DRUG EXPERIENCE

Drug Safety 7 (3): 200-213, 1992 0114-5916/92/0005-0200/$07.00/0 © Adis International Limited. All rights reserved. DRS1

Adverse Effects of Systemic Opioid Analgesics Stephan A. Schug, Detlev Zech and Stefan Grand Section of Anaesthetics, Department of Pharmacology and Clinical Pharmacology, School of Medicine, University of Auckland, Auckland, New Zealand, and Pain Clinic, Department of Anaesthesiology, University of Cologne, Cologne, Federal Republic of Germany

Contents 201 202 202 204 204 204 205 205 205 205 206 206 206 206 207 207 207 207 208 208 208 209 209 209 210 210 210

Summary 1. CNS Effects 1.1 Respiratory Depression 1.2 Cough Suppression 1.3 Nausea and Vomiting 1.4 Psychological Effects 1.5 Rigidity 1.6 Pruritus J.7 Miosis 2. Cardiovascular Effects 3. Gastrointestinal Effects 3.1 Constipation 3.2 Gastrointestinal Reflux 3.3 Biliary Effects 4. Genitourinary Effects 5. Endocrine Effects 6. Effects of Long Term Use 6.1 Systemic Toxicity 6.2 Reproductive Effects 6.3 Tolerance 6.4 Physical Dependence 6.5 Addiction 7. Miscellaneous Effects 7.1 Allergic Reactions 7.2 Haematological Effects 7.3 Immunological Effects 8. Conclusions

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Adverse Effects of Opioids

Summary

Adverse effects of opioids are multiple. They are most often receptor-mediated and inseparable from their desired effects. The most severe mishaps with opioids are related to their respiratory depressant effect, which is widely influenced by factors such as pain, previous opioid experience and awareness. Other relevant central nervous system effects of opioids include cough suppression, nausea and vomiting, rigidity, pruritus and miosis. The cardiovascular adverse effects of opioids are mainly related to histamine release and differ widely between agonists and agonist-antagonists. Gastrointestinal effects such as constipation, reflux and spasms of the bile duct are well described. Adverse effects on endocrine, immunological and haematological functions are possible, while allergic reactions are extremely rare. The adverse effects of long term use are overestimated. Systemic toxicity is negligible and development of tolerance is minimal while treating pain. In the clinical setting of pain control, addiction and withdrawal do not pose significant problems. Nevertheless, the possible effects of opioids on the unborn child should always be considered. Overall, opioids show a good record of safety. Their use should not be unduly limited by unfounded fears of adverse effects, but these effects should be avoided by anticipation and prevention.

Pain is one of the major symptoms that cause patients to seek medical treatment. For this reason it is not surprising that opioids, the most potent pain-relieving agents, are widely used. In the Boston Collaborative Drug Surveillance Program, 29.7% of patients in hospital received at least I opioid medication (Porter & Jick 1980). Nevertheless, opioids are still widely underused, resulting in unnecessary pain (Melzack 1990). This underuse in the short and long term setting is heavily influenced by the fear of adverse effects (Schug et al. 1991). Adverse effects of opioids result either from effects mediated by the specific opioid receptors or

(rarely) from a direct toxic effect of the drug. The receptor-mediated effects depend on specificity (table I), extrinsic activity (affinity) and intrinsic activity of the respective agent. To assess adverse effects of opioids objectively is extremely difficult. The reasons for this are at least 2-fold. First, articles tend to summarise clinical experience with a new opioid and usually claim good analgesic effectiveness with minor adverse effects; most of these studies are not comparative and are rarely critical (Eckenhoff & Oech 1960). Secondly, there is an enormous variation in the spectrum and severity of opioid adverse effects, dependent on the drug, dose, route and speed of

Table I. Clinically relevant receptor types, mediated pharmacological effects and agents acting on these receptors [compiled from data from Lehmann (1990), Martin (1984) and Stoelting (1987)]

Receptor

K

Pharmacological effects

Agonists

Agonist-antagonists

Antagonists

Supraspinal analgesia, respiratory depression, physical dependence, bradycardia, miosiS, euphoria Analgesia, sedation, miosis, respiratory depression (?)

Morphine, pethidine, fentanyl, alfentanil, sufentanil

Pentazocine, buprenorphine, nalorphine, dezocine, nalbuphine (?)

Naloxone

Pentazocine, buprenorphine, butorphanol, bremazocine, dezocine Pentazocine, ketamine (?)

Nalorphine, nalbuphine

Naloxone

Nalorphine, nalbuphine

Naloxone

Tachypnoea, tachycardia, hypertension, mydriasis, dysphoria

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administration used. Even in the same individual, responses to opioids depend on concomitant illness or drug use, tiredness, pain level and emotional state. The following review summarises findings on adverse effects of opioids bearing in mind the wide range of possible responses to these agents. Special consideration is given to the 'dual pharmacology' of opioids, a term used by McQuay (1989) to describe the difference between the use of these agents to treat pain in patients and their administration to pain-free volunteers or animals in a laboratory setting.

1. eNS Effects 1.1 Respiratory Depression Opioids have a direct respiratory effect mediated via II-receptors, but also via K- and (T-receptors, in the respiratory centres of the pontine and bulbar brain stem (Duthie & Nimmo 1987). The measurement of this effect is difficult even under experimental conditions. Most commonly used techniques assess the response to C02 challenge by either steady-state methods of inhaling fixed C02 concentrations or by rebreathing techniques which generate progressively increasing C02 concentrations (Jordan 1982). In all these settings care has to be taken to maintain hyperoxia during the experiment, because hypoxia increases the ventilatory response to hypercapnia. The intramuscular (1M) administration of e.g. morphine 10mg in such a rebreathing experiment results in a marked shift to the right and change in slope of the C02 response curve in pain-free volunteers, indicating an increase in threshold as well as a decrease in sensitivity of the respiratory centre (fig. 1) [Forrest & Bellville 1964]. The reduction in slope of ventilatory response to C02 is in a comparable range of around 40% for 1M injections of morphine lOmg (Jennett et al. 1968), pethidine (meperidine) 75mg and pentazocine 60mg (Engineer & Jennett 1972). These findings confirm that equianalgesic dos-

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ages of all opioids result in comparable effects on the respiratory centre (Eckenhoff & Oech 1960). This is even true for agonist-antagonist agents such as pentazocine (Engineer & Jennett 1972) or nalbuphine (Gal et al. 1982) which show a ceiling effect for respiratory depression paralleled by limited analgesic efficacy. The only advantage of such a ceiling effect therefore is increased safety in the case of accidental overdosage. K-Agonists such as bremazocine might behave differently, but further research is awaited (Roemer et al. 1980). Opioids also have a marked effect on the ventilatory response to hypoxia which is obviously even greater than the depression of the hypercapnic response (Santiago et al. 1979); this problem can be of relevance to patients with chronic C02 retention, where arterial hypoxaemia is the main drive of ventilation. It is almost impossible to extrapolate the findings on' respiratory effects of opioids in normal painfree subjects to patients in pain. It is also difficult to apply the conventional tests for respiratory depression to patients in clinical settings, for they require not only familiarisation with the equipment, but also cooperation, and may be potentially hazardous. Finally, it must be considered that decreased ventilation does not necessarily indicate that ventilation is really depressed, but may also reflect reduced oxygen consumption, as shown by the injection of morphine lOmg (Jennett et al. 1968). Therefore, blood gas estimations are crucial; adequacy of ventilation in a patient must be assessed by measurements of arterial partial C02 pressure, since p02 measurements depend on other factors such as the alveolar-arterial difference and ventilation-perfusion coefficient and are not as useful (Jordan 1982). In the clinical setting opioids reduce respiratory rate, although this is not reproducible; their administration can also result in a slight diminution in tidal volume and finally in an increased alveolar partial C02 pressure. This effect is more profound in the very ill and the elderly, but it must be borne in mind that resting ventilation depends variably on a number of factors. The importance of sensory input in the maintenance of normal respiration

Adverse Effects of Opioids

203

Ventilation

!::,0

c," f'>0

Normal ventilation

---- ----

o~

Shift to right -,~. ~----""'r" 0"~

0"" ~G

?Jj(Ji

.cp ~

q~"'"

Reduced slope ~_....................... ~ Decreased sensitivity /1

Normal C02 level

C02 level

Fig. 1. Schematic illustration of the effect of opioids on the response of ventilation to C02.

needs to be stressed; sleep has a substantial effect on the depression of respiration, so that respiratory depression normally associated with a dose of morphine becomes much greater as soon as consciousness is lost (Forrest & Bellville 1964). Other factors aggravating respiratory depression after opioids beside age and sleep are sedation, e.g. by use of benzodiazepines (Bailey et al. 1990), and pulmonary disease (Eckenhoff & Oech 1960). On the other hand, pain is a major antagonist to respiratory depression after opioids. This can be clearly shown in cancer patients on high opioid doses in whom abolition of pain by cordotomy (Wells et al. 1984) or neural blockade (Hanks et al. 1981) results in respiratory depression because of lack of the 'antagonist pain'. This explains why the use of standard doses of an opioid for the treatment of pain is both ineffective and dangerous, while the individual titration of a patient (using for example a patient-controlled analgesia device) is extremely effective and safe; the patient titrates opioid effect versus pain adapted to his or her own situation. As a consequence of the respiratory depressant effect, postoperative episodes of hypoxaemia are

common in patients receiving opioids, especially while they are asleep. As expected, episodes of central apnoea have been observed, but surprisingly these rarely result in oxygen saturations below 89%. More common and more serious events with saturations below 80% have been commonly associated with upper airway obstruction, resulting in paradoxical motion of the rib cage (Catley et al. 1982). This problem might especially be true for patients with sleep apnoea syndrome. The clinical relevance of these obstructive periods is high because patients on opioids arouse at lower oxygen saturations during apnoea than patients not receiving opioids. It is also relevant that the effect of opioids on respiration under added mechanical load (as in patients with obstructive airway disease) is increased. Here, agents such as meptazinol, which show no significant change of response to hypercapnia, can be respiratory-depressant during inspiratory resistive loading (Jordan et al. 1978). In this context it is interesting to note that while acute methadone administration abolishes the response to hypercapnia with added inspiratory resistance, chronic users have a normal response to the load

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(Santiago et al. 1980). This suggests that tolerance to this opioid effect develops with long term use. It seems that rib cage contribution to breathing may be more affected by opioids than diaphragm movement (Rigg & Rondi 1981). This implies that patients dependent on intercostal accessory muscle activity (e.g. chronic obstructive lung disease, obesity, after abdominal surgery) may be at special risk to the respiratory depressant effects of opioids. Finally, the respiratory centres of newborns are extremely sensitive towards opioids (Way et al. 1965). This must be considered when using opioids during labour and it is also the explanation for the fact that neonatal apnoea episodes are significantly associated with exposure to opioids in breast milk (Naumburg & Meny 1988). In summary, respiratory depression due to opioids is mainly a uniform dose-related effect of an opioid on the JL-receptor and is directly linked to analgesic effects. This respiratory depression is multifactorial and varies inter- and intraindividually in a wide range; its strongest antagonist is pain itself. 1.2 Cough Suppression Cough suppression by opioids occurs most likely via a direct depression of the cough centre in t.he medulla, although there is no direct correlation between the respiratory depression and the cough suppression of different opioids. For example, diamorphine (heroin) or codeine are far stronger cough suppressants than morphine (Lehmann 1990). Cough suppression is often a desired effect or indication for the use of codeine. Nevertheless, it can be an adverse effect if in postoperative patients it impairs the clearing of sputum and inhaled secretions which may then result in pulmonary infection (Jaffe & Martin 1985). In this context it must be acknowledged that pain is a powerful cough suppressant too, and that this adverse effect of opioids should not prevent their use in the postoperative setting. The cough suppressing effect is also the reason why it is not advisable to use opioids in an asthma attack; here cough suppression, respiratory depres-

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sion, histamine release and drying of bronchial secretions combined can lead to disastrous effects. 1.3 Nausea and Vomiting Nausea and vomiting after the administration of opioids is the result of direct stimulation of the chemoreceptor trigger zone in the area prostrema of the medulla; the effect is dose-related and subject to rapid development of tolerance. The effect is most probably mediated via dopaminergic receptors. This would explain why the dopamine agonist apomorphine has the strongest emetic effect and why dopamine antagonists are of therapeutic value in treating opioid-induced nausea and vomiting (Lehmann 1990). Opioid-induced nausea and vomiting is aggravated by stimulation of the vestibular apparatus. Therefore, turning the head, getting up or walking can provoke vomiting in an otherwise comfortable patient. on opioids (Rubin & Winston 1950). Finally, opioid-induced vomiting may be partially explained by delayed gastric emptying (see section 3.2) as proven for morphine (Todd & Nimmo 1983) or buprenorphine (Adelhoj et al. 1985). It should be realised that nausea and vomiting are not only unpleasant and painful to patients after surgery but might even cause fatal outcome after aspiration of gastric contents (Brahams 1984). On the other hand, in assessing the effects of opioids on nausea and vomiting the clinician must consider that pain is a major cause of postoperative nausea; persistence of nausea with relief of pain is uncommon (Anderson & Krohg 1976). 1.4 Psychological Effects Psychological effects of opioids vary dramatically depending on the drug (e.g. its lipophilicity) and route of administration, because rapid receptor occupation seems to result in more profound psychological effects. But even more relevant is the recipient's subjective state, mental functioning, pain and previous opioid experience. An in-depth an-

Adverse Effects of Opioids

alysis of these effects has been presented by Lal ( 1977). In general, morphine induces sedation, feelings of dejection, anxiety, insecurity and slowed performance in healthy, pain-free, opioid-naive volunteers, but little feeling of well-being and euphoria (Smith & Beecher 1962). It is assumed that the often claimed induction of euphoria, the 'high', depends very much on the personality of the drug user and their drug history (Martin 1984). Patients in pain who receive morphine rarely experience euphoria or any psychological effects. On the contrary, pentazocine produces psychomimetic and dysphoric effects in the clinical setting, most probably via a-receptors (Martin 1984). 1.5. Rigidity Rapid administration of intravenous (IV) fentanyl I mg/min results in a high incidence of significant truncal rigidity (80% of cases) which can impair ventilation by decreased chest wall compliance and/or upper airway obstruction (Jaffe & Ramsey 1983). The reason for the occurrence of this phenomenon is still unresolved, but it is likely to be a central nervous effect with involvement of opioid receptors in the substantia nigra and the striatum as well as neurons sensitive to dopamine and f"-aminobutyric acid (GABA). Similarities observed between Parkinsonism and the rigidity associated with high dose opioid use suggest that opioid-induced rigidity may be a form of druginduced Parkinsonism (Severn 1988). Directly related to the problem of rigidity is the still ongoing debate as to whether high dose opioids can induce convulsions. While a study in 1982 claimed reproducibility of this phenomenon with large doses of IV fentanyl (1000 to 1500J.Lg as a bolus resulting in plasma fentanyl concentrations above 600 J.Lg/L) [Rao et al. 1982], this was immediately disputed by Sebel and Bovill (1983), who could not find clinical or electroencephalogram (EEG) evidence of convulsive activity and claimed that unmodified muscle rigidity might be an explanation for the convulsive-type movements de-

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scribed. An examination of electromyograms (EMGs) and EEGs of 127 patients anaesthetised with large doses of opioids revealed clinical and EMG manifestation of rigidity sometimes resembling seizures in over 50%, while the EEG showed no evidence of seizure activity. This study concluded that there was no support for the existence of opioid-induced seizures in the clinical setting (Smith et al. 1989). 1.6. Pruritus While one major cause of itch is clearly the histamine release discussed below, itching can also be caused by spinal opioids, most probably via a central encephalinergic mechanism. For example, one hypothesis formulates that the facial itch after intrathecal opioids is mediated via a spinal reflex through a medullary itch centre at the spinal nucleus of the trigeminal nerve (Scott & Fischer 1982). Comparable mechanisms on other levels are thought to be responsible for the high incidence of itch after low doses of opioids epidurally or intrathecally even on lumbar levels. 1.7 Miosis Opioid agonists which act at the wreceptor routinely cause pupil constriction, mediated via stimulation of the Edinger-Westphal nucleus of the third cranial nerve. The resulting 'pinpoint' pupils are more or less pathognomic of opioid intoxication; there is even a good correlation between the potency of wagonists in inducing miosis and analgesia in humans (Jasinski 1977). Pure K-agonists such as bremazocine do not cause this miosis (Roemer et al. 1980).

2. Cardiovascular Effects The administration of opioids results in significant venodilation after initial short term venoconstriction. The overall impact on the cardiovascular system is therefore a fall in peripheral vascular resistance and a resulting increase in peripheral blood flow. This effect is partially mediated by a reflex

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reduction in a-adrenergic tone, most likely by reducing sympathetic discharge on a CNS level and clearly not by peripheral a-blockade (Zelis et al. 1974). Nevertheless, there is increasing evidence that a relevant part of this cardiovascular response to opioids is mediated via histamine release. The injection of morphine I mg/kg IV resulted in an average 750% peak increase of plasma histamine levels accompanied by significant drops in BP and peripheral vascular resistance. The most significant changes in these cardiovascular parameters occurred in patients with the highest plasma histamine levels (Rosow et al. 1982). Another study came to the same conclusion because no histamine release was observed with fentanyl and sufentanil, medium histamine release with morphine and severe histamine release with pethidine. These findings on histamine release correlate well with the changes in cardiocirculatory parameters after administration ofthese opioids (Flacke et al. 1987). No histamine release was also observed after methadone (Thompson & Walton 1966). These observations show that histamine release is one, if not the, relevant mechanism of peripheral vascular changes after opioid administration. Histamine release is a displacement reaction which is doserelated, but not determined by opioid receptor binding and/or cell membrane damage. In the clinical setting it is of extreme relevance that the resulting hypotension has no significant influence on patient well-being while the patient is supine. It does, however, result in a severe orthostatic dysregulation with consecutive postural hypotension which can become a problem as soon as the patient tries to change position (Zelis et al. 1974). Most opioids induce bradycardia. This bradycardia is at least partially the result of sedation and follows the reduction of sympathetic tone, but it is also caused by increase in vagal tone via stimulation of vagal nuclei in the medulla. Bradycardia does not become obvious in stressful situations (pain, fear). Pethidine, due to its anticholinergic effect, is an exception in that it induces tachycardia (Eckenhoff & Oech 1960).

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The situation becomes far more complicated when the agonist-antagonists are taken into consideration. In general they induce an increase in vasomotor tone, probably as a consequence of antagonising endogenous ligands (Martin 1984). Quite variable profiles are seen depending on their receptor specificity and intrinsic activity; butorphanol, for example, increases cardiac index and pulmonary artery pressure (Popio et al. 1978) and is therefore not useful in the setting of myocardial infarction. Table II summarises the quite complex effects of agonist-antagonists on the cardiovascular system.

3. Gastrointestinal Effects 3.1 Constipation Opioids reduce gastrointestinal (GI) motility. This is caused by reduction of longitudinal peristalsis and increase of sphincter tone (Duthie & Nimmo 1987). This results in constipation, which is a common adverse effect of these agents, for example in cancer pain management. Tolerance to this effect does not develop and treatment of the constipation can become a major problem of morphine use. By the same mechanism, opioids aggravate postsurgical ileus and delay gastric emptying and GI transit time in this setting (Nimmo et al. 1975). 3.2 Gastrointestinal Reflux Due to decreased lower oesophageal sphincter tone, GI reflux as well as aggravation of pre-existing reflux conditions by standard doses of morphine and pethidine have been described (Hall et al. 1975; Hey et al. 1981). This GI reflux is of clinical relevance as it increases the risk of aspiration of gastric contents, especially in the weak or sedated patient and in the anaesthetic setting (Cotton & Smith 1984). 3.3 Biliary Effects Opioids increase common bile duct pressure significantly. This effect is observed after the use

207

Adverse Effects of Opioids

Table II. Cardiovascular effects of common agonist-antagonist-like opioids [compiled from data from Jewitt et al. (1971), Martin (1984), O'Brien & Benfield (1989) and Popio et al. (1978)). Parentheses indicate a slight effect on this parameter Agonist-antagonist

Heart rate

Blood pressure

Buprenorphine Butorphanol Dezocine Nalbuphine Pentazocine

I tIl til I t

I (I) tIl tIl t

Symbols:

Pulmonary artery pressure

(I)

Stroke work index

I

(lJ

(lJ

t

t ttl t

tIl

t

t = increased; I = decreased.

of fentanyl, morphine and pethidine, but does not occur after butorphanol and nalbuphine, which makes it likely that it is mediated via ~-receptors. This is confirmed by the observations that naloxone can antagonise the effect (Radnay et al. 1984) and that opioid receptors can be found in the wall of the common bile duct (Vatashsky et al. 1987). The sphincter pain resulting can be severe enough to be misdiagnosed as acute cholecystitis or even myocardial infarction (Lang & Pilon 1980). This effect can also make opioids unsuitable for use in pain caused by spasms of the bile duct. It is possible that pethidine is less potent than other opioids in increasing intrabiliary pressure because of its antimuscarinic effect and might be more suitable in this indication (Goldberg et al. 1987). Interpretation of cholangiograms can be made difficult by concomitant use of opioids for the same reason (McCammon et al. 1978).

4. Genitourinary Effects The use of opioids can result in retention of urine due to increase in sphincter pressure and decrease of detrusor tone (Doyle & Briscoe 1976). The effect is again receptor-mediated as it can be antagonised by naloxone, which increases detrusor contractility (Murray & Fenely 1982). The location of the involved receptors seems to be the thoracic spinal cord where preganglionic sympathetic neurons are in close proximity to terminals containing encephalins and substance P. This neuronal architecture also explains why a-

adrenergic antagonists such as phenoxybenzamine are effective in treating urinary retention caused by opioids (Murray 1984).

5. Endocrine Effects The use of opioids results in an increase in concentrations of prolactin and growth hormone in rats, most likely via ~-receptor activation (Spiegel et al. 1982). This increase may interfere with in vitro fertilisation because it can impair subsequent endometrial implantation of the fertilised egg. Opioids should be used here with caution (Watson 1986). Induction of hypoadrenalism has been described with the use of methadone (Dackis et al. 1982).

6. Effects of Long Term Use 6.1 Systemic Toxicity It has been claimed that the long term use of opioids results in major organ toxicity, especially to the liver. However, long term surveillance of former drug addicts on maintenance programmes with methadone has revealed no specific organ toxicity, particularly in the healthy liver (Kreek 1973; Kreek & Dodes 1972). One exception is the administration of excessive doses of morphine for cancer pain treatment, where myoclonus has been observed. It is not clear if this is a drug interaction because it is more likely

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to occur with concurrent antidepressant or antipsychotic medication (Potter et al. 1989). Another exception to this is pethidine; in long term use, especially in the patient with renal insufficiency, symptoms of tremor and myoclonus and finally convulsions occur in proportion to the plasma concentrations of the metabolite norpethidine (Armstrong & Bersten 1986). This toxicity of a pethidine metabolite is well documented and precludes pethidine from long term use, especially in high dosage. There is ongoing debate about possible neuropsychological abnormalities which may occur with long term use of opioids and these have been reported in various studies (e.g. Gritz et al. 1975; Turner et al. 1982). Several studies have contradicted these findings (e.g. Lombardo et al. 1969) and at least cognitive and psychological functioning is normal in cancer patients receiving such drugs; they rapidly develop tolerance to the initial cognitive impairment during use of opioids (Bruera et al. 1989). In summary, the available literature permits no final conclusion on subtle neuropsychological impairment as a consequence of long term opioid use. 6.2 Reproductive Effects Pregnant women who are either abusing opioids or on methadone maintenance programmes have been carefully examined with regard to the impact of this drug on their offspring. Although it is difficult to differentiate direct effects of the opioids from psychosocial problems and those of general health in this population, certain effects of fetal exposure have become obvious. The available data suggest that such exposure is associated with lower birthweight, shorter body length and smaller head circumference than in nonexposed infants (Chasnoff 1985). It also results in a 2-fold increase in preterm deliveries and reduced Apgar scores of the newborn (Levy & Koren 1990). The newborns show obvious neonatal withdrawal in the form of irritability, tremor, hypertonicity and sometimes seizures (Herzlinger et al. 1977).

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Later in life they are prone to significant impairment of interactive abilities, motor maturity and organisational response (Chasnoff 1985). Sudden infant death syndrome in this group is increased by a factor of 5 to 10 (Chavez et al. 1979). Zagon et al. (1989) have provided a detailed bibliography on this complicated subject. 6.3 Tolerance Tolerance describes the need for increasing doses to maintain a defined pharmacodynamic effect such as analgesia. The development of acute tolerance has been described in nearly all animal and human studies on opioids. The mechanism of tolerance is still only hypothetical; upregulation of opioid receptors, decr~ased concentration of endogenous opioids, inhibition of cyclic AMP synthesis or reduced sensitivity of opioid receptors are all options under discussion (Way 1978). Tolerance under experimental conditions develops to all receptormediated opioid effects except constipation and miosis. There is a marked difference in the response of pain-free animals or volunteers to opioids and those in pain with respect to tolerance. An animal experiment in which painful stimuli were applied prior to the injection of opioids revealed that development of tolerance does not occur (Colpaert et al. 1980). This has been confirmed in the clinical setting where a pharmacokinetic study failed to demonstrate any change with time of the minimum effective analgesic concentration of pethidine in chronic pain patients (Glynn & Mather 1982). It is also confirmed by our own findings; cancer patients can be maintained on stable morphine dosages for quite a long time and necessary increases in dose were usually explicable by progress of disease (Schug et al. 1992). 6.4 Physical Dependence Physical dependence is defined as the occurrence of withdrawal symptoms after the abrupt discontinuation of a drug or the administration of an antagonist. Physical dependence is quite common

Adverse Effects of Opioids

after use of opioids for periods of more than 10 to 20 days. Typical withdrawal symptoms are yawning and restlessness, accompanied by vegetative symptoms such as sweating, cramps, emesis, fever, hypertension and diarrhoea. These symptoms develop within 10 to 12h after the cessation of drug intake or immediately after administration of an antagonist and reach a maximum after 2 to 3 days. They last normally for 7 to 10 days, although longer lasting slight symptoms are described even weeks after the withdrawal. The administration of opioids terminates withdrawal symptoms immediately. The biological mechanisms leading to withdrawal are not completely understood, but might be similar to those explaining tolerance (Way 1978). One important cause for the development of withdrawal symptoms is the increase of sympathetic activity in the CNS, especially the locus caeruleus. This explains why treatment of withdrawal symptoms with c1onidine, a central lQagonist which blocks the sympathetic activity, is useful (Gold et al. 1980). Again, there is only a quantitative not a qualitative difference between pure agonists and agonist-antagonists; at least in animal experiments maximum withdrawal scores after buprenorphine are lower than those of e.g. morphine, but similar to codeine, dextroproproxyphene (propoxyphene), nalorphine, pentazocine and butorphanol (Heel et al. 1979). Agents which are specific to other receptors might behave differently; the K-agonist bremazocine, for example, does not show any withdrawal effects at all (Roemer et al. 1980). 6.5 Addiction The multiple and severe psychological and social problems related to opioid addiction cannot be discussed in the contents of this review; the reader must be referred to the wide range of literature available on this topic. In the use of opioids in the medical setting, addiction seems to be a far smaller problem than generally assumed and the great fear of creating addicts through the use of opioids is not easy to substantiate in the available literature. Addiction

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in the medical setting is best defined as characterised by psychological dependence, compulsive drug use and/or associated behaviour which may include manipulation of the medical system, acquisition of drugs from other sources, sale of prescribed drugs and unapproved use of other drugs (Portenoy 1990). Under this definition, a study on headache patients found addiction in only 2 out of over 2000 patients (Maruta & Swanson 1981). This is confirmed by the already quoted Boston Collaborative Drug Surveillance Program which showed only a minimal occurrence of drug addiction under the medical use of opioids (Porter & Jick 1980), as well as by our own observations of over 1000 cancer patients, in whom addiction was identified in only I (Schug et al. 1992). It is obvious that the abuse of opioids for psychopathological needs is markedly different from the medical use of the same compounds for the relief of pain. It seems that the reinforcing psychological effects of opioids (e.g. euphoria) are rarely observed in patients on opioid pain medication. This fits into a common concept which does not see the potential for drug abuse solely in the properties of a certain drug, but also in personality factors and living situations (Robins et al. 1974). Nevertheless, it must be seen that drug addiction can occur in some patients on opioids (Maruta et al. 1979) and that patients with operant pain problems are at particular risk (Ziesat 1979). As with physical dependence it seems that development of addiction is related to Il-receptor activity for there is no self-administration of K-agonists such as bremazocine at least in animals (Roemer et al. 1980).

7. Miscellaneous Effects 7.1 Allergic Reactions Allergic reactions to opioids seem to be extremely rare adverse effects (Stoelting 1983). A recent survey of 821 cases of anaphylaxis during anaesthesia showed that opioids were only involved in 2.6% of these events (Laxenaire et al. 1990). There is also, for example, only I published case

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Table III. Treatment proposals for clinically relevant adverse effects of opioids Adverse effect

Acute treatment

Prevention

Remarks

Respiratory depression (an emergency)

(a) Try to keep patient awake (deep breaths) (b) If unrousable, maintain airway and start artificial ventilation (c) Use antagonist: titrate IV naloxone in 0.04-0.1mg steps

(a) Titrate opioids according to pain (b) Avoid standard dosages (c) Take care with continuous infusions, especially in opioid naive patients

Agonist-antagonists are only safer in case of overdose, but can also induce respiratory depression

Nausea and vomiting

(a) Avoid change of position (b) Use antiemetics

(a) Prefer IV over 1M or SC administration (b) Use antiemetics initially as prophylaxis

(a) Tolerance develops rapidly (b) Try another opioid, although there is no evidence that some opioids are better than others

Hypotension

(a) Put patient in Trendelenburg position (b) Fluid replacement (c) Give vasoconstrictors

(a) Be careful in shocked or dehydrated patients (b) Anticipate orthostatic dysregulation

Agonist-antagonists may cause other circulatory problems, so remember their differing effects

(a) Use laxatives (b) Ensure regular bowel motions

There is no development of tolerance in this case

Constipation

Abbreviations: IV

= intravenous; 1M = intramuscular; SC = subcutaneous.

report of an anaphylactic reaction to pethidine (Levy & Rockoff 1982). 7.2 Haematological Effects There are some very rare descriptions of thrombocytopenia and agranulocytosis induced by opioids. Thrombocytopenia has been described in diamorphine addicts (Adams et al. 1978) and may be related to a drug-induced immunological mechanism because antibodies against platelets have been detected in these patients (Fishman 1981). There is another comparable report on the effect of high morphine doses on the platelet count (Cimo et al. 1982). Agranulocytosis with the symptoms of neutropenia and localised infection has been reported after the long term use of pentazocine, again with the underlying mechanism of antibody reaction (Pisciotta 1978).

7.3 Immunological Effects After initial in vitro findings that opioids modulate chemotaxis of mononuclear cells, proliferation of lymphocytes, natural killer cell activity and antibody generation, there is now increasing evidence of comparable effects in vivo. Clinical evidence has been found of effects of opioids on the immune system in the form of suppression of human mononuclear cells by morphine and methadone (Peterson et al. 1989).

8. Conclusions Opioids produce a wide range of adverse effects, of which respiratory depression is the most serious. Respiratory depression is clearly receptor induced and therefore related to analgesia. It is predictable and reversible with antagonists. The importance of most other adverse effects, especially of tolerance, dependence and addiction, has been overemphasised. Overall, opioids show a good record of safety

Adverse Effects of Opioids

reflected in the high therapeutic index of most agents. As with most other drugs, anticipation and avoidance of opioid adverse effects should prevent most problems (Walsh 1990). A list of proposals for treatment and prevention of clinically relevant adverse effects is provided in table III.

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