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ANALGESIA

Disposition and Clinical Outcome After Intraperitoneal Meperidine and Ropivacaine Administration During Laparoscopic Surgery

Michael J. Paech, DM^*, Kenneth F. Ilett, PhD^*, L. Peter Hackett, MRSC, Madhu Page-Sharp, PhD^*, and Richard W. Parsons, PhD

From the *Pharmacology and Anaesthesiology Unit, School of Medicine and Pharmacology, The University of Western Australia, Perth; and Clinical Pharmacology and Toxicology Laboratory, PathWest Laboratory Medicine, Nedlands, Western Australia, Australia; Independent Biostatistician, Perth, Western Australia, Australia.

Address correspondence to Michael J. Paech, DM, Department of Anaesthesia and Pain Medicine, King Edward Memorial Hospital for Women, 374 Bagot Road, Subiaco, Western Australia 6008, Australia. Address e-mail to michael.paech{at}health.wa.gov.au.

Abstract

BACKGROUND: Limited evidence supports the efficacy of intraperitoneal (IP) meperidine or local anesthetic for postoperative analgesia. Our study aims were to investigate analgesic efficacy and to quantify the plasma concentrations of meperidine and ropivacaine after IP administration. The null hypothesis was that there was no significant difference among groups for dynamic pain in the first 24 h after major abdominal laparoscopic surgery.

METHODS: This double-blind, five parallel group, placebo-controlled, two-center trial randomized 250 women having laparoscopic surgery to receive IP meperidine 50 or 100 mg (groups M50 and M100), ropivacaine 150 mg (group R150), meperidine 50 mg and ropivacaine 150 mg (group M50R150), all with intramuscular saline, or IP saline, with intramuscular meperidine 50 mg (group C). The primary outcome was pain during recovery. A pharmacokinetic profile of the drugs was obtained.

RESULTS: There were no significant differences among groups for mean (sd) dynamic pain scores in the postoperative care unit (2.2 [2.8], 2.5 [3.3], 1.6 [2.5], 2.6 [3.2], 2.7 [3.2] for groups C, M50, M100, R150, and M50R150, P = 0.50) or thereafter. There were no significant differences among groups for pain scores at rest, IV morphine use, recovery characteristics and patient satisfaction. After IP administration of meperidine 50 mg the plasma concentration (median average 55–60 µg/L) was approximately half that of an equivalent intramuscular dose (median average 113 µg/L).

CONCLUSIONS: Compared with systemic opioid, IP meperidine and ropivacaine, alone or in combination, did not produce better pain relief or opioid dose-sparing after laparoscopic surgery.

The intraperitoneal (IP) administration of local anesthetic (LA) during gynecologic laparoscopic sterilization results in either improved initial pain relief or opioid dose sparing.1 Evidence for the effectiveness of IP LA is less compelling when used for more extensive intraabdominal and pelvic laparoscopic surgery. Trials involving major gynecologic surgery have been disappointing, mostly showing no benefit2–4 or, at best, a short-term and modest effect.5–7 Only one trial reported a significant reduction in morphine consumption and also less postoperative nausea and vomiting (PONV).8 In 2006, a systematic review of IP bupivacaine administration for laparoscopic cholecystectomy found nine negative and 15 positive trials for significant analgesic benefit and concluded that, because of the low study quality and conflicting results, the use of IP LA could not be recommended.9 In contrast, a second systematic review and meta-analysis of pooled data from 16 studies found LA significantly reduced pain scores at 4 h.10 However, the latter reviewers concluded that the review lent only limited support to use of IP LA and at the time of commencing this study, in the absence of both wound infiltration and IP LA, the clinical utility of IP LA had not been established.1

In addition to LA, IP opioid has also been investigated. When IP bupivacaine and meperidine was compared with IP bupivacaine and/or the equivalent dose of intramuscular (IM) meperidine, women having laparoscopic tubal ligation and laparoscopic cholecystectomy reported lower pain scores at rest and with movement.11,12 These findings have not been confirmed in a larger clinical trial and no information is available about the systemic absorption of IP meperidine.

To investigate whether IP meperidine and LA reduced pain after abdominal laparoscopic procedures involving tissue dissection, we conducted a randomized controlled trial comparing IP meperidine and ropivacaine, alone or in combination, with IP saline and systemic meperidine. The clinical aim was to investigate analgesic efficacy, as assessed by pain intensity and postoperative IV opioid requirement. Our null hypothesis was that there was no significant difference among groups with respect to the dynamic pain scores in the first 24 h after major abdominal laparoscopic surgery. The pharmacologic aim was to measure the plasma concentrations of the IP drugs, to assess safety and shed light on the mechanism of action of IP meperidine.

METHODS

Trial Design and Procedures
This randomized, double-blind, parallel group, two-center trial received Ethics Committee approval at each site and patients provided written informed consent. Patients were recruited between November 2001 and September 2004 at a large tertiary referral trauma and general hospital (Royal Perth Hospital) and a tertiary referral Women’s hospital (King Edward Memorial). Inclusion criteria were as follows: age 18 yr or older; ASA classification 1 or 2; and scheduled for elective laparoscopic abdominal surgery under general anesthesia. Patients with a history of allergy to meperidine or amide LA, taking opioids, or unsuitable for patient-controlled analgesia were excluded. Patients recruited and randomized who did not receive the study drug because of a change in surgical plan or because a nonlaparoscopic procedure was performed were withdrawn and their randomization number reallocated.

Standardized general anesthesia consisted of IV midazolam 1–2 mg, propofol for induction and maintenance, oxygen/air and IV morphine (fixed 0.15 mg/kg initial loading dose then 2 mg boluses at the discretion of the attending anesthesiologist). Neuromuscular block was obtained with rocuronium or vecuronium, because atracurium and cisatracurium had the capacity to interfere with drug assays. Prophylactic antiemetic drugs were permitted, but port and trochar sites were not infiltrated with LA. The carbon dioxide pneumoperitoneum was limited to a pressure of 15 mm Hg during maintenance and was expelled as completely as possible at the end of surgery. Postoperative analgesia was standardized, using IV morphine 2 mg as required in the postanesthesia care unit (PACU), then regular oral acetaminophen (1 g 6 hourly) and patient-controlled IV morphine (1 mg bolus, 5 min lockout interval, no infusion) for 24 h.

According to a computer-generated random number sequence, stratified for type of surgery (upper abdominal such as laparoscopic cholecystectomy or lower abdominal gynecologic, such as hysterectomy, ovarian cystectomy, or treatment of endometriosis) and using opaque sealed envelope allocation, 250 patients were assigned to 1 of 5 groups, to receive the following doses: IP meperidine 50 mg and IM saline (group M50); IP meperidine 100 mg and IM saline (group M100); IP ropivacaine 150 mg (as 20 mL 0.75% ropivacaine) and IM saline (group R150); IP meperidine 50 mg and ropivacaine 150 mg and IM saline (group M50R150); or IP saline and IM meperidine 50 mg (group C). Study solutions (2 mL for IM and 20 mL for IP administration) were prepared in sterile, coded syringes by the hospital pharmacy. At the completion of surgery, the surgeon injected the IP solution onto the operative bed using direct vision and the IM solution was injected into the deltoid muscle by the anesthesiologist.

Research nurses, investigators and nursing staff unaware of study group allocation performed all postoperative observations. Dynamic pain scores were recorded after the patient had sat upright and coughed vigorously. At rest and dynamic pain scores (0–100 visual analog scale [VAS] scores, except in the PACU where a 0–10 numerical rating score was obtained) were recorded on arousal and at 2, 4, 6, 12, and 24 h postoperatively. Intraoperative and postoperative morphine requirements until 24 h postoperatively were noted. In a few cases in which the protocol was violated on clinical grounds and patient-controlled IV fentanyl substituted for morphine, morphine equivalents were determined using a potency ratio of 10 µg fentanyl equivalent to 1 mg morphine.

In the PACU and at 2 h, patients were questioned directly about symptoms potentially suggestive of LA toxicity (e.g., tinnitus, circumoral numbness, twitching). At 2, 4, 6, 12, and 24 h postoperatively, PONV was graded on a four point scale as nil, mild nausea only, nausea or vomiting responding to initial treatment, and nausea or vomiting requiring repeat treatment. Respiratory rate and sedation score were recorded according to hospital routine. At 24 h (or earlier if ready for discharge), patients were asked about intermittent cramping pain, indicative of visceral pain; shoulder tip pain, indicative of subdiaphragmatic peritoneal pain; and satisfaction with pain relief, which was measured using a VAS score. Times to first ambulation, resumption of eating and hospital length of stay were recorded.

Pharmacokinetic Substudy
The pharmacokinetic substudy was conducted on 118 patients (groups M50, n = 23; M100, n = 24; R150, n = 23; M50R150, n = 25; and C, n = 23). Venous blood samples (5 mL, lithium heparin) for drug analysis were collected just before the dose (0 h) and at 0.25, 0.5, 1, 1.5, and 2 h after dose. Plasma was separated by centrifugation and stored at –20°C before analysis by high performance liquid chromatography. After the addition of bupivacaine (200 ng) as an internal standard, 1 mL aliquots of plasma were made alkaline with 0.1 mL 1M NaOH and the meperidine, normeperidine, and/or ropivacaine was extracted into 10 mL diethylether by shaking vigorously for 5 min. After centrifugation, the organic phase was transferred into a clean tube and back-extracted into 0.2 mL 0.05 M HCl by shaking vigorously for 1 min. The organic phase was aspirated to waste and 0.08 mL aliquots of the acid phase were injected onto the high performance liquid chromatograph. Separations were achieved on a Merck LiChrospher RP Select B column (5 µm, 250 x 4.6 mm; E. Merck, Damstadt, Germany), using a mobile phase of 17% v/v CH₃CN in 45 mM KH₂PO₄ (adjusted to pH 3 with H₃PO₄), and pumped at 1.5 mL/min and with ultraviolet detection of the analytes at 210 nm. The assays were linear over the concentration ranges 10–300, 2–150, and 50–2000 µg/L for meperidine, normeperidine, and ropivacaine, respectively. Samples with above range results were reassayed using a smaller sample volume to bring them into the standard curve. Both intra- and inter-day relative standard deviations for the assays were <3.2% for ropivacaine, <3.7% for meperidine, and <3.1% for normeperidine. The limits of detection were 1 µg/L for both meperidine and normeperidine, and 6 µg/L for ropivacaine. Plasma concentrations of meperidine, normeperidine, and/or ropivacaine were plotted against time after dose (0–2 h) and the areas under the plasma concentration-time curves (AUC) were measured using the linear trapezoidal rule, as implemented in SigmaPlot version 9.0 (SPSS, Chicago, IL). The average drug concentrations (C_av) in plasma were calculated as AUC_{0–2 h}/2 and group data were analyzed by Kruskal–Wallis analysis of variance (ANOVA) on ranks.

Statistical Analysis
The primary outcome was the dynamic pain score on arousal in the PACU. A previous study reported mean (sd) pain scores of approximately 50 (±30) after laparoscopic cholecystectomy managed with systemic opioid.13 At 0.05, we calculated that 35 patients per group would provide 80% power to detect a 20-mm reduction in mean pain score (or difference of 2 on a verbal numerical 0–10 rating score) in a treatment group (2-sided two sample t-test). However, to allow for the comparisons between the control group and each treatment group, an adjusted P (Bonferroni correction) of 0.0125 was considered significant for the primary outcome and the required sample size increased to 50 per group or 250 patients.

Descriptive statistics presented were the mean and standard deviation for continuous variables, and frequencies (percentages) for categorical variables. Analysis of the primary endpoint was performed using ANOVA. In addition, 95% confidence intervals (CI) were calculated for the differences between the control group and each active treatment. After leaving the PACU, the pain scores were analyzed as a repeated measures ANOVA. This was implemented using "PROC Mixed" in SAS with the two fixed effects being timing and treatment group, and with the repeated measures having an unstructured covariance matrix. Timing was generally treated as a categorical variable, so as not to impose any linear trend on the pain scores over time. Timing was treated as a continuous variable only in models where any trend over time was explicitly examined. Similarly to pain scores in the PACU, CIs for differences in pain scores between control and active treatment groups were calculated at each time point.

Inferential analyses of other continuous data such as satisfaction were performed using ANOVA. Variables associated with high and low levels of satisfaction were sought using logistic regression. The backward elimination method was used to test for associations with other variables such as sex, age, weight, ASA status, and type and duration of surgery. In this iterative approach, initially all independent variables were included in the model. One at a time, the least significant variable was dropped as long as its P value was more than 0.05. Categorical data were analyzed using the ² statistic. A P value of 0.05 was considered statistically significant. All statistical analyses were performed using the SAS software package (SAS version 8. SAS Institute Inc., Cary, NC, 1999).

RESULTS

We enrolled 250 non-day-surgical patients, but excluded 30 patients who had surgery cancelled or were rescheduled for a nonlaparoscopic operation, to achieve a study population of 220. In two cases (group C n = 1; group M50R150 n = 1), no data were collected, leaving 218 data sets (59 from one site and 159 from the other) for analysis (Appendix). Included in the intention-to-treat population were 13 patients with minor protocol violations (wound infiltration with LA [n = 4]; change to fentanyl patient-controlled analgesia or administration of additional analgesics [n = 9]); and 11 patients for whom patient-controlled analgesia was ceased or hospital discharge permitted after 12 h but before 24 h postoperatively.

There were no significant differences among groups with respect to patient or surgical demographics, with approximately 75% of patients undergoing major gynecologic surgery (Table 1).

Dynamic pain scores in the PACU were low and did not differ significantly among groups (P = 0.44; Table 2). There were also no significant differences among groups at any time for rest pain scores or for subsequent postoperative dynamic pain scores (Table 2). The repeated measures ANOVA on the scores at rest showed that higher scores were associated with upper abdominal surgery (9 mm higher, P = 0.001) and younger age (P = 0.0001). There was no difference between treatment groups (P = 0.96, unadjusted; P = 0.55, adjusted), or over time (P = 0.87), either before or after adjustment for other variables (sex, age, weight, ASA status, type and duration of surgery, presence of nausea or vomiting). Dynamic pain scores were also higher for upper abdominal surgery (36.3 vs 25.7 mm, P = 0.0003) and younger age (pain score decreases by 0.75 points per year of age, P = 0.0001). The difference among groups was again not significant (P = 0.71), but, over time, there was a significant increase (linear trend) in dynamic pain scores (P = 0.0017).

Groups did not differ for IV morphine use. There were no differences in intraoperative use or postoperative use at any time point (P = 0.53, repeated measures ANOVA), in hourly change in use over an assessment epoch (P = 0.61, repeated measures ANOVA), or in cumulative patient-controlled morphine use at 24 h or in total dose administered over the study period (Table 3).

The groups were not significantly different for recovery characteristics such as time to first ambulation or ingestion of food, severity of PONV, the duration of hospital stay, or satisfaction score (Table 4). The percentage of patients reporting satisfaction scores of <75 did not differ significantly (25%, 28%, 10%, 17%, and 14% for groups C, M50, M100, R150, and M50R150, respectively, P = 0.38), but patients having upper abdominal procedures were more likely to have a low score (odds ratio, 3.0; CI, 1.4–6.4; P = 0.003).

One patient reported symptoms in the PACU that were consistent with LA toxicity, but had not received ropivacaine (group C). Respiratory depression, diagnosed on the basis of over-sedation (difficult to rouse, responding to physical contact only) or bradypnea (respiratory rate 8 breaths/min or less) was detected in nine patients (group C, n = 2; group M50, n = 1; group M100, n = 1; group R150, n = 3; group M50R150, n = 2).

The concentrations of meperidine, normeperidine, and ropivacaine in each group over time are summarized in Figures 1–3, respectively.

View larger version (11K): [in this window] [in a new window]   Figure 1. Mean (±95% CI) concentrations of meperidine after 50 mg intramuscular meperidine (group C) (•), 50 mg IP meperidine (group M50) (), 100 mg IP meperidine (group M100) (), or 50 mg IP meperidine with 150 mg IP ropivacaine (group M50R150) (). Error bars have been drawn unidirectionally for clarity.

View larger version (11K): [in this window] [in a new window]   Figure 2. Mean (±95% CI) concentrations of normeperidine after 50 mg intramuscular meperidine (group C) (•), 50 mg IP meperidine (group M50) (), 100 mg IP meperidine (group M100) (), or 50 mg IP meperidine with 150 mg IP ropivacaine (groupM50R150) (). Error bars have been drawn unidirectionally for clarity.

View larger version (10K): [in this window] [in a new window]   Figure 3. Mean (±95% CI) concentrations of ropivacaine after 150 mg IP ropivacaine alone (group R150) (), or 150 mg IP ropivacaine with 50 mg IP meperidine (group M50R150) (). Error bars have been drawn unidirectionally for clarity.

The C_av for meperidine differed significantly among groups. After administration of 50 mg IM, the median C_av (25th to 75th percentiles) of 113 (92–155) µg/L was significantly more than that after 50 mg IP (60 [44–77] µg/L, P < 0.05) and after 50 mg IP with IP ropivacaine (55 [28–73] µg/L, P < 0.05; Fig. 1). Median C_av after administration of 100 mg IP meperidine (120 [89–171] µg/L) was also significantly more than after 50 mg IP, with or without ropivacaine (P < 0.05), but was similar to that after 50 mg IM meperidine (Fig. 1). Regardless of the route or dose of meperidine, the median C_av concentrations of its metabolite normeperidine in plasma were generally low (<10 µg/L) and increased slowly across the 2 h of the study. Median normeperidine C_av was similar after 100 mg IP meperidine (5.2 [2.9–8.6] µg/L), 50 mg IP meperidine (3.4 [0.2–6.8] µg/L), and 50 mg IP meperidine with ropivacaine (2 [0–5] µg/L; Fig. 2). However, median normeperidine C_av after administration of 50 mg IM meperidine (1.5 [0–4.7] µg/L) was significantly lower (P < 0.05) than after 100 mg IP meperidine (Fig. 2). Ropivacaine plasma concentrations peaked at approximately 30 min and C_av was similar regardless of whether the drug was administered alone (mean, 720 µg/L [284 µg/L]) or with meperidine (591 µg/L [330 µg/L]) (Fig. 3).

DISCUSSION

After gynecologic or abdominal laparoscopic surgery involving tissue dissection, we found no significant difference in the postoperative analgesic or opioid dose-sparing effect of IP meperidine, ropivacaine, or their combination compared with IM meperidine. The absorption of IP meperidine resulted in mean plasma concentrations <50% of those seen after IM administration of an equivalent dose and mean plasma ropivacaine concentrations were below the generally accepted toxic range.14,15

The efficacy (by reduction in pain or opioid dose-sparing) of IP LA at diagnostic laparoscopy and laparoscopic tubal ligation has been established16–18 and its safety seems reasonable.19 This method is thus common practice in some countries.20 IP LA seems to block visceral afferent nociception and systemic lidocaine may also have an analgesic effect.21 However, our clinical findings support a lack of analgesic efficacy after laparoscopic cholecystectomy9,22,23 or after major gynecologic surgery.2–4 Of note, one of the few studies to report efficacy provided a prolonged IP infusion via a catheter8 and there is some evidence that high concentrations administered before dissection are more effective.10

Although small doses of IP morphine are not effective after laparoscopic sterilization,24 Colbert et al.11 reported improved analgesia when meperidine 50 mg was added to IP bupivacaine 100 mg and epinephrine, rather than injected IM. Pain relief was maximal at 2 h and better until 6 h postoperatively, although pain scores were very low in both study arms and there was no difference in analgesic requirement. Therefore, the clinical benefit seemed negligible. After equivalent 50-mg doses, O’Hanlon et al.12 found slightly lower pain scores with IP compared with IM administration, the effect persisting for 24 h. Although the mode of action is not clear, meperidine produces spinal anesthesia in the subarachnoid space25 and improves pain relief when infiltrated with LA peripherally.26 Previous investigators have postulated that the analgesic effect of IP meperidine resulted from LA activity at the surgical site and/or from central activity after systemic absorption. In the absence of published data on opioid absorption after IP administration, we studied doses of IP meperidine similar to those in previous investigations and consistent with therapeutic IM dosing but found no advantage compared with systemic administration. Although the peak plasma concentration of IP meperidine was delayed compared with IM administration, mean concentrations in the first 2 h after a 100-mg dose were similar to those after a 50-mg IM dose (100–200 µg/L). These levels are below the minimum analgesic concentration for meperidine,27 although our patients had also previously received IV morphine. It seems unlikely that the IP route is useful for systemic administration of meperidine or that meperidine exerts a LA or opioid effect on peritoneal nociceptors that could be exploited clinically.

The ropivacaine dose selected was based on previous trials that used IP ropivacaine 150 mg or more and that found efficacy without incident.15,28,29 After the study commenced, Labaille et al.30 reported no clinical evidence of toxicity at plasma ropivacaine concentrations resulting from twice the dose we used. Colbert et al.11 studied 50 mg of IP meperidine and we chose the same dose to confirm or refute their findings. To look for a dose-related effect, we also investigated 100 mg on the basis that this is an acceptable systemic dose and that bioavailability from the peritoneal cavity would not be expected to be 100%.

Labaille et al.30 reported median plasma concentrations approaching 3000 µg/L after 300 mg of IP ropivacaine administered both before and after dissection of the gallbladder. The mean maximum tolerated range for central nervous system symptoms in awake volunteers is 2–2500 µg/L,14,16 although the onset of symptoms is seen at a mean concentration of 900 µg/L14 and intolerable symptoms occur in the range 500–3200 µg/L.15 In our study, 96% of patients had a mean plasma ropivacaine concentration <1300 µg/L and none experienced symptoms of toxicity. Concentrations between 2000 and 5600 µg/L have been tolerated without sequele in previous studies that involved larger doses of ropivacaine.28 Boddy et al.10 concluded that "the use of IP local anesthesia is safe." If wound infiltration and IP administration is combined, the lowest effective dose should be administered, but there is no information on this subject. We are not aware of any dose-ranging studies for IP LA. A study using combined IP and infiltration doses of 150–285 mg of ropivacaine did not obtain pharmacokinetic profiles.29

The mean plasma C_av values of meperidine after 50 mg IM were similar to peak concentrations reported previously.31 When normalized to a 50-mg dose, median C_av values for the 3 IP meperidine doses that were administered ranged from 55 to 60 µg/L for meperidine and from 2 to 3.4 µg/L for normeperidine. After 50 mg meperidine IM, median C_av values of 113 µg/L for meperidine and 1.5 µg/L for normeperidine were similar to mean C_av values of 140 µg/L for meperidine and 5 µg/L for normeperidine (normalized to a 50-mg dose) calculated from published data (first 2 h after dose) after a short IV infusion of meperidine.32 The data suggest that the absolute bioavailability of meperidine after IP administration is around 40%, whereas that after IM administration is 100%. Nevertheless, given that our data pertain only to the 2 h after the dose, these conclusions are highly speculative. Importantly, over the 2-h study period, our data clearly showed that 100-mg meperidine IP had approximately the same relative bioavailability as a 50-mg IM dose. From a pharmacokinetic viewpoint, it can be concluded that there is no real advantage to administering meperidine IP instead of IM. The normeperidine concentrations in all groups were low (range of means, 1.5–3.5 µg/L), and about three orders of magnitude lower than those known to cause toxicity.33

The study has several limitations. Ten percent of patients had protocol violations, although most were minor and are unlikely to have biased findings. We chose not to allow wound infiltration because of interference with our pharmacokinetic substudy and because of insufficient evidence for benefit at the time of commencing the trial.17,34 However, there is now good evidence supporting infiltration of trocar wounds at laparoscopic cholecystectomy.9 Other possible limitations relate to the dose, timing, and location of administration. We used a low volume of solution and the rapid dilution of LA within the peritoneal cavity or inadequate concentration has been suggested as a reason for analgesic failure.4,24 Shaw et al.4 reported no benefit from the IP instillation of very dilute LA (1000 mL 0.01% bupivacaine) at gynecologic laparoscopic surgery. The influence of volume on efficacy or absorption from the peritoneal cavity is unknown, but our use of a high concentration should have maximized the chance of detecting an improvement in pain relief.10 Studies comparing presurgical and postsurgical instillation of IP LA have produced conflicting results,9 but recent meta-analysis indicates a larger reduction in pain when administered before surgical dissection,10 and we administered solution at the end of surgery. Although Goldstein et al.8 reported opioid dose-sparing after gynecologic laparoscopy when bupivacaine was instilled, both at the surgical site and bilaterally under the diaphragm, there is insufficient evidence to support a relation between site of instillation and efficacy.9

Our investigation of a mixed surgical population could be criticized, but all patients underwent major tissue dissection, as reflected by the average length of hospital stay of at least 2 days. We detected small differences in the severity of pain between patients having upper abdominal versus pelvic surgery, but did not perform a post hoc substudy analysis of each population because the number of patients having abdominal surgery was small and the scores across groups very similar. Multiple analyses increase the risk of making a type 1 error and a subgroup analysis was likely to be underpowered and unlikely to reveal a clinically important difference among groups.

The dynamic pain scores in all groups were lower than anticipated, so the study may have been underpowered to detect very small differences among groups. We can be 95% confident that the pain scores for each treatment group were no more than 20 mm different on the VAS (two points in PACU) compared with the control group. Because of imprecision in showing an effect of a medication, a change in VAS score of more than 20 mm is needed to confirm a change.35 Twenty-seven of the 28 CIs reported in Table 2 show that there was no such difference between treatment and control groups. The one exception is for M50R150 at 2 h, where the CI is from –1.8 to 21.2. From the definition of the 95% CI, we expect that 5% (1 in 20) of these intervals will show a significant result when there is none. Our findings are consistent with this. The study was powered to detect clinical differences of this magnitude, so we can state that with this clinical criterion, there is no evidence that IP meperidine or ropivacaine produce better analgesia than systemic meperidine to a clinically important extent. In addition, the times to return of normal function were not significantly different but showed less variability in all treatment groups compared with the control group.

In summary, an analgesic regimen involving the IP administration of meperidine, ropivacaine, or their combination failed to provide better postoperative analgesia than systemic opioid alone after abdominal laparoscopy.

ACKNOWLEDGMENTS

We thank the research nurses who coordinated at each site, Mrs Susan March and Shauna Fatovich, and Mrs Tracy Bingham and Desiree Cavill; the Department of Pharmacy at Royal Perth and King Edward Memorial Hospitals; and Dr Andrew Imison, who helped plan the study. The following anesthesiologists contributed substantially to the conduct of this study: Drs Jenny Lain, Emma-Jane Bennett, Philip Dodd, Raymond Goy, Sarah Berridge, Jane Turner, Gail Gillespie, Will Garrett, Kate Stannard, Simon Jackson, Oliver Tweedie, Helen Daly, Martin Hepp, Dominic O’Connor, Sarah Harper, and Kenny Pollock.

APPENDIX

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Footnotes

Accepted for publication August 20, 2007.

Funding: This study was supported by a research grant from the Royal Perth Hospital Medical Research Foundation (Royal Perth Hospital, Wellington St, Perth, Western Australia 6008, Australia) and from departmental research funding at both sites.

Reprints will not be available from the author.

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