Is there any documentation concerning cardiac or ECG effects caused by opiates?

Fråga: Is there any documentation concerning cardiac or ECG effects caused by opiates?

Sammanfattning: To judge from the literature, and considering the widespread and massive use of some of these compounds, opioids in general seem to cause few clinical cardiac effects. The distribution of different opiate receptors and their relevance to cardiac function seem to be under discussion, mainly in animal models.

Svar: Neither a thorough check in handbooks nor Medline searches on cardiac effects by narcotics back to 1966, as well as on opiate receptors and heart back to 1980, have revealed much information about cardiac side-effects caused by opioids. Most of the following statements are quoted from a textbook by Wood (1), and are hard to critically assess as the original work has been very difficult to find.

MORPHINE: There are no significant clinical direct myocardial (e.g. depressive) effects in humans (1). Clinical doses (0.125 mg/kg) as well as high doses (one mg/kg) have been shown to produce little effect on the cardiovascular system in healthy subjects (1). Hypotension may occur, however, and this may be of importance in hypovolaemic patients (1). Morphine decreases peripheral vascular resistance and increases venous capacitance, due at least partly to histamine release (1). Morphine may thus be beneficial in patients with elevated left ventricular end diastolic pressure, as in aortic valvular disease (1).

In a study by Semenkovich and Jaffe from 1985, cited in (2), the question about morphine-induced cardiac conduction defects was dealt with. Of 184 patients (156 subsequently documented to have myocardial infarction) who received morphine, only four patients had symptomatic hypotension. No case of conduction abnormality was seen. The study is said to document that adverse cardiovascular effects due to morphine are rare and consist of inappropriate heart rate responses (perhaps vagally mediated) to hypotension rather than conduction defects, and are not particularly associated with inferior myocardial infarction as was previously thought.

Wood (1) states that sinus bradycardia caused by morphine may occur due to central vagal stimulation and that this may be caused by stimulation of central nervous mu-2 opiate receptors. In fact, most of the cardiovascular effects seen by opiates could be related to mu-2 receptors in the brain (1). However, in an abstract from a Chinese study (3) on isolated rat hearts, cardiac opioid receptors said to be involved in the genesis of arrhythmias during were ischaemia and reperfusion, and cardiac kappa-receptors to be the most likely receptor subtype. In another abstract (4) from a Chinese study on guinea-pig hearts, it was suggested that morphine stimulates different subtypes of cardiac opioid receptors at high and low morphine-concentrations.

MEPERIDINE (PETHIDINE): Analgesic doses of meperidine are said to have no significant cardiovascular effect (1). However, high doses can cause serious cardiovascular depression, and meperidine has been shown to be more likely to depress isolated cat papillary muscle than morphine (1). Meperidine causes tachycardia, rarely bradycardia and is thought to be less suitable for use in high doses in patients with cardiovascular disease (1).

FENTANYL: Cardiovascular stability is said to be good, even with high doses (1). Fentanyl rarely causes hypotension and has minimal peripheral vascular effects (1). Profound bradycardia may occur, however. A Medline search has revealed several case reports of bradycardia and sinus arrest. In most of the cases, other anaesthetics and muscle relaxants were involved. In an abstract from a study by Saini et al (5), fentanyl is said to raise the ventricular fibrillation threshold in normal canine myocardium. This effect is amplified during haemorrhagic stress and ischaemia but the antifibrillatory effect during ischaemia can be abolished by atropine, indicating a vagal efferent protective effect by fentanyl.

ALFENTANIL: There are few haemodynamic differences between alfentanil and fentanyl (1). As for fentanyl there are a number of case reports of bradycardia and sinus arrest.

SUFENTANIL: Sufentanil is said to produce cardiovascular stability (1). Decreases in blood pressure and bradycardia similar to those of fentanyl may occur (1). In a comparative study by Flacke et al cited in (2), sufentanil was shown to cause less haemodynamic disturbance than morphine, pethidine and fentanyl.

DEXTROPROPOXYPHENE: Acute overdosage can cause arrhythmias, cardiac arrest or altered blood pressure (2). These effects may be due to the local anaesthetic properties of the parent compound and the metabolite norpropoxyphene (2,3).

PARTIAL OPIATE ANTAGONISTS: Pentazocine is said to differ from morphine in that it does not produce hypotension or bradycardia (1), and one study (7) has indicated that pentazocine may decrease different supraventricular conduction intervals. It may also increase cardiac load (1), as does butorphanol (1,2), and these drugs should be used with caution in patients with myocardial ischaemia (1). Overdosage of pentazocine has been described as causing ventricular arrhythmias (2). Nalbuphine has not been shown to have significant cardiovascular effects (1,2). The cardiac effects of buprenorphine are said to be similar to those of morphine (1).

OVERDOSAGE with a variety of opiate agents has been reported to cause rhabdomyolysis and signs of myocardial infarction (2). 1 Wood, Drugs and anesthesia. 1990; 2nd ed:137-166 2 Meyler´s, Side effects of drugs. Ed by MNG Dukes. Elsevier, Amsterdam. 1988; 11th ed: 141-155 3 Wong TM, AY L, KK T: Effects of drugs interacting with opioid receptors during normal perfusion or ischemia and reperfusion in the isolated rat heart - an attempt to identify carduac opioid receptor subtype(s) involved in arrhythmogenesis. J Mol Cell Cardiol 1990; 22: 1167-1175 4 Xue GH, Wang ZY, Liao DZ, Pan JY, Zhan CY: Effects of morphine of different concentrations on myocardial action potential. Sheng Li Hsueh Pao 1990; 42: 323-330 5 Saini V, Carr DB, Verrier RL: Comparative effects of the opioids fentanyl and buprenorphine on ventricular vulnerability during acute coronary artery occlusion. Cardiovasc Res 1989; 23: 1001-1006 6 Martindale, The extra pharmacopoeia. 1989; 29th ed: 1294-1321 7 Markiewicz K, Ku:s W, Cholewa M, Bubi:nski R: Electrophysiologic effects of blocking and stimulating the opioid system in patients with unexplained heart palpitations. Clin Cardiol 1991; 14: 813-820