Effect of tramadol on metamizol pharmacokinetics and pharmacodynamics after single and repeated administrations in arthritic rats

Abstract

Combined administration of certain doses of opioid compounds with a non-steroidal anti-inflammatory drug can produce additive or supra-additive effects while reducing unwanted effects. We have recently reported that co-administration of metamizol with tramadol produces antinociceptive effect potentiation, after acute treatment. However, none information about the effect produced by the combination after chronic or repeated dose administration exists. The aims of this study were to investigate whether the antinociceptive synergism produced by the combination of metamizol and tramadol (177.8 + 17.8 mg/kg, s.c. respectively) is maintained after repeated treatment and whether the effects observed are primarily due to pharmacodynamic interactions or may be related to pharmacokinetics changes. Administration of metamizol plus tramadol acute treatment significantly enhanced the antinociceptive effect of the drugs given alone ( < 0.05). Nevertheless, this effect decreased about 53% after the chronic treatment (3 doses per day, for 4 days). No pharmacokinetic interaction between metamizol and tramadol was found under acute treatment ( > 0.05). The mechanism involved in the synergism of the antinociceptive effect observed with the combination of metamizol and tramadol in single dose cannot be attributed to a pharmacokinetic interaction, and other pharmacodynamic interactions have to be considered. On the other hand, when metamizol and tramadol were co-administered under repeated administrations, a pharmacokinetic interaction and tolerance development occurred. Differences found in metamizol active metabolites' pharmacokinetics ( < 0.05) were related to the development of tolerance produced by the combination after repeated doses. This work shows an additional preclinical support for the combination therapy. The clinical utility of this combination in a suitable dose range should be evaluated in future studies.

Pharmacokinetics and pharmacodynamics of metamizol in co-administration with morphine under acute and chronic treatments in arthritic rats

“…In the same way, for the MET‐4D and MET+MOR‐4D schedules, the relationship was also characterized by a counter clockwise hysteresis loop for the MAA metabolite and a clockwise hysteresis loop for the AA metabolite plasma concentrations (Data not shown). For this reason, to define the PK/PD relationships, the AUC of the antinociceptive effect (global antinociceptive effect) instead of FI% to be related to metabolite concentrations was used …”

“…In certain combinations of analgesic drugs, it has been shown that it is not only possible to reduce the risk of incidence of adverse effects associated with the administration of high doses of the individual drugs, but also to increase the antinociceptive effects . However, although some preclinical and clinical studies had shown that such combinations can produce analgesic potentiation, little it is known about the antinociceptive effects after repeated administrations . A useful therapeutic focus within the context of chronic pain treatment is to maximize therapeutic efficacy while minimizing deleterious side effects.…”

“…On the contrary, it was found that while the acute treatment using MET plus tramadol (TRA) significantly enhances the antinociceptive effects of the drugs given alone ( P < 0.05), these effects decreased about 53% after a different schedule of chronic treatment (3 doses/day/4 days). As well, a pharmacokinetic interaction and tolerance development occurred . Differences found in MET active metabolites, 4‐methylaminoantipyrine (MAA) and 4‐aminoantipyrine (AA), pharmacokinetics ( P < 0.05) were related to the development of tolerance produced by the combination after repeated doses …”

“…As well, a pharmacokinetic interaction and tolerance development occurred . Differences found in MET active metabolites, 4‐methylaminoantipyrine (MAA) and 4‐aminoantipyrine (AA), pharmacokinetics ( P < 0.05) were related to the development of tolerance produced by the combination after repeated doses …”

Effect of intravenous continual vs. Bolus doses of tramadol and metamizol sodium combination in acute pain management: Continual vs. Bolus doses of tramadol and metamizol combination: Pilot study

“…Bolus doze tramadola i metamizola se niz godina koriste za kupiranje bola, akutnog i hroničnog. Međutim, na osnovu farmakoloških istraživanja koja su dokazala da ne postoji interakcija između ova dva leka ukoliko se oni primene istovremeno, u istom rastvoru 13 , kontinuirani i istovremeni način primene se u mnogim studijama pokazao kao bolji terapijski izbor [14][15][16][17][18][19][20][21][22] . Takođe, u istim studijama je vršeno poređenje efekta tramadol/metamizol kombinacije sa drugim analgetskim režimima za različite vrste operacija, u kojima se ispitivana kombinacija pokazala različito efikasnom u poređenju sa drugim analgetskim reži-mima.…”