Abstract
Background
Postoperative pain requires effective management. This study reviews the effectiveness and safety of dipyrone/metamizole for postoperative pain management in adults and children.
Materials and methods
The online databases Medline, OVID, Embase, and LILACS were searched in November 2024 for randomized controlled trials comparing dipyrone/metamizole with other drugs or placebo in postoperative settings. Outcomes included immediate postoperative pain scores and opioid consumption (Oral Morphine Equivalence, OME) in the first 24 h.
Results
Thirty studies were included. In adult patients, no significant OME differences were found between dipyrone and NSAIDs (2.1 mg; 95%CI -3.4 to 7.7), paracetamol (−1.3 mg; 95%CI -5.9 to 3.3), or placebo (−2.7 mg; 95%CI -9.2 to 3.8). In the ICU study, dipyrone showed lower OME than paracetamol (−9.9 mg; 95%CI -18.2 to −1.6). In pediatric studies, there were no differences in OME between dipyrone and paracetamol (0 mg; 95%CI -0.1 to 0.1) or placebo (−0.1 mg; 95%CI -0.3 to 0.2). No significant side effects were reported.
Conclusion
Dipyrone is as effective as other non-opioid analgesics commonly used for postoperative analgesia, and more effective than paracetamol in ICU patients. The reviewed studies indicate that its use is safe, and therefore it should be considered as an option for multimodal analgesia in pain management guidelines.
Highlights
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Patients frequently experience high-intensity pain during postoperative period.
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Adequate analgesia management is crucial to reduce postoperative complications.
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Dipyrone is safe and effective for postoperative analgesia in adult and pediatric patients.
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Dipyrone should be considered in multimodal pain management guidelines.
1
Introduction
During the postoperative period, patients frequently experience high-intensity pain, which is one of the most frequent and distressing symptoms according to patients [ ]. Adequate analgesia management is crucial not only to improve these symptoms, but to reduce the length of hospital stay and postoperative complications such as adynamic ileus [ ], atelectasis [ ] and chronic pain [ ]. Currently, this can be achieved by various classes of analgesic drugs and nonpharmacological techniques. Guidelines for postoperative pain management in both adults and children recommend a preemptive and multimodal analgesic approach. This strategy involves combining different medications, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), intravenous lidocaine, dexamethasone, ketamine, and gabapentinoids like gabapentin or pregabalin. The goal is to provide effective pain relief while balancing the benefits and risks of opioid use [ ].
For patients undergoing high-risk surgeries, the intensive care unit (ICU) is often the preferred location for postoperative care. Although the most recent Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (PADIS) recommends non-opioid analgesics as adjuncts to opioid therapy [ ], the guidelines do not specifically mention dipyrone (metamizole). This omission is notable given the complexity of pain management in the ICU, where various patient profiles and organ dysfunction (e.g., gastrointestinal dysfunction, kidney, hepatic) can limit therapeutic options.
Dipyrone is the most commonly used non-opioid analgesic in countries such as Brazil and Germany [ , ]. Despite its clinical effectiveness, its worldwide availability is limited due to outdated safety concerns that have been repeatedly debunked [ ]. For instance, studies have indicated that dipyrone has a safety profile comparable to nonsteroidal anti-inflammatory drugs (NSAIDs) [ ]. Our study aims to summarize the evidence on the effectiveness and safety of dipyrone in managing postoperative pain in adults and children.
2
Materials and Methods
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed in preparing this review (the checklist can be found in the Supplementary Appendix 1 ). The protocol was prospectively registered on the International Prospective Register of Systematic Reviews (PROSPERO) under the identifier CRD42023460668.
2.1
Search strategy
We searched the online databases Medline, OVID, Embase and LILACS from inception to November 2024. Full search strategies are detailed in Supplementary Appendix 2 . This search was supplemented by reviewing all relevant references. An automatic alert system in PubMed was used to identify studies published during the result analysis and manuscript writing phases.
2.2
Study selection
Two independent reviewers (M.L. and, S.L.) screened each title and abstract. Following this step, full-text articles were reviewed for inclusion. We included randomized controlled trials comparing the effects of dipyrone (metamizole) with other drugs or placebo in adult and pediatric postoperative settings. Studies with control groups involving strong opioids, non-pharmacological interventions, or local anesthesia were excluded, as were studies assessing the synergic effect of dipyrone with other drugs, review articles, commentaries, editorials, and secondary data analysis. There were no language or time restrictions. For studies published after 2000 lacking numeric data, authors were contacted to request this information. Any disagreement regarding inclusion was resolved by consensus. Following the instructions from the Cochrane Handbook for Systematic Reviews of Intervention [ ], we did not report kappa statistics. Rayyan software [ ] was used to record inclusion decisions.
2.3
Data extraction
Data extraction was performed independently by two investigators (M.L. and, S.L.) using predefined extraction forms to capture the following data: author, publication year, number of patients included, control group drugs, timing of the first analgesic dose, tool used for pain evaluation, pain evaluation time, adverse effects, opioid rescue use, and respective doses. When analgesic was administered during the procedure, we also extracted the first pain score after surgery. Another investigator (D.G.F.) checked the extracted data. Discrepancies were resolved by consensus. The data were recorded in a Microsoft Excel template (Microsoft, Redmond, WA), and statistical analysis was performed using R software version 3.6.1(R Foundation, Vienna, Austria) through the packages ‘readr’, ‘readxl’ and ‘meta’.
2.4
Quality assessment
Quality assessment was performed at the study level by two independent investigators (S.L. and M.L.) using the Cochrane Risk of Bias tool (RoB2) [ ]. Any disagreements were resolved by consensus.
2.5
Statistical analysis
The outcomes analyzed were: (1) the analgesic effect of dipyrone (metamizole) or control/placebo in the immediate postoperative period in cases where analgesics were administered during the surgery and (2) the difference in opioid consumption between the dipyrone (metamizole) group and the control/placebo group using Oral Morphine Equivalence (OME) in the first 24 h of the postoperative period. OME was calculated when not provided in the study [ ].
Meta-analysis was conducted using the DerSimonian and Laird random-effects model to pool effect sizes for all outcomes of interest. The mean difference for continuous outcomes was calculated along with the respective 95 % confidence intervals (CIs). When necessary, medians were converted to mean and standard deviation [ ]. Heterogeneity was assessed using the I 2 statistic, the χ 2 test for homogeneity, and visual inspection of the forest plots. We considered directionality, the I 2 value (where greater than 50 % might suggest substantial heterogeneity), and perceived heterogeneity in deciding when to downgrade the certainty of the evidence due to inconsistency.
Studies that did not meet criteria for inclusion in the meta-analysis were qualitatively described.
Funnel plots and Egger’s weighted regression plot analysis were not performed, because fewer than 10 studies for each outcome of interest were included. Additionally, subgroup analyses considering risk of bias or surgery type (minor/major) were not performed due to the limited number of studies included in the meta-analysis.
Grading of Recommendations Assessment, Development, and Evaluation was performed [ ] using the software GRADEpro Guideline Development Tool (GRADEpro GDP) to summarize and rate the quality of evidence for each pooled outcome [ ].
3
Results
3.1
Included studies and their characteristics
We identified 322 studies and screened 303 by title and abstract after excluding duplicates. Subsequently, 189 studies were selected for full-text review; however, 15 were not available. Five additional studies were included after reviewing references. After full-text review, 30 studies were included in our systematic review ( Fig. 1 ) [ ]. However, only 12 of those presented sufficient data to be included in the meta-analysis [ , , , , , , ]. We received data from only one author in response to our requests [ ].
The included studies and their characteristics, such as author, country, settings, population (adults or children), number of patients, and outcomes, are presented in Table 1 . Of the selected studies, only three sampled the pediatric population [ , , ], and only one included postoperative patients in the ICU [ ]. Regarding the risk of bias: 7 studies presented high risk [ , , ], 11 presented low risk [ , , , ] and 12 presented some concerns [ , , , , , , , , , ]( Fig. 2 ).
| Author, Year | Country | Population | Sample size | Control | Setting | Type of surgery | Outcome | Overall risk of bias |
|---|---|---|---|---|---|---|---|---|
| Daftary, 1980 [ ] | India | Adult | 299 | Paracetamol, placebo | Ward | Episiotomy | Dipyrone was better than paracetamol and placebo | Some concerns |
| Mukherjee, 1980 [ ] | India | Adult | 267 | Aspirin, placebo | Ward | Episiotomy | Dipyrone was better than aspirin and placebo | High |
| Gómez-Jiménez, 1980 [ ] | Mexico | Adult | 127 | Paracetamol, placebo | Ward | Episiotomy | Dipyrone was similar to paracetamol and better than placebo | High |
| Bloch, 1985 [ ] | South Africa | Adult | 110 | Pethidine | Ward | Hysterectomy | Inconclusive | High |
| Mehtha, 1986 [ ] | India | Adult | 252 | Aspirin, placebo | Ward | Orthopedic surgery | Dipyrone was better than aspirin and placebo | High |
| Bhounsule, 1990 [ ] | India | Adult | 100 | Paracetamol, ibuprofen, aspirin, placebo | Ward | Episiotomy | Dipyrone was worse than ibuprophen and was better than paracetamol and placebo | High |
| Steffen, 1996 [ ] | Germany | Adult | 56 | Placebo | RR and ward | Musculoskeletal Surgery | Dipyrone was better than placebo | Some concerns |
| Rivero, 1997 [ ] | Spain | Adult | 106 | Ibuprofen, placebo | RR and ward | Total Hip Replacement | Dipyrone was similar to ibuprophen and better than placebo | Low |
| Steffen, 1997 [ ] | Germany | Adult | 40 | Placebo | RR and ward | VL abdominal | Dipyrone was better than placebo | Some concerns |
| Cuevas, 1997 [ ] | Mexico | Children | 60 | Ketorolaco | RR | Ophthalmic | Dipyrone was worse than ketorolaco | High |
| Marin-Bertolin, 1997 [ ] | Spain | Adult | 92 | Ketorolaco | Ward | Plastic surgery | Dipyrone was similar to ketorolaco | Some concerns |
| Torres, 2001 [ ] | Spain | Adult | 130 | Tramadol | RR and ward | Abdominal Hysterectomy | Dipyrone was similar to tramadol | Some concerns |
| Saray, 2001 [ ] | Turkey | Adult | 160 | Diclofenac | Ward | Plastic surgery | Dipyrone was better than diclofenac | Low |
| Gómez-Márquez, 2004 [ ] | Mexico | Adult | 50 | Parecoxib | RR | Abdominal surgery | Dipyrone was worse than parecoxib | High |
| Landwehr, 2005 [ ] | Germany | Adult | 38 | Paracetamol, placebo | RR and ward | Retinal surgery | Dipyrone was similar to paracetamol and better than placebo | Some concerns |
| Yilmaz, 2005 [ ] | Turkey | Adult | 120 | Naproxen, meloxicam, rofecoxibe, paracetamol, etodolak | RR and ward | Otolaryngologic surgery | Dipyrone was worse than naproxen and meloxicam, but was similar to other drugs | Some concerns |
| Kampe, 2006 [ ] | Germany | Adult | 40 | Paracetamol | RR and ward | Surgery for breast cancer | Dipyrone was similar to paracetamol | Low |
| Grundmann, 2006 [ ] | Germany | Adult | 80 | Parecoxib, paracetamol, placebo | RR | Microdiscectomy | Dipyrone was better than parecoxib, paracetamol and placebo | Low |
| Soltesz, 2008 [ ] | Germany | Adult | 46 | Parecoxib | RR and ward | Vaginal Hysterectomy | Dipyrone was similar to parecoxib | Low |
| Sener, 2008 [ ] | Turkey | Adult | 105 | Lornoxicam, placebo | RR and ward | Sept rhinoplasty | Dipyrone was worse to Lornoxican and better than placebo | Low |
| Díaz-Chávez, 2009 [ ] | Mexico | Adult | 95 | Ketorolaco | RR and ward | Same-day general surgery | Dipyrone was similar to ketorolaco | Some concerns |
| Karaman, 2010 [ ] | Turkey | Adult | 90 | Dexketoprofen trometamol, paracetamol | RR | Otolaryngologic surgery | Dipyrone was worse than dexketoprofen trometamol and similar to paracetamol | Some concerns |
| Brodner, 2011 [ ] | Germany | Adult | 196 | Paracetamol, parecoxibe, placebo | RR and ward | Miscellaneous | Dipyrone was similar to paracetamol, parecoxib and placebo | Some concerns |
| Abdulla, 2012 [ ] | Germany | Adult | 120 | Paracetamol, parecoxibe, placebo | RR and ward | Thyroidectomy | Dipyrone was similar to paracetamol, parecoxib and placebo | Low |
| Abdulla, 2012 [ ] | Germany | Adult | 120 | Paracetamol, parecoxibe, placebo | RR and ward | Arthroscopic Knee Surgery | Dipyrone was worse than parecoxib and similar to paracetamol and placebo | Low |
| Kocum, 2013 [ ] | Turkey | Children | 120 | Paracetamol, placebo | RR | Tonsillectomy | Dipyrone was better than placebo and similar to paracetamol | Low |
| Oreskovic, 2014 [ ] | Croatia | Adult | 94 | Paracetamol | ICU | Total hip arthroplasty | Dipyrone was better than paracetamol | Low |
| Sener, 2015 [ ] | Turkey | Children | 120 | Paracetamol, placebo | Ward | Tonsillectomy | Dipyrone was better than placebo and similar to paracetamol | Low |
| Santo, 2016 [ ] | Brazil | Adult | 34 | Ibuprofen | RR | Retinal photocoagulation | Dipyrone was similar to ibuprophen | Some concerns |
| Gutiérrez, 2018 [ ] | Colombia | Adult | 70 | Paracetamol | NA | Cholecystectomy | Dipyrone was similar to paracetamol | Some concerns |
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