Respiratory depression by tramadol in the cat: involvement of opioid receptors.
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.
Teppema
Luc J
LJ
Department of Physiology, Leiden University Medical Center, The Netherlands. l.j.s.m.Teppema@LUMC.nl
Nieuwenhuijs
Diederik
D
Olievier
Cees N
CN
Dahan
Albert
A
D000465:Algorithms; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D002245:Carbon Dioxide / Q000494:pharmacology; D002415:Cats; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects*; D012018:Reflex / Q000187:drug effects; D015656:Respiratory Mechanics / Q000187:drug effects*; D014147:Tramadol / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D002245:Carbon Dioxide; D009270:Naloxone; D014147:Tramadol