European Journal of Obstetrics & Gynecology and Reproductive Biology 180 (2014) 83–88

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The effect of a preoperative single-dose methylprednisolone on postoperative pain after abdominal hysterectomy: a randomized controlled trial Anna J.M. Aabakke a,*, Lars B. Holst b, Jørgen C. Jørgensen a, Niels J. Secher c,d a

Department of Obstetrics and Gynecology, University of Copenhagen, Holbæk Hospital, Denmark Department of Anesthesiology, University of Copenhagen, Holbæk Hospital, Denmark The Research Unit Women’s and Children’s Health, The Juliane Marie Center, Copenhagen University Hospital, Denmark d Department of Obstetrics and Gynecology, Aarhus University Hospital, Denmark b c

A R T I C L E I N F O

A B S T R A C T

Article history: Received 20 November 2013 Received in revised form 23 June 2014 Accepted 26 June 2014

Objective: Methylprednisolone has been shown to have analgesic effects after orthopedic surgery. The objective of this trial was to compare the effect of 125 mg methylprednisolone with placebo on postoperative pain after abdominal hysterectomy. Study design: In this randomized double-blinded placebo-controlled trial women scheduled for elective abdominal hysterectomy (n = 59) were randomized to preoperatively receive either 125 mg methylprednisolone or saline intravenously. Primary outcome was postoperative pain measured on a 0.0–10.0 visual analog scale and assessed at rest and during mobilization repeatedly the first 24 h and daily on the 2nd to 7th postoperative day. Secondary outcomes were postoperative use of opioids and antiemetics, vomiting, C-reactive protein levels, and time to mobilization and discharge. Repeated measures including the primary outcome were analyzed with linear mixed models. Results: Forty-nine cases were analyzed (methylprednisolone n = 25, placebo n = 24). Pain scores were significantly higher in the methylprednisolone group compared to the placebo group during mobilization (0.79 [95% confidence intervals (CI) 0.07–1.50] P = 0.03) but not at rest (0.55 [95% CI: 0.06 to 1.16] P = 0.08). There was no difference between the methylprednisolone and placebo group regarding use of opioids (P = 0.24) and antiemetics (P = 0.14), number of vomits (P = 0.26), and time to mobilization (P = 0.24) and discharge (P = 0.28). C-reactive protein levels were significantly higher in the placebo group (P = 0.01). Conclusions: This trial showed no beneficial effect of methylprednisolone on postoperative pain after abdominal hysterectomy. Methylprednisolone significantly lowered postoperative CRP levels. Clinical trial registration: ClinicalTrial.gov: www.clinicaltrials.gov: NCT01106547. ß 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Glucocorticoids Hysterectomy Methylprednisolone Pain Postoperative

Introduction Glucocorticoids reduce the inflammatory response after surgery, which is correlated with postoperative pain and recovery [1–3]. It is widely accepted that glucocorticoids reduce postoperative nausea and vomiting, also after abdominal hysterectomy [4–7]. In addition, a single dose of glucocorticoids has been shown to

* Corresponding author at: Department of Obstetrics and Gynecology, University of Copenhagen, Holbæk Hospital, Smedelundsgade 60, 4300 Holbæk, Denmark. Tel.: +45 5948 4268. E-mail addresses: [email protected], [email protected] (Anna J.M. Aabakke). http://dx.doi.org/10.1016/j.ejogrb.2014.06.026 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.

reduce postoperative pain after some surgical procedures [8]. A previous study found no pain relieving effect of 8 mg dexamethasone (equivalent to 43 mg methylprednisolone) [9] after abdominal hysterectomy [10]. However, studies have shown a postoperative analgesic effect of 125 mg methylprednisolone (MP) after orthopedic surgeries [2,11], and a meta-analysis found no side effects of a single higher dose of MP [9]. The biological action of glucocorticoids sets in 1–2 h after administration, and the surgery induced inflammatory response begins at skin incision [13,14]. The aim of this trial was to compare the effect of a single dose of 125 mg MP administered 60–90 min before surgery with placebo on postoperative pain after abdominal hysterectomy. Primary outcome was pain at rest and during mobilization assessed repeatedly during the first 24 h after surgery and once daily 2–7

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days thereafter. Secondary outcomes were postoperative use of opioids and antiemetics, vomiting, C-reactive protein (CRP) response, and time to mobilization and discharge. We hypothesized that administration of a single dose of a glucocorticoid could reduce the postoperative inflammatory response and thereby postoperative pain after abdominal hysterectomy. Materials and methods This was a single-center, prospective, randomized, doubleblinded, placebo-controlled trial with a 1:1 allocation ratio. The trial was approved by the Regional Committee on Health Research Ethics of Region Zealand (reg. no.: SJ-127) and the Danish Data Protection Agency before patient enrollment. The trial was registered with EudraCT (reg. no.: 2010-018448-15) and ClinicalTrials.gov (reg. no.: NCT01106547), and was monitored by Good Clinical Practice. We followed the CONSORT recommendations for reporting randomized clinical trials [15]. Written informed consent was obtained from all patients before randomization. Participants Eligible participants were women undergoing elective abdominal hysterectomy for benign indications. Patients had to be able to speak and understand Danish and provide informed oral and written consent. Exclusion criteria were age below 18 years; diabetes mellitus; daily use of immunosuppressives, opioids, or sedatives; alcohol and drug abuse; opioid intolerance; diseases with chronic pain (e.g. fibromyalgia and rheumatoid arthritis); malignant indication for hysterectomy; body mass index >35; renal failure; or American Society of Anesthesiologists physical status class 3. Participants were recruited from September 2009 to September 2011 at Holbæk University Hospital. Design Patients were enrolled by the primary investigator and consecutively numbered after written consent was given. The allocation sequence was computer-generated and stored in a locked room by third parties not otherwise involved in the trial. The allocation was concealed in identical, opaque, sequentially numbered sealed envelopes and stored in a locked room at an independent department. Patients were defined as included when surgery had followed protocol (i.e. participants were not double medicated or acutely reoperated). The appropriate numbered envelope was opened within 24 h before surgery, and the trial drug prepared by a health care professional from the independent department not otherwise involved in the trial and the syringe covered by a patient label. The trial drug was refrigerated until use and administered intravenously 1–1½ h before planned start of surgery. Active treatment was MP 125 mg (2 ml) (Solu-Medrol1; Pfizer, Ballerup, Denmark), and the placebo was isotonic saline (2 ml) (Natriumklorid isotonisk ‘‘SAD’’; Amgros I/S, Copenhagen, Denmark). Anesthesia, surgery and pain management Anesthesia was induced with propofol 1.5–2.5 mg/kg and fentanyl 1–8 mg/kg, and maintained with propofol 5–10 mg kg/h or sevoflurane 1.5–2.0% in combination with fentanyl 0.4–1.4 mg/ kg. All patients were given antibiotic prophylaxis of oral metronidazole 1 g and i.v. cefuroxime 1.5 g before surgical incision. No antiemetic prophylaxis was administered. During postoperative recovery, supplementary analgesics of i.v. oxynorm 5 mg or fentanyl 0.7–1.4 mg/kg were administered if patients had a visual analog scale (VAS) score >3. Protocollised postoperative

analgesics consisted of oral paracetamol 1 g four times daily and slow release diclofenac 75 mg twice daily until the 5th postoperative day. Rescue analgesic was oral or i.v. morphine or oxynorm 5 mg administered if patients had a VAS-score 3 at rest or a VASscore 5 during mobilization. Postoperative nausea and vomiting was treated with i.v. ondansetrone 4 mg. Oral metoclopramide 10 mg was second line antiemetic. The surgical procedure followed department standards for abdominal hysterectomy. Outcomes Primary outcome was pain intensity measured on a VAS scale ranging from 0.0 (no pain) to 10.0 (worst pain imaginable) [16] assessed by the patient at rest and during mobilization (from time of mobilization) 3, 6, and 24 h postoperatively and daily at 8 pm on postoperative days 2–7. Secondary outcomes were (a) use of rescue analgesics assessed as cumulated opioid dose (mg) 0–3, 3–6, 6–12, and 12–24 h postoperatively and total cumulated dose 24 h postoperatively, (b) vomiting assessed as cumulated number of postoperative vomiting episodes and number of patients having vomited after 24 and 48 h, (c) use of antiemetics assessed as cumulated dose of ondansetron (mg) after 24 h and number of patients requiring ondansetron 0–3, 3–6, 6–12, and 12–24 h postoperatively, (d) time to mobilization (hours), (e) time to discharge (hours), (f) degree of inflammation assessed by CRP levels in venous blood (mg/L) before administration of allocated treatment and on postoperative days 1 and 2 at 9 am, and (g) unexpected adverse reactions. Mobilization was encouraged and defined as walking. Discharge was allowed when patients were mobilized, had free clear urination, and no complications. Time to mobilization and discharge was calculated from the end of surgery, defined as last suture. Supplementary analgesics were converted to equianalgesic dose of i.v. morphine according to Supplementary Table S1 [17–20]. Secondary outcomes were collected by the primary investigator from patient and medical records. Supplementary Table S1 related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ejogrb. 2014.06.026. Participants, surgeons, care-takers, and outcome assessors were blinded to the allocation. Data were recorded on clinical registration forms, and after completed follow-up entered into EpiData Entry version 3.1 (EpiData Association, Odense, Denmark). Data were cleaned and consecutively locked. A copy of the locked database was passed on in exchange for the allocation list before the allocation was broken. Statistics A study of postoperative pain and reproducibility of pain scores on a VAS scale during a 3-min interval found that 95% repeat ratings were between 2.0 cm [21]. Differences should therefore be above this level to be considered clinically significant. Sample size calculation for the primary outcome was based on a minimal relevant difference (MIREDIF) in VAS of 2 between the two treatment groups and a standard deviation of 2. With a type II error of 10% at a twosided significance level of 5%, we estimated that 22 patients had to be included in each treatment group. Due to the risk of drop-outs, 50 patients were included in the trial. No interim analyses were performed. Patients who completed follow-up were included in the analysis. Repeated measures including the primary endpoint, opioid consumption, and CRP levels were analyzed with linear mixed models, with categorical times, heterogeneous first-order autoregressive, or unstructured repeated covariance type, and random ID. The primary outcome was controlled for surgeon

A.J.M. Aabakke et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 180 (2014) 83–88

Enrollment

85

Assessed for eligibility (n=125)

Excluded (n=66): –

– –

Eligible but not recruited (n=21) o Not recruited (n=15) o Acute operation (n=6) Declined to participate (n=13) Not eligible (n=32 )

Randomised (n=59)

Allocation Allocated to methylprednisolone (n=32) – –

Allocated to placebo (n=27) – –

Received intervention (n=25) Excluded (n=7) o Received intraoperative dexamethasone (n=4) o Acute reoperation (n=1) o Other (n=2)

Received intervention (n=25) Excluded (n=2) o Received intraoperative dexamethasone (n=2)

Follow-Up Excluded (n=0)

Excluded (n=1): – Used different opioid (n=1)

Analysis Analyzed (n=25)

Analyzed (n=24)

Fig. 1. Flow diagram.

experience (more or less than 5 years), surgery type (total or subtotal hysterectomy), and duration of surgery. First order interactions were tested. CRP levels were controlled for baseline CRP. Results were presented as mean difference with 95% confidence intervals (CI). Continuous variables were assessed for normal distribution with the Kolmogorov–Smirnov test. When normally distributed they were presented as mean with standard deviation and analyzed with a t-test, when not, they were presented as median with interquartile range and analyzed with a Mann–Whitney test. Categorical variables were reported as number with percentage. Dichotomous data were analyzed with the x2-test or Fisher’s exact test as appropriate, and the odds ratios presented with 95% CI. Data analyses were carried out using IBM SPSS Statistics 19 (SPSS Inc., Chicago, IL, USA). P values below 0.05 were considered statistically significant. For the repeated measures, a P < 0.013 was considered statistically significant due to a post hoc Bonferroni’s correction equivalent to the number of time intervals investigated (n = 4).

Results Fifty-nine women scheduled for abdominal hysterectomy were randomized. Nine patients were excluded due to surgery not following protocol and their allocations were re-randomized by a third party not otherwise involved in the trial. New patients were consecutively included in their place. Fifty women were included, and 49 completed the trial according to protocol and were included in the analysis, as illustrated in Fig. 1. Patient and surgery characteristics were similar for the treatment and placebo groups and are shown in Table 1. VAS scores at rest and during mobilization are illustrated in Fig. 2A–B. At rest VAS scores did not differ significantly between the two treatment groups overall (mean difference MP vs. placebo 0.55 [95% CI: 0.06 to 1.16] P = 0.08) or at any one time point (P = 0.51). At rest VAS scores were 0.88 higher ([95% CI: 0.23–1.53] P < 0.01) if the surgeon had less than 5 years’ compared to 5 or more years’ experience as a specialist, independent of duration of surgery. During mobilization VAS scores were significantly higher

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A.J.M. Aabakke et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 180 (2014) 83–88 Table 1 Patient, preoperative and surgery characteristics. MP (n = 25) Patient characteristics Age (years) BMI (kg/ m2) Smoking status Smoker Non-smoker Preoperative characteristics Pain at rest (0.0–10.0) Pain during mobilization (0.0–10.0) CRP-levels (mg/L)a Time from administration of trial drug to start of surgery (minutes) Surgery characteristics Indicationb Fibroids Bleeding disorder Pain Other Surgery type Total hysterectomy Subtotal hysterectomy Skin incision Low transverse Midline Unknown Additional surgery Duration of surgery (minutes) Surgeon experience 5 years as specialist

The effect of a preoperative single-dose methylprednisolone on postoperative pain after abdominal hysterectomy: a randomized controlled trial.

Methylprednisolone has been shown to have analgesic effects after orthopedic surgery. The objective of this trial was to compare the effect of 125 mg ...
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