Differential role of 5-HT(1A) and 5-HT (1B) receptors on the antinociceptive and antidepressant effect of tramadol in mice.

Berrocoso E, Rojas-Corrales MO, Mico JA..

Pharmacology and Neuroscience Research Group, Department of Neuroscience (Pharmacology and Psychiatry), School of Medicine, University of Cadiz, Plaza Falla 9, 11003, Cadiz, Spain.

Psychopharmacology (Berl). 2006 Jul

RATIONALE: Tramadol, (1RS,2RS)-2-[(dimethylamine)-methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is an atypical analgesic which binds weakly to i-opioid receptors and enhances the extra-neuronal concentration of noradrenaline and serotonin by interference with both the uptake and release mechanisms. OBJECTIVES: The present study was undertaken to evaluate the potential role of 5-HT(1A) and 5-HT(1B) receptors on the analgesic and antidepressant-like effect of tramadol. METHODS: The effect of either a selective 5-HT(1A) receptor antagonist (WAY 100635; N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide; 0.2-0.8, 8 mg/kg) or a selective 5-HT(1B) receptor antagonist (SB 216641; N-[3-(3-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide; 0.2-0.8, 8 mg/kg) was investigated in mice in combination with tramadol by means of the hot-plate test, a phasic nociceptive model, and the forced swimming test, a paradigm aimed at screening potential antidepressants. RESULTS: The results showed that WAY 100635 enhanced the antinociceptive effect and produced a large decrease in the antidepressant-like effect of tramadol. In contrast, SB 216641 did not significantly modify either the analgesic or the antidepressant-like effects of tramadol. CONCLUSIONS: These findings suggest that 5-HT(1A) receptors modulate the analgesic and the antidepressant-like effects of tramadol in differing ways. The results suggest the involvement of the 5-HT(1A) autoreceptors from the raphe nuclei and spinal 5-HT(1A) receptors in the antinociceptive effect. In contrast, the 5-HT(1A) receptors located in the forebrain may be responsible for the blockade of the antidepressant-like effect of tramadol. 5-HT(1B) receptors seem not to modify these effects in the models investigated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16832657&dopt=Abstract tramadol



Evidence of self-synergism in the antinociceptive effect of tramadol in rats.

Perez-Urizar J.

Facultad de Estomatologia, Universidad Autonoma de San Luis Potosi, Zona Universitaria CP 78290 San Luis Potosi SLP.

Tramadol is an atypical opioid with a complex mechanism of action including the synergistic interaction between the parent drug and an active metabolite. However, the local action of the parent drug is poorly documented. This study was designed to evaluate the site-site interaction of the antinociception produced by tramadol given by two different routes. The effects of individual and fixed-ratio combinations of locally (subcutaneous) and systemically (intraperitoneal) dosed tramadol were evaluated using the formalin test in rats. Isobolographic analysis was employed to identify the synergy produced by combinations. In the second phase of the formalin test, tramadol was active not only by the systemic (ED50 7.15+/-0.46 mg/kg i.p.) but also by the local route (ED50 134.6+/-25.1 microg/paw). The isobolographic analysis evidenced a "self-synergism" in the antinociceptive effect between the two routes of administration since the experimental ED50 (30.8+/-0.1 "dose units") of the combination was significantly lower than the theoretical ED50 (70.9+/-12.6 "dose units"). The mechanism underlying this self-synergism appears to be partially opioid since naloxone reversed the potentiation. The observed site-site interaction in the antinociceptive action of tramadol provides insights for alternatives in the management of pain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15633629&dopt=Abstract tramadol



Randomized double-blind, double-dummy crossover clinical trial of oral tramadol versus rectal tramadol administration in opioid-naive cancer patients with pain.

Ripamonti C.

Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Via San Lorenzo 312, 90146, Palermo, Italy, terapiadeldolore la-maddalena.it.

Tramadol is commonly used as second step drug of the analgesic ladder. In circumstances where the oral route is unavailable, rectal administration of opioids might be a simple alternative. The aim of this study was to compare the analgesic activity and tolerability of tramadol by oral and rectal administration in a double-blind, double-dummy crossover trial. The study included 60 cancer patients with cancer pain no longer responsive to non-opioid drugs. Each patient initially received oral tramadol 50 mg (drops), followed by tramadol sustained release 100 mg orally, and placebo rectally, or tramadol 100 mg rectally and placebo orally, twice a day, in a randomized sequence, on each of 3 days. Patients were allowed to take 50 mg of oral tramadol by drops as needed (four doses per day, to a maximum of 400 mg/day, including the basal dose given by the oral or rectal route). Pain intensity and relief and symptom scores were recorded every day and at the end of each phase of the crossover. The mean age of the patients was 66.1 years (SD 13.5 years); 36 were female, and 44 completed both periods. Patients dropped out due to adverse effects (15 patients) and refusal (1 patient). No differences in the use of rescue dose of oral tramadol were observed between the groups. No differences in pain intensity and relief scores, or in other symptoms between the two treatments were observed. No differences in treatment efficacy as judged by the clinician (P=0.73), in patient compliance (P=0.35), or in patient satisfaction regarding treatment (P<0.35) were found. No differences in adverse effects were found between the two treatments (25.5%, 13 patients, and 20.4%, 11 patients, with oral and rectal treatment, respectively). The proportion of preferences favored oral administration for both physicians (P=0.0002) and patients (P=0.002). Rectal administration of tramadol appears a reliable, noninvasive alternative method of pain control for patients no longer responsive to non-opioid analgesics, unable to take oral tramadol.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15645186&dopt=Abstract tramadol



Isobolographic analysis of the analgesic interactions between ketamine and tramadol.

Ho PC.

Department of Pharmacy, National University of Singapore, Singapore.

Owing to different mechanisms of analgesia, we hypothesized that the combination of ketamine and tramadol could produce synergistic or additive antinociceptive effects. Swiss albino mice were administered intraperitoneally with ketamine, tramadol, a combination of ketamine and tramadol, or saline, and the resulting antinociceptive effects were tested in the mouse tail-flick and formalin tests. The potencies of the two drugs alone or in combination were obtained by fitting data to the Sigmoid Emax equation. Isobolographic analysis was performed to evaluate the interaction. CNS depression was also monitored. Results showed that tramadol exhibited apparent dose-dependent effects in the tail-flick test, and in phase 1 and phase 2 of the formalin test. Ketamine dose-dependently inhibited the phase 2 responses, but failed to modify the phase 1 and tail-flick responses. Combination of tramadol and ketamine produced significant synergistic interactions only in phase 2 of the formalin test (P < 0.05). The synergistic combinations also displayed less CNS depression than when an equianalgesic dose of ketamine was administered alone. We conclude that in the acute thermal or chemical pain model, ketamine is not effective and the net effect of ketamine and tramadol in combination was simply additive after systemic administration. However, the coadministration produced synergistic antinociception in the chemical-induced persistent pain model.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12005357&dopt=Abstract tramadol



Reducing cardiovascular responses to laryngoscopy and tracheal intubation: a comparison of equipotent doses of tramadol, nalbuphine and pethidine, with placebo.

Baloch M.

Dept of Anaesthesia, Riyadh Armed Forces Hospital, Riyadh 11159, KSA.

The stress response to tracheal intubation may be obtunded by opioids given with induction of anesthesia. Tramadol is an opioid acting on mu-receptors and the monoaminergic pain modulating systems. This study examined vasomotor responses to tracheal intubation after equipotent doses of tramadol, nalbuphine and pethidine (3.0, 0.3 mg/kg(-1), and 1.5 mg/kg(-1), respectively), and placebo, given prior to induction of anesthesia in 118 healthy patients. Premedication and induction of anesthesia were standardized. Recordings of HR and SAP were made prior and subsequent to induction of anesthesia, and at 1, 3, 5 and 7 minutes after tracheal intubation. Prior to laryngoscopy and intubation, HR increased in all groups (p < or = 01, all comparisons), but least so after nalbuphine, whilst SAP remained unchanged after placebo, tramadol and pethidine, but fell after nalbuphine (p < 0.025). Maximum increases in HR (p < or = 0.005, all comparisons) and SAP (p < or = 0.02, all comparisons) occurred one minute after intubation. Maximum HR after placebo (108 SD 15 bpm), tramadol (107 SD 20 bpm), pethidine (113 SD 16 bpm) and nalbuphine (110 SD 26 bpm) was similar; with placebo HR remained faster than baseline until the seventh minute but had returned to baseline by the fifth minute with the opioids. Maximum SAP with tramadol (151 SD 26 mmHg) was similar to that with placebo (157 SD 20 mmHg), but was greater than after pethidine (136 SD 27 mmHg; p < 0.05) and nalbuphine (135 SD 19 mmHg; p < 0.02). With each test drug SAP returned to baseline by the third minute. It is concluded that, in these doses, 1) tramadol does not attenuate the chronotropic nor the inotropic response to tracheal intubation, and 2) pethidine and nalbuphine reduce only the inotropic response to airway instrumentation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15651510&dopt=Abstract tramadol