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Histamine-releasing and allergenic properties of opioid analgesic drugs: resolving the two.

TERMINOLOGY AND SCOPE OF REVIEW

The term 'opiate' was originally used to designate drugs derived from the opium poppy plant Papaver somniferum, such as the analgesics morphine and codeine, and semisynthetic derivatives prepared from morphine, for example, heroin. The word 'opioid' was introduced as a generic term for both natural and synthetic drugs with morphine-like actions (1) and it remains conventional to refer to an agent as opioid when it binds specifically to an opium receptor(s). Nalorphine (N-allylnormorphine), synthesised in the early 1940s, showed some analgesic activity but, more interestingly, it antagonised many of the actions of morphine. It became apparent that agonists such as morphine, antagonists such as naloxone and mixed agonist-antagonists such as nalorphine must act on multiple receptors and this was confirmed in the early 1970s with (3) H-labeled levorphanol (2), naloxone (3), etorphine (4) and dihydromorphine (5) that bound specifically to sites in the central nervous system. Identification of endogenous peptide ligands (6,7) that bind to their complementary receptors followed and they were termed, respectively, opioid peptides and opioid receptors. There are two main branches of opioid receptors. Receptors mu ([mu]), kappa ([kappa]) and delta ([delta]), where naloxone acts as an antagonist, form the major branch. The other branch comprising the nociceptin and ORL (1) receptors are not recognised by naloxone (7). Opioid drugs may or may not have actions similar to those produced by the prototypic opiate morphine and may recognise a different pattern of receptors. The terms 'opiate' and 'narcotic' are still often used but with recognition and increased knowledge of opioid peptides, opioid antagonists and association of narcotic with 'drug dependence', the terms are no longer useful in a pharmacological context (1).

Opioid analgesics are amongst the most commonly administered drugs in hospitals (8) and although they are generally well tolerated, they can produce serious side-effects (9). Many are histamine releasers; an effect that may sometimes lead to non-immune-mediated anaphylactic-like (anaphylactoid) (10) symptoms and this property is therefore reviewed here together with opioid-induced true anaphylactic (Type 1) immediate hypersensitivity reactions (11) mediated by specific immunoglobulin E (IgE) antibodies. Antibody-dependent Type 2 cytotoxic reactions, Type 3 reactions due to immune complexes, and Type 4 delayed-type cell-mediated responses (11) (collectively including maculopapular rash, erythema multi-forme (12), pustular rashes, pruritis, eczema (13,14) and so-called pseudoallergies (15)) have not been covered since they fall outside the definition of true, Type 1 allergic responses.

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STRUCTURES AND CLASSIFICATION OF OPIOID ANALGESIC DRUGS

In addition to their analgesic properties (1,16,17), opioid drugs can be classified on the basis of their origin; that is, whether naturally occurring or synthesised, their chemical structure, selectivity for opioid receptors and histamine-releasing properties. In reacting with their complementary receptor(s), opioids show a range of agonist and antagonist effects (16,17). For example, morphine and fentanyl are strong agonists, pethidine (meperidine) is a weak agonist, buprenorphine is a partial agonist, naloxone is an antagonist and pentazocine is a mixed agonist and antagonist. Most opioid drugs used clinically are agonists at the [mu] receptor. Table 1 and Figure 1 show the structures of some clinically important naturally occurring, semi-synthetic and synthetic opioid drugs. Although structural similarities between morphine and the synthetics might not be immediately obvious, a structural sequence corresponding to a 4-phenylpiperidine substituent is common to pethidine and morphine while fentanyl, alfentanil, remifentanil and sufentanil have a 4-anilidopiperidine instead of the phenylpiperidine structure (Figure 1). The structure of methadone, unlike morphine, pethidine and fentanyl, lacks a piperidine ring, but like each of these compounds, it retains a phenylpropylamine structure (Figure 1) and some morphine-like conformers of l-methadone (the active isomer) have been proposed. In one suggested conformer (18,19), the enol tautomer of l-methadone forms an intramolecular hydrogen bond with the nitrogen producing a seven-membered ring (Figure 2.2a-d). The seven-membered ring has characteristics of a six-membered ring containing nitrogen, thus this 'virtual' heterocyclic ring of methadone is seen as the counterpart of the piperidine ring of morphine. The morphine pharmacophore of a tertiary alkylamine at least four atoms away from an aromatic ring and common to methadone, pethidine and fentanyl, is readily seen in the selected conformations of these drugs shown in Figure 2.

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Tramadol (Figure 3), which shows some structural resemblances to codeine and morphine and has low affinity for the [mu] receptor, exists as four stereo-isomers, but the drug administered is a racemic mixture of two enantiomers (1R,2R) or (+)-tramadol and (1S,2S) (-)-tramadol. Like methadone it can be viewed as a phenylpropylamine structure (Figure 1). In addition to opioid receptor recognition, tramadol shows monoaminergic activity; (+)-tramadol is more potent both as a [mu] receptor agonist and in inhibiting serotonin (5-hydroxytryptamine) reuptake than (-)-tramadol, which mainly inhibits nor-adrenaline (norepinephrine) reuptake. These effects lead to inhibitory effects on pain transmission in the spinal cord. Like codeine, tramadol is a prodrug. Its main metabolite, O-desmethyltramadol formed by demethylation of the methoxyphenyl group, is a more potent [mu] receptor agonist than the parent drug and it is also a noradrenaline reuptake inhibitor (20,21).

An additional way of classifying opioids analgesic drugs is on the basis of their histamine releasing capacities. Since the histamine liberating potencies of some of the opioid analgesics differ and the physiological responses to the liberated histamine are variable and depend on a number of different influences, comparisons and studies of histamine release by the different opioid analgesics will therefore be examined below, separately and in detail.

HISTAMINE RECEPTORS

Histamine has a number of biological effects suggesting mediation through different receptors. Application of specific agonists and antagonists revealed three G protein-coupled histamine receptors [H.sub.1], [H.sub.2] and [H.sub.3]. Each receptor mediates distinct effects, for example, contraction of smooth muscle and some allergic effects proceed via [H.sub.1] control, [H.sub.2] receptors regulate gastric acid secretion and [H.sub.3] receptors trigger the release of histamine and neurotransmitters by neurons (22). Postulation and subsequent demonstration of the existence of a fourth histamine receptor [H.sub.4] (23-26) followed the realisation that not all of the effects of histamine could be attributed to the three known receptors. While [H.sub.1] and [H.sub.2] receptors are widely distributed in the cells of the body, the expression of [H.sub.3] receptors is mainly restricted to the central nervous system and expression of [H.sub.4] receptors appears to be confined to haemopoietic cells.

There are three main sources of histamine in humans--mast cells and basophils, enterochromaffin-like cells of the gut and histaminergic nerves in the brain. Although the histamine content and histamine-releasing property of mast cells have long been of considerable interest, little is known about the effect of histamine on this cell. It appeared that the expression of histamine receptors had not been convincingly demonstrated on human mast cells (27) and the effects exerted on cells by many antihistamines did not proceed via [H.sub.1] receptors (28), but in a study using mice, Hofstra et al (29) showed for the first time that mast cells express the [H.sub.4] but not the [H.sub.3] receptor, and histamine does not seem to have any effect on degranulation of mast cells either alone or in combination with IgE-antigen complexes. Lippert et al (30) presented evidence for the expression of [H.sub.2] and [H.sub.4] receptors on human skin and leukaemic mast cells, and the demonstration that histamine mediates signaling and chemotaxis in mouse mast cells via the [H.sub.4] (29) receptor suggests a possible immunomodulatory effect of histamine on the allergic response. This has led to the speculation that "new agents targeted at the [H.sub.4] receptor will soon be developed, providing novel therapeutic regimens for the modulation of allergic diseases" (30). Other findings pointing to a possible immunomodulatory effect of histamine are the demonstrations of the expression of functional H receptors in human T- and dendritic cells (31,32).

OPIOID ANALGESIC DRUGS AND HISTAMINE RELEASE

Many opioids are potent releasers of histamine, a property thought to be responsible for reactions that occur more frequently than true Type 1 immediate hypersensitivity reactions to these drugs. It is one hundred years since Dale et al isolated and began studies on histamine including its physiological actions. They found it stimulated smooth muscle from the gut and respiratory tract, was a powerful "vasodepressant" and caused shock when injected into experimental animals (33-36). In 1913 Eppinger (37) was the first to show the involvement of histamine in vascular reactions of the skin and in 1917 Sollmann and Pilcher (38) reported that morphine caused the triple response in human skin; that is, an initial red spot followed by a red irregular flare and then a fluid-filled wheal. However, the authors rejected the possibility that opium alkaloids release histamine. Later, in studies on vascular reactions in the skin, Lewis elicited the triple response following prick testing with morphine solution and concluded that morphine stimulates the release of a histamine-like substance, or so-called, H-substance (39,40), which Dale argued was histamine itself (41).

Since these early studies implicating morphine in histamine release, many investigations of the histamine releasing and cardiovascular effects of morphine and other opioids have been undertaken on live laboratory animals and their cardiovascular tissues (see extensive list of references in Grundy (42)). Evidence of the release of histamine by alkaloids of opium was provided by Nasmyth and Stewart (43), who showed that wheals caused by morphine in human skin were reduced by antihistamines and Feldberg and Paton (44,45) who detected several micrograms of histamine in the effluent after injection of opium alkaloids into the artery of isolated perfused cat gastrocnemius muscle. They also showed that histamine was released from cat skin and raised levels were found in plasma after intravenous injection of morphine and other opium alkaloids. In summarising in 1971 some of the main findings of animal studies accumulated over more than 40 years, Grundy (42) concluded that when morphine or pethidine was given intravenously to anesthetised laboratory animals, the predominant effect recorded was hypotension, sometimes with a transient ressor effect due to the release of catecholamines (46).

The significance of histamine release in humans and its importance in a number of clinical conditions (47) stems from its action in increasing cardiac output as a result of increased heart rate and force of myocardial contraction, and its dilatator effect on small blood vessels which leads to flushing, decreased vascular resistance and hypotension (48). Morphine-induced histamine release can have clinical relevance and, in examining our current view of the effects in humans of histamine release by opioid drugs, it is somewhat surprising to review the many relevant studies in laboratory animals and man beginning with the findings of Dale and Laidlaw (34-36) and note the protracted delay in applying the many insights obtained from this early work to the modern continuing study and understanding of the actions of opioid drugs in anaesthesia and pain management. Over 50 years ago, Birt et al, in studies on urticaria pigmentosa, were able to link opioids with flushing of the skin and histamine liberation (49,50). In relation to the cardiovascular system, morphine has little effect on blood pressure or heart rate in the doses normally used for analgesia and anaesthesia, but at higher doses histamine released by morphine may sometimes play a role in arteriolar and venous dilatation, decreased peripheral resistance and, in some situations, hypotension (51). Results have often been conflicting and, until about the early 1970s, information on peripheral vascular effects of morphine had mostly been obtained from studies on laboratory animals. In dogs, for example, morphine at a dose of 1 mg/ kg produced a marked reduction of total systemic resistance (52). Later studies in healthy human subjects revealed that dosages of up to 2 mg/kg of morphine produced significant decreases in peripheral (53) and total systemic (54) vascular resistance.

Infusion of histamine was used to examine the relationship between plasma histamine levels in humans and symptoms (55). From resting levels of 0.62 ng/ml the following correlations between elevated serum concentrations and symptoms were obtained: 1.61 ng/ml produced a 30% increase in heart rate; 2.39 ng/ml, significant flush and headache; 2.45 ng/ml, 30% increase in pulse pressure. A minimal invasive procedure to measure histamine levels in venous blood draining the site of intradermal challenges with histamine, morphine and antigen was utilised to monitor cutaneous mast cell degranulation in vivo in man (56). After injection of morphine sulphate, peak plasma histamine levels, reached after one to eight minutes, ranged from 2.3 to 12.7 ng/ml and returned to baseline of 0.6 ng/ml within 30 minutes. The corresponding figures for histamine were two to 10 minutes, 1.4 to 85.2 ng/ml and 30 minutes and for antigen, five to 15 minutes, 1.1 to 24.4 ng/ml and more than 60 minutes. For all three challenges, histamine levels peaked at five to 10 minutes before maximum development of the wheal and flare reactions.

Examinations of central haemodynamic and forearm vascular effects of doses of up to 10 mg/ 70 kg of morphine (that is, subanaesthetic doses) in patients recovering from trauma or after open heart surgery showed significant increases in blood flow, a corresponding decrease in vascular resistance and a sustained decrease in cardiac output (57,58). Early indirect evidence that the vasodilator effect of morphine in man is due to its histamine releasing property (38-40,49,50) was taken a step closer to, but still short of, direct proof provided by measurements, when antihistamines were shown to reduce peripheral vascular resistance by only 25% in patients given 0.5 or 1 mg/kg morphine compared to a reduction of 46% in patients who were not pretreated with the antihistamine (59). This result is inconsistent with the finding of Zelis et al (60) who sought to evaluate whether histamine release or activation of sympathetic responses could account for morphine-induced vasodilation in the human forearm. Intra-arterial promethazine did not block the forearm arteriolar dilator response of intravenous morphine, but the alpha-adrenergic antagonist phentolamine did. Promethazine is an [H.sub.1] histamine receptor blocker, but the vascular effects of histamine are expressed via its interaction with both [H.sub.1] and [H.sub.2] receptors, a fact recognised by Philbin et al (61) who examined plasma histamine levels and cardiovascular effects in patients given morphine 1 mg/kg without or with an [H.sub.1] (diphenhydramine) and [H.sub.2] (cimetidine) antagonist either alone or in combination. In the absence of the receptor blockers, histamine levels were markedly elevated, systemic vascular resistance and diastolic blood pressure both decreased and cardiac index increased. Administration of diphenhydramine or cimetidine alone provided minimal protection from these effects, but administration of both antagonists together caused a significant attenuation of the reduction in systemic vascular resistance. The authors concluded that "the haemodynamic effects of morphine can be attributed to histamine release", histamine antagonists can provide "significant haemodynamic protection" and dosage with [H.sub.1] and [H.sub.2] antagonists together are superior to either given alone. In questioning these conclusions, Hirshman et al (62) drew attention to the increases in heart rate and blood pressure in the patients receiving the [H.sub.1] and [H.sub.2] blockers, pointed out that morphine itself has direct effects on the vasculature and that individual responses to histamine can vary widely. These criticisms of the Philbin et al (61) study were summarised as follows: "... the relationship between magnitude of histamine release and magnitude of cardiovascular effects appears unpredictable. Furthermore, although changes in histamine level following morphine have shown some correlation (r=0.81) with decreases in systemic vascular resistance, this in no way implies causation".

In addition to comparing plasma histamine changes with changes in haemodynamic function, Fahmy (63) measured plasma adrenaline (epinephrine) and noradrenaline (norepinephrine) levels in a patient who had an anaphylactoid reaction to intravenous morphine 0.3 mg/kg. A 30-fold increase in the plasma histamine concentration was accompanied by decreased systemic vascular resistance and arterial blood pressure, an increase in heart rate and stroke volume and augmented cardiac output. The plasma catecholamines were also increased. In an extension of this study design, Fahmy et al (64) examined the role of histamine in the haemodynamic and plasma catecholamine responses to intravenous morphine in adult subjects with no history of drug allergy or clinical evidence of cardiovascular, pulmonary or metabolic disease. Findings indicated that morphine increased histamine and adrenaline concentrations and cardiac output, and decreased arterial blood pressure and systemic vascular resistance leading to the conclusion that histamine release has an important role in the haemodynamic effects induced by morphine.

Not all opioids are equivalent in their capacity to release histamine as shown in a number of human studies. In one of the first (65), patients prior to coronary artery bypass surgery were infused over a 10 minute period with morphine (1 mg/kg) or high dose fentanyl (50 [micro]g/kg) and plasma histamine levels, arterial pressure, cardiac output and heart rate were monitored. Patients in the morphine group showed a 750% increase in plasma histamine, a significant decrease in mean arterial pressure and systemic vascular resistance, and the biggest decreases in vascular resistance occurred in the patients with the highest histamine levels. No change in plasma histamine and no decrease in arterial pressure or systemic vascular resistance were seen in the fentanyl group, and with cardiac output and heart rate being comparable between the groups, the authors concluded that differences in the release of histamine accounted for most, if not all, of the different effects of the two drugs on the peripheral vasculature. It was also suggested that the amount of histamine released may be due to the concentration of drug acting on the mast cell membrane and since the concentration is low with potent drugs such as fentanyl, histamine release may also be low.

In a comparison of histamine release by morphine, fentanyl and oxymorphone from human skin mast cells (66), release was first detected with morphine at 1.5x[10.sup.-4] M, but the other two opioids were negative even at a concentration of 5x[10.sup.-4] M. At the same higher concentration, naloxone did not release histamine and did not inhibit morphine-induced histamine release, suggesting that release of histamine by morphine is not dependent on recognition and mediation of opioid receptors. Marone's group (67,68) also found that morphine, but not fentanyl, induced histamine release from human skin mast cells. In a study (69) similar to the earlier in vitro investigations of Hermens et al (66), solutions of fentanyl, sulfentanil and pethidine as well as morphine, but not alfentanil, nalbuphine and naloxone (all at 5x[10.sup.-4] M), were shown to produce wheal and flare responses after intradermal injection in human volunteers and naloxone attenuated both the wheal and flare to fentanyl and the flare to morphine.

Electron micrographs of biopsies of fentanyl-induced wheals revealed no mast cell degranulation and the authors stated that opioid-induced vascular responses are mediated by both histamine release from skin mast cells and direct effects on the vasculature (69) (see below for further discussion). Cutaneous mast cells were also suggested as the source of opioid-induced plasma histamine in an examination of histamine releasing effects of intravenously administered morphine (0.15 mg/kg) and nalbuphine (0.3 mg/kg). Six of 15 and five of 14 normal subjects receiving morphine and nalbuphine respectively responded with plasma histamine levels greater than 2 ng/ml, but these levels were not associated with haemodynamic changes (70). Significant histamine release with no associated changes in haemodynamic parameters was seen following the administration of morphine (0.16 mg/kg) or diamorphine (0.08 mg/kg) to patients after abdominal surgery. No histamine was released in basophil studies, suggesting that mast cells were the source of the mediator (71). In a comparison of histamine release and haemodynamic changes induced by four opioids used in anaesthesia, and administered in the study over a period of 10 minutes or less, five of 16 patients given pethidine (4.3 mg/kg) developed hypotension, tachycardia, erythema and elevated plasma histamine and adrenaline levels. Only one of 10 patients given morphine (0.6 mg/kg) developed hypotension, tachycardia and an increase in plasma histamine while none of 34 patients given either fentanyl (7 [micro]g/kg) or sufentanil (1.3 [micro]g/kg) responded with increases in histamine levels or clinical signs of histamine release (72).

The apparent consensus on the histamine liberating action of morphine was challenged by Warner et al (73) who essentially repeated the original study by Rosow et al (65) with morphine 1 mg/kg. No significant changes in plasma histamine levels were detected, perhaps, as the authors suggest, because the double isotopic radio-enzymatic assay they used to measure histamine might be superior to the older, less reproducible assay used in the earlier study. Using high performance liquid chromatography with a cation exchange column, post column derivatisation and fluorescence detection to measure histamine, Mildh et al (74) also detected no significant elevation in plasma after intravenous injection over two minutes of low doses (0.07 or 0.14 mg/kg) of morphine into eight healthy adults, although signs of local histamine release, including redness and itching were seen at the injection sites. Plasma catecholamine levels were also unaffected. Bearing in mind that plasma histamine levels required to elicit symptoms range from 1.6 ng/ml (significant increase in heart rate, flush and headache) to 2.4 ng/ml (increase in pulse pressure) (55), levels in this study were well below 0.4 ng/ml after morphine and oxycodone administration. Other studies also concluded that histamine release by oxycodone is minimal (75,76). Despite initial and transient increases in mean arterial pressure and heart rate after morphine, no overall increases were seen, leading to the conclusion that the "the immediate effect of morphine on the haemodynamics of healthy volunteers was stimulation not hypotension" (74).

Intradermal microdialysis, a technique that permits the measurement of drugs and some other agents in the dermis after application of drugs to the skin (77), was used to examine the stimulatory effect on mast cells of the opioids codeine, pethidine, fentanyl, alfentanil, sufentanil, remifentanil, buprenorphine and the opioid antagonist naloxone. Only codeine and pethidine stimulated the release of histamine and tryptase leading to protein extravasation, flare reactions and itching, and because naloxone failed to prevent or lessen these effects, histamine release was judged to be a non-specific rather than a [mu] receptor-mediated effect (78), a conclusion reached nearly 20 years ago by Hermens et al (66). Following a review of the histamine-releasing properties of opioid drugs, Barke and Hough (79) concluded that there was no evidence that opioid receptors account for opioid-induced histamine release.

In considering strategies for the attenuation of adverse reactions resulting from opioid-induced haemodynamically significant histamine release, Moss and Rosow (80) noted that the same quantity of drug administered over a one-minute period has a significantly less haemodynamic effect than when administered as a bolus and this conclusion is now well accepted (81). An example of the large single-dose effect and variability of patient responses was seen with methadone, which although claimed not to induce histamine release in humans, produced substantial increases in plasma histamine concentrations in two of 23 patients when given as a large push bolus although no haemodynamic instability was detected (82).

Morphine is a vasodilator in human veins (83), but its direct effect on the peripheral arterial vasculature has not been well understood. A recent mechanistic study on forearm blood flow in man (84) showed that intra-arterial infusion of morphine caused a dose-dependent vasodilatation mediated by a combination of two known vasodilators, histamine and nitric oxide. The authors concluded that since morphine is a vasodilator in both arteries and veins at clinically acceptable doses, locally vasoactive opioid drugs might be "a potential new investigative tool for the treatment of cardiovascular disease".

Apart from morphine, the histamine liberating properties of only two opioid analgesics, pethidine and fentanyl, have received much investigative attention. Pethidine is a potent releaser of histamine, producing wheal, flare and itch reactions in the skin (69,78) and hypotension, tachycardia, erythema and adrenaline release following intravenous injection (72). Most studies on fentanyl have demonstrated little or no release of histamine from mast cells in vitro (66-68) and no release with associated clinical signs when given intravenously (65,72,73,85). In their studies on histamine release by fentanyl and nalbuphine, Dick et al (86) saw histamine release in only one of 11 subjects, but no direct correlation between histamine release, haemodynamic changes and skin reactions. Histamine liberated from skin mast cells increases capillary permeability (wheal) and causes cutaneous vasodilation (flare) (87). In skin tests, Levy et al (69) found that there were no significant differences in both wheal and flare responses produced by morphine or pethidine compared to histamine controls, and that fentanyl-induced wheal and flare reactions were significant only at a concentration of 5x[10.sup.-4] M or greater. The failure of fentanyl to degranulate mast cells and antagonism of the fentanyl wheal and flare responses by naloxone led Levy et al (69) to suggest that the fentanyl-induced skin reactions are the result of direct opioid-mediated capillary vasodilation, unlike morphine's effect, which involves both histamine release and a direct opioid effect and therefore, "attempts to antagonize the adverse haemodynamic effects of histamine-releasing opioids with antihistamines will not be completely effective due to direct vascular responses".

In addition to morphine, pethidine and fentanyl, the histamine-releasing property of codeine is well known (88,89), but of the other clinically important opioid analgesics, only oxymorphone (66,73), oxycodone (74), sufentanil (69,72,78,85), alfentanil (69,78), remifentanil (78), buprenorphine (67,68,78) and methadone (82) have been studied to any extent. The most significant findings so far for this group of opioids have been with sufentanil and buprenorphine. Sufentanil, but not alfentanil, produced an elevation of plasma histamine, clinical signs of histamine release and a wheal and flare skin response, but the general consensus is that "fentanyl, sufentanil, alfentanil and remifentanil do not cause histamine release" (90). Buprenorphine in the range [10.sup.-5] to [10.sup.-4] M and in a concentration-dependent manner induced histamine and tryptase release from lung, but not skin mast cells (67). Bearing in mind morphine's selectivity for skin mast cells (67,68,89,91), and that fentanyl did not liberate histamine from any mast cells (66-68), there thus appear to be functional differences between human basophils and mast cells and between mast cells from different anatomical sites in response to some opioid drugs. Perhaps that is why opioids such as morphine seem to produce histamine-induced cutaneous reactions rather than systemic responses resembling anaphylaxis. Evidence has been accumulating that human heart mast cells may be implicated in anaphylaxis. Mast cells have been identified in all sections of the heart, and anti-IgE or anti-F[??]RI and C5 induce the release of histamine and tryptase. It has been suggested that anaphylactic reactions could be particularly severe in patients with certain cardiovascular diseases (92).

Investigations of possible histamine release by tramadol have been limited but conclusive. Barth et al (93) injected 100 mg of tramadol intravenously (a single dose often administered) into 13 healthy volunteers and looked for histamine release, systemic or cutaneous anaphylactoid reactions and changes in blood pressure, heart rate and electrocardiogram variables. Results showed no change in plasma histamine concentration, no systemic anaphylactoid reactions, itching and erythema in only one subject and only slight and transient elevations in blood pressure and heart rate without abnormalities in electrocardiogram readings.

ALLERGENICITY OF OPIOID ANALGESIC DRUGS

As discussed above, opioids such as morphine, codeine and pethidine provoke non-specific wheals in the skin by causing direct degranulation of mast cells without the involvement of either opioid receptors or opioid-specific IgE antibodies (88,94,95). Human mast cells from different anatomical sites display heterogeneity. For example, a morphine challenge causes degranulation of skin mast cells, but the same stimulus does not induce the release of histamine from human lung, heart or intestinal mast cells (67,68,89,91). This apparent non-specific degranulation and release of histamine by opioids in the skin makes skin testing with these drugs extremely uncertain, and in fact, codeine has been widely used for many years as a positive control for skin prick testing (96). In a study designed to examine the place of skin testing in the diagnosis of opioid allergic sensitivity, Nasser and Ewan (97) prick tested eight opioid-sensitive patients and 100 control subjects, 32 of whom were atopic. On the basis of opioid-induced symptoms of rapid onset, including asthma, rhinitis, urticaria and anaphylaxis, reactions of all eight patients were classified as IgE antibody-mediated. Wheal diameters to four different concentrations of morphine, pethidine and papaveretum were similar in both sensitive and control subjects, clearly demonstrating that skin testing was not of diagnostic value. The authors concluded that placebo-controlled challenge is necessary to accurately diagnose allergic sensitivity to opioid drugs. It should be pointed out here that although the histamine-liberating properties of opioid drugs are often said to preclude their employment in skin testing, the drugs may sometimes be used if diluted beyond their histamine-releasing concentrations. Examples of prick test and intradermal test concentrations are up to a maximum of 3x[10.sup.-3] M and 3x[10.sup.-5]-[10.sup.-7] M respectively for morphine and up to 1.5x[10.sup.-4] M and 1.5x[10.sup.-5] M respectively for fentanyl.

Naturally occurring and semi-synthetic opioid drugs

Despite the heavy and widespread prescribing of opioids, particularly the analgesics morphine, codeine, pethidine and fentanyl, and the use of heroin and methadone by addicts, true immediate, Type 1 IgE antibody-mediated reactions to this large group of drugs are rare (98-100). It is not clear if IgE antibodies mediated the reactions to morphine described in three reports (63,101,102), since appropriate and adequate immunological investigations were not undertaken. Although Fahmy (63) obtained a positive wheal reaction to morphine when the patient was injected intra-dermally

one month after the reaction with a 1:1000 (0.35x[10.sup.-2] M) solution, this is a high skin test concentration for this known cutaneous histamine-releasing drug. No control skin tests were carried out and, on the basis of the patient's lack of previous exposure and non-elevated serum IgE levels, an anaphylactoid reaction caused by liberated histamine seemed likely. In another case, a diagnosis of anaphylaxis during surgery to intravenous morphine sulphate (102) was made on the basis of the time between administration of the drug and the patient's reaction and a positive serum tryptase test. No skin testing or challenge was undertaken. A thorough immunochemical investigation was undertaken on a suspected anaphylactic reaction involving profuse sweating, nausea, chest pains, palpitations, hypotension and loss of consciousness in an adult patient given papaveretum-hyoscine intramuscularly as pre-anaesthetic medication (103). In the late 1980s when the reaction occurred, papaveretum contained 47.5 to 52.5% morphine, 2.5 to 5.0% codeine, 16.0 to 20.0% narcotine (noscapine) and 2.5 to 7.0% papaverine (104). Intradermal tests for papaveretum (20 mg/ml, 1:100,000 dilution) and morphine (0.3x[10.sup.-6] M) were positive while tests for pethidine, fentanyl and hyoscine were negative but again control subjects were not skin tested. Immunoassays for the detection of IgE antibodies to morphine, codeine and hyoscine showed strong positive reactions for the opioid drugs and a weak to equivocal reaction to hyoscine. Competitive binding experiments designed to inhibit the reaction between the patient's serum IgE antibodies and a morphine solid phase showed that morphine and codeine were equally the best-recognised structures. Comparative quantitative inhibition results with selected structurally-related morphine analogues revealed that the most important fine structural features of the morphine allergenic (that is, IgE-binding) determinant comprised the cyclohexenyl ring, a hydroxyl group at C-6 and, most important of all, a methyl substituent attached to the nitrogen atom (Figure 4).

[FIGURE 4 OMITTED]

As with morphine, structurally closely related codeine (3-methylmorphine) has rarely been implicated in true Type 1 allergic reactions. Despite its capacity to release histamine in skin, allergic or pseudoallergic skin reactions to normally used doses have rarely been described but, at higher doses used in anaesthesia, maculopapular and urticarial rashes (105) are seen. Codeine has also been reported to cause recurrent pseudo scarlet fever (106,107) and adverse reactions involving tachycardia, cutaneous vasodilation, severe hypotension and apnoea in children when administered intravenously (108). A case of fever and urticaria following ingestion of a tablet containing codeine was reported by Vidal et al (105). Implication of codeine was established by oral challenge, which caused hot and cold sensations, oral pruritus, generalised urticaria, palpebral and labial oedema and petechiae. What appear to be two immediate hypersensitivity reactions to heroin (diacetylmorphine) have been recorded but, again, the reactions to this opioid are notable for their apparent rarity. The reports were of a patient who experienced allergic asthma and urticaria after exposure to heroin powder (109) and an episode of anaphylaxis to the drug delivered intrathecally and confirmed by positive mast cell tryptase and skin prick tests (110).

Deaths due to no clearly demonstrable cause are common in opioid drug addicts (111) and this has led to speculation that acute anaphylaxis may be involved (112,113). With this in mind, attention was drawn to the binding of morphine to the gamma-globulin fraction of sera from addicts (113,114), the implication being that the non-dialysable drug-protein complex could act as a sensitising allergen. Mast cell tryptase determinations on post-mortem blood from 22 heroin addicts revealed significantly elevated levels of the enzyme but no correlation with total IgE antibody levels (111). No tests were undertaken for morphine- or heroin-specific IgE antibodies. It was concluded that many heroin fatalities might be due to anaphylactoid reactions mediated by the direct action of heroin, liberating mediators such as histamine and tryptase from mast cells. Immuno-histological investigations on post-mortem samples from a total of 71 heroin and other opioid addicts also demonstrated elevated serum tryptase concentrations but failed to produce evidence that deaths were the result of Type 1 IgE-antibody-mediated allergic reactions (115,116). These findings with addicts are consistent with the conclusion of others that tryptase, like histamine, can be released from mast cells non-immunologically (117,118).

Synthetic opioid drugs

The synthetic opioids pethidine, fentanyl and methadone are widely used and while one might expect use to influence the incidence of allergic responses, such reactions are again rare and the frequencies of reactions to these three drugs are different. A single report of 'allergic' reactions describing red skin lesions with associated forearm pain following intravenous administration of methadone provides no supporting evidence that the reactions were Type 1 allergic responses (119). There are a few more reports of hypersensitivity to pethidine and although some cases raise doubts about whether the cases were true immediate hypersensitivities (e.g. Waisbren and Smith (120)), other descriptions seem to be of genuine immediate allergic responses. In an early case report by Butler (121), administration of pethidine 100 mg by intramuscular injection to a woman in labour caused cyanosis, urticarial rash and a dramatic fall in blood pressure. After recovery and following challenge with 50 mg of pethidine, the patient again experienced a fall in blood pressure together with puffiness of the face. This may be the first reported case of true anaphylaxis to pethidine. Levy and Rockoff (122) detected IgE antibodies to pethidine in a child who developed anaphylaxis to the drug and, more recently, an allergic case of pethidine-induced urticaria and angioedema was confirmed by skin testing the patient and control subjects (123). Limited quantitative hapten inhibition studies carried out on a small serum sample from a subject with "suspected narcotic allergy" showed marked IgE antibody reactivity with morphine, pethidine and fentanyl (124). Although the tiny volume of serum available precluded structural identification of the allergenic determinants and details of patient history were minimal, the findings suggested that antibodies to fentanyl and pethidine might be found more often if suitable immunoassay procedures are employed in investigating suspected allergic cases.

Case studies of suspected allergic reactions to fentanyl are more frequent than cases of suspected morphine and pethidine allergies and, at first sight, they appear to be increasing. The first documented case of possible fentanyl anaphylaxis appears to be by Pevny and Danhauser (125), where the diagnosis was supported by a positive intradermal test to the drug. Unlike pethidine, fentanyl does not provoke the release of histamine from skin mast cells (65-68,72,73,78). Fentanyl anaphylaxis was suspected as the cause of the last of three intraoperative reactions experienced by a female adult patient, but no supporting skin test data was obtained (126). Likewise, no, or unconvincing, skin test evidence was advanced to support the claims of an anaphylactic reaction to fentanyl in a patient who had previously had an allergic reaction to pethidine (127) and in a case of propofol- and fentanyl-induced perioperative anaphylaxis (128).

A positive intradermal skin test to fentanyl supported by control tests was seen in a patient who suffered vascular collapse and urticaria approximately 70 minutes after fentanyl administration during general anaesthesia (129). In reporting the 5 mm wheal and flare response to fentanyl citrate 0.5 ng/ml, the authors drew attention to negative skin test findings by Fisher in tests on 30 normal subjects with fentanyl citrate 500 ng/ml. The diagnostic conclusion was a definite anaphylactic reaction to fentanyl with a comment on the delay of the appearance of profound hypotension after the administration of fentanyl. An unusual delay of symptoms was also seen in an 11-year-old boy with anaphylaxis and a positive skin test to fentanyl (130). Interestingly, the patient developed bronchospasm and a positive skin test to methylprednisolone prior to a planned subsequent anaesthetic without fentanyl.

A case of intraoperative anaphylaxis involving sudden onset of hypotension, bronchospasm and pulmonary oedema occurred 20 minutes after the patient was induced with a variety of drugs including fentanyl and rocuronium (131). Subsequent scratch and intradermal tests demonstrated positive responses to fentanyl and succinylcholine but a negative reaction to the neuromuscular blocker used, rocuronium. On the bases that the patient did not receive succinylcholine, that most skin test errors with neuromuscular blocking drugs (NMBD) are false positives (132) and the reaction to succinylcholine "may also have been spurious" since there is claimed to be a 9.3% prevalence of positive skin tests to NMBDs in the general population (133), the authors concluded that fentanyl was the likely cause of the anaphylaxis. Fentanyl, like all but a few N-demethylated naturally occurring and synthetic opioid derivatives, contains a tertiary nitrogen group and therefore may indeed cross-react with antibodies to NMBDs (134,135). Even though the skin test for the NMBD used (rocuronium) proved negative, a finding not unknown in skin testing with these drugs (136), without supporting IgE antibody tests for individual NMBDs the conclusion reached seems premature. Dewachter et al (137) recently reported an anaphylactic reaction to transdermally delivered fentanyl. Generalised erythema and bronchospasm were experienced four hours after the first application of the drug. A prick test to fentanyl was negative, but the intradermal test was positive to both fentanyl and sufentanil. Serum tryptase levels were not measured.

"Allergic" reactions to tramadol, whether anaphylactoid in nature or IgE-antibody-mediated, are generally said to be rare and the drug is considered safe with a low potential for adverse reactions. One report mentioned an incidence of less than 0.1% (21). The only report of likely Type 1 IgE antibody-mediated reactions possibly related to tramadol concerned 11 cases of angioedema in Sweden. Of the six most serious cases involving the oral cavity, pharynx and/or upper respiratory tract, four patients needed emergency treatment and two of these treatments were in the intensive care unit (138). Apart from possible IgE antibody-mediated responses, other induced or suspected hypersensitivities to the drug include hypersensitivity pneumonitis (139), a maculopapular toxic skin reaction (140) and possible cases of Stevens-Johnson and Lyell's syndromes, although causal associations were in doubt for the syndromes (141).

DISCUSSION

A review of the findings from studies on the histamine releasing properties of opioid analgesics reveals a picture that is still not clear and, in some instances, confusing and apparently contradictory, with important questions still incompletely examined or answered. This conclusion is reinforced by the often-different results obtained with the most studied opioid analgesic morphine, summarised in Table 2. Apart from possible technical differences in some studies (for example, the possible influence on results of a claimed improved method for measuring histamine by Warner et al (73)), other possible influences affecting differences found in plasma histamine concentrations and haemodynamic changes include the dose of opioid, its mode and rate of administration, the site of injection and distribution of histamine receptors in different tissues, the effects of concomitant medication and, importantly, the heterogeneity of patient responses to histamine. For a given dose of opioid, inter-individual variations in serum concentrations of histamine and haemodynamic changes may range from little or no change to significantly large increases (71,72,82). As pointed out by Lorenz over 35 years ago (47), this presents a major problem in trying to assess the incidence of histamine release to a drug. In addition, once released, individual sensitivities to the physiological effects of histamine may vary widely (47,142,143). With regard to opioid analgesics and haemodynamic effects, the relationship to the concentration of histamine in plasma is complex and there is no direct and invariable relationship between the two (62). The distribution of histamine receptors means that responses to the autacoid vary in different vascular beds (1,144), making the site of injection of antigen or histamine releasing drug an important variable. Morphine itself has multiple direct effects on the vasculature (145,146) and it was suggested (62,82,147), and is now known to be so, that other haemodynamically-active mediators (148) released along with histamine contribute to the variable response to histamine liberators.

Given the rarity of IgE antibody-mediated immediate hypersensitivity reactions to opioid analgesics despite their heavy and constant worldwide usage, the question of why is intriguing. As demonstrated here, literature searches reveal relatively few reactions and surveys of drugs most frequently involved in perioperative anaphylaxis (117,149,150) show that opioids account for only about one percent of reactions, putting these drugs behind NMBDs (the most frequently involved group), latex, antibiotics, hypnotics and colloids. As previously assessed and stated after an earlier review, their antigenic safety is impressive (98). Given this large and curious disparity between use and rarity of allergic reactions, one tends to look for possible explanations. An early and obvious consideration is the potential immunogenicity, and more particularly allergenicity, of the opioid structures. The dogma that "small" organic molecules (that is, molecules of molecular weights of less than about 1000 Daltons) need to be presented as haptens bound to a macromolecular carrier (151) to be immunogenic may not always hold true (135), but in any case, morphine at least may bind to serum proteins (114) and numerous laboratory studies have demonstrated ready formation of immunoglobulin G and immunoglobulin M antibodies to protein-coupled opioids (152-164). With regard to the formation of IgE antibodies in man, however, there appears to be only a single report of the clear identification and specificity studies on an opioid drug responsible for a Type 1, IgE-mediated allergic reaction (103). Identification in this study of the allergenic (IgE-antibody-binding) fine structural determinants of morphine (Figure 4) showed that the structures recognised are similar to the regions of the morphine molecule recognised by anti-morphine antibodies raised in laboratory animals (154-156). Antisera in experimental animals have also been prepared to other important opioids, including codeine (156-158), oxycodone (157), hydromorphone (158), naloxone (159), levorphanol (160), pethidine (161,162), fentanyl (163) and methadone (164) so it seems that lack of inherent immunogenicity of opioid drugs in man is unlikely. Morphine-reactive antibodies, principally of the immunoglobulin M class, occur in the sera of some drug addicts (165) and serum IgE antibodies to morphine were detected in 5% of Norwegian blood donors and 10% of allergic patients (166).

Evidence suggests that opioids modulate both innate and acquired immunity (167). There is already a voluminous literature describing a bewildering diversity of effects on immune cells when opioids are added to leukocytes in vitro and when administered in vivo. Effects on cytokine production, T cell functions, natural killer cell activity, some macrophage functions and a variety of other immune cell changes have been documented (168), but perhaps most significant of all, opioids suppress in vitro antibody formation by human B lymphocytes (169). In almost all of the cellular immune studies with morphine, the effects induced by the drug were blocked with naloxone or failed to eventuate when [mu] opioid receptor-deficient animals were used (168). For reasons unknown, production of IgE antibodies to opioid drugs may be a rare event, but even if antibodies are induced, opioid antigens may not be in a form suitable for cross-linking complementary cell-bound IgE antibodies. While it is believed that unconjugated "small" molecules such as the NMBDs are able to cross-link IgE molecules at the surface of mast cells and basophils because they are allergenically di- (or multi-) valent (134,135), this, and the capacity to form multi-valent drug-protein complexes in vivo that are immunogenic, may not be the case with the opioid drugs. As yet, there is little information on both of these subjects. If indeed opioid drugs do not normally, or rarely, induce IgE antibody responses, the explanation might be found in the restricted immune response resulting from non-recognition of 'self' components. The natural and synthetic opioid drugs act at the same receptors and show the same activities as the natural endogenous peptide ligands. The pharmacophore of the opioid peptides, generally the four N-terminal residues Tyr1-Gly2-Gly3-Phe4, is the 'message' responsible for the opioid activities (170) while the remainder of the sequence, or 'address', is responsible for receptor recognition (171). Although molecular definitions of the precise structures involved are still inadequate (172), the fact that the opioid drugs and peptides share both pharmacological activity and receptor recognition properties indicates that the 'message' and 'address' sections of the respective molecules must also show some close resemblances of overall shape in space, size and conformation. In other words, from an immunological perspective, the natural and synthetic drugs as well as the endogenous peptides might be recognised as 'self' components.

In both clinical practice and research, the subject of adverse reactions to opioid drugs seems bedevilled by a lack of understanding of what constitutes a true allergic reaction and what distinguishes such a reaction from other side-effects. The literature reveals that over the years many reactions to opioid analgesics have been interpreted as allergic even in the absence of any reliable diagnostic evidence. Given that these drugs are histamine releasers, that many anaphylactoid reactions caused by direct release of inflammatory mediators may show some features of a true IgE-antibody-mediated anaphylactic response and that skin testing with known histamine releasers is often uncertain and requires careful attention to the dilutions employed, it seems likely that some reactions due to direct release of mediators as well as some true immediate allergic reactions to opioid analgesics are misdiagnosed. The mechanism involved in a reaction is often not defined: for example, a retrospective assessment of the risks of anaphylaxis and histamine release from anaesthetic agents in 975 anaphylactoid cases revealed that the mechanism was confirmed in only half the patients (173). The uncertainties associated with skin testing and the histamine-releasing properties of the drugs are compounded by the widespread unavailability of specific IgE antibody tests for individual opioid drugs. Consequences of failing to investigate suspected cases (174) and inappropriately describing some patients as allergic to opioid drugs have been highlighted by Gilbar and Ridge (175), who in a hospital study found that most documentation on the reactions was incomplete, the nature of the reactions was seldom recorded and the subsequent prescribing of opioids did not appear to be influenced by a reported allergy, thus putting patients at risk. Use of loose terminology in relation to opioid drug-induced reactions can also lead to misunderstanding and confusion as illustrated by a recent report of sublingual desensitisation of a patient with a history of opioid dependence and said to be showing buprenorphine "hypersensitivity" (176). In addition to buprenorphine, the patient reacted to heroin, hydrocodone, oxycodone and methadone with symptoms including hives, vomiting and a sensation of throat closing and coughing. Despite the fact that neither skin tests nor tests for drug-reactive IgE antibodies were carried out and the authors argued that these tests had not been validated as useful for diagnosing opioid "sensitivity", it was concluded that "buprenorphine hypersensitivity, and potentially any opioid hypersensitivity, can be treated with sublingual desensitization". It was further suggested "that mechanisms of rapid allergen desensitization include direct effects on mast cells, which can occur independently of IgE". This was not explained further. In the absence of tests that might help identify the underlying mechanism, the precise diagnosis of the opioid-addicted patient's reaction remains unclear and mixing the terms 'opioid sensitivity' and 'opioid hypersensitivity' gives no indication whether the response was a true Type 1 immediate hypersensitivity or some other adverse reaction.

Clinical implications for diagnosis of opioid drug-induced anaphylactoid and anaphylactic reactions

Symptoms of an opioid drug-induced pseudoallergic reaction resulting from direct release of histamine and involving, for example, flushing, rash, urticaria, pruritis, hypotension and mucous production may be sufficiently similar to those of an antibody-mediated true immediate hypersensitivity reaction to make distinguishing them difficult (177). For this reason, it is essential that in investigating opioid drug-induced adverse reactions, diagnostic investigations designed to reveal underlying immunological processes should be employed. Clearly, IgE-mediated allergies to opioid analgesics are rare. However careful attention to the history and clinical signs of a suspected anaphylactic reaction, the use of appropriate dilutions of drugs in skin tests and/or placebo-controlled challenge tests (97,178), the sampling of serum tryptase levels performed at appropriate time intervals and the application of specific IgE antibody immunoassays for individual drugs, together with appropriate inhibition studies of antibody-binding, will no doubt increase significantly the number of reactions that can be confidently classified as true Type 1 hypersensitivities.

Clinical manifestations are generally more severe and often life-threatening in anaphylactic than in anaphylactoid patients with cardiovascular collapse and bronchospasm significantly more frequent in the former, and cutaneous symptoms seen more often in the latter (149,150). In fact, cutaneous symptoms were found to be the sole feature in 136 of 271 anaphylactoid reactions (150).

In determining appropriate therapy for a patient with an IgE antibody-mediated allergy, recognition of structural differences between opioid analgesics (for example, the phenanthrenes such as morphine and oxycodone versus the synthetic drugs such as pethidine and fentanyl) has historically been recommended (179), but our current ignorance of opioid drug allergenic determinants and cross-reactions detected by IgE antibodies should be kept in mind. Cross-reactivities between structurally different opioid drugs are thought to be rare (180), but the demonstration of IgE antibody recognition of pethidine and methadone (103) and pethidine and fentanyl (124) in the only two morphine-allergic patients adequately studied so far, should be a warning to proceed cautiously in prescribing alternative drugs. For the management of acute pain, alternative non-opioid analgesics such as the nonsteroidal anti-inflammatory drugs or regional analgesia techniques may be able to be substituted, but if an alternative opioid analgesic is selected for administration, skin tests using appropriate dilutions and with suitable controls and/or challenge tests undertaken with care should be performed prior to administration. If appropriate specific IgE antibody tests are available, these should also be employed, but caution should be exercised in their interpretation as serum IgE antibodies from NMBD-allergic subjects with specificity for substituted ammonium ions react with the tertiary ammonium group of morphine (134,135,181-183). Since some opioid analgesics show differences in both the amount of histamine they release (65-68,72) and the anatomical sites where this action occurs (66-68,89,91,92), avoiding an anaphylactoid reaction may sometimes be effected by simply substituting one opioid drug for another; for example, substituting fentanyl for morphine following cutaneous release of histamine, or fentanyl or morphine for buprenorphine following histamine release in the lungs. Pretreatment with [H.sub.1] and [H.sub.2] histamine antagonists is an alternative where the reaction is due to histamine release.

CONCLUSION

Although anaphylactic and anaphylactoid reactions to opioid analgesic drugs may produce the same clinical picture and the immediate management of each is the same, the key to distinguishing them often lies in the relative severity of the clinical features (particularly cardiovascular collapse and bronchospasm) and, more importantly, in identifying the underlying mechanism. As considered here, anaphylactic reactions are immunologically mediated by drug-reactive IgE antibodies while anaphylactoid reactions are not. Therefore, central to distinguishing the two types of reactions are the key immunological tests--skin tests with the suspected drug(s) and, if available, drug-specific IgE antibody assays preferably with confirmatory specific inhibition tests. A positive serum tryptase test is also important in helping to identify an anaphylactic reaction, but note that positive cell tryptase measurements do not always distinguish between anaphylactic and anaphylactoid reactions (117,118,150,184). The correlation between plasma histamine levels and hypotension is poor (62) and evidence, though not conclusive, suggests that direct histamine release induced by opioid analgesics does not produce, or rarely produces, bronchospasm (98,184). If bronchospasm does in fact occur in an apparent 'anaphylactoid' reaction, the reaction is more likely to be immunemediated (98,150,184,185). The direct histamine-releasing effects of opioid analgesic drugs given in normal doses do not appear to provoke true antibody-mediated anaphylactic reactions in normal patients.

For accurate diagnosis of a suspected anaphylactic reaction to an opioid analgesic and for safe future pharmacological therapy, a thorough and accurate knowledge of the patient's history and an understanding of the underlying mechanism of the reaction are essential. For the opioid analgesics, these requirements have not consistently been met.

ACKNOWLEDGEMENTS

The authors thank Dr N. J. McDonnell, FANZCA, MClinRes, Staff Specialist, King Edward Memorial Hospital for Women, Perth, Western Australia for helpful comments on part of this manuscript.

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B. A. BALDO *, N. H. PHAM ([dagger])

Sydney, New South Wales, Australia

* AUA (Pharmacy), BSc (Hons), PhD, Retired.

([dagger]) MSc, PhD, Retired.

Address for correspondence: Dr B. A. Baldo, 11 Bent Street, Lindfield, NSW 2070. Email: babaldo@iinet.net.au

Accepted for publication on December 7, 2011.
Table 1
Structure of morphine and some chemically-related naturally occurring
or semi-synthetic clinically-important opioid drugs

 Substituent at position
Drug
 3 6 14 17

Morphine -OH -OH -H -C[H.sub.3]
Codeine -OC[H.sub.3] -OH -H -C[H.sub.3]
Heroin -OCOC[H.sub.3] -OCOC[H.sub.3] -H -C[H.sub.3]
Hydromorphone -OH = O -H -C[H.sub.3]
Oxymorphone -OH = O -OH -C[H.sub.3]
Hydrocodone -OC[H.sub.3] = O -H -C[H.sub.3]
Oxycodone -OC[H.sub.3] = O -OH -C[H.sub.3]
Buprenorphine * -OH -OC[H.sub.3] ** ** -C[H.sub.2][??]
Naloxone -OH =O -OH -C[H.sub.2]CH=
 C[H.sub.2]

Drug Bond(s) at
 positions 7-8

Morphine Double
Codeine Double
Heroin Double
Hydromorphone Single
Oxymorphone Single
Hydrocodone Single
Oxycodone Single
Buprenorphine * Single
Naloxone Single

* Has a 1-hydroxy-1,2,2-trimethylpropyl sustituent at C-7. ** Endo-
ethano bridge between C-6 and C-14.

Table 2
Summary of studies on morphine-induced histamine release, subsequent
haemodynamic and skin test changes in patients and in vitro findings

Morphine dose and Histamine release
route of
administration or
concentration(s) used
in in vitro study

0.5 or 1 mg/kg rapid NT
IV

1 mg/kg IV at 5/10 [up arrow]
mg/min

0.3 mg/kg IV at 10 [up arrow]
mg/min

0.3 mg/kg IV at 5/10 [up arrow]
mg/min

1 mg/kg IV at 100 [up arrow] ([double dagger])
[micro]g/kg/min over
10 mins

1.5 X [10.sup.-5] M- [up arrow] ([section])
4.5 X [10.sup.-3] M
in vitro with
leukocytes and skin
mast cells

0.6 mg/kg IV over [up arrow] **
[less than or equal
to] 10 mins

5 X [10.sup.-6] M- [up arrow] (A)
1.5 X [10.sup.-3] M
intradermal skin
tests

1 mg/kg IV over 10 [right arrow]
mins

0.16 mg/kg IV [up arrow] [infinity]

[10.sup.-5] M-3 X [up arrow] *
[10.sup.-4] M in
vitro with human
basophils, skin, lung
and heart mast cells

0.15 mg/kg IV [up arrow] ~

0.07/0.14 mg/kg IV [right arrow] (B)
over 2 mins

Morphine dose and Haemodynamic and Reference
route of other effects
administration or
concentration(s) used
in in vitro study

0.5 or 1 mg/kg rapid [down arrow] PVR *, Hsu et al (59)
IV [up arrow]
 capacitance

1 mg/kg IV at 5/10 [down arrow] SVR, Philbin et al (61)
mg/min [down arrow] DBP, [up
 arrow] ([dagger])

0.3 mg/kg IV at 10 Hypotension, Fahmy (63)
mg/min tachycardia,
 erythema. [down
 arrow] SVR,

0.3 mg/kg IV at 5/10 [up arrow] CO, [up Fahmy et al (64)
mg/min arrow] catecholamines
 [down arrow] SVR,
 [down arrow] MAP,
 [down arrow] SBP, [up
 arrow] CO, [up arrow]
 HR, [up arrow] SV,
 [up arrow] plasma
 adrenaline

1 mg/kg IV at 100 [down arrow] MAP, Rosow et al (65)
[micro]g/kg/min over [down arrow] SVR
10 mins ([double dagger])

1.5 X [10.sup.-5] M- Hermens et al (66)
4.5 X [10.sup.-3] M
in vitro with
leukocytes and skin
mast cells

0.6 mg/kg IV over Hypotension, Flacke et al (72)
[less than or equal tachycardia **
to] 10 mins

5 X [10.sup.-6] M- Wheal and flare Levy et al (69)
1.5 X [10.sup.-3] M
intradermal skin
tests

1 mg/kg IV over 10 Warner et al (73)
mins

0.16 mg/kg IV Withington et al (71)

[10.sup.-5] M-3 X Stellato et al (67),
[10.sup.-4] M in Marone et al (68)
vitro with human
basophils, skin, lung
and heart mast cells

0.15 mg/kg IV "Symptoms" of Doenicke et al (70)
 histamine release but
0.07/0.14 mg/kg IV no haemodynamic Mildh et al (74)
over 2 mins changes [up arrow]
 MAP [approximately
 equal to], [up arrow]
 HR, [right arrow]
 catecholamine

IV=intravenous infusion, NT=not tested [down arrow]=histamine or
effect decreased, PVR=peripheral vascular resistance, T=histamine or
effect elevated. SVR=systematic vascular resistance, DBP=diastolic
blood pressure, CI=cardiac index, CO=cardiac output, MAP=mean
arterial pressure, SBP=systolic blood pressure, HR=heart rate,
SV=stroke volume, [right arrow]=histamine or effect unchanged. * 46%
increase at two minuntes. Returned to control values at nine minutes.
When promethazine preceded, morphine decrease in PVR was 25%.
[dagger] Minimal effects on responses by [H.sub.1] and [H.sub.2]
blockers alone but significant attenuation by [H.sub.1] + [H.sub.2].
([double dagger]) Biggest decreases in SVR occurred in patients with
highest levels of plasma histamine. ([section]) Histamine released
from skin mast cells only--detected at 1.5 X [10.sup.-4] M and
maximum at 5 X [10.sup.-4] M morphine. ** In 1 of 10 patients. (A)
Relative to histamine control. [infinity] In 9 of 38 patients. * From
skin mast cells only. ~ In 13 of 15 patients within five minutes of
injection. (B) Local signs (redness, itching) at injection site.
[approximately equal to] Transient increase.
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Publication:Anaesthesia and Intensive Care
Article Type:Report
Geographic Code:8AUST
Date:Mar 1, 2012
Words:14405
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