Is there a suitable analgesic drug for a warfarin-treated patient who reacts to morphine and codein

Fråga: Is there a suitable analgesic drug for a warfarin-treated patient who reacts to morphine and codeine by hypotension?

CLINICAL BACKGROUND: A sixty-seven year old male patient has had a myocardial infarction and a lung embolus. He is treated with warfarin. He has back pain for which he needs to be treated.

He has previously been treated with morphine and codeine whence he experienced episodes of decreased blood pressure.

Sammanfattning: Histamine release from mast cells by opioids is dose dependent. Potent opioids like fentanyl, sufentanyl, or buprenorphine are used clinically in doses which don´t cause histamine release. These potent opioids and tramadol may be tried in patients suffering from hypotensive side-effects or other opioids in an attempt to avoid hemodynamic changes.

Svar: Opioids can cause release of histamine which can result in some hemodynamic changes like decreased systemic vascular resistance (SVR), hypotension (1) and venodilation (2). The dose and type of opioid as well as co-administration of other drugs also affects the hemodynamic changes (1-9).

In one study, morphine (0.3mg/kg) was used in patients undergoing surgery (10). Histamine concentrations in serum increased about fourfold after administration of morphine. This was associated with decreased SVR (10). The subjects with high levels of histamine as a response to opiate were called responders. In another study, morphine acted as a venodilator of human hand veins in vivo, possibly an effect indirectly mediated by histamine release (2).

Other mu-opiate receptor agonists, fentanyl, sufentanyl, buprenorphine (5) and oxymorphone, did not cause vasodilatation or histamine release from skin mast cells (8) in patients undergoing elective coronary bypass surgery (2). Fentanyl produced little change in peripheral vascular tone and systemic concentrations of histamine in human (2).

The mechanism of histamine release by opioids is unlikely to be mediated by mu-opiate receptor stimulation (2). Direct activation of a G-protein may be the cause of the histamine release (2). It was also shown in a clinical trial that the patient group given both 1.0 mg/kg morphine and H1 and H2 histamine antagonists demonstrated significant attenuation of the morphine induced hemodynamic effects (11). Similarly, blockade of H1- and H2-receptors completely antagonised the morphine induced human hand venodilation (2).

Such hemodynamic changes have not been well documented for the more commonly used analgesic or subanesthetic doses of the opiates. Morphine (0.15 mg/kg) or nalbuphine (0.3 mg/kg) was administered iv to normal volunteers. Thirteen of 15 subjects receiving morphine and 10 of 14 subjects receiving nalbuphine had elevations in plasma histamine levels (3). Even this low dose of morphine generated elevated plasma histamine levels (3) but it was not associated with hemodynamic changes.

Significant hypotension after morphine may also be attributed in part to the interaction of co-administered drugs like benzodiazepines (3, 10).

Studies comparing human mast cells derived from different organs reveal that the usual clinical doses of morphine do not stimulate histamine release from mast cells of lung, heart, intestine, or basophils. Only cutaneous mast cells reacted with histamine release at clinically relevant doses (3).

In vivo release of histamine by opioids is dose dependent and varies roughly inversely to the analgesic potency (5, 6). It may relate to the concentration of the drug achieved at the mast cell´s cell membrane. There are evidence that potent opioid drugs such as fentanyl, sufentanyl and buprenorphine are used at concentrations which do not cause release of histamine (5). Conversely meperidine (4.3 mg/kg) caused the highest incidence of histamine release (6). On the other hand, another opioid analgesic, tramadol, did not cause histamine release in 13 healthy volunteers with 100 mg dose (7) and postural hypotension had almost no effect in multiple dose studies of trandol (12).

The metabolism of warfarin is mainly carried out by CYP2C9. This isozyme is not involved in the metabolism of narcotics (13, 14). There is no information about warfarin drug interaction with narcotics in the literature.

Recently mu-3 opioid receptor has been shown to be present in human arterial endothelial cells. The mu-3 receptor is coupled to nitric oxide release and vasodilatation (15). An alternate way of hypotension may be activation of these receptors but there is no information about the clinical importance of these receptors in endothelial cells. 1 Warner MA, Hosking MP, Gray JR, Squillace DL, Yunginger JW, Orszulak TA: Narcotic-induced histamine release: a comparison of morphine, oxymorphone, and fentanyl infusions. J Cardiothorac Vasc Anesth 1991; 5: 481-4 2 Grossmann M, Abiose A, Tangphao O, Blaschke TF, Hoffman BB: Morphine-induced venodilation in humans. Clin Pharmacol Ther 1996; 60: 554-60 3 Doenicke A, Moss J, Lorenz W, Hoernecke R: Intravenous morphine and nalbuphine increase histamine and catecholamine release without accompanying hemodynamic changes. Clin Pharmacol Ther 1995; 58: 81-9 4 Stellato C, Cirillo R, de Paulis A, Casolaro V, Patella V, Mastronardi P, Mazzarella B, Marone G: Human basophil/mast cell releasability. IX. Heterogeneity of the effects of opioids on mediator release. Anesthesiology 1992; 77: 932-40 5 Girotra S, Atray R, Mittal M: No cutaneous histamine release with buprenorphine? Acta Anaesthesiol Scand 1990; 34: 301-3 6 Flacke JW, Flacke WE, Bloor BC, Van Etten AP, Kripke BJ: Histamine release by four narcotics: a double-blind study in humans. Anesth Analg 1987; 66: 723-30 7 Barth H, Giertz H, Schmal A, Lorenz W: Anaphylactoid reactions and histamine release do not occur after application of the opioid tramadol. Agents Actions 1987; 20: 310-3 8 Hermens JM, Ebertz JM, Hanifin JM, Hirshman CA: Comparison of histamine release in human skin mast cells induced by morphine, fentanyl, and oxymorphone. Anesthesiology 1985; 62: 124-9 9 Tammisto T, Takki S, Toikka P: A comparison of the circulatory effects in man of the analgesics fentanyl, pentazocine and pethidine. Br J Anaesth 1970; 42: 317-24 10 Fahmy NR, Sunder N, Soter NA: Role of histamine in the hemodynamic and plasma catecholamine responses to morphine. Clin Pharmacol Ther 1983; 33: 615-20 8 (Abstract) 11 Philbin DM, Moss J, Akins CW, Rosow CE, Kono K, Schneider RC, VerLee TR, Savarese JJ: The use of H1 and H2 histamine antagonists with morphine anesthesia: a double-blind study. Anesthesiology 1981;55: 292-6 (Abstract) 12 Cossmann M, Kohnen C, Langford R, McCartney C: Tolerance and safety of tramadol use. Results of international studies and data from drug surveillance. Drugs 1997; 53 Suppl 2: 50-62 (Abstract) 13 Aasmundstad TA, Xu BQ, Johansson I, Ripel A, Bjorneboe A, Christophersen AS, Bodd E, Morland J: Biotransformation and pharmacokinetics of ethylmorphine after a single oral dose. Br J Clin Pharmacol 1995; 39: 611-20 (Abstract) 14 Tateishi T, Krivoruk Y, Ueng YF, Wood AJ, Guengerich FP, Wood M: Identification of human liver cytochrome P-450 3A4 as the enzyme responsible for fentanyl and sufentanil N-dealkylation. Anesth Analg 1996; 82: 167-72 (Abstract) 15 Stefano GB, Hartman A, Bilfinger TV, Magazine HI, Liu Y, Casares F, Goligorsky MS: Presence of the mu3 opiate receptor in endothelial cells. Coupling to nitric oxide production and vasodilation. J Biol Chem 1995; 270: 30290-3