Analgesic Effects of Tramadol in Combination with Adjuvant Drugs: An Experimental Study in Rats

Abstract

Background: Tramadol is often coadministered subcutaneously with adjuvants to treat pain, nausea/vomiting, dyspnea and delirium in cancer patients. The aim of the study was to investigate analgesia of tramadol coadministered with adjuvants in rats. Materials and Methods: Male rats (Wistar race) received a single tramadol dose separately (0.45 mg/kg) or tramadol with haloperidol (0.45 mg/kg), midazolam (0.3 mg/kg), levomepromazine (0.35 mg/kg), metoclopramide (1.0 mg/kg), hyoscine butylbromide (1.7 mg/kg) or ketamine (0.3 mg/kg) as a single subcutaneous injection. Analgesia was measured by a tail flick test after 15, 30, 60 and 90 min of drug administration. Results: Tramadol analgesia was enhanced with haloperidol (30, 60 and 90 min) and with midazolam (60 and 90 min). Tramadol with levomepromazine (30, 60 and 90 min) and tramadol with metoclopramide (30 and 90 min) attenuated tramadol analgesia. Tramadol with hyoscine butylbromide and tramadol with ketamine did not change tramadol analgesia. Conclusions: Significant changes in tramadol analgesia after the administration of different adjuvants could be demonstrated in this experimental single-dose study. Future clinical trials have to further explore the benefits of these drug combinations.

Investigational sigma-1 receptor antagonists for the treatment of pain

“…Correlating with behavioral effects, pretreatment or short-term treatment with haloperidol inhibited morphineinduced up-regulation of supraspinal and spinal Ca 2+ /calmodulin-dependent protein kinase II activity [45]. Potentiation of the analgesia of the atypical opioid tramadol by haloperidol was also reported in rats [46]. When given alone (without opioids), subcutaneous administration of haloperidol reduced mechanical hypersensitivity induced by intraplantar capsaicin in mice.…”

Analgesic and Anti–Inflammatory Effects of Oxycodone with Adjuvant Drugs in an Experimental Study of Nociceptive and Neuropathic Pain

“…was taken from the Kanbara et al study, wherein after OXY administration (SC), this dose was effective in the treatment of NP in rats [17]. The choice of adjuvants and their doses were based on our earlier studies, in which concurrent analgesic effects of selected adjuvants with tramadol [18] and morphine [19] were explored. …”

“…However, in contrast to the presented study, HYO coadministration did not enhance tramadol analgesia. Contrary to co-administration with morphine, MID enhanced tramadol analgesia and MET and LEV attenuated tramadol antinociception [18]. Results of an experimental study indicate a synergistic interaction of OXY and morphine with pregabalin, combinations that are often used in clinical practice for the treatment of NP in cancer patients [49].…”

Analgesic Effects of Morphine in Combination with Adjuvant Drugs in Rats

“…These differences may be evoked by both differences in pharmacodynamic interactions of the tested opioids and possible pharmacokinetic interactions with adjuvants as there are significant differences in pharmacodynamics and pharmacokinetic properties of tramadol and morphine. In contrast to morphine, which acts exclusively via activation of (predominantly μ) opioid receptors and undergoes the process of glucuronidation, tramadol displays a non-opioid component of analgesia; μ-opioid receptors are activated predominantly by an active metabolite (O-desmethyltramadol, M1) that is formed through tramadol O-demethylation catalysed by CYP2D6 [30]. …”