Tilidine and dipyrone (metamizole) in cold pressor pain: A pooled analysis of efficacy, tolerability, and safety in healthy volunteers

Abstract

The cold pressor test (CPT) is widely implemented and offers a simple, experimental acute pain model utilizing cold pain. 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-controlled, double-blind substudies using the CPT following a pre-test-post-test-design. These substudies allow for comparing a single dose of 800 mg dipyrone with two different doses of the opioid tilidine/naloxone (50/4 mg and 100/8 mg, respectively). Outcomes included pain intensity ratings, pain tolerance, medication-attributed 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-reported 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.

FIGURE 1

Combined study design of all substudies—after a baseline assessment using the cold pressor test (CPT) with a 6°C cold water bath (see section cold pressor test), the randomization (R) followed. All study medications (tilidine/naloxone, dipyrone, purified aqua) were encapsulated in white tasteless capsules to prevent unblinding through color, taste, or smell. After medication intake, a test phase was performed identically to the baseline assessment

FIGURE 2

Dose‐dependent analgesic effects, safety, and tolerability of tilidine versus control. Illustrated are changes of the percent area under the pain curve (%AUPC) (a) and the pain tolerance (b) as measures of pain intensity. Self‐reported side effects are illustrated as medication‐attributed symptom count (GASE) (c). Filled dots show means ± SD for each group separately. Light dots show individual participant data

FIGURE 3

Analgesic effects, safety, and tolerability of dipyrone versus control. Illustrated are changes of the percent area under the pain curve (%AUPC) (a) and the pain tolerance (b) as parameters of pain intensity. Self‐reported side effects did not significantly differ between groups (data not shown). Filled dots show means ± SD for each group separately. Light dots show individual participant data

FIGURE 4

Direct comparison of analgesic effects, safety, and tolerability of dipyrone, low‐ and high‐dose tilidine substudies. Illustrated are changes of the percent area under the pain curve (%AUPC) (a) and the pain tolerance (b) as measures of pain intensity. Self‐reported side effects are illustrated as medication‐attributed symptom count (c). Filled dots show means ± SD for each group separately. Light dots show individual participant data