Propacetamol-Induced Injection Pain Is Associated with Activation of Transient Receptor Potential Vanilloid 1 Channels

Abstract

Propacetamol (PPCM) is a prodrug of paracetamol (PCM), which was generated to increase water solubility of PCM for intravenous delivery. PPCM is rapidly hydrolyzed by plasma esterases to PCM and diethylglycine and shares some structural and metabolic properties with lidocaine. Although PPCM is considered to be comparable to PCM regarding its analgesic properties, injection pain is a common side effect described for PPCM but not PCM. Injection pain is a frequent and unpleasant side effect of numerous drugs in clinical use, and previous reports have indicated that the ligand gated ion channels transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) can mediate this effect on sensory neurons. This study aimed to investigate molecular mechanisms by which PPCM, in contrast to PCM, causes injection pain. Therefore, human TRPV1 and TRPA1 receptors were expressed in human embryonic kidney 293 cells and investigated by means of whole-cell patch clamp and ratiometric calcium imaging. PPCM (but not PCM) activated TRPV1, sensitized heat-induced currents, and caused an increase in intracellular calcium. In TRPA1-expressing cells however, both PPCM and PCM evoked calcium responses but failed to induce inward currents. Intracutaneous injection of PPCM, but not of PCM, in human volunteers induced an intense and short-lasting pain and an increase in superficial blood flow, indicating activation of nociceptive C fibers and subsequent neuropeptide release. In conclusion, activation of human TRPV1 by PPCM seems to be a relevant mechanism for induction of pain upon intracutaneous injection and thus also for pain reported as an adverse side effect upon intravenous administration.

A study of the regional differences in propacetamol-related adverse events using VigiBase data of the World Health Organization

“…Time to onset of initial adverse events across Asia and Europe. The median (IQR) time-to-onset of initial AEs ranged from 2.5 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) days for contact dermatitis/eczema to 11 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) days for anaphylactic reaction in Europe. However, in Asia, the median time-to-onset for anaphylactic reaction was 3 (1-10) days, which was much shorter to that reported in Europe (Fig.…”

“…However, safety concerns of propacetamol, along with the release of intravenous paracetamol (substitute to propacetamol) that had a better safety profile, led to its withdrawal from the European Medicines Agency in 2009 3 . In brief, propacetamol had risks of serious hypersensitivity reactions, cases of thrombosis and administration site reactions [4][5][6][7][8] . Ever since, South Korea, China, and Taiwan are the only regions to use propacetamol to date.Existing data on the safety of propacetamol unfortunately remain inconclusive overall and across Asia and Europe.…”

Reactive metabolites of acetaminophen activate and sensitize the capsaicin receptor TRPV1

“…Indeed, intraplantar injections of APAP in mice did neither cause analgesic nor algesic effects 5 . Furthermore, 50 mM acetaminophen injected intracutaneously in human volunteers was neither painful nor influenced quantitative sensory testings 59 . Both findings argue against peripheral nerve endings as important site of acetaminophen-induced effects and against a relevant metabolism of acetaminophen into NAPQI and pBQ in the skin.…”

“…All of the seven volunteers could be included in the study. Sample sizes were based on previous experience 31 , 74 and elements of the human subjects data have been part of another study 59 . Informed consent contained the following termination criterion: if procedures were experienced as too unpleasant or if the general wish to interrupt the study at any time during the testing was stated, this would lead to the immediate termination of the study without the necessity to give any reasons.…”