Respiratory depression by tramadol in the cat: involvement of opioid receptors.

Dahan A.

Department of Physiology, Leiden University Medical Center, The Netherlands. l.j.s.m.Teppema LUMC.nl

BACKGROUND: Tramadol hydrochloride (tramadol) is a synthetic opioid analgesic with a relatively weak affinity at opioid receptors. At analgesic doses, tramadol seems to cause little or no respiratory depression in humans, although there are some conflicting data. The aim of this study was to examine whether tramadol causes dose-dependent inhibitory effects on the ventilatory carbon dioxide response curve and whether these are reversible or can be prevented by naloxone. METHODS: Experiments were performed in cats under alpha-chloralose-urethane anesthesia. The effects of tramadol and naloxone were studied by applying square-wave changes in end-tidal pressure of carbon dioxide (Petco2; 7.5-11 mmHg) and by analyzing the dynamic ventilatory responses using a two-compartment model with a fast peripheral and a slow central component, characterized by a time constant, carbon dioxide sensitivity, time delay, and a single offset (apneic threshold). RESULTS: In five animals 1, 2, and 4 mg/kg tramadol (intravenous) increased the apneic threshold (control: 28.3 +/- 4.8 mmHg [mean +/- SD]; after 4 mg/kg: 36.7 +/- 7.1 mmHg; P < 0.05) and decreased the total carbon dioxide sensitivity (control: 109.3 +/- 41.3 ml x min(-1) x mmHg(-1) ) by 31, 59, and 68%, respectively, caused by proportional equal reductions in sensitivities of the peripheral and central chemoreflex loops. Naloxone (0.1 mg/kg, intravenous) completely reversed these effects. In five other cats, 4 mg/kg tramadol caused an approximately 70% ventilatory depression at a fixed Pet co2 of 45 mmHg that was already achieved after 15 min. A third group of five animals received the same dose of tramadol after pretreatment with naloxone. At a fixed Petco of 45 mmHg, naloxone prevented more than 50% of the expected ventilatory depression in these animals. CONCLUSIONS: Because naloxone completely reversed the inhibiting effects of tramadol on ventilatory control and it prevented more than 50% of the respiratory depression after a single dose of tramadol, the authors conclude that this analgesic causes respiratory depression that is mainly mediated by opioid receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12552202&dopt=Abstract tramadol



Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids.

Schneider J.

Department of Biochemical Pharmacology, Grunenthal GmbH, Aachen, Fed. Rep. of Germany.

The influence of replacing the phenolic hydroxyl by the methoxy group on opioid receptor binding, analgesic and antitussive action was investigated in the corresponding couples morphine-codeine, hydromorphone-hydrocodone and O-desmethyltramadol (L 235)-tramadol. Binding was studied on rat whole brain membranes (without cerebellum) with the radioligands dihydromorphine (mu-site), ethylketocyclazocine (k-site), D-Ala2-D-Leu5-enkephalin (delta-site) and naloxone (no selective binding). Analgesia (tail flick) and antitussive action (NH3-vapour induced cough) was investigated in rats and ED50 values 10 min after i.v. application were calculated to compare efficacy. All free hydroxyl compounds had higher opioid receptor affinities than the corresponding methoxy derivatives and were more active at the mu-site. The methoxy derivatives codeine and tramadol only had low affinities lacking selectivity towards mu-, kappa-, or delta-binding. Hydrocodone in contrast showed strong and mu-selective binding. The hydroxy compounds had higher analgesic activity than the methoxy congeners and analgesia appeared to correlate with mu-binding affinity. Codeine and hydrocodone were weaker antitussives than the corresponding hydroxy compounds, whereas no significant difference was found between O-desmethyltramadol and tramadol. Only in the tramadol group the methoxy substitution increased antitussive potency in relation to analgesic potency.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2849950&dopt=Abstract tramadol



[General pharmacological studies on tramadol, a potent analgetic agent (author's transl)]

[Article in German]

Ishii I.

The general pharmacological properties of 1-(m-methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol (tramadol; Tramal) are described and compared with those of other strong narcotic analgetics. In behavioral studies tramadol in high doses had a primarily stimulating effect in mice and rats and a sedative effect in rabbits and dogs. The Straub tail phenomenon, a reaction typical for mice administered morphine, was observed only after subtoxic doses of tramadol. In i.v. doses tramadol generally caused a weak central inhibition of non-stimulated and electrically stimulated brain activity in unanesthetized rabbits. Muscle tone and motor coordination in rats and mice were only slightly affected by the drug, in contrast to the effect of morphine. Unlike other strong analgesics tramadol in doses of 5--20 mg/kg i.v. did not cause respiratory depression and even clearly increased respiratory volume and rate in conscious rabbits and anesthetized dogs. In cats and dogs i.v. doses of tramadol up to 10 mg/kg were well tolerated in the cardiovascular system. Tramadol has a slight, papaverine-like spasmolytic effect and no effect on gastrointestinal motility or urinary and electrolyte excretion. The drug showed no antipyretic properties in rabbits. It inhibited edema in rats and guinea pigs but had no antiproliferative effect in the cotton pellet test in rats. Tramadol did not inhibit monoamine oxidase activity or cause enzyme induction in the rat liver.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=305247&dopt=Abstract tramadol



Effects of tramadol on motor and sensory responses of the spinal nociceptive system in the rat.

Jurna I.

Institut fur Pharmakologie der Universitat des Saarlandes, Homburg, F.R.G.

The analgesic agent, tramadol, was tested on motor and sensory responses of the nociceptive system in rats. The tail-flick response to radiant heat was dose dependently depressed by tramadol (1-10 mg/kg i.p.), and the antinociceptive effect of the drug was reduced by naloxone in the same range of doses that antagonized the effect of morphine. Tramadol (100 micrograms) microinjected into the periaqueductal grey (PAG) prolonged the tail-flick latency and this effect was abolished by naloxone (0.2 mg/kg i.p.). Aminophylline (25 mg/kg i.p.) did not prevent the antinociceptive effect of tramadol (5 mg/kg i.p.). Tramadol (20 and 40 mg/kg injected i.v.; 100 and 200 micrograms injected intrathecally (i.t.); 100 micrograms injected into the PAG) depressed both the spontaneous activity in ascending axons and their activity due to stimulation of afferent C fibres and co-activation from afferent A delta fibres in the sural nerve. Naloxone injected i.v. at a dose (0.2 mg/kg) that had proven fully effective against the effects of morphine antagonized only the effect on spontaneous activity caused by i.v. injection of tramadol. A high dose of naloxone (1 mg/kg i.v.) not only abolished the depression of spontaneous activity caused by an i.t. injection of tramadol (200 micrograms) but also significantly reduced (but did not abolish) the activity in ascending axons evoked from afferent C fibres while the depression of co-activation from afferent A delta fibres remained unchanged. Aminophylline (50 micrograms i.t.) failed to abolish the depression by tramadol of ascending nociceptive activity. The activity elicited in ascending axons by stimulation of afferent A beta fibres was not changed by i.t. injection of tramadol (200 micrograms), which was evidence that the antinociceptive effect of tramadol is not due to a local anaesthetic action. It is concluded that tramadol produces its antinociceptive and analgesic effects through spinal and supraspinal sites of action. Since the effects of tramadol and morphine differ in some respects, it must be assumed that they are due to binding to different opiate receptors or that some of the effects of tramadol are not mediated by opiate receptors alone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3653236&dopt=Abstract tramadol