Br. J. clin. Pharmac. (1979), 7, 309s-313S

PHARMACOLOGICAL AND CLINICAL IMPORTANCE OF NARCOTIC ANTAGONISTS AND MIXED ANTAGONISTS - USE IN CARDIOLOGY

D. JOHN COLTART & ALASDAIR D. MALCOLM Department of Cardiology, St Thomas' Hospital, London SE1 7EH, UK

1 The treatment of pain of cardiac origin requires a knowledge of the haemodynamic action of the analgesic agents used. 2 The haemodynamic effects of , diamorphine, pavaveretum, and are reviewed. 3 Clinical experience with the new antagonist analgesic is reported. 4 These studies indicate that buprenorphine may be the agent ofchoice for the relief of severe pain in patients with unstable circulation.

Introduction THE experience of severe pain after surgery and practice (Mirsky et al., 1974; Kolettis et al., 1976; trauma requires the therapeutic use of powerful Mason et al., 1976) and data so far are scanty. analgesic agents. When the heart and circulation are In the following sections we shall survey available normal, the administration of doses of drugs data on the reviewed analgesic agents. sufficient to provide adequate analgesia is rarely precluded by unwanted haemodynamic effects. However, when the pain is of cardiac origin the Morphine clinical situation is more precarious and requires a knowledge of the haemodynamic action of the drug This is considered first because it is so widely used used in order to ensure therapeutic safety. In this and tends to be the yardstick against which other paper particular emphasis will be placed on the analgesic agents are judged. It has been known since treatment of pain in the early phase following acute the work of Drew et al. (1946) that the effects of myocardial infarction or following cardiac surgery therapeutic doses are relatively unimportant in the with cardiopulmonary bypass. supine normal subject, but hypotension and fainting There are five strong analgesic agents commonly in are often seen with 750 head-up tilting or standing use in the United Kingdom - morphine, diamor- following intramuscular or intravenous injections of phine, papaveretum, pethidine and pentazocine. We the drug. These effects are attributed largely to shall deal first with these and conclude by mentioning peripheral vasodilatation and are exacerbated in the some of our own work on buprenorphine which we presence of hypovolaemia. They are also exacerbated believe to be a promising new alternative to if phenothiazine drugs are administered concurrently morphine. (Jaffe & Martin, 1975). The are It has been traditional to focus attention on those histamine liberators, eliciting the triple response aspects of cardiocirculatory status most readily when injected in human skin, but this is probably not measured. Heart rate and arterial systolic, diastolic the sole mechanism of vasodilatation for there is also and mean BPs can readily be monitored in patients at evidence of a depressor effect on the vasomotor the bedside or in the operating theatre, and such centre (Reynolds & Randall, 1975). Rapid injection, observations therefore form the bulk of available large doses and hypoxaemia accentuate the data on effects in clinical use. However, in recent hypotensive effect, which may then become manifest years interest has increased in the interrelationship even in the supine subject (Lowenstein et al., 1969; between arterial BP, blood flow and the effective Wood-Smith et al., 1973). When hypotension does hydraulic resistance or 'impedance' of the circulation occur, it can be reversed by postural adjustments, (Greenfield, 1975; Milnar, 1975). Furthermore, blood volume expansion or vasoactive agents measurement of left ventricular myocardial (Lowenstein et al., 1969; Wood-Smith et al., 1973). performance is a desirable element in the Larger doses of morphine slow the heart, chiefly by a comprehensive evaluation of the circulatory effects central effect with some direct stimulation of the of drugs but it is difficult to achieve in clinical vagal nucleus (Reynolds & Randall, 1957). 0306-5251/79/150309-05 $01.00 ©Macmillan Journals Ltd. 1979 310S D. JOHN COLTART & ALASDAIR D. MALCOLM

In patients with acute myocardial infarction, indirect and the result of sympathoadrenal discharge. Thomas et al. (1965) have given intravenous morphine Pending definitive corroboration of this mechanism 3-10 mg with variable effects on heart rate and BP in man, caution should be exercised in administering changes ranging from a small fall in pulse pressure morphine to P-blocked patients with cardiac to a large fall in mean arterial BP. The hypotensive dysfunction or to those with adrenal insufficiency. effect occurred soon after the intravenous injection, Morphine is a traditional therapeutic agent in left and in one patient dramatic restoration of the arterial ventricular failure and its mechanism of effect in this BP was effected by raising the legs. In some patients setting has been studied by Vasko et al. (1966b). whose BP fell, cardiac output increased due to an Acute pulmonary oedema was provoked in dogs by increase in heart rate with or without an increase in producing mitral stenosis, aortic regurgitation, stroke volume. Systemic vascular resistance remained myocardial infarction or acute volume loading with unchanged in some patients and fell in others. The saline given to animals with a previously constructed studies of Alderman et al. (1972) in patients with aortic coarctation. Morphine 0.5 mg/kg resulted in arteriographically proven coronary artery disease the subsidence of pulmonary oedema in all animals, showed no consistent change in individual aortic and improvement was concomitant with striking and BPs; the group mean value for aortic mean BP was parallel decreases in pulmonary artery BP and flow slightly, though not significantly, diminished. and in left atrial and ventricular end-diastolic BPs. It Pulmonary artery mean BP did not change. Whole seems that the principal mechanism of morphine's body oxygen consumption, cardiac index and left beneficial effect in pulmonary oedema is by ventricular end-diastolic BP all fell significantly after increasing the capacity of the peripheral vascular bed morphine 8 mg intravenously. and so producing a 'pharmacologic phlebotomy' Morrison et al. (1972) have studied patients 1 h (Vasko et al., 1966b). after open heart surgery and measured heart rate, arterial and right atrial BPs, cardiac index and systemic vascular resistance. Morphine given intravenously in doses of 2.5-10.0 mg/70 kg body Diamorphine weight caused no change in group mean values for any of the quantities. However, in individual The evidence of studies in various animal species patients, both elevation and reduction in cardiac suggests that the circulatory effects of diamorphine index were seen, unrelated to dose and with are similar to those of morphine (Reynolds & unpredictable alterations in arterial BP. This Randall, 1957). MacDonald et al. (1967) have studied variability is probably due to the different degrees of the effects of diamorphone 5 mg intravenously in hypovolaemia, anaemia, hypoxaemia, catecholamine eight patients with acute myocardial infarction. Six drive, electrolyte disturbance and myocardial patients were studied supine, and aortic mean BP, dysfunction after cardiopulmonary bypass. In seven cardiac output, heart rate, stroke volume, systemic patients with aortic valve disease about to undergo vascular resistance, pulmonary arterial BP and right aortic valve replacement (Lowenstein et al., 1969) atrial BP were measured. The only consistent and enormous doses of morphine 0.5-1.0 mg/kg given significant finding was a small fall in aortic mean BP intravenously resulted in significant increases in in the first 10 min after injection. In two additional cardiac index, stroke index, central venous and patients diamorphine 5 mg was administered pulmonary artery BPs and a significant decrease in intravenously with the patient tilted head-up at an systemic vascular resistance. These changes were not angle of 100, and there were no striking changes in seen in control subjects without cardiac disease or any of the haemodynamic measurements in either those subjects who received 1.0 mg/kg. The data of patient, one of whom was markedly hypotensive. Lowenstein et al. (1969) in patients with chronically When the results of this study are compared with pressure- or volume-stressed hearts showed no those of Thomas et al. (1965), using morphine 3-10 evidence of cardiac depression with these high doses mg intravenously in the same clinical setting, it seems of morphine. Experiments by Vasko et al. (1966a) on that diamorphine is superior for it provides adequate anaesthetized, open-chested dogs maintained on right analgesia and sedation without unpleasant or heart bypass with crushed sinoatrial nodes and fixed- harmful side-effects and with less haemodynamic rate right atrial pacing showed improved left perturbation than with morphine. ventricular function curves, improved myocardial contractile force and augmented left ventricular dp/dt with morphine I mg/kg. However, when the Papaveretum dog experiments were extended to examine the effects of bilateral adrenalectomy or Papaveretum is a preparation of the water-soluble pharmacological (i-adrenoceptor blockade it seemed alkaloids of opium, standardized to contain 50% that the cardiostimulatory effects of morphine were anhydrous morphine. The remainder consists of USE IN CARDIOLOGY 311S

hydrochlorides of other alkaloids including levels were unchanged and noradrenaline levels fell , , narcotine and (Wood- slightly. Smith et al., 1973). Analgesic effects are principally In additional experiments the effects of the same due to the morphine content, although there are dose of intravenous pethidine on arterial BP and additional beneficial effects from the other alkaloids heart rate response to exogenous catecholamines for papaverine reduces the tendency of morphine to were assessed and it was found the pressor responses cause nausea and vomiting. Depression of respiration to adrenaline and to noradrenaline were slightly by morphine is less when papaverine is present, and augmented. narcotine potentiates the analgesic action of morphine. In the absence of information on haemodynamic effects with papaveretum, it can only be assumed that the effects of the morphine Pentazocine component predominate and in situations of compromised cardiovascular function the same A dose of pentazocine 20-30 mg has an analgesic precautions should be taken as with morphine. effect approximately equivalent to morphine 10 mg (Wood-Smith et al., 1973). Pentazocine given intravenously in the rather high dose of 1.2 mg/kg to patients without heart disease causes an increase in Pethidine circulating adrenaline and noradrenaline levels which is paralleled by an increase in both BP and heart rate Pethidine is structurally similar to atropine but there (Tammisto et al., 1971). There was slight is no consistent effect on heart rate and its vagolytic augmentation of the pressor response to exogenous effect is inconsequential (Reynolds & Randall, 1957; catecholamines, but less than with pethidine. Reports Wood-Smith et al., 1973). It has a quinidine-like (Lal et al., 1969; Scott & Orr, 1969; Jewitt et al., effect, reducing cardiac irritability (Wood-Smith et 1970) have shown that smaller doses of pentazocine al., 1973). BP is rarely affected by normal doses, but augment arterial pressure in more than 80% of with intravenous injection an abrupt, brief fall in BP subjects, and pulmonary arterial BP is also may be observed (Reynolds & Randall, 1957; Wood- augmented in the majority of such patients (Scott & Smith et al., 1973). Orr, 1969; Jewitt et al., 1970). Fifteen patients Rees et al. (1967) gave pethidine 100 mg intra- studied by Jewitt et al. (1970) just after acute venously to eight patients with acute myocardial myocardial infarction were given pentazocine 30 or infarction and noted a biphasic response with an 60 mg intravenously; and with only one exception initial slight increase in arterial mean BP, systemic (given 60 mg) the pulmonary arterial mean BP vascular resistance and heart rate, and then from 10- increased after 10 minutes. Aortic BP increased, but 15 min a decline in these variables to below control remained elevated only with the 60 mg dose: levels. Half of these patients experienced distressing Systemic vascular resistance increased after the dizziness and nausea. Rees et al. (1967) have 60 mg dose. Left ventricular minute work increased concluded that 'because of its circulatory effects, in all patients, but this was significant only at 20 min pethidine does not seem to be the ideal drug for the after 60 mg. relief of pain of myocardial infarction'. An initial Alderman et al. (1972) have studied the effects of increase in mean aortic BP after pethidine has also pentazocine 48 mg intravenously in nine patients been reported in healthy individuals by Prescott et al. with proven coronary disease and have found that (1949) and in obstetric patients by Gallen & Prescott aortic mean BP is augmented by 13%, left (1944). ventricular end-diastolic BP by 20%, pulmonary Pethidine is effective in the treatment of arterial mean BP by 36%; cardiac work is increased pulmonary oedema. Nadasdi & Zsoter (1969) gave by 22% with pulmonary vascular resistance by 79% pethidine 1 mg/kg intravenously to 46 volunteers, six and systemic vascular resistance by 11%I with of whom had cardiac failure, and found that pentazocine in contrast to an 8% decrease in similar pethidine significantly increased blood flow in the patients who were given a morphine 8 mg intra- forearm and leg with a concomitant fall in arterial venously. Because an increase in cardiac work and and venous resistance. This is evidence that pethidine left ventricular afterload is generally held to be acts, like morphine, by promoting peripheral pooling undesirable in the period immediately following of blood. acute myocardial infarction, morphine seems to be a Tammisto et al. (1971) have given pethidine 2 mg/ superior analgesic for most patients in this situation. kg intravenously to 10 patients with heart disease and However, where pre-existing hypotension have found a brief increase in systolic BP and then a complicates the situation and where there is reason to fall to below control levels beyond 30 minutes. Heart suspect that compensatory sympathetic activity is rate showed a sustained elevation. Plasma adrenaline already maximal, pentazocine might be a preferable 312S D. JOHN COLTART & ALASDAIR D. MALCOLM alternative, as has been argued by Alderman et al. analgesic agent for, as has been shown with (1972). morphine in the situation of acute myocardial infarction, it is in the patients with depressed cardiac reserve that undesirable haemodynamic effects may Buprenorphine be apparent even when no such effects have been seen in other studies on patients with normal hearts. Studies in volunteers (Orwin et al., 1976; Orwin, The cardiovascular effects of buprenorphine were 1977) have indicated that in general the cardio- studied in patients following valve replacement or circulatory effects of intramuscular buprenorphine coronary artery surgery. Five males and five females are directionally similar with those of morphine. aged 37-66 yr were given buprenorphine 5 Mg/kg in Buprenorphine does not seem to cause histamine the first 24 h post-operatively. All were ventilated release. Malcolm & Coltart (1977) and Rosenfeldt et artificially and were haemodynamically stable. The al. (1978) have reported no marked changes in following parameters were monitored: cardiac cardiovascular parameters other than a slight output using an extractable aortic electromagnetic reduction in heart rate following buprenorphine 5 or flow probe, arterial BP, right and left atrial BPs and 6 Mg/kg intravenously) in patients after open heart ECG. Data were recorded on magnetic tape and surgery. Studies by Devaux et al. (1976) using analyzed using an off-line digital computer. There buprenorphine as a per-operative analgesic have was no significant change in any of 21 shown a dose-dependent response in certain cardio- haemodynamic parameters computed in the first 15 circulatory measurements. At doses of 1.5 and min following administration of buprenorphine. 2.0,g/kg no statistically significant effects were Seven patients were studied for 60 min during which identified but at 3.0 and 4.0 pg/kg there were time heart rate declined from a control value of reductions in heart rate, cardiac output, arterial 105±5 to 99±6 beats/min (P <0.005). No other systolic and diastolic BPs, left ventricular work, and significant change was observed. Analgesic efficacy oxygen consumption. There was no alteration in was judged to be comparable to papaveretum given systemic vascular resistance. Rather different effects to the same patients at a dose of 70-150 Ag/kg. If were reported by De Castro & Parmentier (1976) further studies confirm its minimal activity on the when buprenorphine 0.8 mg was given intravenously cardiovascular system, buprenorphine may prove to at the end of analgesic anaesthesia. Some degree of be the drug of choice for strong pain relief in patients cardiovascular stimulation was noted with increases with unstable circulation. in heart rate, arterial BP, central venous BP and right ventricular BP. These effects were always transient. At St Thomas' Hospital we are now able to make We thank Mr B.T. Williams, consultant cardiothoracic detailed measurements of cardiocirculatory status in surgeon, and the staff of the Intensive Care Unit, St human subjects soon after open-heart surgery. Thomas' Hospital, for making it possible to carry out Cardiopulmonary bypass during such procedures is postoperative patient studies. Buprenorphine data were collected by Drs B. Houston and F. Rosenfeldt. Financial associated with myocardial damage (Archie & support was provided by Messrs Reckitt and Colman, Kirklin, 1973) and thus patients studied under these Pharmaceutical Division, and by the Ernest Kleinwort circumstances would be expected to have impaired Charitable Trust and the Cyril Kleinwort Charitable myocardial performance. We feel that this is a Settlement. The secretarial services of Fiona Baile are particularly useful situation in which to study a new gratefully acknowledged.

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