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Administration of a co-crystal of tramadol and celecoxib in a 1:1 molecular ratio produces synergistic antinociceptive effects in a postoperative pain model in rats.
Eur J Pharmacol. 2018 Aug 15; 833:370-378.EJ

Abstract

Drug combination for the treatment of pain is common clinical practice. Co-crystal of Tramadol-Celecoxib (CTC) consists of two active pharmaceutical ingredients (APIs), namely the atypical opioid tramadol and the preferential cyclooxygenase-2 inhibitor celecoxib, at a 1:1 molecular ratio. In this study, a non-formulated 'raw' form of CTC administered in suspension (referred to as ctcsusp) was compared with both tramadol and celecoxib alone in a rat plantar incision postoperative pain model. For comparison, the strong opioids morphine and oxycodone, and a tramadol plus acetaminophen combination at a molecular ratio of 1:17 were also tested. Isobolographic analyses showed that ctcsusp exerted synergistic mechanical antiallodynic (experimental ED50 = 2.0 ± 0.5 mg/kg, i.p.; theoretical ED50 = 3.8 ± 0.4 mg/kg, i.p.) and thermal (experimental ED50 = 2.3 ± 0.5 mg/kg, i.p.; theoretical ED50 = 9.8 ± 0.8 mg/kg, i.p.) antihyperalgesic effects in the postoperative pain model. In contrast, the tramadol and acetaminophen combination showed antagonistic effects on both mechanical allodynia and thermal hyperalgesia. No synergies between tramadol and celecoxib on locomotor activity, motor coordination, ulceration potential and gastrointestinal transit were observed after the administration of ctcsusp. Overall, rat efficacy and safety data revealed that ctcsusp provided synergistic analgesic effects compared with each API alone, without enhancing adverse effects. Moreover, ctcsusp showed similar efficacy but improved safety ratio (80, measured as gastrointestinal transit vs postoperative pain ED50 ratios) compared with the strong opioids morphine (2.5) and oxycodone (5.8). The overall in vivo profile of ctcsusp supports the further investigation of CTC in the clinical management of moderate-to-severe acute pain as an alternative to strong opioids.

Authors+Show Affiliations

Drug Discovery and Preclinical Development, Esteve Pharmaceuticals, S.A., Parc Científic de Barcelona, Baldiri Reixac 4-8, 08028 Barcelona, Spain. Electronic address: mmerlos@esteve.com.Drug Discovery and Preclinical Development, Esteve Pharmaceuticals, S.A., Parc Científic de Barcelona, Baldiri Reixac 4-8, 08028 Barcelona, Spain.Drug Discovery and Preclinical Development, Esteve Pharmaceuticals, S.A., Parc Científic de Barcelona, Baldiri Reixac 4-8, 08028 Barcelona, Spain.Drug Discovery and Preclinical Development, Esteve Pharmaceuticals, S.A., Parc Científic de Barcelona, Baldiri Reixac 4-8, 08028 Barcelona, Spain.Drug Discovery and Preclinical Development, Esteve Pharmaceuticals, S.A., Parc Científic de Barcelona, Baldiri Reixac 4-8, 08028 Barcelona, Spain.Drug Discovery and Preclinical Development, Esteve Pharmaceuticals, S.A., Parc Científic de Barcelona, Baldiri Reixac 4-8, 08028 Barcelona, Spain.Drug Discovery and Preclinical Development, Esteve Pharmaceuticals, S.A., Parc Científic de Barcelona, Baldiri Reixac 4-8, 08028 Barcelona, Spain.Drug Discovery and Preclinical Development, Esteve Pharmaceuticals, S.A., Parc Científic de Barcelona, Baldiri Reixac 4-8, 08028 Barcelona, Spain.Drug Discovery and Preclinical Development, Esteve Pharmaceuticals, S.A., Parc Científic de Barcelona, Baldiri Reixac 4-8, 08028 Barcelona, Spain.Drug Discovery and Preclinical Development, Esteve Pharmaceuticals, S.A., Parc Científic de Barcelona, Baldiri Reixac 4-8, 08028 Barcelona, Spain.

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

29932927

Citation

Merlos, Manuel, et al. "Administration of a Co-crystal of Tramadol and Celecoxib in a 1:1 Molecular Ratio Produces Synergistic Antinociceptive Effects in a Postoperative Pain Model in Rats." European Journal of Pharmacology, vol. 833, 2018, pp. 370-378.
Merlos M, Portillo-Salido E, Brenchat A, et al. Administration of a co-crystal of tramadol and celecoxib in a 1:1 molecular ratio produces synergistic antinociceptive effects in a postoperative pain model in rats. Eur J Pharmacol. 2018;833:370-378.
Merlos, M., Portillo-Salido, E., Brenchat, A., Aubel, B., Buxens, J., Fisas, A., Codony, X., Romero, L., Zamanillo, D., & Vela, J. M. (2018). Administration of a co-crystal of tramadol and celecoxib in a 1:1 molecular ratio produces synergistic antinociceptive effects in a postoperative pain model in rats. European Journal of Pharmacology, 833, 370-378. https://doi.org/10.1016/j.ejphar.2018.06.022
Merlos M, et al. Administration of a Co-crystal of Tramadol and Celecoxib in a 1:1 Molecular Ratio Produces Synergistic Antinociceptive Effects in a Postoperative Pain Model in Rats. Eur J Pharmacol. 2018 Aug 15;833:370-378. PubMed PMID: 29932927.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Administration of a co-crystal of tramadol and celecoxib in a 1:1 molecular ratio produces synergistic antinociceptive effects in a postoperative pain model in rats. AU - Merlos,Manuel, AU - Portillo-Salido,Enrique, AU - Brenchat,Alex, AU - Aubel,Bertrand, AU - Buxens,Jordi, AU - Fisas,Angels, AU - Codony,Xavier, AU - Romero,Luz, AU - Zamanillo,Daniel, AU - Vela,José Miguel, Y1 - 2018/06/19/ PY - 2017/09/23/received PY - 2018/06/18/revised PY - 2018/06/18/accepted PY - 2018/6/23/pubmed PY - 2018/11/6/medline PY - 2018/6/23/entrez KW - Acute pain KW - CTC KW - Celecoxib KW - Isobologram KW - Tramadol KW - ctc(susp) SP - 370 EP - 378 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 833 N2 - Drug combination for the treatment of pain is common clinical practice. Co-crystal of Tramadol-Celecoxib (CTC) consists of two active pharmaceutical ingredients (APIs), namely the atypical opioid tramadol and the preferential cyclooxygenase-2 inhibitor celecoxib, at a 1:1 molecular ratio. In this study, a non-formulated 'raw' form of CTC administered in suspension (referred to as ctcsusp) was compared with both tramadol and celecoxib alone in a rat plantar incision postoperative pain model. For comparison, the strong opioids morphine and oxycodone, and a tramadol plus acetaminophen combination at a molecular ratio of 1:17 were also tested. Isobolographic analyses showed that ctcsusp exerted synergistic mechanical antiallodynic (experimental ED50 = 2.0 ± 0.5 mg/kg, i.p.; theoretical ED50 = 3.8 ± 0.4 mg/kg, i.p.) and thermal (experimental ED50 = 2.3 ± 0.5 mg/kg, i.p.; theoretical ED50 = 9.8 ± 0.8 mg/kg, i.p.) antihyperalgesic effects in the postoperative pain model. In contrast, the tramadol and acetaminophen combination showed antagonistic effects on both mechanical allodynia and thermal hyperalgesia. No synergies between tramadol and celecoxib on locomotor activity, motor coordination, ulceration potential and gastrointestinal transit were observed after the administration of ctcsusp. Overall, rat efficacy and safety data revealed that ctcsusp provided synergistic analgesic effects compared with each API alone, without enhancing adverse effects. Moreover, ctcsusp showed similar efficacy but improved safety ratio (80, measured as gastrointestinal transit vs postoperative pain ED50 ratios) compared with the strong opioids morphine (2.5) and oxycodone (5.8). The overall in vivo profile of ctcsusp supports the further investigation of CTC in the clinical management of moderate-to-severe acute pain as an alternative to strong opioids. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/29932927/Administration_of_a_co_crystal_of_tramadol_and_celecoxib_in_a_1:1_molecular_ratio_produces_synergistic_antinociceptive_effects_in_a_postoperative_pain_model_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(18)30353-4 DB - PRIME DP - Unbound Medicine ER -