pyrazolone and Pain

Although still used by hundreds of millions of people worldwide, the mechanism of the analgesic action of the pyrazolone derivatives (PDs), dipyrone, propyphenazone and antipyrine remains unknown. The transient receptor potential ankyrin 1 (TRPA1) channel, expressed by nociceptors, is emerging as a major pain transduction pathway. We hypothesized that PDs target the TRPA1 channel and by this mechanism produce their analgesic effect.. Calcium responses and currents were studied in cultured TRPA1-expressing rodent dorsal root ganglion neurons and human cells. Acute nociception and mechanical hypersensitivity were investigated in naïve and genetically manipulated mice.. Pyrazolone and PDs selectively inhibited calcium responses and currents in TRPA1-expressing cells and acute nocifensor responses in mice evoked by reactive channel agonists (allyl isothiocyanate, acrolein and H2 O2 ). In line with recent results obtained with TRPA1 antagonists and TRPA1 gene deletion, the two most largely used PDs, dipyrone and propyphenazone, attenuated TRPA1-mediated nociception and mechanical allodynia in models of inflammatory and neuropathic pain (formalin, carrageenan, partial sciatic nerve ligation and the chemotherapeutic drug, bortezomib). Notably, dipyrone and propyphenazone attenuated carrageenan-evoked mechanical allodynia, without affecting PGE2 levels. The main metabolites of PDs did not target TRPA1 and did not affect TRPA1-dependent nociception and allodynia.. Evidence that in rodents the nociceptive/hyperalgesic effect produced by TRPA1 activation is blocked by PDs suggests that a similar pathway is attenuated by PDs in humans and that TRPA1 antagonists could be novel analgesics, devoid of the adverse haematological effects of PDs.

Topics: Analgesics; Animals; Calcium Channels; Dipyrone; HEK293 Cells; Humans; Hyperalgesia; Male; Mice, Inbred C57BL; Nerve Tissue Proteins; Nociception; Pain; Pyrazolones; Rats, Sprague-Dawley; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPC Cation Channels

A 4-year-old boy presented with fever, septic arthritis, and persistent neutropenia. Bone marrow biopsy revealed no evidence of neoplasia. Additional history disclosed that the patient had been given metamizole for pain before onset of his illness. Metamizole, a nonsteroidal antiinflammatory agent, is prohibited in the United States because of the risk of agranulocytosis but is widely used in Mexico and other countries. The increasing number of Latinos in the United States and the extensive cross-border transfer of medicines raise concerns that metamizole use and associated complications may become more frequent. After identification of the index patient, additional inquiry revealed that the patient's mother was hospitalized previously for overwhelming sepsis associated with metamizole use. These cases prompted an investigation of metamizole use in an urban pediatric clinic, which revealed that 35% of Spanish-speaking Latino families had used metamizole; 25% of these families had purchased the medication in the United States. We conclude that metamizole use is common and may be underrecognized in immigrant Latino patients. Physicians in the United States, especially those who practice primary care, hematology/oncology, and infectious diseases, must be aware of the availability and use of metamizole in specific patient populations and its potential for harmful side effects.

Topics: Agranulocytosis; Anti-Inflammatory Agents, Non-Steroidal; Child, Preschool; Dipyrone; Emigration and Immigration; Hispanic or Latino; Humans; Legislation, Drug; Male; Medicine, Traditional; Mexico; Neutropenia; Pain; Pyrazoles; Pyrazolones; Sepsis; United States

Topics: Acetaminophen; Analgesics; Dental Care; Drug Combinations; Humans; Pain; Pain, Postoperative; Pyrazoles; Pyrazolones; Salicylates