Effects of tramadol on minimum alveolar concentration (MAC) of isoflurane in rats.

Wouters PF.

Centre for Experimental Surgery and Anaesthesiology, Katholieke Universiteit Leuven, Belgium.

It has been suggested previously that tramadol increases central nervous system activity and 'lightens' anaesthesia with volatile agents. We assessed the effects of tramadol on the minimum alveolar concentration (MAC) of isoflurane in 56 Wistar rats, instrumented chronically with an arterial and central venous catheter. The MAC of isoflurane was determined using the tail clamp method under three conditions: (1) after injection of saline (control); (2) after administration of tramadol 10 mg kg-1 i.v.; and (3) after administration of morphine 1 mg kg-1 i.v. The studies were repeated after treatment with the antagonists naloxone or yohimbine. Tramadol and morphine both reduced the MAC of isoflurane from mean 1.38 (SEM 0.05)% to 1.22 (0.06)% and 1.17 (0.06)%, respectively (P < 0.05). Concomitant administration of yohimbine did not abolish this reduction in MAC. In contrast, after pretreatment with naloxone, tramadol (1.47 (0.04)%) or morphine (1.38 (0.07)%) did not cause a reduction in the MAC of isoflurane compared with controls (1.39 (0.06)%). We conclude that tramadol and morphine reduced the MAC of isoflurane to a small but significant extent. For both drugs, this effect was related to their action at opioid receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10690143&dopt=Abstract tramadol



Interactions in the antinociceptive effect of tramadol in mice: an isobolographic analysis.

Miranda HF.

Department of Pharmacology, Faculty of Medicine

Tramadol is a widely-used analgesic for pre- and post-operative pain which has a different pharmacological profile to that of classical opioids, since it does not induce respiratory depression, constipation, sedation, tolerance or dependence. However, tramadol frequently produces nausea and vomiting as side-effects. In the present study, the interactions between tramadol and several adrenergic and serotonergic compounds with antinociceptive activity were studied by isobolographic analysis. Antinociceptive activity was evaluated using the acetic acid writhing test in mice. Dose-response curves for the antinociceptive effect of tramadol, prazosin, clonidine, xylamine, clomipramine and cyproheptadine were obtained, and ED(50)s were calculated for isobolographic analysis, which was performed by administration of fixed-ratios of tramadol with each of these drugs, given both systemically and intrathecally. The isobolograms of all combinations tested, either systemically or intrathecally showed superadditivity. The synergies observed with these combinations suggest a complex modulation of the descending noradrenergic and serotonergic systems that exert inhibitory influences on the transmission of nociceptive information, probably in addition to effects on receptors in the primary neurons of the spinal cord. The co-administration of analgesic drugs that produce superadditive effects constitutes a significant new avenue for the treatment of pain, since a similar level of antinociception can be obtained with considerable reductions in the dose of each analgesic. Copyright 1998 European Federation of Chapters of the International Association for the Study of Pain.

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Patient-controlled extradural analgesia after caesarean section: a comparison between tramadol, sufentanil and a mixture of both.

Adriaensen HA.

Department of Anaesthesia, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem, Belgium

In a double-blind randomised study into post-operative pain relief by extradural PCA, 66 Caesarean section patients were divided in to three groups to receive either sufentanil (2 micro g/ml), tramadol (10 mg/ml) or a mixture of both. After a loading dose of 10 ml, patients were allowed to ask for additional boluses of 2.5 ml, respecting a lock-out time of 10 min and a 1-h limit of 10 ml. Every 6 h, VAS pain scores, consumption of drugs, number of demands and side-effects were registered.At 6 h, pain was significantly less in the combination group compared to patients receiving tramadol alone. The 24-h dose requirements for sufentanil and tramadol when used alone were 123.5+/-10.3 micro g and 652+/-42 mg, respectively. Combining both drugs decreased the consumption and number of demands for tramadol only (22%, p<0.05 vs 18% for sufentanil, NS). In the tramadol groups, more failures and significantly more side-effects, mainly nausea and vomiting, were noticed.It may be concluded that the extradural use of tramadol is less beneficial than previously reported. Due to disturbing side-effects, relatively high dose requirements (even after the addition of a lipophilic opioid) and somewhat inferior analgesic quality, its extradural administration for postoperative pain relief cannot be recommended. Copyright 1999 European Federation of Chapters of the International Association for the Study of Pain.

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Effects of tramadol stereoisomers on norepinephrine efflux and uptake in the rat locus coeruleus measured by real time voltammetry.

Stamford JA.

Academic Department of Anaesthesia and Intensive Care, St Bartholomew's and the Royal London School of Medicine and Dentistry, Royal London Hospital, UK.

Despite its structural similarity to codeine, tramadol is an unusual analgesic whose antinociceptive efficacy is not solely a result of opioid actions but also of its apparent capacity to block monoamine uptake. Tramadol is a mixture of stereoisomers. In this study, we have examined the actions of racemic, (+)- and (-)-tramadol, in addition to O-desmethyltramadol (the main human metabolite), on electrically evoked norepinephrine efflux and uptake in the locus coeruleus brain slice, measured by fast cyclic voltammetry. Racemic tramadol and its (+)- and (-)-enantiomers (all at 5 mumol litre-1) significantly increased stimulated norepinephrine efflux (P < 0.01) by mean 66 (SEM 10)%, 57 (7)% and 64 (13)%, respectively. However, only (-)-tramadol blocked norepinephrine reuptake (P < 0.01), increasing the reuptake half-time to 499 (63)% of pre-drug values. The metabolite O-desmethyl tramadol was inactive at the concentration tested (5 mumol litre-1). In the case of (-)-tramadol, the effect on norepinephrine efflux was directly proportional to, but significantly smaller than, the effect on norepinephrine uptake (P < 0.01). This appeared to be a result of compensatory alpha 2A autoreceptor tone as the selective alpha 2A autoreceptor antagonist BRL 44408 (1 mumol litre-1) eliminated this difference when its own effects on norepinephrine reuptake were taken into account. The efficacy of (-)-tramadol on norepinephrine uptake, at clinically relevant concentrations, may contribute to its antinociceptive efficacy.

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