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Previous trials have frequently paired the CPT with opioids in order to investigate the mechanisms underlying pharmacological analgesia, due to their known analgesic efficacy. However, opioid side effects may lead to unblinding and raise concerns about the safety of the experimental setting. Despite the established clinical efficacy of dipyrone (metamizole), its efficacy, tolerability, and safety in cold pressor pain has not been systematically addressed to date. This pooled analysis included data of 260 healthy volunteers from three randomized, placebo\u2010controlled, double\u2010blind substudies using the CPT following a pre\u2010test\u2010post\u2010test\u2010design. These substudies allow for comparing a single dose of 800\u00a0mg dipyrone with two different doses of the opioid tilidine\/naloxone (50\/4\u00a0mg and 100\/8\u00a0mg, respectively). Outcomes included pain intensity ratings, pain tolerance, medication\u2010attributed side effects, as well as changes of blood pressure and heart rate. We demonstrate that both opioid doses and dipyrone had a comparable, significant analgesic effect on cold pressor pain. However, dipyrone was associated with significantly less self\u2010reported adverse effects and these were not significantly different from those under placebo. These results indicate that the combination of dipyrone and the CPT provides a safe, tolerable, and effective experimental model for the study of pharmacological analgesia. In combination with a CPT, dipyrone may be useful as a positive control, or baseline medication for the study of analgesic modulation.<\/jats:p>","DOI":"10.1111\/cts.13058","type":"journal-article","created":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T18:14:25Z","timestamp":1622484865000},"page":"1997-2007","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Tilidine and dipyrone (metamizole) in cold pressor pain: A pooled analysis of efficacy, tolerability, and safety in healthy volunteers"],"prefix":"10.1111","volume":"14","author":[{"given":"Julian","family":"Kleine\u2010Borgmann","sequence":"first","affiliation":[{"name":"Clinical Neurosciences, Department of Neurology University Hospital Essen Essen Germany"},{"name":"Center for Translational Neuro\u2010 and Behavioral Sciences University Hospital Essen Essen 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