In view of the relative absence of major complications, postoperative pain should be considered as one of the primary endpoints after day case surgery.1–3 Particularly in the ambulatory setting, adequate postoperative analgesia is challenging because patients have to control pain at home by themselves with various types of feedback loops4 and the type of analgesics (i.e. no strong opioids) as well as the route of administration (i.e. not epidural, intravenous, subcutaneous or intramuscular) are limited compared with the inpatient setting. Despite increased awareness and improvements in postoperative pain management over recent decades, the proportion of outpatients suffering moderate to severe acute postoperative pain at home still remains high and varies from 9 to 40%.5–8 More specifically, recent studies suggest that patients undergoing haemorrhoid surgery, arthroscopic shoulder or knee surgery and inguinal hernia repair seem to be at highest risk of developing moderate-to-severe pain and of being poorly recovered on the fourth postoperative day (POD).3,6
A multimodal approach to control pain has been advocated after day case surgery. A multimodal approach is primarily based on a combination of oral paracetamol, NSAIDs, weak opioids and infiltration with local anaesthetics.5,9,10 Furthermore, a meta-analysis has shown that a combination of paracetamol and an NSAID may offer superior analgesia compared with either drug alone.11 Consequently, ibuprofen, an NSAID with a favourable analgesic profile,12 in combination with paracetamol comprise our standard multimodal pain treatment model for patients at home after painful day case surgery. However, NSAIDs are not always sufficiently effective,6 have numerous contraindications13–16 and, as a result of this, NSAIDs are not suitable in up to 25% of all patients.17
A potential alternative is metamizole, a nonopioid compound with potent analgesic, antipyretic and spasmolytic effects18 which was first marketed in Germany in 1922.19 Metamizole is used in a variety of settings; however, administration can cause metamizole-induced agranulocytosis (MIA) on rare occasions20 and is therefore not commonly used in many countries.
The analgesic efficacy of intravenous or intramuscular metamizole for pain relief after inpatient surgery is well described.20–26 The analgesic efficacy of metamizole for postoperative analgesia at home after ambulatory hand surgery has also been analysed.27 However, the analgesic efficacy of a combination of paracetamol and metamizole for pain relief at home after day case surgery has never been studied.
In the current study, we aimed to assess whether a combination of metamizole and paracetamol is noninferior to a combination of ibuprofen and paracetamol in the treatment of acute postoperative pain at home after painful day case surgery. We hypothesised that ambulatory patients treated postoperatively with paracetamol/metamizole would achieve equal or even better pain relief compared with patients treated with paracetamol/ibuprofen.
This study is reported according to the Consolidated Standards of Reporting Trials statement as well as the extension to noninferiority trials.
The complete study protocol has been published in Trials.28 Briefly, this investigator-initiated, double-blind, randomised controlled, noninferiority trial was approved by the ethical committee of the JESSA Hospital Hasselt, Belgium (Chairperson Dr Koen Magerman, registration number 15.105/pijn15.02) on 21 September 2015 and by the European Union Drug Regulating Authorities Clinical Trials (EudraCT Number 2015-003987-35).
After obtaining written informed consent, we recruited 200 patients scheduled for elective haemorrhoid surgery (n=50), arthroscopic shoulder (n=50) or knee (n=50) surgery, or inguinal hernia repair (n=50) in a day care setting between 28 January 2016 and 31 March 2017. Patients with American Society of Anesthesiologists’ (ASA) physical status 1 to 3 were between 18 and 70 years of age and had a body weight more than 50 kg. Exclusion criteria included inpatient surgery, pregnancy, cognitive impairment, no understanding of the Dutch language, pre-operative pharmacological pain treatment and/or a history of chronic pain, a history of substance abuse or use of medication with a suppressive effect on the central nervous system, allergy or a contraindication to taking the study medication (e.g. paracetamol, metamizole, ibuprofen or another NSAID), fever or other signs of infection, and, for patients undergoing arthroscopic shoulder surgery, refusal of an interscalene block. Baseline assessment measurements included the participants’ age, sex, BMI, ASA classification, work status, highest level of education, fear of the surgical procedure (using an eight-item surgical fear questionnaire),3,29 pre-operative pain [the baseline numerical rating score (NRS)], expected pain (NRS) and the history of previous (related) surgery.
Using a computer-generated random allocation sequence (created by the study statistician), patients were randomly assigned in a 1 : 1 ratio to one of the two study groups: a combination of metamizole and paracetamol group or a combination of ibuprofen and paracetamol group. Patients in the metamizole and paracetamol group (experimental arm) were instructed to take metamizole 1 g orally three times a day for 4 days and patients in the ibuprofen and paracetamol group (control arm) were instructed to take ibuprofen 600 mg orally three times a day for 4 days. All patients were also treated with paracetamol 1 g orally four times a day during the entire study period. The first dose of study medication (metamizole and paracetamol or ibuprofen and paracetamol) was given 30 min before surgery. Rescue medication consisted of tramadol 50 mg orally up to three times a day. Randomisation was stratified for type of surgery. Each patient received a unique randomised test number corresponding to the specified drug, according to the group allocation. The randomisation list remained with the study statistician and the hospital pharmacy for the whole duration of the study. Consequently, the patients participating in the trial, the treating physicians, the researchers dispensing the medication and assessing outcomes (four trained resident physicians and one study nurse) and the data managers were blinded to group allocation. For test drug blinding, the metamizole tablets and the ibuprofen tablets were made to be visually indistinguishable. Furthermore, the hospital pharmacy packaged study medication in identical blister packs.
All patients scheduled for an arthroscopic shoulder procedure received an interscalene block pre-operatively. In accordance with local practice, general anaesthesia was induced with alfentanil 10 μg kg−1, sufentanil 0.15 μg kg−1 and propofol 2 mg kg−1 intravenously. Patients undergoing arthroscopic shoulder surgery or laparoscopic inguinal hernia repair also received rocuronium 0.6 mg kg−1 before tracheal intubation. A laryngeal mask airway was inserted in all other patients. Anaesthesia was maintained with sevoflurane in a mixture of 50 : 50 air/oxygen. Before the end of surgery, all patients received ondansetron 4 mg intravenously. Wound infiltration with local anaesthesia (bupivacaine 0.5%) was performed in all patients except those who had received an interscalene block. The duration of surgery was recorded.
Postoperatively, all patients were treated with subsequent bolus injections of piritramide 2 mg intravenously until an NRS score of 3 or less was achieved in the postanaesthesia care unit (PACU). Before hospital discharge, patients received the study medication and instructions for use. If a surgical complication occurred which led to re-operation or unanticipated hospital admission, the patient was excluded from the study.
The primary noninferiority outcome measure was average postoperative pain intensity measured by an 11-point NRS (where 0 = no pain, and 10 = worst pain imaginable) at POD 1. Secondary noninferiority outcome measures were postoperative pain intensity measured before discharge and at POD 2 and 3, total postoperative intravenous piritramide consumption in PACU and the use of rescue medication (tramadol at home) on POD 1, 2 and 3, adverse effects of study medication and adherence to study medication. These outcome measures were assessed at baseline, before discharge and by telephone call on POD 1, 2 and 3. Overall patient satisfaction with study medication was assessed with an 11-point NRS scale (where 0 = not satisfied at all and 10 = extremely satisfied) by phone call on POD 7.
The necessary sample size was determined for the primary outcome with the aim to reject inferiority of metamizole and paracetamol compared with ibuprofen and paracetamol. A difference in mean average NRS score of 1 point or less is considered noninferior. Based on previous studies, we assumed a standard deviation of the NRS scores of 2.5.3,5 The required sample size for each group was consequently determined to be at least 78 to obtain a power of 80% to reject inferiority (α = 0.05). To account for a possible 22% loss to follow-up, the sample size was increased to 100 participants per group. All primary and secondary endpoints were analysed by an independent statistician on a per-protocol basis and compared with an intention to treat (ITT) analysis according to the guidelines for noninferiority studies. Missing baseline values were imputed using multiple imputation. The number of imputations was set to 10. To determine noninferiority for the difference in mean average NRS pain scores we computed 95% confidence intervals (CIs). Secondary outcome measures were analysed using the Student's t test for parametric data, the Mann–Whitney U test for nonparametric data and the Pearson's χ2 test or the Fisher's exact test (in case of an observed count <10) for categorical data. All analyses were performed using SPSS version 21. Graphs were made using Prism 7.0 (Prism; GraphPad Software, Inc, La Jolla, California, USA).
A study flow chart is shown in Fig. 1. Four hundred and two patients were screened for eligibility, of whom 202 patients were excluded. Baseline and peri-operative characteristics of all included patients are shown in Table 1.
Figure 2 shows box plots of the distribution of average postoperative pain scores on POD 1, 2 and 3. For the primary outcome, noninferiority was confirmed because the upper bound of the two-sided 95% CI for the absolute difference in mean average pain intensity at POD 1 between groups did not exceed the predefined noninferiority margin of 1, both in the per-protocol sample (−0.158, CI −0.913 to 0.596) and in the ITT sample (0.032, CI −0.647 to 0.710) (Fig. 3). On POD 2 and POD 3, noninferiority was also confirmed in the per-protocol sample (Fig. 3). In the ITT population however, the upper bound of the 95% CI was slightly exceeded (0.236, CI −0.540 to 1.011) on POD 3, yielding inconclusive results (Fig. 3.). Before discharge, the difference was also inconclusive, both in the per-protocol sample (0.852, CI +0.067 to 1.637) and in the ITT sample (0.541, CI −0.189 to 1.270) (Fig. 3).
The number of patients who received intravenous piritramide in the PACU for additional pain relief was small. In total, 128 patients (65.3%) received 0 mg, 42 patients (21.4%) received 2 to 4 mg and 26 patients (13.3%) received a piritramide dose ranging between 5 and 12 mg. There was no significant difference between treatment groups for the amount of piritramide administration (P = 0.724) (Table 2).
Box plots of the number of rescue medication that was used (tramadol at home) on POD 1, 2 and 3 are shown in Fig. 4. The use of rescue medication was reported by 29 patients (29.6%) in the ibuprofen and paracetamol group and 28 patients (28.6%) in the metamizole and paracetamol group on POD 1 (P = 0.987), 28 patients (28.8%) in the ibuprofen and paracetamol group and 14 patients (14.3%) in the metamizole and paracetamol group on POD 2 (P = 0.024), and 18 patients (18.4%) in the ibuprofen and paracetamol group and 11 patients (11.2%) in the metamizole and paracetamol group on POD 3 (P = 0.209). The number of administered tablets (tramadol 50 mg) was also significantly higher in the ibuprofen and paracetamol group on POD 2 (P = 0.042).
Patient-reported adverse effects of study medication are shown in Table 3. These side effects were reported by 48 patients (49.0%) in the control group and 56 patients (57.1%) in the study group during the telephone follow-up on POD 1, 2 and/or 3 and were not significantly different between treatment groups (P = 0.252). Also, no agranulocytosis or other serious adverse effects of the study medication were reported during the study period.
Patient satisfaction with the study medication was not significantly different between treatment groups (P = 0.272) with a median score of 8.0 [IQR 9.0 to 10.0] for the study group and 8.5 [7.00 to 10.0] for the control group.
In the current study, a combination of metamizole and paracetamol provided noninferior analgesia compared with a combination of ibuprofen and paracetamol in the first 3 days at home after painful day case surgery. Similarly, postoperative opioid consumption in the PACU and intake of oral rescue analgesics at home on POD 1 and 3 were not significantly different between treatment groups. In contrast, intake of oral rescue analgesics at home on POD 2 was significantly higher in the control group. This may suggest a superior analgesic effect of a combination of metamizole and paracetamol on POD 2. However, the difference may be due to a statistical deficiency and needs to be verified in a future study with an increased number of patients. Patient-reported adverse effects of study medication and overall patient satisfaction were comparable between the two groups. During the study period, no serious adverse effects of the study medication were reported.
Metamizole is a pyrazolone derivative with potent analgesic, antipyretic and spasmolytic effects and has been in clinical use since 1922.19 The molecular mechanism of analgesic and antipyretic action of metamizole is still not fully explained. After oral administration, metamizole is rapidly metabolised into its bioactive metabolites.30 These metabolites mediate antinociceptive effects via multiple mechanisms, including the involvement of endogenous opioids and inhibition of cyclo-oxygenase 1 and 2.31,32 Recently, there has been growing evidence that the endocannabinoid/endovanilloid system may also be involved in the mode of action of metamizole.19,30,33,34 Indeed, the metabolites of metamizole may also inhibit endocannabinoid inactivation and/or directly activate cannabinoid receptors.19,30,33,34
The most important advantage of metamizole compared with NSAIDs is its favourable gastro-intestinal35,36 and cardiovascular side effect profile.13–16 Metamizole-associated adverse effects include platelet aggregation inhibition37 and a dose-dependent increased risk of development of acute kidney injury in adult ICU patients.38 Furthermore, due to its association with agranulocytosis, metamizole has been withdrawn from the market in many countries.39 This restriction is based on two studies, both observing a very high incidence of MIA.40,41 However, recent literature reported a limited incidence of 05 to 20 MIA cases per million per year.18,39,42,43 Also, the mortality rate of MIA has decreased to 10 to 20%44 due to better treatment options, including therapy with granulocyte-colony stimulating factor and with broad spectrum antibiotics.39 Consequently, on the basis of epidemiological evidence, the excess mortality due to agranulocytosis, aplastic anaemia, anaphylaxis and serious gastrointestinal complications is estimated to be in favour of metamizole compared with the NSAID diclofenac (25 per 100 million vs. 592 per 100 million).45 Therefore, it is concluded that metamizole can alternatively be used, at least in those patients presenting with an increased risk of gastrointestinal and/or renal complications.44 Furthermore, the actual debate about relevant side effects of NSAIDs has renewed the interest in metamizole and may explain why the substance is the preferred nonopioid analgesic in the peri-operative and chronic pain setting in German-speaking countries46 and why it is even considered as first-line treatment in the peri-operative period following the German guidelines for the treatment of acute postoperative pain.47
In our study, 13% of all patients assessed for eligibility had at least one contraindication to the use of NSAIDs. This percentage may be as much as 25%17 or even 90%48 in different patient cohorts.
In view of the advocated multimodal oral analgesic approach for pain relief at home after painful day case surgery, the question of which types of oral analgesics have additive or even synergistic effects should be studied. Recent studies suggest that the co-administration of tramadol and metamizole results in a clinically relevant synergistic effect.49,50 Obviously, a potential additive or synergistic analgesic effect of a combination of other analgesics with different pathways and mechanisms of action such as paracetamol and metamizole should also be examined. The current study suggests that, similar to a combination of paracetamol and ibuprofen,11 a combination of paracetamol and metamizole may also provide superior analgesia compared with either drug alone, but this should be proved in future research.
Although not statistically significant, more patients discontinued the intervention (29 vs. 18) in the metamizole group (Fig. 1). Frequently reported reasons for not following the predefined treatment schedule were the presence of unwanted side effects (i.e. nausea, heartburn and fatigue) and the absence of pain.
Our study has some limitations. First, the study was not powered for secondary outcomes such as adverse effects of pain medication and overall patient satisfaction. Therefore, no firm conclusions can be drawn about medication safety. Second, intake of tramadol at home on POD 2 was, surprisingly, higher in the control group. This may not be clinically relevant and needs to be verified in a future study with an increased number of patients. Third, due to rigorous exclusion criteria, about one-third of patients screened for eligibility were excluded from the study. As a result, the generalisability of our results to daily practice is limited to a selection of patients. Finally, four different types of surgery where included in this study. Every type of surgery has its own unique postoperative pain trajectory which can influence study outcome. Therefore, randomisation was stratified for type of surgery.
In conclusion, paracetamol/metamizole and paracetamol/ibuprofen are equally effective in treatment of acute postoperative pain at home after ambulatory surgery with comparable patient satisfaction level. We suggest paracetamol/metamizole to be a valuable alternative for the current paracetamol/ibuprofen gold standard, particularly in patients with a contraindication to the use of NSAIDs.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: the study was funded solely by departmental funding.
Conflicts of interests: none.
Presentation: data from this study were presented as a poster at the Euroanaesthesia 2018 conference of the European Society of Anaesthesiology in Copenhagen, Denmark in June 2018.
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