hoc analysis was performed with the Bonferroni test. Cat-egorical data were analysed with a x2 test. Data were analysed using SPSS 16.0 for Windows (SPSS, Chicago, IL, USA). All ana- lyses were performed on the intent-to-treat population, which included all patients who were randomized into the study and received at least one dose of study medication. For intention-to-treat analysis, missing data were managed with the ‘last observation carried forward’ imputa-tion method.25 26 A sensitivity analysis was performed with the results of the pain score and analgesic consumption compared with those from ‘per protocol’ analysis, and also those assuming the best and worst outcome analysis. In ‘per protocol’ analysis, only data that were available were analysed. The other analysis was conducted by imputing the best or worst outcome (pain score or analgesic require- ment) for the missing data.26 Sample size was calculated based on the null hypothesis of no difference across all groups following the methods described by Pandey and colleagues.27 On the basis of Pandey and colleagues’ gabapentin study in laparoscopic cho-lecystectomy patients, we estimated that a sample of 41 patients per treatment group would be sufficient to detect a power of 0.8 with a mean difference of 25 mm (out of 100 mm) NRS between any t