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Unexceptional seizure potential of tramadol or its enantiomers or metabolites in mice.
J Pharmacol Exp Ther. 2008 May; 325(2):500-6.JP

Abstract

Tramadol is one of the most widely used centrally acting analgesics worldwide. Because of its multimodal analgesic mechanism (opioid plus nonopioid), the adverse effects profile of tramadol, similar to its analgesic profile, can be atypical compared with single-mechanism opioid analgesics. The comparison is often favorable (e.g., less respiratory depression or abuse), but it is sometimes cited as unfavorable in regard to seizure potential. As part of a broader study of this analgesic, we compared seizure induction in mice produced by administration of tramadol, the enantiomers and metabolites [M1 (O-desmethyl tramadol), M2 (N-desmethyl tramadol), M3 (N,N-didesmethyl tramadol), M4 (O,N,N-tridesmethyl tramadol), and M5 (O,N-didesmethyl tramadol)] of tramadol, and opioid and nonopioid reference compounds. We found that tramadol, its enantiomers, and M1 to M5 metabolites were of intermediate potency in this endpoint (on either a milligram per kilogram or millimole per kilogram basis). The SD50 (estimated dose required to induce seizures in 50% of test group) of tramadol to antinociceptive ED50 ratio was almost identical to that of codeine. The enantiomers of tramadol were about equipotent to tramadol on this endpoint. The M1 to M5 metabolites (and M1 enantiomers) of tramadol were less potent than tramadol. The relative potency of tramadol to opioids was not altered by quinidine (an inhibitor of CYP4502D6), noxious stimulus (48 degrees C hot-plate), multiple dosing, or in reserpinized mice. Tramadol seizures were increased by naloxone, principally at high tramadol doses and due to an effect on the (-)enantiomer that overcame the opposite effect on the (+)enantiomer. No synergistic effect on seizure induction was observed between concomitant tramadol and codeine or morphine.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania, USA. robert.raffa@temple.eduNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18292293

Citation

Raffa, Robert B., and Dennis J. Stone. "Unexceptional Seizure Potential of Tramadol or Its Enantiomers or Metabolites in Mice." The Journal of Pharmacology and Experimental Therapeutics, vol. 325, no. 2, 2008, pp. 500-6.
Raffa RB, Stone DJ. Unexceptional seizure potential of tramadol or its enantiomers or metabolites in mice. J Pharmacol Exp Ther. 2008;325(2):500-6.
Raffa, R. B., & Stone, D. J. (2008). Unexceptional seizure potential of tramadol or its enantiomers or metabolites in mice. The Journal of Pharmacology and Experimental Therapeutics, 325(2), 500-6. https://doi.org/10.1124/jpet.108.137273
Raffa RB, Stone DJ. Unexceptional Seizure Potential of Tramadol or Its Enantiomers or Metabolites in Mice. J Pharmacol Exp Ther. 2008;325(2):500-6. PubMed PMID: 18292293.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Unexceptional seizure potential of tramadol or its enantiomers or metabolites in mice. AU - Raffa,Robert B, AU - Stone,Dennis J,Jr Y1 - 2008/02/21/ PY - 2008/2/23/pubmed PY - 2008/5/20/medline PY - 2008/2/23/entrez SP - 500 EP - 6 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 325 IS - 2 N2 - Tramadol is one of the most widely used centrally acting analgesics worldwide. Because of its multimodal analgesic mechanism (opioid plus nonopioid), the adverse effects profile of tramadol, similar to its analgesic profile, can be atypical compared with single-mechanism opioid analgesics. The comparison is often favorable (e.g., less respiratory depression or abuse), but it is sometimes cited as unfavorable in regard to seizure potential. As part of a broader study of this analgesic, we compared seizure induction in mice produced by administration of tramadol, the enantiomers and metabolites [M1 (O-desmethyl tramadol), M2 (N-desmethyl tramadol), M3 (N,N-didesmethyl tramadol), M4 (O,N,N-tridesmethyl tramadol), and M5 (O,N-didesmethyl tramadol)] of tramadol, and opioid and nonopioid reference compounds. We found that tramadol, its enantiomers, and M1 to M5 metabolites were of intermediate potency in this endpoint (on either a milligram per kilogram or millimole per kilogram basis). The SD50 (estimated dose required to induce seizures in 50% of test group) of tramadol to antinociceptive ED50 ratio was almost identical to that of codeine. The enantiomers of tramadol were about equipotent to tramadol on this endpoint. The M1 to M5 metabolites (and M1 enantiomers) of tramadol were less potent than tramadol. The relative potency of tramadol to opioids was not altered by quinidine (an inhibitor of CYP4502D6), noxious stimulus (48 degrees C hot-plate), multiple dosing, or in reserpinized mice. Tramadol seizures were increased by naloxone, principally at high tramadol doses and due to an effect on the (-)enantiomer that overcame the opposite effect on the (+)enantiomer. No synergistic effect on seizure induction was observed between concomitant tramadol and codeine or morphine. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/18292293/Unexceptional_seizure_potential_of_tramadol_or_its_enantiomers_or_metabolites_in_mice_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=18292293 DB - PRIME DP - Unbound Medicine ER -