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Opioid analgesics and narcotic antagonists
A.H. Ghodse
8
Opioid analgesics and narcotic antagonists
Newer opiate drugs have been reviewed by Bullingham (1 R) who claims that with the advent of mixed agonist-antagonist drugs a low-abuse potential has become a reality. One can only hope that such optimism will be confirmed with the passage of time. Unfortunately, all of the newer opiate drugs cause the undesirable side effects of ventilatory depression. The mixed a g o n i s t s antagonists do display a limitation of respiratory depression as the dose increases, but it is not clear when, and at what level of effect, analgesia will also reach a ceiling. The complete separation of analgesia and respiratory depression is still an unattained goal. OPIOID AGONISTS
Morphine, heroin, methadone Extensive clinical experience has been obtained in the use of opiates during the last decade in special units devoted to symptom control in advanced cancer; Walsh (2 c R ) summarized clinical experience in the use of oral morphine for cancer pain at St. Christopher's Hospice where more than 1700 patients received this drug. The commonest side effect is constipation which, the author recommends, should be anticipated and prevented by the use of laxatives. Sedation is usually a transient problem if the dose of morphine is not increased too rapidly. Nausea and vomiting appear to be less of a problem in those confined to bed and is a greater problem in women. Respiratory depression does not pose clinical problems even when morphine Side Effects of Drugs Annual 9
M.N.G. Dukes, editor 9 ElsevierSciencePublishersB.V., 1985 ISBN 0 444 90394 1 $0.85 per articleper page (transactionalsystem) $0.20 per articleper page (licensingsystem)
is being taken in large doses by patients with primary or secondary respiratory tract disease. Walsh points out that the presence of pain is itself an antagonist to respiratory depression, and suggests that an individualized, gradual approach to changes in dosage and in the morphine plasma levels consequent on oral administration perhaps allows pharmacological tolerance to the respiratory depressant effect of morphine to develop while still allowing pain to be relieved. Snir-Mor et al (3 cr) investigating the mechanisms b y which opiates cause respiratory depression postulate that morphine diminishes the sensitizing of the brainstem respiratory center to CO2 by reducing the amount of acetylcholine in the area of the respiratory center that can be released in response to hypercarbia. They found that physostigmine could reverse the respiratory depressant effect of morphine and restore the sensitivity of the respiratory center to CO2, presumably b y raising acetylcholine levels in the brain. Krause (4 c) has described a rare complication o f heroin addiction. Following attempted heroin injection into the right external jugular vein the patient, a 36-yearold male, suffered from the Brown-S6quard syndrome. A right-sided hemiparalysis with a contralateral sensory loss of touch, pain, proprioception and temperature developed over several hours, to the C3 dermatome level. A myelogram showed a vasculitis pattern in the lower cervical region. Treatment was with high-dose dexamethasone for 10 days. After 6 weeks of inpatient physical therapy, only minimal m o t o r and sensory return was seen. Although this syndrome is usually due to lateral hemisection of the spinal cord by a stab wound or a gunshot wound, in this case the authors believe that it resulted from chemical transection due to the heroin or quinine diluent or both.
64 A better-known complication of heroin addiction is pulmonary edema, and Sauder et al (5 or) report a hemodynamic study in 2 cases. In both, the severity of respiratory failure, attested by profound hypoxemia (Pao2 28 and 32 mmHg) and a metabolic and respiratory acidosis (pH 7.07 and 7.14) necessitated artificial ventilation with positive end-expiratory pressure (PEEP). Hemodynamic study revealed non-cardiogenic edema. In both cases, cardiac insufficiency was also present: in the first case its etiology remained unclear; in the second it was a complication of hyperkalemia. Nanji and Filipenko (6 cr) describe a case of methadone intoxication in a 31year-old male. The clinical manifestations were rhabdomyolysis and myogiobinuric acute renal failure. The authors point out that in most cases of drug intoxication, these features occur secondary to previous coma or prolonged immobilization. Since their patient was neither comatose nor immobilized, they suggest that a toxic action of methadone was responsible for the rhabdomyolysis. Codeine
The analgesic response to codeine of patients with postpartum uterine-cramp pain has been investigated by Bloomfield et al (7 Cr) who conducted a study comparing codeine sulfate 60 mg (N=32) and 120 mg (N=31) with aspirin 650 mg (N=34) and placebo (N=32) in hospitalized women with moderate or severe postpartum uterine cramps treated with single oral doses in a parallel, stratified, randomized, double-blind trial. Subjective reports were used as indices of response, and patients rated pain intensity, pain relief and side effects at periodic, uniformly conducted interviews for 6 hours. The most common side effects were drowsiness and dizziness; of the 4 treatments, 120 mg codeine was clearly associated with the highest incidence (18 cases drowsiness, 13 cases dizziness); nausea was the only gastrointestinal side effect reported with codeine, but the authors point out that others, e.g. constipation, might have been elucidated with a longer period of observation. In an elegant, double-blind, cross-over study, Skjelbred and I.~kken (8 cr) performed identical oral surgical procedures on 2 separate occasions with 24 outpatients.
Chapter 8
A.H. Ghodse
At one operation they were given tablets containing paracetamol + codeine phosphate (400 mg + 30 mg), and at the other plain paracetamol (400 mg). On the day of operation, 2 tablets were taken 3, 6 and 9 hours after surgery and on the following 2 days 1 tablet was taken 4 times daily. Several measurements/assessments were recorded for a paired comparison o f the postoperative courses. No increase in the analgesic effect could be demonstrated by addition of codeine to paracetamol, but on the day of operation 18 patients reported adverse effects such as nausea, dizziness and drowsiness with paracetamol + codeine, while only 3 patients experienced side effects with paracetamol alone (P < 0.001). There was a striking lack of complaints when medication stopped (days 3, 4, 5, 6 after operation). The authors admit to being surprised by the large number of complaints with paracetamol and codeine, as this combination had previously been well tolerated. They conjecture that ambulatory patients (as in this study) may be more attentive to the effects of opioids on the vestibular apparatus than patients confined to bed. There was a marked tendency towards more pronounced adverse effects in females, particularly the younger ones. Side effects due to codeine, although rarely serious, assume importance because of doubts that have been expressed about its efficacy (7 c r , 8 Cr, 9Cr). Desjardins et al (9Or), for example, in their study comparing propiram with aspirin and codeine for the treatment of dental pain, found that codeine 60 mg was not significantly superior to placebo. Nevertheless, 18 patients (out of 40) complained of side effects such as drowsiness, headache and dizziness. Pethidine (meperidine) Techniques of fetal heart monitoring continue to become more sophisticated and Barrett and Boehm (10 C) carried out a study to evaluate the effects of 3 regimens of intrapartum analgesia upon fetal heart rate characteristics. Either meperidine 50 mg (M50), meperidine 50 mg + propiomazine 20 mg (M50/P20), or meperidine 25 mg + propiomazine 10 mg (M25/P10) was given intravenously for intrapartum analgesia to 204 patients in the first stage of labor, and the effects were evaluated upon fetal heart rate variability (FHRV) and fetal heart
Opioid analgesics and narcotic antagonists
Chapter 8
rate reactivity (FHRR). Reduced FHRV is related to fetal acidosis as well as other factors such as fetal sleep, fetal tachycardia, prematurity and various drugs. In contrast, FHRR - the long-term acceleration of the fetal heart rate associated with fetal movements or uterine contractions - is apparently a good prognostic sign of fetal wellbeing. M25/P10 was found to cause a decrease in FHRV in fewer patients than M50/P20 (13.6% vs 36.5%, P < 0.005) while still providing adequate analgesia for most patients. Although M50 also caused a decrease in FHRV in fewer patients than M50/P20 (19.1% vs 36.5%, P < 0.05), it produced emesis in 20% of patients. When FHRV was minimal or moderate before the analgesic was given FHRV became absent in only 8 of 222 doses (3.6%). FHRR was lost in fewer patients given M50 than in those given M50/P20 (45% vs 71%; P <0.01); there was no significant difference between M50 and M25/ P10. The authors conclude that the effects of meperidine upon fetal heart rate characteristics are both potentiated by propiomazine and, when meperidine is given with propiomazine, dose-related. They also conclude that absent FHRV is rarely caused by meperidine; when FHRV becomes absent after meperidine administration, the patient should be fully evaluated for the possibility of fetal distress before the absence of variability is attributed to analgesia. Alfentanll Alfentanil, an analog of fentanyl, has been reviewed by Owen (11R). It is a potent opioid agonist with an onset of action 4 times as rapid as an equianalgesic dose of fentanyl. Transient hypotension may occur following alfentanil administration and significant respiratory depression will occur following administration of alfentanil doses in excess of 1000 /ag. Bradycardia, antagonized by atropine, and muscular rigidity may also occur; and if other narcotic or central nervous system depressant drugs are used concurrently with alfentanil the effects can be expected to be additive. Other side effects include nausea, vomiting and dizziness. Kay et al (12 c) made a double-blind comparison between alfentanil and fentanyl as analgesic components of anesthesia. Sixty-six women undergoing laparoscopy received methohexitone, alcuronium, nitrous oxide and oxygen, with either alfentanil
65 0.75 mg or fentanyl 0.25 mg. Ten of the patients who received alfentanil and 1 patient who received fentanyl required supplementation of anesthesia by enflurar:e. Recovery from anesthesia was similar in both groups of patients, although the onset of spontaneous breathing occurred more quickly after alfentanil. The injection of fentanyl was followed by a fall in blood pressure and the the mean minimum value for pulse rate occurring after fentanyl was slower than after alfentanil and fentanyl on 40 healthy, ceived alfentanil vomited in the immediate post-operative period, and 1 complained of abdominal pain. In another study, Scamman et al (13 c g ) compared the ventflatory and mental effects of alfentanil and fentanyl on 40 healthy, young volunteers who received intravenously, in a double-blind and random fashion, 7.5 or 15 /.tg/kg of alfentanfl, 1.5 or 3 /ag/kg of fentanyl, or saline. The ventilatory response to CO2 was measured before and at 4, 20, 30, 50, 80 and 120 minutes post-treatment. Mental and psychomotor functions were measured before and at 10, 40, 100, 130 and 180 minutes posttreatment. Low- and high-dose fentanyl caused significant respiratory depression up to 30 and 80 minutes post-treatment, respectively, while there was no depression with low-dose alfentanfl and only at 4 minutes with high-dose alfentartil. The fentanyl/ alfentanil potency ratio for respiratory depression was 13/1. High-dose fentanyl caused more intense and prolonged mental effects than other treatments. Neither drug affected learning or recall, although highdose fentanyl impaired motor activity. Nausea and vomiting rates were similar between high-dose alfentanil and low-dose fentanyl. Bovill et al (14 c R) studied the influence of high-dose alfentanil anesthesia on the electroencephalogram in 10 patients undergoing elective coronary artery surgery. Anesthesia was induced with alfentanil 125 pg/kg/h and maintained by a continuous infusion at a rate of 0 . 2 5 - 0 . 5 mg/ kg/h. It was associated with large increases in delta-activity and a reduction in higherfrequency components. There was less synchronization of the EEG than is observed with fentanyl or sufentanil. Spindle activity was prominent in 70% of patients. The changes in the EEG during recovery tended to occur abruptly, and there was no obvious correlation between the EEG and plasma concentrations of alfentanil.
66
Fentanyl Chest wall rigidity is a recognized complication o f fentanyl anesthesia (SED-10, 125) and because high-dose fentanyl anesthesia is often employed for patients with cardiac disease, this side effect assumes greater significance. Muller et al (15 c r ) undertook a study to determine the hemodynamic and arterial blood gas changes caused by fentanyl rigidity. They found that although rigidity did not last longer than 3 minutes in any patient, there were large individual decreases in Pao 2 during the period of rigidity, perhaps due to increased oxygen consumption due to intense muscle contraction. The only significant change in the measured hemodynamic data was a pulmonary artery diastolic pressure which increased significantly during the period of rigidity. The authors comment that these fentanyl-induced effects can be detrimental to the patient with cardiac disease and demonstrate the need for aggressive preventive measures. Safwat and Daniel (16 c) reported the case o f a 79-year-old woman who had a grand mal seizure following the administration of fentanyl 200/ag in the course of anesthetic induction. The authors emphasize the small dose of fentanyl that produced the fit, and the fact that diazepam 5 mg administered just before the fentanyl had failed to prevent the convulsion. This case-report prompted another about a 17-year-old man who also had a grand-mal seizure following an even smaller dose (100 /ag) of fentanyl (17c). In an elegant investigation, Bent et al (18 c r ) studied the effect of the administration of fentanyl 50 pg/kg body weight on the established metabolic response to pelvic surgery. In comparison with a control group o f patients in whom anesthesia was supplemented with halothane, fentanyl was associated with significant decrease in blood lactate concentration and heart rate. There were no significant differences in blood glucose, plasma non-esterifled fatty acids, and plasma cortisol values between the 2 anesthetic techniques. It is concluded that the administration of highdose fentanyl has little effect on the estabfished metabolic response to surgery, compared with the marked changes observed when the same dose is given before the onset of surgical stimulation, when it prevents the increases in glucose, lactate,
Chapter 8
A.H. Ghodse
cortisol and growth hormone normally associated with surgical techniques. In their comprehensive review of the postoperative respiratory complications of opiates, Bennett and Adams (19 R) emphasize the risk of delayed respiratory depression following fentanyl anesthesia.
Sufentanil Sufentanil citrate has been comprehensively reviewed by Roscow (20R). It is another potent analog of fentanyl and appears to be a typical pure opioid agonist, highly selective for mu-receptors, and producing the typical spectrum o f opioid effects. The major side effects are truncal rigidity and prolonged respiratory depression. In doses o f 4 - 3 0 /tg/kg, sufentanil produces hypnosis and suppresses most hemodynamic and hormonal responses to surgery without producing significant cardiovascular depression. In this respect, sufentanfl and fentanyl have clear advantages over morphine, pethidine and potent inhalation anesthetics. Compared to fentanyl, sufentanil has a more rapid onset and shorter duration o f action; the author points out that due to extensive redistribution of lipophilic drugs, large quantities are still present in muscle and other tissues at the time o f awakening. Increased perfusion of muscle beds during the wake-up period may cause a secondary rise in plasma opioid levels, and one must assume that a delayed onset of respiratory depression may occur with sufentanil as with fentanyl. Propoxyphene Although the dependence liability of propoxyphene has been recognized in the past (SED-10, 124), there have been comparatively few case-reports. D'Abadie and Lenton (21 c) describe 6 cases in which the patients presented difficult treatment problems. The patients' subjective discomfort and concomitant craving during gradual withdrawal o f the drug were more intense and more poorly tolerated than those observed with other narcotic analgesic agents and, of the 6 patients, only 1 achieved successful detoxification. In contrast, Johnson and Bohan (22 c) achieved successful detoxification of a 45year-old woman with a long history (5 years) of propoxyphene abuse. Administration of clonidine over a 9-day period reduced or
Opioid analgesics and narcotic antagonists
Chapter 8
eliminated most of the symptoms of prop o x y p h e n e withdrawal, namely nausea, vomiting, agitation, tremulousness, muscle cramping, headaches and seizures. Clonidine has previously been used for withdrawal from other opiates (SED-10, 121). Hasday and Weintraub (23 c R ) accomplished morphine withdrawal b y propoxyphene substitution in 4 children with iatrogenic morphine sulfate tolerance and dependence. One child experienced increasing lethargy and respiratory depression and responded to naloxone hydrochloride and a decrease in the dose of propoxyphene; another had transient agitation, which may have been related to high levels o f propoxyphene. The authors, reviewing other literature, report that untoward effects of high-dose propoxyphene therapy include dysphasia, slurred speech, sedation, visual hallucinations and toxic psychosis. In his review paper of d e x t r o p r o p o x y phene overdosage, Young (24 R) considers the adverse effects o f both long-term excessive dosage and acute overdosage. In the former, he too describes a psychotic state that may be associated with confusion, stammer, ataxia, diplopia and vertigo. However, intravenous abuse of the drug is not possible for more than 12 days because it is very destructive to the veins and other soft tissues. Acute overdosage with dextroprop o x y p h e n e produces clinical signs in many body systems: central nervous system constricted pupils, fits, coma; cardiovascular system - tachycardia, hypertension or hypotension, stroke, cardiac conduction defects, cardiac arrest; respiratory system depression, respiratory arrest; gastrointestinal system - vomiting. The cardiac effects are thought to be due to the local anesthetic properties o f dextropropoxyphene and its metabolite, norpropoxyphene; they are not reversed by naloxone (25R). Young (24 R) comments that rapid absorption of the drug may explain why cardiorespiratory arrest may occur as soon as 15 minutes after drug ingestion; and that slow elimination of norpropoxyphene may account for the unpredictability o f the course of poisoning in the first 24 hours. Rapid absorption is a property of dextropropoxyphene hydrochloride. The napsylate salt is more slowly absorbed and is acutely less toxic than the hydrochloride, at least in animals (25R). Turner (27 r) has sug-
67 gested that the risk of death from overdose could be reduced if the drug was available as the napsylate rather than the hydrochloride. The hepatotoxicity of d e x t r o p r o p o x y p h e n e has been well reviewed b y the Swedish Adverse Drug Reactions Committee (28 R) who comment that reactions chiefly concern combination with an antipyretic and/or muscle relaxant. Of the muscle relaxants, chlorzoxazone is combined with dextropropoxyphene in Paraflex comp. The first reports of reversible h e p a t o p a t h y in connection with d e x t r o p r o p o x y p h e n e and chlorzoxazone were received b y the Committee in 1970 (Paraflex comp.) Since then a total of 13 reports have been submitted for Paraflex comp. and 10 for other drugs. The dosage of the various preparations containing dextropropoxyphene and chlorzoxazone varied from 1 to 8 tablets/24 hours. Characteristic signs of biliary stasis usually appeared 1 - 5 weeks after the start of treatment. In most cases, liver tests showed markedly increased alkaline phosphatase concentrations, accompanied b y a slight to marked elevation of transaminase levels. Icterus occurred in many cases. In 2 patients the symptoms appeared after treatment for just a few days. One o f them had definitely been exposed to dextropropoxyphene earlier and the picture here included exanthema, which suggests an earlier sensitization. One other patient had concurrent exanthema. Laparotomy was performed in 2 patients to rule out extrahepatic biliary stasis. In a third case the presence of intrahepatic biliary stasis was verified b y puncturing the liver. Two of these verified cases concerned Paraflex comp. and 1 case Distalgesic. Symptoms subsided soon after the medicine had been withdrawn and liver tests normalized after some weeks. In 1 patient, re-exposure to Doloxene led to icterus and elevated transaminase levels. When combination drugs are involved, it can be difficult to tell which agent may have caused a hepatic reaction. There do not seem to be any earlier reports of liver damage from phenazone, phenacetin, carteine or phenprobamate. Neither does acetylsalicylic acid or paracetamol - in the low doses used in the reported cases - give rise to the t y p e of hepatic reaction described above. The authors conclude that d e x t r o p r o p o x y p h e n e can elicit a hepatocanalicular reaction,
68 which may represent a hypersensitivity reaction. At the same time, there are several cases where ehiorzoxazone cannot be ruled out as a cause. Neither can one exclude the possibility that d e x t r o p r o p o x y p h e n e and chlorzoxazone may have an additive effect. Recently, new combinations containing dextropropoxyphene, but not chlorzoxazone, have been prescribed on a larger scale than Paraflex t e m p . (consumption statistics from the National Corporation of Swedish Pharmacies), whereas it is the latter drug that dominates the number of reported cases.
EPIDURAL AND INTRATHECAL ADMINISTRATION O F OPIATES Brownridge et al (29 c) describe a case of profound respiratory depression following accidental subarachnoid pethidine. The patient was a 24-year-old gravida 3 who had an elective cesarean section and tubal ligation under combined epidural and subarachnoid block. Nine hours after the insertion o f the block the patient requested a second dose of analgesia and epidural pethidine 50 mg in saline 10 ml was administered as it had been 4 hours previously without any ill-effect. However, on this second occasion, although pain relief was rapid and immediate, the patient felt nauseated and vomited, and within 5 minutes became drowsy and was taking slow, deep, gasping breaths. She became unconscious and her pulse rate dropped to 50. Intermittent positive pressure ventilation was applied b y face-mask and A m b u bag, and atropine 0.6 mg followed b y naloxone 0.4 mg was administered intravenously. Spontaneous respiration returned within 2 minutes and after a period of drowsiness and another episode of vomiting, recovery was uneventful. X-Ray screening confirmed that the epidural catheter was in the subarachnoid space. The authors discuss whether the catheter was misplaced at the outset or subsequently 'migrated' into the subarachnoid space, and whether rostral spread of the hypobaric pethidine solution would have been facilitated by the patient's sitting position. Whatever the mechanism, they emphasize the need for the ready availability of a narcotic antagonist and suggest that acute onset of vomiting should perhaps be regarded as a warning sign.
Chapter 8
A.H. Ghodse
The efficacy of epidurat morphine during labor and delivery was assessed by Hughes et al (30 cR) in 40 healthy parturients who were randomly given either a single injection o f morphine sulfate (2 rag, n=9; 5 mg, n=10; or 7.5 mg, n=l 1) or 0.5% bupivacaine (n=10). The only side effect was pruritus, which occurred in 3 patients. Epidural morphine did not produce neonatal depression, as evidenced by Apgar scores and neurological and adaptive capacity scores. The authors reviewed other studies using epidural morphine, in which side effects were reported more commonly. One problem associated with long-term use of epidural opiates (and indeed the limiting factor in their successful application for chronic therapy) is the development of spinal tolerance, manifested by 'analgesic tachyphylaxis'. It was apparently reported that this could be reversed with epidural local anesthetics. Coombs (31 c) however, was unable to achieve such a reversal and points out that given the likely biochemical basis for opiate tolerance and the time required to reverse this in animal models such a reversal is theoretically unlikely. In an interesting case report he describes a 60year-old patient treated over a 2-week period with increasing doses of epidural morphine to control pain due to carcinoma of the lung with brachial plexus invasion. Subsequently, attempts to control the pain with parenteral morphine resulted in rapid tolerance to even massive doses of morphine (up to 175 me/h). An unusual side effect was reported by Pickar et al (25 cr) in a patient with a disseminated malignancy who received 3 mg of synthetic ~-endorphin administered intrathecally b y lumbar puncture. A marked behavioral syndrome, characterized b y confusion, hypomanic/manic behavior and psychosis, followed drug administration and persisted for more than 2 days. The authors conjecture that the unique effects of /~endorphin in their patient may have been related to the stimulation of specific populations of opiate receptors by pharmacological doses of an endogenous llgand and the relatively long half-life o f ~-endorphin when administered directly into the cerebrospinal fluid. The side effects o f epidural buprenorphine included difficulties with micturition, nausea and vomiting, and itching; they occurred 3 times less frequently than with epidural morphine (32c).
Opioid analgesics and narcotic antagonists Chapter8 DRUG DEPENDENCE IN PREGNANCY
(SED-IO, 121; SEDA-8, 83) In a long-term study of children born to drug-dependent mothers, Olofsson et al (33 er) investigated 89 infants born to mothers addicted to heroin, morphine and methadone. They found that 20% were pre-term and 31% were Hght for gestational age. Mean gestational age and birth weight were lower in infants of mothers who had taken mainly heroin or morphine than in infants of mothers who had taken mainly methadone. Pre-term labor was more frequent amongst women who had been acutely withdrawn on methadone within the last m o n t h before birth than amongst women who were maintained on methadone at birth. Eighty-five percent of the newborns had withdrawal symptoms and 12% had convulsions, the severity of which did not correlate with the type of drug abuse. The duration of withdrawal, however, correlated with the amount of methadone taken by the mother at birth. Twenty percent had signs of perinatal asphyxia and had an increased frequency of neonatal convulsions. The authors comment that these babies represent a special high-risk group of newborns. Seventy-two of these 89 children were then reinvestigated 1 - 1 0 years after birth (34CR). Only 25% were found to be physically, mentally and behaviorally normal; 56% were hyperactive and aggressive, with a lack of concentration and social inhibition; 10% had a severely and 11% a moderately impaired psychomotor development, due mainly to deprivation; 43% of the children had been removed from their mother by the Courts. These findings indicate to the authors that there is an urgent need for politicians, social welfare and health personnel to re-examine their roles in helping these children, who will otherwise develop into a new generation of social losers. NARCOTIC ANTAGONISTS
Naloxone There have now been several reports of adverse effects following naloxone. They include hypertension, pulmonary edema, ventricular arrhythmias and cardiac arrest (SEDA-5-8). Taft (35 cr) now reports a case of pulmonary edema after naloxone in
69
a healthy 26-year-old male without heart disease who was anesthetized with fentanyl for an operative arthroscopy. Postoperatively a total dose of naloxone 0.3 mg was given, but Taft emphasizes that the recommendations for smaller, incremental doses ( 0 . 0 4 - 0 . 0 8 mg) over a longer period ( 5 - 1 0 min) were followed.
A G O N I S T - A N T A G O N I S T OPIOIDS
Bupre'norphine Despite early optimism about the lack of abuse potential of buprenorphine (SEDA-4 and 5), its increasing use has been followed by reports of addiction (36crt). Richert et al (37 cr) report on 3 such cases. The drug dependence developed following treatment for pain caused by an organic disease in 2 cases and a psychosomatic disease in the others. Nevertheless, buprenorphine is being widely used as an analgesic in a variety of situations. Rifat et (38 c R ) injected buprenorphine (5 /ag/kg i.v.) into 25 non-premedicated patients 30 minutes before laparoscopic sterilization under general anesthesia. Following the intravenous injection, no significant modification of the arterial systolic and diastolic blood pressure was observed, but postoperative bradycardia occurred. Tidal volume and minute ventilation decreased, whereas the respiratory rate remained stable. Arterial blood gas analysis showed slight hypoxemia, and a significant rise in Paco2 with postoperative acidosis similar to that in the control group. Good postoperative analgesia was achieved, but with profound sedation and a high incidence of nausea and vomiting. In a randomized double-blind study comparing postoperative buprenorphine (0.3 mg i.v.) with pentazocine (30 mg i.v.) (39CR), 60 patients who had undergone epigastric and hypogastric interventions under thiopental-sodium-induced halothane anesthesia received intravenous injections of 1 of the 2 analgesics as soon as they requested a pain killer. The respiratory rate (19.5 --* 17.5 min) decreased significantly and continuously under buprenorphine (20.8 --* 13.5/min) and both buprenorphine and pentazocine caused increases of Paco2 (buprenorphine 37.3 -+ 46.8 mmHg; pentazocine 36.3 --* 43.0 mmHg), values greater
Chapter 8 A.H. Ghodse
70 than 50 mmHg being attained in individual cases. Side effects observed after buprenorphine were marked sedation and occasional sweating and heat sensation. The authors comment t h a t buprenorphine represents a valuable addition to postoperative pain therapy by virtue o f its strong analgesic efficacy, long duration of action and practicable application, with side effects otherwise typical for opiates. A previously unreported side effect o f buprenorphine has been described by Lock'hart and Baron (40 c) in a brief case-report. A woman aged 82 developed a painless 2-cm diameter ulcer on the upper surface of her tongue 4 days after starting buprenorphine which she put on rather than under her tongue. The ulcer had a deep base and a well-demarcated border and caused dysphagia and oropharyngeal erythema. Candida was cultured from the ulcer. Although she was taking other drugs, she was seen to swallow these. Butorphanol (SED-IO, 131; SEDA-8, 84) Butorphanol is now being used more frequently as the intravenous analgesic component o f nitrous o x i d e - n a r c o t i c - o x ygen anesthesia and Stanley et al (41Cr) studied the cardiovascular effects of high doses o f butorphanol ( 0 . 3 - 0 . 4 5 mg]kg) plus 60% nitrous oxide anesthesia in 17 patients undergoing elective gastric or gall bladder surgery. Butorphanol and nitrous oxide produced unconsciousness with only small decreases in heart rate and cardiac output, but did not result in sufficient analgesia to block or treat stimulation of the cardiovascular system secondary to tracheal intubation or surgical incision, even when supplemented with additional butorphanol to high cumulative dose levels (1.0 mg/kg). The data suggest that even high-dose butorp h a n o l - n i t r o u s oxide anesthesia requires supplementation with other anesthetics or anesthetic adjuvants to prevent cardiovascular stimulation during general abdominal surgery. Sung et al (42 c) carried out a retrospective study to compare butorphanol (12 cases), with morphine (9 cases) in a balanced anesthetic technique with nitrous oxide, oxygen and neuromuscular relaxants. Patients in the butorphanol group proved to have less postoperative respiratory depression as determined by PaCe 2 on arrival in
the recovery room (42.8 vs 51.1 mmHg). The patients who received butorphanol also had less nausea (8.3 vs 44.4%) and less vomiting (8.3 vs 33.3%) than those given morphine. Neither group had any recall o f procedure, hallucination or dysphoria as determined by postoperative interview. The small number of patients in this retrospective study o f case-notes emphasizes the authors' own comment that a prospective controlled double-blind comparison o f butorphanol and morphin e is necessary before firm conclusions can be drawn. Nalbuphine
(SED-IO, 131; SEDA-8, 85)
Nalbuphine is another opiate a g o n i s t antagonist and, in view o f its increasing use, Errick and Heel (43 R) have produced a timely review of its pharmacological properties and therapeutic efficacy. They comment that after parenteral administration o f 'usual' doses, it is approximately equipotent in analgesic activity to morphine on a weight basis. In studies with patients in moderate to severe pain, usually following surgery, the characteristics o f analgesia with nalbuphine were comparable to those seen with equianalgesic doses of morphine or pentazocine. It also appears to produce satisfactory anesthesia when used as a component of a 'balanced' anesthesia technique, although a relatively low 'ceiling' effect for reduction o f anesthetic requirements with nalbuphine may limit its usefulness in this regard. As with other a g o n i s t - a n t a gonist analgesics, a 'ceiling' effect to nalbuphine-induced respiratory depression is also seen, beyond which further depression does not readily occur. However, with usual analgesic doses, respiratory depression seen with nalbuphine is comparable to that with morphine. Important h e m o d y n a m i c changes have not occurred after usual doses of nalbuphine, even in patients with cardiac disease. Like other agonist-antagonist analgesic drugs, the abuse potential of nalbuphine seems relatively low, but only wider clinical use for longer periods can establish this with certainty. The most frequent adverse effect appears to be sedation, with an overall incidence estimated to be about 36%, whereas nausea and vomiting, another relatively frequent side effect, occurs in about 6% o f cases. Infrequent psychotomimetic reactions (hallucinations, depersonalization, feelings of unreality,
Opioid analgesicsand narcotic antagonists Chapter8 delusions and dysphasia) have also been reported (<1%). Other side effects include 'sweaty' or clammy feelings, dizziness, vertigo, dry mouth and headache. Transient burning at the site of intravenous injection has also been reported. After long-term administration (up to 32 weeks) the only noted side effects were sedation and confusion. Yanulevich (44 Cr) has reported the findings of a study in which nalbuphine was used as a component of a balanced anesthetic technique in 100 female patients undergoing laparoscopy and tubal ligation; nalbuphine 0.2 mg/kg appeared a safe and effective analgesic with cardiovascular stability and a lack of marked respiratory depression. The majority of patients experienced no adverse side effects, but amongst those reported were dizziness (15%), light-headedness (12%) and blurred vision (12%). One feature of nalbuphine that the authors felt warranted further investigation was the moderate sedation experienced by 82% of patients. Pentazocine At the recommendation of the World Health Organization (WHO), the United Nations (UN) Commission on Narcotic Drugs at its eighth special session in February, 1984, decided to place pentazocine under international control (Schedule 111 of the 1971 Convention on Psychotropic Substances). Perceptual disturbances following pentazocine administration are generally believed to occur more often than after the use of other opiates (SED-10, 130), although the evidence for this assumption is not clear. In their study of the incidence of postoperative dreaming following the use of morphine and pentazocine as prenaedicants, Jago and Restall (45 Cr) found no statistically significant difference between the 2 drugs. The causes of psychotominaetic problems in the postoperative period and the difficulty of precise definition of hallucinations are discussed and the authors comment that although all potent analgesics have the potential to provoke psychotomimetic side effects, case-reports tend to implicate newer ones more often than their wellknown counterparts. They believe that this probably reflects the current tendency to analyze any innovation critically, while accepting traditional doctrine at face value.
71
Heaney and Gotlieb (46 r report the case of a patient with agranulocytosis after intravenous abuse o f pentazocine (Talwin) and tripelennamine (pyribenzamine, PBZ). They point out that because intravenous abuse o f these 2 agents is increasing, agranulocytosis may be seen more often. When pentazocine abuse involves intramuscular injections, local complications are not infrequent. Two further cases of fibrous nayopathy with severe joint restriction have been reported by Roberson and Dimon (47 c) and by Adams et al (48 c) who discuss the mechanism of the condition. Stacher et al (49 CR) investigated the effects of single oral doses of meptazinol 100, 200 and 400 nag in comparison with pentazocine 50 and 100 mg and with placebo on experimentally induced pain. Side effects were similar for naeptazinol and pentazocine and the number o f subjects reporting side effects increased with increasing dose o f both drugs. Tiredness, light-headedness and dizziness were reported most frequently. Mild euphoria was reported once after naeptazinol 100 nag and twice after each of the 2 higher naeptazinol doses, compared to 3 times after pentazocine 100 nag. Mild dysphoria was reported by 1 subject after naeptazinol 400 nag, whereas after pentazocine 100 rag 1 subject complained of severe dysphoria. The latter reaction was the only severe adverse effect reported or observed in the entire study. Ciramadol The efficacy and s~de effects of ciramadol, a comparatively new synthetic analgesic with mixed agonist-antagonist properties, has been explored in three studies. Fragen et al (50 Cr) studied ciranaadol in the management o f postoperative pain in 139 patients given single, doubleblind, intramuscular injections o f either 30 nag ciranaadol, 60 nag ciranaadol, l 0 nag morphine or 0.9% saline on the first or second postoperative day. Differences in pain intensity and relief of pain, changes from baseline on a pain analog scale, percentage of patients with moderate or greater pain relief, and cumulative treatment failures were measured for 6 hours after injection. Morphine proved to be superior to all other treatments, and neither dose of ciranaadol could be statistically differentiated from placebo. During the first hour after administration, some measurements showed that
72 30 mg ciramadol was superior to 60 mg ciramadol. Patients experienced little or no drowsiness in any of the 4 groups; other side effects were transient. However, the incidence of nausea (12 cases) and vomiting (6 cases) was significantly higher in the patients receiving 60 mg ciramadol than in the other treatment groups, and was severe enough to require treatment in 6 cases. The authors point out that their results should be interpreted in the light o f the fact that some patients had been receiving narcotic analgesics before entering the study, and suggest that antagonism of the residual effect o f the previous narcotic by ciramadol might account for an acute increase in pain intensity experienced by some patients after administration o f 60 nag ciramadol. Further, better-designed studies would be necessary to clarify this point, but it should be remembered that hy.peralgesia after opioid analgesics is not a new phenomenon and alternative hypotheses have been put forward (SEDA-7, 82; SEDA-8, 76). Oral ciramadol has been compared with oral codeine in 2 separate studies. In the first, a randomized double-blind trial was carried out in 54 women to evaluate the effectiveness o f ciramadol in a single (60 or 30 nag) oral dose regimen, compared with 60 mg codeine and placebo, in the treatment o f post-episiotomy pain. Ciramadol gave a significantly better analgesic effect, at b o t h 2 and 6 hours, and produced negligible side effects, limited to 1 case o f transient dizziness (51c). In the second study, 180 patients received 1 o f 3 oral analgesics (ciramadol 20 mg, ciramadol 60 mg or codeine 60 mg) on a double-blind random basis for the relief o f pain 2 4 - 4 8 hours after
Chapter 8 A.H. Ghodse major general surgical, gynecological or orthopedic operations. All 3 analgesics proved equally effective and caused mild sedation only. No patient showed signs of clinical cardiorespiratory depression, and other side effects were infrequent. They included dizziness, giddiness, headache, nausea and vomiting, but occurred no more frequently after ciramadol than after codeine. Downing et al (52 C) concluded that ciramadol may prove a useful clinical alternative to conventional oral analgesics, provided its lack of respiratory depressant properties and addiction potential in monkeys can be substantiated in man.
Propiram The relative analgesic efficacy of propiram fumarate, codeine, aspirin, and placebo in post-irnpaction dental pain was evaluated in 159 patients by a single-dose, double-blind, stratified, parallel-group study (9Or). Pripiram 50 rag produced a level of analgesia approaching that of 650 nag aspirin in peak effect, total effect and duration o f action, and was statistically superior to 60 nag codeine and placebo for every measure of analgesic efficacy. Several mild adverse effects were observed; however, they appeared to be evenly distributed amongst the active treatments. Drowsiness was reported by 13 patients out of the 40 who received propiram, but many had received intravenous dlazepam preoperatively, making the significance of these symptoms difficult to interpret, Other, rarely reported, side effects of propiram were headache (3 cases), nausea (3 cases), dizziness (1 case) and double vision (1 case).
REFERENCES 1. Bullingham RES (1983) Opiate development: new opiates and the future. Clin. Anaesthesiol., 1/1,139. 2. Walsh TD (1984) Oral morphine in chronic cancer pain. Pain, 18/1, 1. 3. Snir-Mor I, Weinstoek M, Davidson JT, Bahar M (1983) Physostigmine antagonizes morphineinduced respiratory depression in human subjeets. Anesthesiology, 59/1,6. 4. Krause GS (1983) Brown-Sequard syndrome following heroin injection. Ann. Emerg. Med., 12,581. 5. Sander Ph, Kopferschmitt J, Flecsh F et al (1983) Heroin induced pulmonary edema: hemodynamic study in two cases. Toxicol.
Eur. Res., 5/1, 37. 6. Nanji AA, Filipenko ]D (1983) Rhabdomyolysis and acute myoglobinuric renal failure associated with methadone intoxication. J. Toxicol. Clin. ToxicoL, 20/4, 353. 7. Bloomfield SS, Cissell GB, Mitchell J, Barden TP (1983) Codeine and aspirin analgesia in postpartum uterine cramps: qualitative aspects of quantitative assessments. Clin. Pharmacol. Ther., 34/4,488. 8. Skjelbred P, l.~kken P (1982) Codeine added to paracetamol induced adverse effects but did not increase analgesia. Br. J. Clin. Pharmacol., 14, 539. 9. Desjardins PJ, Cooper SA, Gallegos TL et al
Opioid analgesics and narcotic antagonists
Chapter 8
(1984) The relative analgesic efficacy of propiram fumarate, codeine, aspirin, and placebo in post-impaction dental pain. Z Clin. Pharmacol., 24/1, 35. 10. Barrett JM, Boehm FH (1983) Fetal heart rate response to meperidine alone and in combination with propiomazine. South. Med. J., 76/12, 1480. 11. Owen RT (1984) Alfentanil. Drugs Today,
2o/1, lO. 12. Kay B, Chen AT, Shaw F, Healy TEJ (1983) Anaesthesia for laparoscopy: alfentanfl and fentanyl compared. Ann. R. Coll. Surg. Engl.,
65/5,316. 13. Scamman FL, Ghoneim MM, Korttila K (1984) Ventilatory and mental effects of alfentanil and fentanyl. Acta Anaesthesiol. Scand., 28/1, 63. 14. BoviU JG, Sebel PS, Wauquier A e t al (1983) Influence of high-dose alfentanil anaesthesia on the electroencephalogram: correlation with plasma concentrations. Br. J. Anaesth., Suppl, 55, 199S. 15. Muller BJ, Hill AB, Fletcher IR, Lowrey BA (1984) Adverse hemodynamic and ventilatory effects of fentanyl induced chest wall rigidity. Anesthesiol. Rev., 11, 12. 16. Safwat AM, Daniel D (1983) Grand mal seizure after fentanyl administration (Letter to Editor). Anesthesiology, 59/1, 78. 17. Hoien AO (1984) Another case of grand mal seizure after fentanyl administration. Anesthesiology, 60/4, 387~ 18. Bent JM, Paterson JL, Mashiter K, Hall GM (1984) Effects of high-dose fentanyl anaesthesia on the established metabolic and endocrine response to surgery. Anaesthesia, 39/1, 19. 19. Bennett MRD, Adams AP (1983) Postoperative respiratory complications of opiates. Clin. Anaesthesiol., 1/1, 41, 20. Rosow CE (1984) Sulfentanil citrate: a new opioid analgesic for use in anesthesia. Pharma-
cotherapy, 4, 11. 21. D'Abadie NB, Lenton JD (1984) Propoxyphene dependence: problems in management. South. Med. J., 77/3, 299. 22. Johnson DA, Bohan ME (1983) Propoxyphene withdrawal with clonidine. Am. Z Psychiatry, 140, 1217. 23. Hasday JD, Weintraub M (1983) Propoxyphene in children with iatrogenic morphine dependence.Am. J. Dis. Child., 137, 745. 24. Young ILl (1983) Dextropropoxyphene overdosage - pharmacological considerations and clinical management. Drugs, 26/1, 70. 25. Pickar D, Dubois M, Cohen MR (1984) Behavioral change in a cancer 9atient following intrathecal #-endorphin administration. A n t J. Psychiatry, 141/1, 103. 26. Nickander RC, Emmerson JL, Hynes MD et al (1984) Pharmacological and toxic effects of dextropropoxyphene and its major metabolite n?rpropoxyphene: a review. Hunt Toxicol.,
73
.~, Suppl, 13 S. 27. Turner P (1984) Final Remarks - Distalgesic Symposium. Hum Toxicol., 3, Suppl, 237S. 28. Swedish Adverse Drug Reaction Committee (1980), Hepatic effect of analgesic containing dextropropoxyphene and/or chlorzoxazone: report. 29. Brownridge P, Wrobel J, Watt-Smith J (1983) Respiratory depression following accidental subarachnoid pethidine. Anaesth. Intensive Care,
11,237. 30. Hughes SC, Rosen MA, Shnider SM et al (1984) Maternal and neonatal effects of epidural morphine for labor and delivery. Anesth. Analg. {Cleveland), 63/3, 319. 31. Coombs DW (1983) Mechanism of epidural lidocaine reversal of tachyphylaxis to epidural morphine analgesia. Anesthesiology, 59/5, 486. 32. Sardnal F, Maneglia R, Cousin MTh (1983) Analg6sie par voie p6ridurale: comparaison de la morphine et de la bupr6norphine. Cah. Anesth~siol., 31/5, 459. 33. Olofsson M, Buckley W, Andersen GE, Friis-Hansen B (1983) Investigation of 89 children born by drug-dependent mothers. I. Neonatal course. Acta Paediatr. Scand., 72, 403. 34. Olofsson M, Buckley W, Andersen GE, FriisHansen B (1983) Investigation of 89 children born by drug-dependent mothers. II. Follow-up 1 - 1 0 years after birth. Acta Paediatr. Scand., 72, 407. 35. Taft RH (1983) Pulmonary edema follwing naloxone administration in a patient without heart disease. Anesthesiology, 59/6, 576, 36. Benos J (1983) A case of addiction to buprenorphine. Nervenarzt, 54, 259. 37. Richert S, Straub A, Von Arnim A e t al (1983) Drug dependence on buprenorphine. Miinch. Med. Wochenschr., 125/51, 1195. 38. Rifat K, Magnin C, Morel D (1984) L'analg6sie per et postop6ratoire ~ la bupr6norphine: effets cardio-circulatoires et respiratoires. Cah. Anesth~siol., 32/1, 33. 39. Piepenbroek S, Zenz M, Gorus R e t a l (1983) Buprenorphine and pentazocine in postoperative analgesia: a double-blind study following abdominal surgery. Anaesthesist, 32/12, 601. 40. Lockhart SP, Baron JH (1984) Tongue ulceration after lingual buprenorphine. Br. Med. J., 288, 1346. 41. Stanley TH, Reddy P, Gilmore S, Bennett G (1983) The cardiovascular effects of high-dose butorphanol-nitrous oxide anaesthesia before and during operation. Can. Anaesth. Soc. J., 50, 337. 42. Sung Y-P, Weistein S, Ghani GA (1984) Balanced anesthesia: a comparison of butorphanol and morphine. South. Med. J., 77/2, 180. 43. Errick JK, Heel RC (1983) Nalbuphine a preliminary review of its pharmacological properties and therapeutic efficacy. Drugs, 26, 191.
74 44. Yanulevich J (1983) Outpatient anesthesia with -nalbuphine hydrochloride. J. Am. Assoc. Nurse Anesth,, 51/4, 395. 45. Jago RH, RestaU J (1983) Postoperative dreaming: a comparison of the incidence following pentazocine and morphine premedication. Anaesthesia, 38, 438. 46. Heaney RM, Gotlieb N (1983) Granulocytopenia after intravenous abuse of pentazocine and tripelennamine ('Ts and Blues').
South. Med. J., 76/5,654. 47. Roberson JR, Dimon JH (1983) Myofibrosis and joint contractures caused by injections of pentazocine. J. Bone Joint Surg. Set. A, 65/7, 1007. 48. Adams BM, Morowits HW, Sundstrom WR (1983) Fibrous myopathy in association with pentazocine. Arch. Intern. Med., 143/11, 2203. 49. Stacher G, Steinringer H, Winklehner S e t al
Chapter 8 A.H. Ghodse (1983) Effects of graded and oral doses of meptazinol and pentazocine in comparison with placebo on experimentally induced pain in healthy humans. Br. J. Clin. Pharmacol., 16/2, 149. 50. Fragen RJ, Kouzmanoff RN, Caldwell NJ (1983) Intramuscularly administered ciramadol for management of postoperative pain: a comparative study. J. Clin. Pharmacol., 23/5-6, 219. 51. Defoort P, Thiery M, Martens G, Van Maele G (1983) A double-blind trial of single-dose ciramadol for the treatment of post-episiotomy pain. Curt. Med. Res. Opin., 8/7, 481. 52. Downing JW, Brock-Utne JG, Holloway AM (1983) Ciramadol - a new synthetic analgesic: a double-blind comparison with oral codeine for postoperative pain relief. S. Aft. Med. J., 64/25, 978.
8
Opioid analgesics and narcotic antagonists
Newer opiate drugs have been reviewed by Bullingham (1 R) who claims that with the advent of mixed agonist-antagonist drugs a low-abuse potential has become a reality. One can only hope that such optimism will be confirmed with the passage of time. Unfortunately, all of the newer opiate drugs cause the undesirable side effects of ventilatory depression. The mixed a g o n i s t s antagonists do display a limitation of respiratory depression as the dose increases, but it is not clear when, and at what level of effect, analgesia will also reach a ceiling. The complete separation of analgesia and respiratory depression is still an unattained goal. OPIOID AGONISTS
Morphine, heroin, methadone Extensive clinical experience has been obtained in the use of opiates during the last decade in special units devoted to symptom control in advanced cancer; Walsh (2 c R ) summarized clinical experience in the use of oral morphine for cancer pain at St. Christopher's Hospice where more than 1700 patients received this drug. The commonest side effect is constipation which, the author recommends, should be anticipated and prevented by the use of laxatives. Sedation is usually a transient problem if the dose of morphine is not increased too rapidly. Nausea and vomiting appear to be less of a problem in those confined to bed and is a greater problem in women. Respiratory depression does not pose clinical problems even when morphine Side Effects of Drugs Annual 9
M.N.G. Dukes, editor 9 ElsevierSciencePublishersB.V., 1985 ISBN 0 444 90394 1 $0.85 per articleper page (transactionalsystem) $0.20 per articleper page (licensingsystem)
is being taken in large doses by patients with primary or secondary respiratory tract disease. Walsh points out that the presence of pain is itself an antagonist to respiratory depression, and suggests that an individualized, gradual approach to changes in dosage and in the morphine plasma levels consequent on oral administration perhaps allows pharmacological tolerance to the respiratory depressant effect of morphine to develop while still allowing pain to be relieved. Snir-Mor et al (3 cr) investigating the mechanisms b y which opiates cause respiratory depression postulate that morphine diminishes the sensitizing of the brainstem respiratory center to CO2 by reducing the amount of acetylcholine in the area of the respiratory center that can be released in response to hypercarbia. They found that physostigmine could reverse the respiratory depressant effect of morphine and restore the sensitivity of the respiratory center to CO2, presumably b y raising acetylcholine levels in the brain. Krause (4 c) has described a rare complication o f heroin addiction. Following attempted heroin injection into the right external jugular vein the patient, a 36-yearold male, suffered from the Brown-S6quard syndrome. A right-sided hemiparalysis with a contralateral sensory loss of touch, pain, proprioception and temperature developed over several hours, to the C3 dermatome level. A myelogram showed a vasculitis pattern in the lower cervical region. Treatment was with high-dose dexamethasone for 10 days. After 6 weeks of inpatient physical therapy, only minimal m o t o r and sensory return was seen. Although this syndrome is usually due to lateral hemisection of the spinal cord by a stab wound or a gunshot wound, in this case the authors believe that it resulted from chemical transection due to the heroin or quinine diluent or both.
64 A better-known complication of heroin addiction is pulmonary edema, and Sauder et al (5 or) report a hemodynamic study in 2 cases. In both, the severity of respiratory failure, attested by profound hypoxemia (Pao2 28 and 32 mmHg) and a metabolic and respiratory acidosis (pH 7.07 and 7.14) necessitated artificial ventilation with positive end-expiratory pressure (PEEP). Hemodynamic study revealed non-cardiogenic edema. In both cases, cardiac insufficiency was also present: in the first case its etiology remained unclear; in the second it was a complication of hyperkalemia. Nanji and Filipenko (6 cr) describe a case of methadone intoxication in a 31year-old male. The clinical manifestations were rhabdomyolysis and myogiobinuric acute renal failure. The authors point out that in most cases of drug intoxication, these features occur secondary to previous coma or prolonged immobilization. Since their patient was neither comatose nor immobilized, they suggest that a toxic action of methadone was responsible for the rhabdomyolysis. Codeine
The analgesic response to codeine of patients with postpartum uterine-cramp pain has been investigated by Bloomfield et al (7 Cr) who conducted a study comparing codeine sulfate 60 mg (N=32) and 120 mg (N=31) with aspirin 650 mg (N=34) and placebo (N=32) in hospitalized women with moderate or severe postpartum uterine cramps treated with single oral doses in a parallel, stratified, randomized, double-blind trial. Subjective reports were used as indices of response, and patients rated pain intensity, pain relief and side effects at periodic, uniformly conducted interviews for 6 hours. The most common side effects were drowsiness and dizziness; of the 4 treatments, 120 mg codeine was clearly associated with the highest incidence (18 cases drowsiness, 13 cases dizziness); nausea was the only gastrointestinal side effect reported with codeine, but the authors point out that others, e.g. constipation, might have been elucidated with a longer period of observation. In an elegant, double-blind, cross-over study, Skjelbred and I.~kken (8 cr) performed identical oral surgical procedures on 2 separate occasions with 24 outpatients.
Chapter 8
A.H. Ghodse
At one operation they were given tablets containing paracetamol + codeine phosphate (400 mg + 30 mg), and at the other plain paracetamol (400 mg). On the day of operation, 2 tablets were taken 3, 6 and 9 hours after surgery and on the following 2 days 1 tablet was taken 4 times daily. Several measurements/assessments were recorded for a paired comparison o f the postoperative courses. No increase in the analgesic effect could be demonstrated by addition of codeine to paracetamol, but on the day of operation 18 patients reported adverse effects such as nausea, dizziness and drowsiness with paracetamol + codeine, while only 3 patients experienced side effects with paracetamol alone (P < 0.001). There was a striking lack of complaints when medication stopped (days 3, 4, 5, 6 after operation). The authors admit to being surprised by the large number of complaints with paracetamol and codeine, as this combination had previously been well tolerated. They conjecture that ambulatory patients (as in this study) may be more attentive to the effects of opioids on the vestibular apparatus than patients confined to bed. There was a marked tendency towards more pronounced adverse effects in females, particularly the younger ones. Side effects due to codeine, although rarely serious, assume importance because of doubts that have been expressed about its efficacy (7 c r , 8 Cr, 9Cr). Desjardins et al (9Or), for example, in their study comparing propiram with aspirin and codeine for the treatment of dental pain, found that codeine 60 mg was not significantly superior to placebo. Nevertheless, 18 patients (out of 40) complained of side effects such as drowsiness, headache and dizziness. Pethidine (meperidine) Techniques of fetal heart monitoring continue to become more sophisticated and Barrett and Boehm (10 C) carried out a study to evaluate the effects of 3 regimens of intrapartum analgesia upon fetal heart rate characteristics. Either meperidine 50 mg (M50), meperidine 50 mg + propiomazine 20 mg (M50/P20), or meperidine 25 mg + propiomazine 10 mg (M25/P10) was given intravenously for intrapartum analgesia to 204 patients in the first stage of labor, and the effects were evaluated upon fetal heart rate variability (FHRV) and fetal heart
Opioid analgesics and narcotic antagonists
Chapter 8
rate reactivity (FHRR). Reduced FHRV is related to fetal acidosis as well as other factors such as fetal sleep, fetal tachycardia, prematurity and various drugs. In contrast, FHRR - the long-term acceleration of the fetal heart rate associated with fetal movements or uterine contractions - is apparently a good prognostic sign of fetal wellbeing. M25/P10 was found to cause a decrease in FHRV in fewer patients than M50/P20 (13.6% vs 36.5%, P < 0.005) while still providing adequate analgesia for most patients. Although M50 also caused a decrease in FHRV in fewer patients than M50/P20 (19.1% vs 36.5%, P < 0.05), it produced emesis in 20% of patients. When FHRV was minimal or moderate before the analgesic was given FHRV became absent in only 8 of 222 doses (3.6%). FHRR was lost in fewer patients given M50 than in those given M50/P20 (45% vs 71%; P <0.01); there was no significant difference between M50 and M25/ P10. The authors conclude that the effects of meperidine upon fetal heart rate characteristics are both potentiated by propiomazine and, when meperidine is given with propiomazine, dose-related. They also conclude that absent FHRV is rarely caused by meperidine; when FHRV becomes absent after meperidine administration, the patient should be fully evaluated for the possibility of fetal distress before the absence of variability is attributed to analgesia. Alfentanll Alfentanil, an analog of fentanyl, has been reviewed by Owen (11R). It is a potent opioid agonist with an onset of action 4 times as rapid as an equianalgesic dose of fentanyl. Transient hypotension may occur following alfentanil administration and significant respiratory depression will occur following administration of alfentanil doses in excess of 1000 /ag. Bradycardia, antagonized by atropine, and muscular rigidity may also occur; and if other narcotic or central nervous system depressant drugs are used concurrently with alfentanil the effects can be expected to be additive. Other side effects include nausea, vomiting and dizziness. Kay et al (12 c) made a double-blind comparison between alfentanil and fentanyl as analgesic components of anesthesia. Sixty-six women undergoing laparoscopy received methohexitone, alcuronium, nitrous oxide and oxygen, with either alfentanil
65 0.75 mg or fentanyl 0.25 mg. Ten of the patients who received alfentanil and 1 patient who received fentanyl required supplementation of anesthesia by enflurar:e. Recovery from anesthesia was similar in both groups of patients, although the onset of spontaneous breathing occurred more quickly after alfentanil. The injection of fentanyl was followed by a fall in blood pressure and the the mean minimum value for pulse rate occurring after fentanyl was slower than after alfentanil and fentanyl on 40 healthy, ceived alfentanil vomited in the immediate post-operative period, and 1 complained of abdominal pain. In another study, Scamman et al (13 c g ) compared the ventflatory and mental effects of alfentanil and fentanyl on 40 healthy, young volunteers who received intravenously, in a double-blind and random fashion, 7.5 or 15 /.tg/kg of alfentanfl, 1.5 or 3 /ag/kg of fentanyl, or saline. The ventilatory response to CO2 was measured before and at 4, 20, 30, 50, 80 and 120 minutes post-treatment. Mental and psychomotor functions were measured before and at 10, 40, 100, 130 and 180 minutes posttreatment. Low- and high-dose fentanyl caused significant respiratory depression up to 30 and 80 minutes post-treatment, respectively, while there was no depression with low-dose alfentanfl and only at 4 minutes with high-dose alfentartil. The fentanyl/ alfentanil potency ratio for respiratory depression was 13/1. High-dose fentanyl caused more intense and prolonged mental effects than other treatments. Neither drug affected learning or recall, although highdose fentanyl impaired motor activity. Nausea and vomiting rates were similar between high-dose alfentanil and low-dose fentanyl. Bovill et al (14 c R) studied the influence of high-dose alfentanil anesthesia on the electroencephalogram in 10 patients undergoing elective coronary artery surgery. Anesthesia was induced with alfentanil 125 pg/kg/h and maintained by a continuous infusion at a rate of 0 . 2 5 - 0 . 5 mg/ kg/h. It was associated with large increases in delta-activity and a reduction in higherfrequency components. There was less synchronization of the EEG than is observed with fentanyl or sufentanil. Spindle activity was prominent in 70% of patients. The changes in the EEG during recovery tended to occur abruptly, and there was no obvious correlation between the EEG and plasma concentrations of alfentanil.
66
Fentanyl Chest wall rigidity is a recognized complication o f fentanyl anesthesia (SED-10, 125) and because high-dose fentanyl anesthesia is often employed for patients with cardiac disease, this side effect assumes greater significance. Muller et al (15 c r ) undertook a study to determine the hemodynamic and arterial blood gas changes caused by fentanyl rigidity. They found that although rigidity did not last longer than 3 minutes in any patient, there were large individual decreases in Pao 2 during the period of rigidity, perhaps due to increased oxygen consumption due to intense muscle contraction. The only significant change in the measured hemodynamic data was a pulmonary artery diastolic pressure which increased significantly during the period of rigidity. The authors comment that these fentanyl-induced effects can be detrimental to the patient with cardiac disease and demonstrate the need for aggressive preventive measures. Safwat and Daniel (16 c) reported the case o f a 79-year-old woman who had a grand mal seizure following the administration of fentanyl 200/ag in the course of anesthetic induction. The authors emphasize the small dose of fentanyl that produced the fit, and the fact that diazepam 5 mg administered just before the fentanyl had failed to prevent the convulsion. This case-report prompted another about a 17-year-old man who also had a grand-mal seizure following an even smaller dose (100 /ag) of fentanyl (17c). In an elegant investigation, Bent et al (18 c r ) studied the effect of the administration of fentanyl 50 pg/kg body weight on the established metabolic response to pelvic surgery. In comparison with a control group o f patients in whom anesthesia was supplemented with halothane, fentanyl was associated with significant decrease in blood lactate concentration and heart rate. There were no significant differences in blood glucose, plasma non-esterifled fatty acids, and plasma cortisol values between the 2 anesthetic techniques. It is concluded that the administration of highdose fentanyl has little effect on the estabfished metabolic response to surgery, compared with the marked changes observed when the same dose is given before the onset of surgical stimulation, when it prevents the increases in glucose, lactate,
Chapter 8
A.H. Ghodse
cortisol and growth hormone normally associated with surgical techniques. In their comprehensive review of the postoperative respiratory complications of opiates, Bennett and Adams (19 R) emphasize the risk of delayed respiratory depression following fentanyl anesthesia.
Sufentanil Sufentanil citrate has been comprehensively reviewed by Roscow (20R). It is another potent analog of fentanyl and appears to be a typical pure opioid agonist, highly selective for mu-receptors, and producing the typical spectrum o f opioid effects. The major side effects are truncal rigidity and prolonged respiratory depression. In doses o f 4 - 3 0 /tg/kg, sufentanil produces hypnosis and suppresses most hemodynamic and hormonal responses to surgery without producing significant cardiovascular depression. In this respect, sufentanfl and fentanyl have clear advantages over morphine, pethidine and potent inhalation anesthetics. Compared to fentanyl, sufentanil has a more rapid onset and shorter duration o f action; the author points out that due to extensive redistribution of lipophilic drugs, large quantities are still present in muscle and other tissues at the time o f awakening. Increased perfusion of muscle beds during the wake-up period may cause a secondary rise in plasma opioid levels, and one must assume that a delayed onset of respiratory depression may occur with sufentanil as with fentanyl. Propoxyphene Although the dependence liability of propoxyphene has been recognized in the past (SED-10, 124), there have been comparatively few case-reports. D'Abadie and Lenton (21 c) describe 6 cases in which the patients presented difficult treatment problems. The patients' subjective discomfort and concomitant craving during gradual withdrawal o f the drug were more intense and more poorly tolerated than those observed with other narcotic analgesic agents and, of the 6 patients, only 1 achieved successful detoxification. In contrast, Johnson and Bohan (22 c) achieved successful detoxification of a 45year-old woman with a long history (5 years) of propoxyphene abuse. Administration of clonidine over a 9-day period reduced or
Opioid analgesics and narcotic antagonists
Chapter 8
eliminated most of the symptoms of prop o x y p h e n e withdrawal, namely nausea, vomiting, agitation, tremulousness, muscle cramping, headaches and seizures. Clonidine has previously been used for withdrawal from other opiates (SED-10, 121). Hasday and Weintraub (23 c R ) accomplished morphine withdrawal b y propoxyphene substitution in 4 children with iatrogenic morphine sulfate tolerance and dependence. One child experienced increasing lethargy and respiratory depression and responded to naloxone hydrochloride and a decrease in the dose of propoxyphene; another had transient agitation, which may have been related to high levels o f propoxyphene. The authors, reviewing other literature, report that untoward effects of high-dose propoxyphene therapy include dysphasia, slurred speech, sedation, visual hallucinations and toxic psychosis. In his review paper of d e x t r o p r o p o x y phene overdosage, Young (24 R) considers the adverse effects o f both long-term excessive dosage and acute overdosage. In the former, he too describes a psychotic state that may be associated with confusion, stammer, ataxia, diplopia and vertigo. However, intravenous abuse of the drug is not possible for more than 12 days because it is very destructive to the veins and other soft tissues. Acute overdosage with dextroprop o x y p h e n e produces clinical signs in many body systems: central nervous system constricted pupils, fits, coma; cardiovascular system - tachycardia, hypertension or hypotension, stroke, cardiac conduction defects, cardiac arrest; respiratory system depression, respiratory arrest; gastrointestinal system - vomiting. The cardiac effects are thought to be due to the local anesthetic properties o f dextropropoxyphene and its metabolite, norpropoxyphene; they are not reversed by naloxone (25R). Young (24 R) comments that rapid absorption of the drug may explain why cardiorespiratory arrest may occur as soon as 15 minutes after drug ingestion; and that slow elimination of norpropoxyphene may account for the unpredictability o f the course of poisoning in the first 24 hours. Rapid absorption is a property of dextropropoxyphene hydrochloride. The napsylate salt is more slowly absorbed and is acutely less toxic than the hydrochloride, at least in animals (25R). Turner (27 r) has sug-
67 gested that the risk of death from overdose could be reduced if the drug was available as the napsylate rather than the hydrochloride. The hepatotoxicity of d e x t r o p r o p o x y p h e n e has been well reviewed b y the Swedish Adverse Drug Reactions Committee (28 R) who comment that reactions chiefly concern combination with an antipyretic and/or muscle relaxant. Of the muscle relaxants, chlorzoxazone is combined with dextropropoxyphene in Paraflex comp. The first reports of reversible h e p a t o p a t h y in connection with d e x t r o p r o p o x y p h e n e and chlorzoxazone were received b y the Committee in 1970 (Paraflex comp.) Since then a total of 13 reports have been submitted for Paraflex comp. and 10 for other drugs. The dosage of the various preparations containing dextropropoxyphene and chlorzoxazone varied from 1 to 8 tablets/24 hours. Characteristic signs of biliary stasis usually appeared 1 - 5 weeks after the start of treatment. In most cases, liver tests showed markedly increased alkaline phosphatase concentrations, accompanied b y a slight to marked elevation of transaminase levels. Icterus occurred in many cases. In 2 patients the symptoms appeared after treatment for just a few days. One o f them had definitely been exposed to dextropropoxyphene earlier and the picture here included exanthema, which suggests an earlier sensitization. One other patient had concurrent exanthema. Laparotomy was performed in 2 patients to rule out extrahepatic biliary stasis. In a third case the presence of intrahepatic biliary stasis was verified b y puncturing the liver. Two of these verified cases concerned Paraflex comp. and 1 case Distalgesic. Symptoms subsided soon after the medicine had been withdrawn and liver tests normalized after some weeks. In 1 patient, re-exposure to Doloxene led to icterus and elevated transaminase levels. When combination drugs are involved, it can be difficult to tell which agent may have caused a hepatic reaction. There do not seem to be any earlier reports of liver damage from phenazone, phenacetin, carteine or phenprobamate. Neither does acetylsalicylic acid or paracetamol - in the low doses used in the reported cases - give rise to the t y p e of hepatic reaction described above. The authors conclude that d e x t r o p r o p o x y p h e n e can elicit a hepatocanalicular reaction,
68 which may represent a hypersensitivity reaction. At the same time, there are several cases where ehiorzoxazone cannot be ruled out as a cause. Neither can one exclude the possibility that d e x t r o p r o p o x y p h e n e and chlorzoxazone may have an additive effect. Recently, new combinations containing dextropropoxyphene, but not chlorzoxazone, have been prescribed on a larger scale than Paraflex t e m p . (consumption statistics from the National Corporation of Swedish Pharmacies), whereas it is the latter drug that dominates the number of reported cases.
EPIDURAL AND INTRATHECAL ADMINISTRATION O F OPIATES Brownridge et al (29 c) describe a case of profound respiratory depression following accidental subarachnoid pethidine. The patient was a 24-year-old gravida 3 who had an elective cesarean section and tubal ligation under combined epidural and subarachnoid block. Nine hours after the insertion o f the block the patient requested a second dose of analgesia and epidural pethidine 50 mg in saline 10 ml was administered as it had been 4 hours previously without any ill-effect. However, on this second occasion, although pain relief was rapid and immediate, the patient felt nauseated and vomited, and within 5 minutes became drowsy and was taking slow, deep, gasping breaths. She became unconscious and her pulse rate dropped to 50. Intermittent positive pressure ventilation was applied b y face-mask and A m b u bag, and atropine 0.6 mg followed b y naloxone 0.4 mg was administered intravenously. Spontaneous respiration returned within 2 minutes and after a period of drowsiness and another episode of vomiting, recovery was uneventful. X-Ray screening confirmed that the epidural catheter was in the subarachnoid space. The authors discuss whether the catheter was misplaced at the outset or subsequently 'migrated' into the subarachnoid space, and whether rostral spread of the hypobaric pethidine solution would have been facilitated by the patient's sitting position. Whatever the mechanism, they emphasize the need for the ready availability of a narcotic antagonist and suggest that acute onset of vomiting should perhaps be regarded as a warning sign.
Chapter 8
A.H. Ghodse
The efficacy of epidurat morphine during labor and delivery was assessed by Hughes et al (30 cR) in 40 healthy parturients who were randomly given either a single injection o f morphine sulfate (2 rag, n=9; 5 mg, n=10; or 7.5 mg, n=l 1) or 0.5% bupivacaine (n=10). The only side effect was pruritus, which occurred in 3 patients. Epidural morphine did not produce neonatal depression, as evidenced by Apgar scores and neurological and adaptive capacity scores. The authors reviewed other studies using epidural morphine, in which side effects were reported more commonly. One problem associated with long-term use of epidural opiates (and indeed the limiting factor in their successful application for chronic therapy) is the development of spinal tolerance, manifested by 'analgesic tachyphylaxis'. It was apparently reported that this could be reversed with epidural local anesthetics. Coombs (31 c) however, was unable to achieve such a reversal and points out that given the likely biochemical basis for opiate tolerance and the time required to reverse this in animal models such a reversal is theoretically unlikely. In an interesting case report he describes a 60year-old patient treated over a 2-week period with increasing doses of epidural morphine to control pain due to carcinoma of the lung with brachial plexus invasion. Subsequently, attempts to control the pain with parenteral morphine resulted in rapid tolerance to even massive doses of morphine (up to 175 me/h). An unusual side effect was reported by Pickar et al (25 cr) in a patient with a disseminated malignancy who received 3 mg of synthetic ~-endorphin administered intrathecally b y lumbar puncture. A marked behavioral syndrome, characterized b y confusion, hypomanic/manic behavior and psychosis, followed drug administration and persisted for more than 2 days. The authors conjecture that the unique effects of /~endorphin in their patient may have been related to the stimulation of specific populations of opiate receptors by pharmacological doses of an endogenous llgand and the relatively long half-life o f ~-endorphin when administered directly into the cerebrospinal fluid. The side effects o f epidural buprenorphine included difficulties with micturition, nausea and vomiting, and itching; they occurred 3 times less frequently than with epidural morphine (32c).
Opioid analgesics and narcotic antagonists Chapter8 DRUG DEPENDENCE IN PREGNANCY
(SED-IO, 121; SEDA-8, 83) In a long-term study of children born to drug-dependent mothers, Olofsson et al (33 er) investigated 89 infants born to mothers addicted to heroin, morphine and methadone. They found that 20% were pre-term and 31% were Hght for gestational age. Mean gestational age and birth weight were lower in infants of mothers who had taken mainly heroin or morphine than in infants of mothers who had taken mainly methadone. Pre-term labor was more frequent amongst women who had been acutely withdrawn on methadone within the last m o n t h before birth than amongst women who were maintained on methadone at birth. Eighty-five percent of the newborns had withdrawal symptoms and 12% had convulsions, the severity of which did not correlate with the type of drug abuse. The duration of withdrawal, however, correlated with the amount of methadone taken by the mother at birth. Twenty percent had signs of perinatal asphyxia and had an increased frequency of neonatal convulsions. The authors comment that these babies represent a special high-risk group of newborns. Seventy-two of these 89 children were then reinvestigated 1 - 1 0 years after birth (34CR). Only 25% were found to be physically, mentally and behaviorally normal; 56% were hyperactive and aggressive, with a lack of concentration and social inhibition; 10% had a severely and 11% a moderately impaired psychomotor development, due mainly to deprivation; 43% of the children had been removed from their mother by the Courts. These findings indicate to the authors that there is an urgent need for politicians, social welfare and health personnel to re-examine their roles in helping these children, who will otherwise develop into a new generation of social losers. NARCOTIC ANTAGONISTS
Naloxone There have now been several reports of adverse effects following naloxone. They include hypertension, pulmonary edema, ventricular arrhythmias and cardiac arrest (SEDA-5-8). Taft (35 cr) now reports a case of pulmonary edema after naloxone in
69
a healthy 26-year-old male without heart disease who was anesthetized with fentanyl for an operative arthroscopy. Postoperatively a total dose of naloxone 0.3 mg was given, but Taft emphasizes that the recommendations for smaller, incremental doses ( 0 . 0 4 - 0 . 0 8 mg) over a longer period ( 5 - 1 0 min) were followed.
A G O N I S T - A N T A G O N I S T OPIOIDS
Bupre'norphine Despite early optimism about the lack of abuse potential of buprenorphine (SEDA-4 and 5), its increasing use has been followed by reports of addiction (36crt). Richert et al (37 cr) report on 3 such cases. The drug dependence developed following treatment for pain caused by an organic disease in 2 cases and a psychosomatic disease in the others. Nevertheless, buprenorphine is being widely used as an analgesic in a variety of situations. Rifat et (38 c R ) injected buprenorphine (5 /ag/kg i.v.) into 25 non-premedicated patients 30 minutes before laparoscopic sterilization under general anesthesia. Following the intravenous injection, no significant modification of the arterial systolic and diastolic blood pressure was observed, but postoperative bradycardia occurred. Tidal volume and minute ventilation decreased, whereas the respiratory rate remained stable. Arterial blood gas analysis showed slight hypoxemia, and a significant rise in Paco2 with postoperative acidosis similar to that in the control group. Good postoperative analgesia was achieved, but with profound sedation and a high incidence of nausea and vomiting. In a randomized double-blind study comparing postoperative buprenorphine (0.3 mg i.v.) with pentazocine (30 mg i.v.) (39CR), 60 patients who had undergone epigastric and hypogastric interventions under thiopental-sodium-induced halothane anesthesia received intravenous injections of 1 of the 2 analgesics as soon as they requested a pain killer. The respiratory rate (19.5 --* 17.5 min) decreased significantly and continuously under buprenorphine (20.8 --* 13.5/min) and both buprenorphine and pentazocine caused increases of Paco2 (buprenorphine 37.3 -+ 46.8 mmHg; pentazocine 36.3 --* 43.0 mmHg), values greater
Chapter 8 A.H. Ghodse
70 than 50 mmHg being attained in individual cases. Side effects observed after buprenorphine were marked sedation and occasional sweating and heat sensation. The authors comment t h a t buprenorphine represents a valuable addition to postoperative pain therapy by virtue o f its strong analgesic efficacy, long duration of action and practicable application, with side effects otherwise typical for opiates. A previously unreported side effect o f buprenorphine has been described by Lock'hart and Baron (40 c) in a brief case-report. A woman aged 82 developed a painless 2-cm diameter ulcer on the upper surface of her tongue 4 days after starting buprenorphine which she put on rather than under her tongue. The ulcer had a deep base and a well-demarcated border and caused dysphagia and oropharyngeal erythema. Candida was cultured from the ulcer. Although she was taking other drugs, she was seen to swallow these. Butorphanol (SED-IO, 131; SEDA-8, 84) Butorphanol is now being used more frequently as the intravenous analgesic component o f nitrous o x i d e - n a r c o t i c - o x ygen anesthesia and Stanley et al (41Cr) studied the cardiovascular effects of high doses o f butorphanol ( 0 . 3 - 0 . 4 5 mg]kg) plus 60% nitrous oxide anesthesia in 17 patients undergoing elective gastric or gall bladder surgery. Butorphanol and nitrous oxide produced unconsciousness with only small decreases in heart rate and cardiac output, but did not result in sufficient analgesia to block or treat stimulation of the cardiovascular system secondary to tracheal intubation or surgical incision, even when supplemented with additional butorphanol to high cumulative dose levels (1.0 mg/kg). The data suggest that even high-dose butorp h a n o l - n i t r o u s oxide anesthesia requires supplementation with other anesthetics or anesthetic adjuvants to prevent cardiovascular stimulation during general abdominal surgery. Sung et al (42 c) carried out a retrospective study to compare butorphanol (12 cases), with morphine (9 cases) in a balanced anesthetic technique with nitrous oxide, oxygen and neuromuscular relaxants. Patients in the butorphanol group proved to have less postoperative respiratory depression as determined by PaCe 2 on arrival in
the recovery room (42.8 vs 51.1 mmHg). The patients who received butorphanol also had less nausea (8.3 vs 44.4%) and less vomiting (8.3 vs 33.3%) than those given morphine. Neither group had any recall o f procedure, hallucination or dysphoria as determined by postoperative interview. The small number of patients in this retrospective study o f case-notes emphasizes the authors' own comment that a prospective controlled double-blind comparison o f butorphanol and morphin e is necessary before firm conclusions can be drawn. Nalbuphine
(SED-IO, 131; SEDA-8, 85)
Nalbuphine is another opiate a g o n i s t antagonist and, in view o f its increasing use, Errick and Heel (43 R) have produced a timely review of its pharmacological properties and therapeutic efficacy. They comment that after parenteral administration o f 'usual' doses, it is approximately equipotent in analgesic activity to morphine on a weight basis. In studies with patients in moderate to severe pain, usually following surgery, the characteristics o f analgesia with nalbuphine were comparable to those seen with equianalgesic doses of morphine or pentazocine. It also appears to produce satisfactory anesthesia when used as a component of a 'balanced' anesthesia technique, although a relatively low 'ceiling' effect for reduction o f anesthetic requirements with nalbuphine may limit its usefulness in this regard. As with other a g o n i s t - a n t a gonist analgesics, a 'ceiling' effect to nalbuphine-induced respiratory depression is also seen, beyond which further depression does not readily occur. However, with usual analgesic doses, respiratory depression seen with nalbuphine is comparable to that with morphine. Important h e m o d y n a m i c changes have not occurred after usual doses of nalbuphine, even in patients with cardiac disease. Like other agonist-antagonist analgesic drugs, the abuse potential of nalbuphine seems relatively low, but only wider clinical use for longer periods can establish this with certainty. The most frequent adverse effect appears to be sedation, with an overall incidence estimated to be about 36%, whereas nausea and vomiting, another relatively frequent side effect, occurs in about 6% o f cases. Infrequent psychotomimetic reactions (hallucinations, depersonalization, feelings of unreality,
Opioid analgesicsand narcotic antagonists Chapter8 delusions and dysphasia) have also been reported (<1%). Other side effects include 'sweaty' or clammy feelings, dizziness, vertigo, dry mouth and headache. Transient burning at the site of intravenous injection has also been reported. After long-term administration (up to 32 weeks) the only noted side effects were sedation and confusion. Yanulevich (44 Cr) has reported the findings of a study in which nalbuphine was used as a component of a balanced anesthetic technique in 100 female patients undergoing laparoscopy and tubal ligation; nalbuphine 0.2 mg/kg appeared a safe and effective analgesic with cardiovascular stability and a lack of marked respiratory depression. The majority of patients experienced no adverse side effects, but amongst those reported were dizziness (15%), light-headedness (12%) and blurred vision (12%). One feature of nalbuphine that the authors felt warranted further investigation was the moderate sedation experienced by 82% of patients. Pentazocine At the recommendation of the World Health Organization (WHO), the United Nations (UN) Commission on Narcotic Drugs at its eighth special session in February, 1984, decided to place pentazocine under international control (Schedule 111 of the 1971 Convention on Psychotropic Substances). Perceptual disturbances following pentazocine administration are generally believed to occur more often than after the use of other opiates (SED-10, 130), although the evidence for this assumption is not clear. In their study of the incidence of postoperative dreaming following the use of morphine and pentazocine as prenaedicants, Jago and Restall (45 Cr) found no statistically significant difference between the 2 drugs. The causes of psychotominaetic problems in the postoperative period and the difficulty of precise definition of hallucinations are discussed and the authors comment that although all potent analgesics have the potential to provoke psychotomimetic side effects, case-reports tend to implicate newer ones more often than their wellknown counterparts. They believe that this probably reflects the current tendency to analyze any innovation critically, while accepting traditional doctrine at face value.
71
Heaney and Gotlieb (46 r report the case of a patient with agranulocytosis after intravenous abuse o f pentazocine (Talwin) and tripelennamine (pyribenzamine, PBZ). They point out that because intravenous abuse o f these 2 agents is increasing, agranulocytosis may be seen more often. When pentazocine abuse involves intramuscular injections, local complications are not infrequent. Two further cases of fibrous nayopathy with severe joint restriction have been reported by Roberson and Dimon (47 c) and by Adams et al (48 c) who discuss the mechanism of the condition. Stacher et al (49 CR) investigated the effects of single oral doses of meptazinol 100, 200 and 400 nag in comparison with pentazocine 50 and 100 mg and with placebo on experimentally induced pain. Side effects were similar for naeptazinol and pentazocine and the number o f subjects reporting side effects increased with increasing dose o f both drugs. Tiredness, light-headedness and dizziness were reported most frequently. Mild euphoria was reported once after naeptazinol 100 nag and twice after each of the 2 higher naeptazinol doses, compared to 3 times after pentazocine 100 nag. Mild dysphoria was reported by 1 subject after naeptazinol 400 nag, whereas after pentazocine 100 rag 1 subject complained of severe dysphoria. The latter reaction was the only severe adverse effect reported or observed in the entire study. Ciramadol The efficacy and s~de effects of ciramadol, a comparatively new synthetic analgesic with mixed agonist-antagonist properties, has been explored in three studies. Fragen et al (50 Cr) studied ciranaadol in the management o f postoperative pain in 139 patients given single, doubleblind, intramuscular injections o f either 30 nag ciranaadol, 60 nag ciranaadol, l 0 nag morphine or 0.9% saline on the first or second postoperative day. Differences in pain intensity and relief of pain, changes from baseline on a pain analog scale, percentage of patients with moderate or greater pain relief, and cumulative treatment failures were measured for 6 hours after injection. Morphine proved to be superior to all other treatments, and neither dose of ciranaadol could be statistically differentiated from placebo. During the first hour after administration, some measurements showed that
72 30 mg ciramadol was superior to 60 mg ciramadol. Patients experienced little or no drowsiness in any of the 4 groups; other side effects were transient. However, the incidence of nausea (12 cases) and vomiting (6 cases) was significantly higher in the patients receiving 60 mg ciramadol than in the other treatment groups, and was severe enough to require treatment in 6 cases. The authors point out that their results should be interpreted in the light o f the fact that some patients had been receiving narcotic analgesics before entering the study, and suggest that antagonism of the residual effect o f the previous narcotic by ciramadol might account for an acute increase in pain intensity experienced by some patients after administration o f 60 nag ciramadol. Further, better-designed studies would be necessary to clarify this point, but it should be remembered that hy.peralgesia after opioid analgesics is not a new phenomenon and alternative hypotheses have been put forward (SEDA-7, 82; SEDA-8, 76). Oral ciramadol has been compared with oral codeine in 2 separate studies. In the first, a randomized double-blind trial was carried out in 54 women to evaluate the effectiveness o f ciramadol in a single (60 or 30 nag) oral dose regimen, compared with 60 mg codeine and placebo, in the treatment o f post-episiotomy pain. Ciramadol gave a significantly better analgesic effect, at b o t h 2 and 6 hours, and produced negligible side effects, limited to 1 case o f transient dizziness (51c). In the second study, 180 patients received 1 o f 3 oral analgesics (ciramadol 20 mg, ciramadol 60 mg or codeine 60 mg) on a double-blind random basis for the relief o f pain 2 4 - 4 8 hours after
Chapter 8 A.H. Ghodse major general surgical, gynecological or orthopedic operations. All 3 analgesics proved equally effective and caused mild sedation only. No patient showed signs of clinical cardiorespiratory depression, and other side effects were infrequent. They included dizziness, giddiness, headache, nausea and vomiting, but occurred no more frequently after ciramadol than after codeine. Downing et al (52 C) concluded that ciramadol may prove a useful clinical alternative to conventional oral analgesics, provided its lack of respiratory depressant properties and addiction potential in monkeys can be substantiated in man.
Propiram The relative analgesic efficacy of propiram fumarate, codeine, aspirin, and placebo in post-irnpaction dental pain was evaluated in 159 patients by a single-dose, double-blind, stratified, parallel-group study (9Or). Pripiram 50 rag produced a level of analgesia approaching that of 650 nag aspirin in peak effect, total effect and duration o f action, and was statistically superior to 60 nag codeine and placebo for every measure of analgesic efficacy. Several mild adverse effects were observed; however, they appeared to be evenly distributed amongst the active treatments. Drowsiness was reported by 13 patients out of the 40 who received propiram, but many had received intravenous dlazepam preoperatively, making the significance of these symptoms difficult to interpret, Other, rarely reported, side effects of propiram were headache (3 cases), nausea (3 cases), dizziness (1 case) and double vision (1 case).
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