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Opioid analgesics and narcotic antagonists

Note on receptor nomenclature: Opioid receptors, originally called d, k, and m receptors, are also referred to as OP1, OP2, and OP3 receptors, or DOR, KOR, and MOR receptors respectively.

GENERAL Observational studies Tincture of opium is a preparation of powdered opium, which contains morphine, codeine, papaverine, and alcohol. It is used as an antidiarrheal agent, to treat neonatal abstinence syndrome, in the management of pain, and traditionally for the management of opioid dependency in some Asian countries. In an open study, opium-dependent subjects were allocated to three different doses of tincture of opium twice a day: 10 ml (6.66 mg morphine equivalents; n ¼ 13), 20 ml (13.3 mg morphine equivalents; n ¼ 8), and 30 ml (20 mg morphine equivalents; n ¼ 11) [1c]. In all the subjects tincture of opium effectively suppressed withdrawal symptoms without causing significant adverse effects. Nervous system Opioid-related sleep disorders are increasingly being recognized as a Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00008-8 # 2011 Elsevier B.V. All rights reserved.

common cause for concern. Of 98 patients with chronic pain, long-term opioid therapy was associated with obstructive, central, and combined sleep apnea in 83 [2c]. Of six patients with central sleep apnea, who were receiving opioids (morphine equivalent doses of 120–420 mg/day) for chronic pain, four achieved symptomatic improvement when treated with bi-level ventilation, correcting nocturnal hypoxemia and reducing sleep fragmentation [3A]. Three cases of central sleep apnea induced by acute ingestion of opioids have been described [4A]. In the first case, ingestion of unknown quantities of oxycodone was associated with an increase in the apnea–hypopnea index from 3.3 to 93 and an increase in the central apnea index from 0 to 76. In the second case, oxycodone 15 mg was associated with an increase in the apnea–hypopnea index from 0.6 to 28 and an increase in the central apnea index from 0 to 28. In the third case, extendedrelease morphine 120 mg was associated with an increase in the apnea–hypopnea index from 38 to 120 and an increase in the central apnea index from 2.1 to 76. Respiratory Practice guidelines have been proposed to reduce the incidence and severity of neuraxial opioid-related respiratory depression, improving the quality of anesthetic care and patient safety [5R]. The authors suggested guidelines for the identification of patients at increased risk, the prevention of respiratory depression after administration, the detection of respiratory depression, and management. 205

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Psychological The cognitive effects of long-term opioid treatment for management of cancer pain has been reviewed, highlighting the paucity of studies and the fact that existing studies only showed minor cognitive deficits, such as reaction time, attention, balance, and memory. Cognitive impairment was also associated with dosage increases and short-acting opioid supplementation [6R]. The cognitive effects of fentanyl given by intravenous patient-controlled analgesia and patient-controlled epidural analgesia have been compared in patients who were randomized to intravenous administration (n ¼ 30), epidural administration (n ¼ 30), or no treatment (n ¼ 20) [7C]. The intravenous group had impairment of attention, sustained attention, attention span and memory, and processing speed ability. The epidural group had only impaired processing speed ability, which is regarded as a very sensitive measure, even after minor neurological insults. Opioids are associated with a longer duration of a first episode of delirium, which was associated with opioids, including morphine and fentanyl, often combined with benzodiazepines in an older population of 304 patients admitted for intensive care treatment [8C]. Endocrine Reduced cortisol concentrations were reported in 44 newly admitted critical care patients. Cortisol concentrations were lower after parenteral opioid administration in opioid-naïve patients (n ¼ 33) but not in patients with a recent history of long-term opioid use [9c]. Gastrointestinal Narcotic bowel syndrome, defined as chronic and/or frequent recurring abdominal pain aggravated by use of narcotics, has been investigated in a random cohort of 4898 people in the community. Narcotic bowel syndrome was rare (n ¼ 5), but those who used narcotics reported more gastrointestinal symptoms and tended to use more laxatives [10C]. The effects of long-term treatment with oral sustained-release hydromorphone, transdermal fentanyl, and transdermal

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buprenorphine on nausea, vomiting, and constipation, have been prospectively explored in 174 patients with cancer pain [11C]. There was constipation in 15% and nausea and vomiting in 21%. There was a higher incidence of 72 hours stool-free periods among those who used transdermal opioids, suggesting that transdermal opioids do not offer much benefit with gastrointestinal adverse effects. Sexual function Sexual behavior and sexual dysfunction have been explored in 60 patients taking buprenorphine (n ¼ 30) or methadone maintenance treatment (n ¼ 30). Those who took methadone had more problems with sexual excitation (33% versus 3.3%) and difficulty in reaching orgasm (40% versus 10%) than those who took buprenorphine. Sexual satisfaction was also significantly greater in those who used buprenorphine (90% versus 63%) [12r]. There was sexual dysfunction in 47 women who used sustained-action oral or transdermal opioids for non-malignant pain [13c]. Concentrations of testosterone, estradiol, and dehydroepiandrosterone were 48–57% lower than concentrations in the control group (n ¼ 68). Luteinizing hormone and follicle-stimulating hormone concentrations were also lower in both premenopausal and postmenopausal women. Oophorectomized women also had 39% lower concentrations of free testosterone. These findings suggested hypogonadotrophic hypogonadism and reduced adrenal androgen production. Similar findings have been found in both men and women in a systematic review [14M]. The authors recommended routine screening of patients taking long-term opioids and management of opioid-induced hypogonadism by opioid rotation, non-opioid pain management, or sex hormone supplementation. Death Lack of consensus and disparities in clinical practice are seen as common contributors to deaths related to prescription opioids [15r]. The main sources of diverted prescription opioids are patients for whom

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opiates are prescribed for pain, elderly patients, “doctor shoppers”, and pill brokers. Education of physicians and patients could address these concerns [16r, 17c]. Drug abuse In body packing, multiple packets of substances are packed generally in the bowel. A 45-year-old man developed miosis and respiratory depression; he had multiple packets in the bowel, seen on abdominal radiography [18A]. Safety concerns related to medication adherence have been explored in 91 methadone-maintained patients attending community pharmacies [19C]. There was nonadherence to prescribing recommendations in 42% of cases. Non-adherent behaviors included splitting of the dose, storage of the dosage form, missed pick up, formulation given away, sold, or exchanged, and formulation stolen or lost. The authors suggested that medication adherence should be regularly reviewed. Oxycodone, hydrocodone, and hydromorphone have been compared with regards to abuse liability. They did not differ substantially from one another, suggesting that analgesic potencies did not reflect relative differences in abuse liability [20c]. In an epidemiological study of pain and attendant psychopathology in opioid analgesic abusers, 60–70% of all those started on a legitimate prescription of opioids for pain later misused opioids [21C]. In an exploratory qualitative study of 25 street drug users in Toronto, Canada, 14 had a history of fentanyl use in at least the past 3 months [22c]. Abuse practices included extracting fentanyl from its matrix patch with vinegar and water; sharing the extracted fentanyl with other users by loading syringes from one container, hence increasing the risk of infection with bloodborne viruses; and overdosing because of difficulty in gauging the concentration of fentanyl in the extract. Hence, fentanyl patches on the street pose a significant public health risk. The abuse potential of opioids is evident through the experience of withdrawal symptoms. In a prospective study, 79 children receiving midazolam and/or opioids

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for more than 5 days, and were followed up for withdrawal symptoms [23c]. Most of them (73 out of 79) received both medications and withdrawal symptoms were attributable to both. Agitation, anxiety, muscle tension, sleep difficulties, diarrhea, fever, sweating, and tachypnea were the most common symptoms. In a cross-sectional study of abuse and dependence of drugs used for self-medication over 2 months, among those who had used codeine in the previous month (n ¼ 53), there was misuse by 15%, abuse by 7.5%, and lack of control and dependence in 7.5% [24C]. In a randomized study, the abuse potential of ALO-01 extended-release capsules containing morphine sulfate and naltrexone was studied with regards to pharmacodynamic effects, including drug-liking and euphoria [25C]. Participants were randomized to either two 60-mg capsules, two 60-mg capsules crushed, morphine sulfate 120 mg, or placebo. There was reduced desirability associated with ALO-01, whether whole or crushed. Fetotoxicity Exposure to opioids in utero can lead to the development of the neonatal abstinence syndrome, especially in infants born to mothers who have misused these drugs. Neonatal abstinence syndrome in neonates born to mothers taking treatment has been investigated in 68 neonates. Pre-delivery higher doses of maternal methadone were associated with an increased incidence of treatment for withdrawal and with longer episodes of neonatal abstinence syndrome. There was a dose–response relationship— for every 1 mg increase in last maternal methadone dosage before delivery, an extra 0.18 days of infant treatment for neonatal abstinence syndrome were required; furthermore, breastfeeding reduced the duration of neonatal abstinence syndrome by 7.76 days [26c]. In a similar study, involving 450 singleton pregnancies in drug misusing women taking methadone, 46% of the neonates developed the neonatal abstinence syndrome [27C]. Breastfeeding was associated with amelioration of symptoms. Admissions to

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the neonatal unit were necessary in 48%, 40% being due to neonatal abstinence syndrome. Infants born to poly-drug misusing women, compared with those only taking prescribed methadone, were more vulnerable, and required longer hospital stays (11 versus 8 days), and used more health-care resources. Infants born to mothers who had misused drugs accounted for 2.9% of all births but disproportionately used 18% of neonatal unit days. In a prospective study, the neonatal abstinence syndrome has also been described in 58 infants who had been exposed to buprenorphine in utero. There was neonatal abstinence syndrome in 38 infants, most of whom had been hospitalized for around 28 days. There was a positive correlation between urinary norbuprenorphine concentrations over the first 3 days of life and the duration of morphine treatment and length of hospital stay. The authors also studied social problems, which were evident in all infants and contributed to the length of hospital stay [28c]. Sublingual buprenorphine has been proposed as an effective and well-tolerated treatment for neonatal abstinence syndrome. In a randomized trial, infants with neonatal abstinence syndrome, who had been born to mothers taking maintenance methadone, were randomized to either sublingual buprenorphine 13–39 micrograms/ kg per day (n ¼ 13) or standard-of-care oral neonatal opium solution (n ¼ 13) [29C]. Buprenorphine administration was associated with a 31% reduction in length of treatment and a 29% reduction in the length of hospital stay. One infant had seizures after buprenorphine, but it was not clear whether buprenorphine was causal. Susceptibility factors Age Susceptibility to adverse effects in patients with chronic non-malignant pain has been reviewed [30R]. Opioid prescribing in the elderly is indicated for severe pain that has not responded to non-opioid drugs. Slow titration of the dose until adequate benefit is achieved. Opioids to be avoided in such patients include pethidine, because of the

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risk of seizures; pentazocine, because of associated neuropsychiatric toxicity; dextropropoxyphene, because of neural and cardiac toxicity; and methadone, because of its long half-life. Combinations of drugs should also be avoided. Critically ill patients Management of pain in critically ill patients has been reviewed [31R]. Opioids remain the mainstay of treatment in intensive care units. The benefit–harm balance of opioid analgesics requires continued assessment. The choice of opioid and dosage regimen should take into account the evidence base, as well as the physicochemical, pharmacokinetic, and pharmacodynamic characteristics of the drugs. The potential and actual development of adverse effects needs to be monitored and doses titrated accordingly. Lean rather than total body weight should be used when calculating weight-based dosing regimens. The determination of effective equianalgesic alternative doses or routes of administration is complex, and factors such as age, comorbidities, and tolerance need to be considered. Opioid adjuncts need to be considered case by case. The authors also supported the use of non-pharmacological interventions, such as music and relaxation techniques. Adjunct techniques can provide opioidsparing effects, reducing the incidence of opioid-related adverse effects. According to the results of a meta-analysis, adjunctive acupuncture reduced the consumption of opioid-related adverse effects such as nausea, dizziness, sedation, pruritus, and urinary retention [32M]. Of 2169 patients who received palliative care in 95 general practices in the Netherlands during the 3 months before their death, a significant proportion (16%) were given strong opioids before a trial of weak opioids; in 48% of all patients who were given opioids, laxatives were not prescribed and antiemetics were prescribed in 29% [33C]. Pharmacological tolerance of analgesic effects, symptoms of withdrawal, opioidinduced hyperalgesia, and psychological factors have been reported as contributing

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to analgesic failure, giving rise to controversy around the efficacy of long-term opioids. The increased risk of abuse and diversion necessitates monitoring, taking into consideration reliable predictors, such as a history of prior substance use, younger age, depression, and anxiety. Opioidinduced hyperalgesia presents another challenge, which, if recognized, could affect the efficacy of opioids in the management of pain [34r, 35R, 36R, 37R]. Management of adverse drug reactions The translation of knowledge about drug safety into clinical practice has been studied through the creation of a “Patient-orientated Prescription for Analgesia”, which contained evidence-based medical knowledge at the point of prescribing [38C]. Such a method of prescribing was shown to reduce the occurrence of opioid-associated severe/fatal adverse events.

OPIOID RECEPTOR AGONISTS Alfentanil

[SED-15, 72; SEDA-31, 153; SEDA-32, 187] Observational studies In a study involving 50 patients with osteoporotic vertebral fractures, scheduled for percutaneous vertebroplasty, an infusion of alfentanil 1.05 mg/hour was effective for intraoperative pain relief; transient apnea of less than 10 seconds occurred in only two patients and nausea and vomiting in three [39c].

Nervous system Emergence agitation has again been described in a randomized placebo-controlled study in 105 children having adenotonsillectomy, who were given alfentanil 10 or 20 micrograms/kg after loss of the eyelash reflex. Induction and maintenance was with sevoflurane 1.5–2.5% [40C]. Emergence delirium was measured using Aono's scale and the pediatric anesthesia emergence delirium (PAED) scale.

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The incidence of severe agitation postoperatively was significantly lower with alfentanil than placebo, but there were no differences between the two doses of alfentanil. Adverse events were rare, but significantly more children given 20 micrograms/ kg of alfentanil became hypotensive on induction. There was no difference in respiratory adverse effects or recovery times. Higher doses of alfentanil can cause respiratory adverse effects, and therefore a dose of 10 micrograms/kg should have the most benefit in reducing emergence delirium and fewer adverse effects.

Codeine [SED-15, 880; SEDA-31, 156; SEDA-32, 187] Lactation Breastfeeding by mothers taking codeine may be ill-advised, particularly if they are ultrarapid metabolizers of codeine, in whom morphine is formed in large amounts, because of the risk of adverse effects on the baby [SEDA-31, 154]. Reports of this association continue to appear. For example, a baby died after its breastfeeding mother took codeine and paracetamol, although the death could not be directly linked to codeine [41A]. It is important to consider interindividual variations in drug response, such as genotypes linked with increased opioid concentrations, the dose–response relation to drug toxicity, and the susceptibility of the very young or premature infant whose drug-excretory mechanisms are underdeveloped [42r]. In a case–control study, neonatal CNS depression was reported in 24% of breastfed infants whose mothers used codeine [43C]. The mothers of these infants had consumed 59% more codeine than mothers whose infants did not experience toxicity. Toxicity also occurred in some babies whose mothers had taken low doses (mean 0.63 mg/kg/day), highlighting increased sensitivity of infants to the CNS depressant effects of opioids. Susceptibility factors Genetic The use of codeine as an antitussive in children can be associated with severe and even fatal

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adverse effects. When 3-year-old twins were given 10 drops of codeine per day for 6 days for an upper respiratory tract infection, one was found lying in vomit and apneic, and required mechanical ventilation and the other died following aspiration of gastric contents [44A]. Blood codeine concentrations were high (total codeine 489 ng/ml and 645 ng/ml). Both were extensive metabolizers by CYP2D6. These cases also highlight the danger posed by inaccurate dosing when giving codeine “by drops” [45R]. • A healthy 2-year-old boy with a history of sleep apnea was given 10–12.5 mg codeine orally every 4–6 hours after elective adenotonsillectomy [46A]. After 2 days, he developed fever and wheezing due to bronchopneumonia and the next day had absent vital signs. The blood concentration of codeine was 0.70 mg/l and of morphine 32 ng/ml. He was an ultrarapid metabolizer.

Dextromethorphan [SED-15, 1088; SEDA-30, 109; SEDA-31, 158; SEDA-32, 187] Comparative studies In 90 children undergoing adenotonsillectomy who were randomized to placebo, dextromethorphan cough syrup (1 mg/kg), or tramadol syrup pre-operatively plus intravenous tramadol 1 mg/kg during induction of anesthesia, the incidence of nausea and vomiting was highest in the tramadol group (10% compared to 5.5% with dextromethorphan group and 6.6% with placebo); however, significantly fewer patients (6.6% versus 40%) who received tramadol required supplementary pethidine [47c]. Psychiatric A 60-year-old lady developed agitation, paranoia, and psychosis after taking dextromethorphan, propoxyphene, and hydrocodone [48A]. She had no history of previous mental illness. She had taken propoxyphene and hydrocodone þ paracetamol for pain and dextromethorphan for cough in higher than recommended doses associated with a respiratory tract infection.

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Dextropropoxyphene [SED-15, 1092; SEDA-30, 109; SEDA-31, 156] Death Co-proxamol, a combination of dextropropoxyphene and paracetamol, was gradually withdrawn from the UK market following a change in legislation in 2005. In a retrospective observational study of mortality data in Scotland over the period 2000–2006, the change in legislation was associated with a reduction in co-proxamol-related deaths, without a compensatory rise in mortality from other analgesics [49C].

Diamorphine (heroin) [SED-15, 1096; SEDA-30, 110; SEDA-31, 158; SEDA-32, 188] Comparative studies In a randomized comparison of injectable diamorphine (mean dose 392 mg/day; n ¼ 115), oral methadone (mean dose 96 mg/day; n ¼ 111), and injectable hydromorphone (n ¼ 25) in patients with opioid dependence refractory to treatment, those who received diamorphine had more adverse events (51 events) than those who received methadone (18 events) or hydromorphone (10 events) [50C]. The most serious events were seizures (seven events with diamorphine in six patients) and overdose (11 events with diamorphine and two with hydromorphone). However, outcome measures were more favorable with diamorphine. The authors suggested that although diamorphine was beneficial it should be delivered in settings where prompt medical intervention could be provided. Cardiovascular In 21 diamorphine-related deaths, myocarditis was found at autopsy [51c]. There was a fivefold increase in inflammatory cells in the myocardial interstitium. The effect of potential contaminants was unclear. • A 29-year-old with a history of substance abuse presented with cardiac arrest and coma [52A]. Toxicology showed that he had used

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benzodiazepines and opiates. He received therapeutic hypothermia, maintaining his core temperature at 32–34 C. He eventually recovered fully.

Nervous system Heroin-associated spongiform leukoencephalopathy has been described in a 36-year-old heroin abuser who had a 3-day history of lethargy and increasing unresponsiveness [53A]. A CT scan showed scattered small foci of hemorrhage and an MRI scan showed injury in the bilateral subcortical white matter consistent with restricted diffusion and T2 hyperintense lesions 3 months later. Psychiatric Hallucinations occurred in a patient who had received diamorphine by subcutaneous infusion for several months; they resolved when he switched to oxycodone [54Ar]. Musculoskeletal A 21-year-old man who had recently used heroin and cocaine developed atraumatic rhabdomyolysis, with extensive swelling of his left leg, drowsiness, and agitation [55A]. He had a high creatine kinase activity and myoglobinuria, and methadone, heroin, and benzodiazepines were found in his urine. The rhabdomyolysis was attributed to the coma, rather than a direct effect of the drugs.

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Drug overdose The prevalence, characteristics, and outcomes of non-fatal diamorphine overdoses presenting to a large hospital in Western Australia over 12 months have been studied prospectively [58C]. Of all emergency department presentations, 249 (0.5%) were for non-fatal diamorphine overdose. Individuals had a mean age of 19 years and 61% were men. The highest proportion of overdoses occurred on Wednesdays, and most had used the heroin in the presence of others. There was a trend to an increasing frequency in teenage girls and repeat overdosing was common. Other substances were commonly used: benzodiazepines 27%, alcohol 16%, cannabis 11%, amphetamines 5.8%, hallucinogens 1.3%, and other drugs 4%. In a community hospital in the USA, there was a significant increase in diamorphine overdoses over a 1-month period (June–July 2006) [59r]. There were 30 overdoses in this period and nine of these reported having used “blue bag” heroin, diamorphine laced with fentanyl. During a similar period in the previous year, only six overdoses had been due to diamorphine. The authors suggest that fentanyllaced heroin may have contributed to the increased increase.

Dihydrocodeine

[SED-15, 1125;

SEDA-32, 190] Drug dependence The prescribing of diamorphine for the management of dependence has been reviewed [56R]. In one survey, adverse reactions to diamorphine included pruritus, sweating, reddening of the skin, dry mouth, nausea, vomiting, constipation, dizziness, impaired vision, headache, muscle twitching, fatigue, impaired concentration and memory, and impaired sex drive [57C]. However, these were not necessarily solely related to diamorphine, since most of the patients were using other substances or medications. More severe adverse reactions included death, seizures, and respiratory depression. The authors mentioned the importance of ensuring adequately supervised treatment models to reduce the potential risk of diversion.

Nervous system Generalized convulsions and a mixed acidosis have been attributed to intoxication with an over-the-counter antitussive medication containing dihydrocodeine and chlorphenamine (SS Bron); however, the effects were attributed to the chlorphenamine [60A].

Fentanyl

[SED-15, 1346; SEDA-30, 110; SEDA-31, 159; SEDA-32, 191] Comparative studies In a comparison of fentanyl 0.5 micrograms/kg and remifentanil 0.5 micrograms/kg in patients undergoing gastroscopy, those who received intravenous

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fentanyl (n ¼ 99) took significantly longer to recover (8.7 minutes) compared with those who received remifentanil (n ¼ 100; 7.6 minutes). The latter required less propofol, which contributed to the faster recovery time [61C]. In a randomized blind comparison, patients undergoing sedation for emergency procedures received either ketamine 0.3 mg/kg or fentanyl 1.5 micrograms/kg followed by intravenous propofol 0.4 mg/ kg bolus [62c]. All five severe events were in those who received fentanyl and fentanyl caused more mild (OR ¼ 5.9), moderate (OR ¼ 3.8), and severe (OR ¼ 12.3) adverse events. Desaturation was the main contributor to this difference. Fentanyl was 5.1 times more likely to cause sedation than ketamine, and this persisted after adjustment for age, weight, procedure type, and pre-procedure pain (OR ¼ 4.6). Cardiovascular In patients undergoing orthopedic reduction or abscess drainage who were randomized to ketamine 0.3 mg/ kg (n ¼ 32) or fentanyl 1.5 micrograms/kg (n ¼ 31) intravenously, the latter had significantly more cardiorespiratory events (5.1 times the odds for serious events); only 16% did not experience any cardiorespiratory events, compared with 53% of those who received ketamine [63c]. Of those who received fentanyl, 32% reported mild cardiorespiratory events, 36% moderate, and 16% severe. In those who received ketamine, the incidences were 25%, 22%, and 0% respectively. Fentanyl enhances vagal tone and can cause bradycardia. In 27 children undergoing catheter ablation under propofol anesthesia, which has minimal effect on the sinus node, electrophysiological stimulation was performed before and after a bolus dose of fentanyl 2 micrograms/kg and a subsequent infusion of 0.075 micrograms/kg/minute [64c]. There was an increase in calculated sinus node recovery time but no change in sinoatrial conduction time after fentanyl, suggesting that fentanyl þ propofol impairs sinus node recovery and therefore

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reduces automaticity without affecting conduction time. Respiratory The incidence of fentanylinduced cough has been investigated and correlated with the speed and dose of injection in 476 non-smoking patients free from respiratory tract infections and bronchial hyper-reactivity undergoing elective surgery [65C]. They received fentanyl 1.5 micrograms/kg over 2 seconds (n ¼ 120), over 5 seconds (n ¼ 118), or over 10 seconds (n ¼ 119); 119 received placebo. The incidences of cough within 5 minutes after injection were similar in all the groups, at 3–6%. Upper respiratory tract events and postoperative hypoxemia were more common in 18 children undergoing elective orchidopexy who received intravenous fentanyl than in 18 who received caudal analgesia in a randomized comparison (seven versus one) [66c]. Nervous system In a 58-year-old man with a history of Parkinson's disease, fentanyl as an anesthetic and for postoperative analgesia was associated with severe bradykinesia and rigidity [67A]. The mechanism was unclear but probably resulted from an effect on the dopaminergic nigrostriatal system. Endocrine Secondary adrenal insufficiency was reported in a 64-year-old man with a history of diffuse large B cell lymphoma after he was given transdermal fentanyl 75 micrograms/hour for multifactorial pain [68A]. Adrenal insufficiency recurred when he was re-started on fentanyl by his general practitioner. Musculoskeletal Muscle rigidity resulting in reduced thoracic wall compliance occurred intraoperatively in a 2-year-old child soon after fentanyl administration, although the dose was low (1 microgram/kg) [69A]. Immunologic A 46-year-old woman developed generalized erythema, bronchospasm, and hypotension 4 hours after exposure to

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transdermal fentanyl [70A]. She had had a previous allergic reaction to fentanyl. The delayed onset was thought to have been due to the cutaneous route of administration. Susceptibility factors Age In a comparison of 30 elderly patients (>75 years) undergoing cardiac surgery and 20 younger ones (< 60 years), the former had higher fentanyl plasma concentrations (mean 5.7 versus 3.8 ng/ml) 2 hours postoperatively [71C]. Concentrations of oxycodone were similar, but the elderly patients had less pain, with longer intervals between dose requirements, and were more sedated. Drug administration route Transdermal The efficacy and safety of a fentanyl iontophoretic transdermal system have been explored in a meta-analysis of six trials [72M]. In comparisons of the fentanyl transdermal system and morphine in patientcontrolled analgesia, fewer of those who received fentanyl withdrew because of adverse effects, fewer had nausea and pruritus, and none had respiratory depression; however, more had headaches. Nebulizer Nebulized fentanyl has been studied in children with suspected limb fractures who were randomized to nebulized fentanyl 4 micrograms/kg (n ¼ 36) or intravenous morphine 0.1 mg/kg (n ¼ 37) [73c]. There were no reported adverse effects in those who received nebulized fentanyl, but one patient was withdrawn from the study because of inadequate analgesia. Drug–drug interactions Paroxetine Serotonin syndrome in a 49-year-old woman after cardiac surgery was linked to an interaction of paroxetine 40 mg/day with perioperative fentanyl 5 micrograms/kg [74A]. Ropivacaine In 108 children who were given epidural fentanyl (0.2 micrograms/ kg/hour) in combination with ropivacaine (1.25 or 1.5 mg/ml) for postoperative analgesia after hypospadias repair, adverse effects were more common in those who

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received the combination than in those who received ropivacaine alone [75c]. Management of adverse drug reactions 5HT3 receptor antagonists The addition of ondansetron and ketorolac to fentanyl was associated with less nausea and vomiting and dizziness in 135 patients undergoing thyroid surgery [76c]. In a prospective, randomized, doubleblind comparison of ramosetron or ondansetron in the management of opioidinduced postoperative nausea and vomiting, 94 patients received fentanyl 25 micrograms/kg in a total volume of 100 ml at a rate of 2 ml/hour and 0.5 ml per demand with a 15-minute lockout period [77c]. Ramosetron was superior to ondansetron in preventing vomiting and reducing the severity of nausea. Ketamine In 202 adults, low-dose ketamine (1 mg/kg þ 42 and 83 micrograms/kg/hour for 24 hours) improved the analgesic effects of fentanyl (0.5 micrograms/kg basal and 0.5 micrograms/kg on demand with 6 minutes lockout for 48 hours) and was associated with lower incidence of postoperative nausea and vomiting [78C]. In contrast, in women who underwent abdominal hysterectomy, the use of ketamine and fentanyl (infusion of ketamine 15 micrograms/kg/min þ three boluses of fentanyl 1 microgram/kg) was associated with hallucinations (in seven out of 15 patients) during and after surgery [79c]. Those who received ketamine alone also had hallucinations (in nine out of 15 cases). Propofol In a randomized study in 60 children who underwent interventional radiology and were allocated to propofol 0.5 mg/kg þ fentanyl 1 microgram/kg þ ketamine 0.5 mg/kg (n ¼ 30) or propofol 0.5 mg/kg þ fentanyl 1 microgram/kg þ saline 0.9% (n ¼ 30) intravenously, there was oxygen desaturation in three of those who received ketamine and nine of those who did not [80c]. Those who received ketamine also had agitation (n ¼ 2) and tachycardia (n ¼ 1), which did not occur in the other group. Nystagmus was also a common adverse reaction (19 cases versus

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one). The addition of low-dose ketamine reduced the risk of desaturation.

Hydromorphone [SED-15, 1703; SEDA-31, 162; SEDA-32, 193] Observational studies In 223 patients who were given intravenous hydromorphone 1 mg followed by an optional 1 mg 15 minutes later, there was oxygen desaturation in 5%, bradycardia in 10%, nausea in 13%, vomiting in 7%, and pruritus in 5%; no serious adverse events were reported [81c]. Comparative studies A fixed dose of intravenous hydromorphone 1 mg followed by an optional 1 mg 15 minutes later (n ¼ 112) has been compared with analgesia provided at the discretion of the clinician (n ¼ 112) in patients who presented to an emergency department [82C]. There was adequate analgesia in both groups and the adverse effects profiles were similar. Adverse events in those who received hydromorphone included oxygen desaturation (5%), nausea (17%), vomiting (4.7%), and pruritus (6.5%). In a randomized controlled comparison of hydromorphone and morphine in patientcontrolled analgesia, 50 patients were randomized to either hydromorphone 0.2 mg/ ml or morphine 1 mg /ml; there was no difference in the adverse reactions profile between the two regimens [83c].

Levacetylmethadol (levo-aacetylmethadol, LAAM) [SEDA-32, 193] Cardiovascular The effects of levacetylmethadol (n ¼ 31) on the QT interval have been studied in a randomized controlled comparison with racemic methadone (n ¼ 22) [84C]. After 24 weeks, levacetylmethadol caused significant prolongation of the QTc interval (0.409 versus 0.418 seconds), while methadone had no effect. There was no statistically significant change in QT dispersion in either group. There were more patients with

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borderline prolonged and prolonged QTc intervals among those who received levacetylmethadol (seven versus one). The authors recommended careful electrocardiographic monitoring in patients receiving levacetylmethadol.

Methadone [SED-15, 2270; SEDA-30, 112; SEDA-31, 163; SEDA-32, 196] Observational studies The adverse effects profile of methadone has been compared with that of morphine [95c]. Methadone was associated with fewer adverse events, because it is more lipophilic and has no active metabolites. Symptoms due to methadone overdose generally occur within 9 hours of ingestion with a mean onset of symptoms at 3.2 hours. In an open study in 21 opioid-tolerant patients with severe cancer pain who were switched to methadone, the switch was generally well tolerated; only one patient required treatment withdrawal, because of respiratory depression [85c]. Drowsiness was one of the most frequent adverse effects (in six patients) but it was of moderate intensity and responded to dosage reduction. Constipation was problematic in six. Other effects included nausea and vomiting (n ¼ 2), sweating (n ¼ 2), and confusion (n ¼ 1). Cardiovascular A 56-year-old man was successfully switched from methadone 100 mg/day to buprenorphine after methadone-induced torsade de pointes [86A]. Morphine was used to counteract withdrawal symptoms. The QT interval normalized over the 3 days and remained normal even 12 months later. The factors that predispose to methadone-induced QT interval prolongation have been reviewed [87R]. It was associated with female sex, hypokalemia, high-dose methadone, drug interactions (for example, with medications that inhibit the metabolism of methadone or with protein-bound drugs), underlying cardiac problems or congenital unrecognized QT prolongation, and

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DNA polymorphisms. The authors suggested that despite the risk of mortality associated with methadone-induced QT prolongation, the high mortality in untreated drug users tips the balance in favor of methadone. In 10 of 109 patients receiving methadone maintenance treatment in whom the QTc interval was prolonged (>400 ms), the susceptibility factors were older age, higher methadone dose, and the use of antidepressants (trazodone and mirtazapine) [88C].

Sensory systems Acute bilateral sensorineural hearing loss followed methadone overdose (75 mg) in an opioid-naïve individual; there was gradual improvement in hearing over 10 days [89A].

Skin Necrolytic migratory erythema has been attributed to methadone [90A]. • An 18-year-old woman presented with severe symptoms of thick scales, pustules, and hair loss suggestive of seborrheic dermatitis in the scalp area. Descaling measures, antifungal agents, potent topical steroids, and systematic antibiotics produced limited benefit. Over the next 12 months she developed an erythematous, scaly, weepy rash in the axillae and toe webs, which waxed and waned. Skin scrapings were repeatedly negative for fungi. She was then lost to follow up for 2 years. When she returned, her seborrheic dermatitis had become much worse, having spread to the groin and perianal area. She admitted to using heroin, underwent detoxification, and was enrolled into a methadone maintenance program. Her symptoms were difficult to control after 6 months of additional treatment and she was admitted with septicemia secondary to cutaneous herpes simplex and staphylococcal infection of the groin. Recurrent viral and bacterial infections of the groin area remained a problem. Immunodeficiency was ruled out. Some symptom control was achieved with prophylactic systemic antiviral drugs, antibiotics, systemic and topical steroids, antifungal drugs, and antibiotics. Glucagonoma syndrome and zinc deficiency were ruled out. A biopsy from the groin area showed a combination of parakeratosis and keratinocyte vacuolar changes, supporting a diagnosis of necrolytic migratory erythema. This was considered to be secondary to

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opiates. After patient was off methadone for 4 months, the rash cleared and the hair completely regrew. The rash returned when she restarted methadone.

Necrolytic migratory erythema is usually part of the glucagonoma syndrome, which is characterized by an alpha cell tumor of the pancreas, leading to adult onset diabetes mellitus, weight loss, and glossitis. It is often mistaken for intertrigo or seborrheic dermatitis. Its pathogenesis is not well understood. The role of opiates in this case was not clear, but it was not due to poor nutrition or poor absorption of nutrients. The authors speculated that opiates had had a direct effect on epidermal metabolism. Death Mortality from a naltrexone implant (n ¼ 376) and methadone (n ¼ 658) have been compared in opioid-dependent individuals [91C]. Methadone was associated with increased mortality during the induction period. Fetotoxicity Visual evoked potentials, indicators of the integrity and maturity of the visual pathway, were recorded within 4 days from birth of 21 full-term infants of mothers who had taken methadone [92c]. The drugexposed infants had small-amplitude or non-detectable immature waveforms compared with 20 controls. This suggests that maternal methadone and other illicit drugs altered on visual development in infants. Pregnancy Preterm births were reported as being more prevalent in 258 opiateaddicted pregnant women who were taking methadone in a retrospective cohort study [93C]. The preterm rate was 29% (almost 3 times the national average of 11%). The higher rate was not affected by medical or infectious co-morbidity, but there was a correlation between preterm birth and the use of more than one substance. Susceptibility factors HIV infection A 36year-old woman with advanced HIV infection and taking methadone 70 mg/day and diazepam 20 mg/day had recurrent attacks

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of syncope due to prolongation of the QT interval (QTc 540 ms) and torsade de pointes [94A]. The authors postulated that she had acquired HIV-induced long QT syndrome. Drug–drug interactions The use of methadone in treating cancer pain is limited by its potential for interactions and its adverse effects profile [95R]. Some drugs (for example, antifungal azoles, quinolones, macrolides, selective serotonin reuptake inhibitors) can inhibit the metabolism of methadone, increasing the risk of QT interval prolongation, respiratory depression, or other adverse effects; others (such as anticonvulsants, antituberculosis drugs, antiretroviral drugs, high doses of glucocorticoids, risperidone, St John's wort, fusidic acid, spironolactone, alcohol consumption, and cigarette smoking) increase the speed of methadone metabolism, potentiating withdrawal effects. Conversely, methadone can reportedly inhibit the metabolism of other drugs (for example, tricyclic antidepressants), increasing the risk of QT interval prolongation, NSAIDs (affecting analgesia), or benzodiazepines (causing nervous system toxicity). Of the selective serotonin re-uptake inhibitors, fluvoxamine, fluoxetine, and paroxetine significantly inhibit methadone metabolism, whereas with sertraline and citalopram the effect is minimal; the interaction with venlafaxine is unclear. Antiretroviral drugs In 12 healthy HIVnegative volunteers, nelfinavir reduced plasma methadone concentrations by 40–50%, increased its renal clearance, and increased hepatic metabolism, extraction, and clearance [96c]. Nevirapine and efavirenz increase the R/S enantiomer concentration ratio, hence increasing the therapeutic effects of methadone, which are almost exclusively mediated by the R enantiomer, as has been shown in five patients taking nevirapine and nine taking efavirenz [97c]. These interactions are thought to be mediated by induction of CYP2B.

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Cannabis The combination of cannabis with methadone has been studied in 77 Australian and 74 Swiss methadone maintenance patients [98c]. There were lower 24-hour dose-corrected trough plasma concentrations of both (R)-methadone and (S)-methadone; there was no effect of sex, alcohol, tobacco smoking, or duration of methadone treatment. Nicotine In 40 patients taking methadone maintenance treatment, nicotine enhanced opioid withdrawal suppression and methadone attenuated nicotine withdrawal [99C]. The interaction of nicotine with methadone increased ratings of euphoria and drug liking and reduced restlessness, irritability, and depression. Non-pharmacological effects were also reported, with experiences of positive effects and reduced negative effects. These findings could explain the high prevalence of smoking among patients who take methadone.

Morphine

[SED-15, 2386; SEDA-30, 113; SEDA-31, 164; SEDA-32, 199]

Comparative studies An evaluation of the use of postoperative intravenous patientcontrolled analgesia across a decade highlighted that this method of administration has become more popular and is associated with reduction in morphine consumption and respiratory depression; however, there are significant risks of nausea (47%) and vomiting (19%) [100C]. In the emergency treatment of acute severe pain, intravenous morphine titration (median 0.16 mg/kg with three boluses) was associated with adverse effects in 11% of patients (67 events) [101c]. Nausea and vomiting were the most common events, followed by dizziness, urinary retention, respiratory depression (not severe), pruritus, and allergy. Intrathecal morphine (400 micrograms) combined with intravenous patient-controlled analgesia using fentanyl has been compared with intravenous patientcontrolled analgesia alone in 40 patients

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undergoing liver surgery [102c]. The incidences of adverse effects were comparable except for pruritus, which was significantly more common in those who received intrathecal morphine. Epidural morphine 4 mg has been compared with epidural morphine 5 mg as patient-controlled analgesia for postoperative analgesia in women after cesarean section; the latter had more nausea and vomiting (16% versus 72%) and more pruritus (29% versus 82%) [103c]. In a comparison of oral sustained-release morphine (mean 94 mg/day) and hydromorphone (138 or 206 mg/day) with regard to nausea, vomiting, and constipation, in patients receiving opioids for cancer pain, morphine provided better pain relief at lower doses (after accounting for dose conversion) but was associated with more nausea, constipation, and higher consumption of antiemetic and gastroprotective drugs [104C]. Morphine (mean dose 112 mg) and mexiletine (mean dose 933 mg) have been compared in the management of postamputation pain in a double-blind, randomized, placebo-controlled, crossover study in 60 patients [105c]. Morphine was associated with a higher rate of adverse effects, mainly constipation (17 versus two), drowsiness (nine versus four), and nausea (four versus zero). Systematic reviews In a meta-analysis of the benefits and harms associated with intrathecal morphine without local anesthetic in patients undergoing major surgery, morphine was associated with respiratory depression; the NNTH was 84 [106M]. The authors also reported that the NNTH was worse (15) when only the data from three studies that specifically reported respiratory depression were used. The NNTH for pruritus was 6. The incidence of urinary retention was 12% (compared with 8.5% in controls). There was no difference in the incidence of nausea and vomiting. Respiratory The safety of intravenous morphine 0.05–0.1 mg/kg has been explored in 43 non-intubated neonates undergoing central line placement. Five

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had respiratory depression compared with none of the 43 controls; however, these infants had underlying respiratory insufficiency and two of them were given an overdose of morphine [107c]. Morphine should be used with caution in this population. • A 38-year-old woman undergoing laparotomy with removal of intra-abdominal abscess following a duodenectomy developed acute lung injury after switching from sufentanil to morphine 0.1 mg/kg/hour; her symptoms developed within 3–4 hours and resolved after withdrawal of morphine [108A].

Nervous system A 74-year-old man developed downbeat nystagmus after receiving epidural morphine 3 mg every 12 hours for postoperative pain (total dose 12 mg over 48 hours) [109A]. The nystagmus resolved 36 hours after morphine withdrawal. A 50-year-old woman who was given intrathecal morphine 0.5 mg in conjunction with general anesthesia for lung surgery did not regain consciousness postoperatively [110A]. A brain scan showed cortical and subcortical increased fluid-attenuated inversion recovery intensities in the occipitoparietal and upper frontal regions, effacement of sulci, and cortical and leptomeningeal enhancement. She gradually recovered over the next few days. This presentation suggested posterior reversible encephalopathy syndrome, which the authors suggested might have been caused by intrathecal morphine. Gastrointestinal Postoperative nausea due to morphine is associated with genetic variation at position 118 of the m opioid receptor. In 270 women who received intrathecal morphine 0.1 mg as postoperative analgesia, those who were homozygous for the A118G polymorphism had a higher incidence of nausea and vomiting [111C]. Musculoskeletal Muscle rigidity, laryngospasm, and respiratory compromise occurred twice in a 2-day-old full-term neonate, first after a bolus dose of morphine 100 micrograms/kg and then after a continuous infusion of 4.4 micrograms/kg/hour [112A].

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Drug administration route The effects of intravenous morphine 10 mg given to 38 patients with moderate pain after surgery have been compared with those of intramuscular morphine 10 mg [113c]. There was quicker analgesia with intravenous morphine, without serious respiratory depression. The level of sedation was greater after intravenous morphine, but this lasted for only 5 minutes. Intranasal morphine 7.5 mg (n ¼ 45) or 15 mg (n ¼ 45) has been compared with intravenous morphine 7.5 mg (n ¼ 45) and oral morphine 60 mg (n ¼ 45) in a placebo-controlled study in 225 patients with moderate to severe pain after third molar extraction [114C]. Intranasal morphine 15 mg had similar efficacy to intravenous morphine and caused typical systemic opioid effects. The highest incidence of adverse events was experienced by those who received oral morphine. Nasal irritation was most common in those who received intranasal morphine 15 mg (11%).

Drug–drug interactions Itraconazole Itraconazole 200 mg/day for 4 days increased the absorption and plasma concentrations of oral morphine by 20–30% in 12 healthy volunteers; the pharmacodynamic effects of morphine were not enhanced [115c]. Oprelvekin An interaction of oprelvekin (50 micrograms/kg/day) with morphine (120 mg orally bd) was suggested as the probable cause of respiratory depression and sedation in a 20-year-old woman with thrombocytopenia associated with chemotherapy [116A]. Oprelvekin was thought to have reduced the renal excretion of morphine metabolites.

Management of adverse drug reactions Dexmedetomidine Combining dexmedetomidine 5 micrograms/ml and morphine 1 mg/ml in intravenous patient-controlled analgesia resulted in better analgesia, reduced morphine consumption, and a reduced incidence of nausea and vomiting

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in a double-blind randomized study in 100 women undergoing hysterectomy [117c]. In a similar study, 64 patients undergoing laminectomy received morphine 0.15 mg/kg and were later randomized to receive morphine alone (0.02 mg/kg intravenous with 15 minutes lockout time) or morphine and dexmedetomidine (0.02 mg/kg intravenous morphine þ 0.1 microgram/kg dexmedetomidine, lock out interval 15 minutes); the combination treatment produced higher sedation scores but a lower incidence of nausea [118c]. 5HT receptor antagonists In a systematic review of nine randomized controlled studies, serotonin receptor antagonists significantly reduced the severity of pruritus and the need for treatment, but did not affect its incidence; the incidence of postoperative nausea and vomiting was reduced [119M]. Gabapentin Preoperative gabapentin 1200 mg reduced the incidence and severity of morphine-induced pruritus and delayed its time of onset compared with placebo (48% versus 78%) in 86 patients who received preservative-free morphine 0.2 mg intrathecally [120c]. Ketamine In 81 patients undergoing abdominal surgery, who were randomized to intraoperative and postoperative ketamine (0.5 mg/kg bolus þ 2 micrograms/kg/minute for 48 hours), intraoperative ketamine only (0.5 mg/kg bolus þ 2 micrograms/kg/ minute), or placebo, ketamine significantly reduced morphine requirements and the frequency of nausea [121c]. The addition of ketamine as an opiate sparer, 1.5 or 5 mg per bolus morphine dose, has been studied in 58 patients undergoing transthoracic heart and lung surgery, a procedure that is associated with severe pain [122c]. Those who took ketamine used 50% less morphine and required less rescue diclofenac for pain control. Pain scores were consistently lower with ketamine, despite reduced amounts of morphine administered. Respiratory parameters were much better with ketamine: none compared with seven patients requiring oxygen for hypoxia. The

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morphine group had increased postoperative nausea and vomiting, but the difference did not reach significance and there were no psychotomimetic adverse effects with ketamine. Although small in numbers this wellpowered study suggests a significant morphine-sparing effect of ketamine, accompanied by fewer adverse effects. In another study, postoperative ketamine as an adjuvant to morphine (1 mg morphine þ 5 mg ketamine with a 7minute lock out time) was associated with fewer adverse effects; one patient who received the combination regimen reported lightheadedness, which resolved spontaneously [123c]. In 75 patients who were randomly assigned to placebo, ketamine, or nefopam, those in the two treatment groups consistently required less morphine at all times compared with placebo (59, 39, and 39 mg in the placebo, nefopam, and ketamine groups respectively) and had a longer time to first analgesia during recovery [124c]. There were no differences in the two treatment groups with regard to morphine consumption at any time. There was significantly more postoperative nausea and vomiting after placebo, but there were no other differences in the incidence of adverse effects. Mirtazapine In a placebo-controlled study, 110 patients undergoing lower limb surgery, who received morphine 0.2 mg as spinal anesthesia, were randomized to preoperative placebo or mirtazapine 30 mg [125C]. The incidence of pruritus was significantly reduced by mirtazapine (52% versus 75%) and the period of onset was longer (7.2 versus 3.2 hours). Nalbuphine The combination of morphine þ nalbuphine reduced the incidence of morphine-induced pruritus [126C]. Patients undergoing gynecological operations were randomly allocated to five groups, each of which received varying ratios of the combination regimen: 1. morphine 1 mg/ml (n ¼ 65)—ratio 1:0; 2. morphine 0.75 mg/ml þ nalbuphine 0.25 mg/ ml (n ¼ 65)—ratio 1:3;

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3. morphine 0.5 mg/ml and nalbuphine 0.5 mg/ ml (n ¼ 59)—ratio 1:1; 4. morphine 0.25 mg/ml and nalbuphine 0.75 mg/ml (n ¼ 63)—ratio 3:1; 5. nalbuphine 1 mg/ml (n ¼ 59)—ratio 0:1.

The incidence of pruritus gradually fell from group 1 to 5 showing that the beneficial effect of nalbuphine was ratio-dependent. Naloxone Co-infusion of morphine (median dose 1.14 mg/kg on day 1; 1.50 mg/kg on day 2) with low-dose naloxone (0.25 micrograms/ kg/hour) and high-dose naloxone (1 micrograms/kg/hour) for amelioration of pruritus has been studied in 18 children with sickle cell pain crises [127c]. Pruritus was rated as less severe in the high-dose group. The combination treatment was feasible and acceptable. However, one patient was withdrawn from the trial because of excessive somnolence; nausea and vomiting were also reported. In 15 male volunteers, naloxone-3-glucuronide 0.16 mg/kg reversed constipation due to morphine without altering its analgesic effects; colonic transit time was delayed with the addition of naloxone-3glucuronide [128c]. In infants treated with continuous morphine infusion (0.04 mg/ml), those who were also given oral naloxone hydrochloride (3 micrograms/kg qds) had improved mean stool frequency and mean total food intake [129c]. Ondansetron In a randomized, double-blind study in 150 patients undergoing abdominal surgery with patient-controlled analgesia using morphine 1.5 mg, the combination of ondansetron 30 mg and prochlorperazine 20 mg reduced postoperative nausea and vomiting in the first 24 hours after surgery but not during the next 24 hours [130c].

Oxycodone [SED-15, 2651; SEDA-30, 115; SEDA-31, 167; SEDA-32, 202] The use of oxycodone has been reviewed, highlighting the importance of hepatic and renal dysfunction [131R]. In severe hepatic impairment the clearance of oxycodone falls by 75% and the volume of distribution

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increases by 50%; renal impairment also reduces clearance. Rifampicin increases the clearance of oxycodone, reducing exposure by 85%, and hence providing inadequate analgesia. Observational studies In patients with moderate to severe cancer pain taking OxyContinÒ (controlled-release oxycodone hydrochloride), adverse reactions occurred in 25% in the first week and the incidence gradually fell with time, to 12% in the 8th week [132C]. The most common adverse effects reported in the first week were constipation (26%), nausea (13%), vomiting (6.2%), dizziness (5%), and lethargy (3.7%). Other effects included dysuria, fatigue, headache, pruritus, and thirst. There was a similar pattern at 8 weeks. Five patients had delusions after dosage reduction or withdrawal, and another had delirium on days 2 and 3. The authors suggested that the adverse effects of OxyContinÒ could be reduced with preventive medication. In 236 patients taking OxyContinÒ for moderate to severe postherpetic neuralgia adverse effects abated with time on treatment; they included nausea (18%), constipation (10%), dizziness (10%), and somnolence (5.1%) [133C]. In 67 patients with malignant or nonmalignant neuropathic pain, dizziness and nausea were reported under 5%; respiratory depression and excessive sedation were not reported [134c]. Comparative studies In 14 patients using controlled-release oxycodone for postoperative pain and nine using patient-controlled morphine, there was a lower incidence of postoperative nausea and vomiting with oxycodone (14% versus 20%) [135c]. There was no somnolence, respiratory depression, confusion, or pruritus in either group. In a comparison of controlled-release oxycodone 20 mg and controlled-release tramadol 200 mg in the management of postoperative pain after surgery for breast cancer in 54 patients, there were no significant differences in adverse events [136c].

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The effects of oxycodone, methadone, morphine, and tramadol on the QT interval and HERG channels involved have been studied in 100 patients taking opioids for chronic non-malignant pain [137C]. Oxycodone and methadone caused prolongation of the QT interval, while morphine and tramadol did not; oxycodone blocked HERG channels in vitro. An increase in oxycodone dose of 100 mg was associated with a 10 msec increase in QTc interval. Gastrointestinal In a randomized study, 87 patients with pain due to herpes zoster infection taking famciclovir were allocated to controlled-release oxycodone, gabapentin, or placebo; eight patients withdrew, in four cases because of constipation, and of the others, 15 also had constipation [138c, 139r]. Drug–drug interactions Rifampicin Rifampicin reduced the therapeutic effect of oxycodone by inducting CYP3A in 12 healthy volunteers [140c]. Voriconazole Voriconazole markedly caused a 3.6-fold increase in plasma oxycodone concentrations after oral oxycodone in 12 healthy subjects, by inhibiting CYP3Amediated N-demethylation of oxycodone [141c]. Eight subjects reported adverse events, but none was severe. Management of adverse drug reactions Naloxone The combination of rectal oxycodone 40, 60, or 80 mg/day and rectal naloxone 10, 20, or 40 mg/day has been studied in a randomized, placebo-controlled 202 patients with chronic pain [142c]. The addition of naloxone reduced opioid-induced constipation. The combination of prolonged-release oxycodone 40, 60, or 80 mg/day and prolonged-release naloxone has been studied in 202 patients with chronic pain [143C, 144r]. Naloxone 20 and 40 mg significantly improved bowel function. A 2:1 oxycodone: naloxone combination ratio was identified as most suitable and there were no unexpected adverse events. With the higher doses

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of naloxone there was a tendency to an increased incidence of diarrhea. Pregabalin The combination of controlledrelease oxycodone with pregabalin reduced the incidence of somnolence associated with oxycodone in 169 patients compared with 106 on oxycodone alone [145c].

Oxymorphone

[SED-15, 2270;

SEDA-32, 203] Systematic reviews In a review of nine trials of oxymorphone alone or compared with placebo or other active agents, concentrating on its use in elderly patients, there were few adverse events [146M]. The authors suggested that oxymorphone should be considered appropriate for use in elderly, particularly those in whom there is concern about interactions with drugs that are metabolized by CYP isoenzymes, which oxymorphone does not inhibit. Death Two opiate abusers using oxymorphone by inhalation died; the post-mortem blood concentrations were 50 and 120 mg/l [147A].

Papaverine [SED-15, 2678; SEDA- 30, 115; SEDA-31, 168; SEDA-32, 205] Nervous system In a 67-year-old woman who had had a subarachnoid hemorrhage, intra-arterial papaverine was associated with development of a lesion in the left mesencephalon without a significant mass effect [148A]. The authors postulated that the papaverine had disrupted the blood–brain barrier, causing extravasation of blood and radiographic contrast agents, possibly facilitated by secondary hyperperfusion. Sensory systems Ears Topical papaverine for the treatment of vasospasm in neurosurgery was associated with transient disturbance for neurophysiological function of the ascending auditory pathway [149c].

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There was a temporal relation between papaverine and changes in brainstem auditory evoked potentials, leading to waveform loss. Other cases have been reported, as have patients with focal seizures [150r]. Sexual function In penile smooth muscle cells, endothelial cells, and fibroblasts intracavernosal injection of papaverine causes dose-dependent cytotoxicity and muscle hypertrophy and fibrosis [151r]. However, these effects tend to be limited to minor structural changes at the injection site and no significant effects on penile architecture. The incidence of fibrotic changes was low. Drug administration route Intracavernosal papaverine has been studied in 60 patients with normal Doppler studies of the penis. Injecting on one side of the penis affected the sinusoids and cavernosal artery on that side more than on the other side; five patients had priapism [152c]. The authors suggested dividing the dose and injecting both sides.

Pentazocine

[SED-15, 2777; SEDA-30, 115; SEDA-31, 168; SEDA-32, 205]

Skin A 54-year-old man developed deep punched-out ulcers with yellowish exudates and hyperpigmented and sclerotic surrounding skin on both thighs after using subcutaneous and intramuscular pentazocine for paraplegia and chronic back pain [153A]. A few months before the appearance of the ulcers he had increased the dosage to 30 mg up to 20 times a day. The lesions improved with a local antibiotic cream under occlusion.

Pethidine (meperidine) [SED-15, 2791; SEDA-30, 115; SEDA-31, 168; SEDA-32, 206] Systematic reviews Pethidine has been compared with dihydroergotamine, antiemetics, and ketorolac in acute migraine [154M]. Pethidine caused more dizziness and sedation and was less efficacious than the antiemetics, although they were associated with akathisia. There were no

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differences in efficacy or adverse effects between pethidine and ketorolac.

Remifentanil

Nervous system Pethidine is not recommended in the management of chronic pain because its active metabolite, norpethidine (normeperidine), is excitatory and can cause seizures [155R].

Observational studies When remifentanil was given by intravenous infusion pump at a rate of 0.1–0.15 micrograms/kg/minute to 186 patients undergoing percutaneous transhepatic biliary drainage (mean total dose 116 micrograms), 10% had transient bradycardia and 2% had respiratory depression [160C].

• A 27-year-old pregnant woman underwent cesarean section under epidural anesthesia and was given patient-controlled epidural analgesia, resulting in a total dose of 180 mg of pethidine over 9 hours; she had a tonic–clonic seizure, thought to be secondary to a high CSF concentration of norpethidine [156A].

Piritramide Respiratory When piritramide (mean dose 64 micrograms/kg) was given to 39 neonates and infants for postoperative analgesia, respiratory depression occurred in one case [157c].

Pholcodine

[SEDA-32, 206]

Immunologic Anaphylactic reactions have been attributed to the use of a cough syrup containing pholcodine, explaining the difference in risk between Norway and Sweden, and leading to the withdrawal of pholcodine from the Norwegian market and to examination of the role of pholcodine-containing products in other countries [158R]. In a multinational study of the effect of pholcodine-containing cough mixtures on the prevalence of IgE antibodies to various drugs, using the United Nations International Narcotics Control Board (INCB) database, there was a significant positive association between pholcodine consumption and the prevalence of IgE sensitization to pholcodine and morphine, but not to suxamethonium and p-aminophenyl-phosphoryl choline [159C]. This could be associated with an increased risk of allergic reactions.

[SED-15, 3030; SEDA-30, 116; SEDA-31, 168; SEDA-32, 207]

Comparative studies In a randomized study, 30 ASA I and II patients undergoing hysteroscopy were given propofol, mean dosage 90 micrograms/kg/minute) and either fentanyl 1 microgram/kg followed by boluses of 0.5 micrograms/kg if there were signs of insufficient analgesia or remifentanil 0.5 micrograms/kg followed by an infusion of 0.05 micrograms/kg/minute [161c]. Remifentanil was associated with a significantly lower mean arterial pressure after 1 minute but other adverse events (hypotension, respiratory depression) were similar between the two groups and all were successfully remedied by improving airway patency and reducing the dose. When intravenous remifentanil 2 micrograms/kg was compared with fentanyl 2 micrograms/kg and sufentanil 0.2 micrograms/kg in 315 patients undergoing elective abdominal surgery, there was a higher incidence of cough with remifentanil (54% versus 33% with fentanyl and 31% with sufentanil); the severity of cough was also greater with remifentanil [162C]. Cardiovascular In 132 patients undergoing elective craniotomy, remifentanil was in 12 different doses (0.10–0.21 micrograms/kg/ minute) was associated with hypotension at a median dose of 0.13 micrograms/kg/minute and bradycardia at 0.17 micrograms/kg/ minute [163c]. Respiratory In a comparison of remifentanil 1 microgram/kg and alfentanil 10 micrograms/kg in preventing withdrawal movements after rocuronium injection in 115 adults undergoing elective surgery,

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remifentanil was associated with a higher frequency of cough (24% versus 2%); one patient who received remifentanil developed apnea [164c]. Bolus remifentanil can be associated with thoracic muscle rigidity and consequent difficulty in mask or pressure-controlled ventilation [166R]. Drug tolerance Tolerance to remifentanil has been studied after short-term administration of remifentanil to 36 healthy volunteers [165C]. After a 3-hour infusion its analgesic potency fell by 5–24%, the risk of respiratory depression fell by 20–48%, and the risk of sedative effects fell by 32%. The authors concluded that short-term clinically useful doses of remifentanil were not associated with significant tolerance. Drug withdrawal A withdrawal syndrome has been described after the use of remifentanil by infusion in intensive care units [166R]. Within 10 minutes of withdrawal, patients experienced tachycardia, hypertension, sweating, mydriasis, and myoclonus. These symptoms persisted despite the use of morphine and clonidine and only resolved on readministration of remifentanil. Gradual tapering of remifentanil reduces the incidence of withdrawal symptoms. Susceptibility factors Intensive care The use of remifentanil in intensive care has been reviewed [167R]. Remifentanil is metabolized by unspecific blood and tissue esterases and its clearance is independent of organ insufficiency. The most commonly reported adverse events in mechanically ventilated critically ill patients include hypotension, bradycardia, and nausea. Thoracic and muscle rigidity and shivering have been reported with higher doses. Other reported concerns include tolerance and withdrawal pain. Drug administration route Remifentanil by manually controlled continuous infusion (0.125 micrograms/kg/minute for 2 minutes þ a continuous infusion of 0.05 micrograms/ kg/minute) has been compared with

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target-controlled infusion [168c]. In targetcontrolled infusion, the amount of medication received is the amount required to achieve the target. When 57 patients were given manually controlled continuous infusion remifentanil, target-controlled infusion remifentanil, or placebo, fewer of those who received the target-controlled infusion had bradypnea (five versus eight), apnea (two versus eight), or drowsiness (two versus five) compared with those who received manually controlled continuous infusion. Drug–drug interactions Morphine In a randomized double-blind study in 40 children undergoing surgical correction of idiopathic scoliosis, pre-treatment with morphine 150 micrograms/kg did not attenuate remifentanil-induced hyperalgesia, and there were trends to the use of more opioid after surgery and an increase in opioid-related adverse effects [169c].

Sufentanil

[SED-15, 3210; SEDA-31, 169; SEDA-32, 208] Comparative studies In a comparison of epidural sufentanil 0.015 micrograms/kg and fentanyl 0.1 micrograms/kg in children undergoing urological surgery, the former was associated with a higher incidence of pruritus (in six out of 32 compared with none) [170c].

Drug–drug interactions Midazolam A combination of midazolam (5 mg initially followed by 2.5 mg) and sufentanil 15 micrograms was given to a 3-year-old 14-kg girl as sedation for a dental procedure [171A]. She developed laryngospasm, airway obstruction, and deep sedation. She was given positive pressure ventilation, 0.4 mg naloxone intranasally, and two doses of flumazenil 100 micrograms intranasally. She recovered rapidly.

Tilidine Tilidine is a low to medium potency analgesic. It undergoes rapid first-pass metabolism

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to its active metabolites, nortilidine and bisnortilidine. Its analgesic activity is largely exerted through nortilidine which is a potent agonist at m opioid receptors. Drug–drug interactions Voriconazole In 16 volunteers, there was an interaction of tilidine with voriconazole, resulting in a 20fold increase in tilidine exposure [172c]. Voriconazole inhibits the metabolism of tilidine, resulting in increased exposure to the active metabolite nortilidine. This interaction was associated with an increased incidence of adverse drug reactions (from 40 to 79). The adverse reactions included dizziness (94%), nausea (75%), headache (56%), visual disturbances/photophobia (50%), vomiting (38%), and pruritus (31%).

Tramadol

[SED-15, 3469; SEDA-30, 117; SEDA-31, 170; SEDA-32, 208]

Comparative studies In 90 children undergoing adenotonsillectomy who were randomized to placebo, dextromethorphan cough syrup 1 mg/kg, or tramadol syrup pre-operatively plus intravenous tramadol 1 mg/kg during induction of anesthesia, the incidence of nausea and vomiting was highest in the tramadol group (10% compared to 5.5% with dextromethorphan group and 6.6% with placebo); however, significantly fewer patients (6.6% versus 40%) who received tramadol required supplementary pethidine [47c]. Tramadol 100 mg/day has been compared with ibuprofen and pregabalin in 20 healthy volunteers [173c]. Tramadol was associated with mild adverse effects, mainly fatigue/drowsiness (eight episodes), nausea/ vomiting (seven), dizziness/headache/difficulty in concentrating (seven). The NNTH for tramadol was 1.6. Placebo-controlled studies In a placebocontrolled study of the use of tramadol 50 mg tds in 35 patients with neuropathic pain due to spinal cord injuries adverse effects were substantial and resulted in withdrawal in 43% of patients compared

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A.H. Ghodse and S. Galea

with 17% of those on placebo [174c]. Adverse events were experienced by 91%; the common events included tiredness (74%), dry mouth (52%), dizziness (52%), sweating (39%), nausea (39%), and constipation (35%). Respiratory Respiratory depression is rare after the use of tramadol. A 66-year-old man developed respiratory depression after being given tramadol for postoperative pain [175A]. He responded to assisted mask ventilation and intravenous naloxone 0.4 mg. He had renal impairment and was an ultrarapid CYP2D6 metabolizer of tramadol, which has an active metabolite Odesmethyltramadol. Nervous system A 74-year-old man with Parkinson's disease was given tramadol 100 mg qds and his tremor worsened after 2 weeks, causing significant functional impairment [176A]. There was rapid improvement within 2 weeks of tramadol withdrawal. The authors speculated that the mechanism of this adverse effect might be related to effects on serotonergic pathways. Gastrointestinal In a randomized prospective comparison of lornoxicam 16 mg and tramadol 1 mg/kg every 6 hours for 24 hours for postoperative pain after inguinal hernia repair, tramadol caused nausea in 10% [177C]. Multiorgan failure Acute respiratory distress and multiple organ dysfunction occurred in a 19-year-old with a 6-month history of tramadol abuse; the blood tramadol concentration was 9.5 mg/l, which is well above the lethal blood concentration of 2 mg/l [178A]. Drug withdrawal A withdrawal syndrome has been described in a neonate born to a mother who was taking tramadol 400 mg/ day for chronic low back pain [179A]. During the last weeks of pregnancy, the dose was reduced to 200 mg/day. At 35 hours of age, the neonate had signs of severe withdrawal. The symptoms occurred earlier

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Chapter 8

and lasted for a shorter time than symptoms after withdrawal of methadone or buprenorphine. The authors suggested that the shorter course was related to the half-life of the tramadol metabolite, O-demethyl-tramadol hydrochloride. Drug overdose Tramadol intoxication was responsible for 4.9% of admissions to an Iranian poisoning ward over a 2-month period (114 patients) [180c]. Most were men and the most common age group was 21–30 years. The most common adverse effects of tramadol toxicity were nausea, vomiting, nervous system depression, tachycardia, and seizures. Most of the toxic effects resolved within 24 hours. Patients who did not survive were reported to have taken high doses, ranging from 5000 to 8200 mg.

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respiratory depression with buprenorphine is lower than with other opioids and it is not associated with immunosuppression. Older age and severe impairment of renal function do not alter buprenorphine pharmacokinetics. There is a relatively low incidence of adverse effects, such as nervous system effects and constipation with transdermal buprenorphine, making it suitable for administration to at-risk patients, such as those requiring hemodialysis. Observational studies The role of buprenorphine in the treatment of non-psychotic major depression has been explored in six treatment-resistant patients with severe non-psychotic depression [183c]. They received buprenorphine 0.8–2 mg/day and their depressive symptoms improved within 1 week. In the initial days, they had adverse effects such as nausea, constipation, sedation, dizziness, and sweating.

Drug–drug interactions Paracetamol The synergistic effects and associated adverse effects of tramadol and paracetamol have been compared with those of codeine þ paracetamol (co-codamol) and dextropropoxyphene þ paracetamol (co-proxamol) [181C]. The combination of tramadol þ paracetamol was associated with the highest reporting rate and seriousness of adverse events. The most common adverse events were gastrointestinal, vascular, neurological, psychiatric, and cutaneous. There were fewer hepatobiliary events.

Respiratory Buprenorphine-induced respiratory depression has been studied in 24 subjects who received buprenorphine 0.2 mg and increasing doses of naloxone [184c]. Reversal of buprenorphine-induced respiratory depression required high doses of naloxone (over 2 mg) and further increases in naloxone dose (to over 4 mg) resulted in recurrent respiratory depression.

PARTIAL OPIOID RECEPTOR AGONISTS

• A 33-year-old man with a history of heroin addiction, alcohol abuse, and hepatitis C infection, developed hepatic and renal failure after switching from methadone to buprenorphine 20 mg/day. Investigations excluded the possibility of hepatitis reactivation.

Buprenorphine

[SED-15, 571; SEDA30, 118; SEDA-31, 171; SEDA-32, 209]

The safety of transdermal buprenorphine has been reviewed [182R]. Buprenorphine can be effectively and safely combined with full m receptor agonists, and switching between buprenorphine and other opioids at equianalgesic doses is not associated with inadequate analgesic efficacy. The risk of

Liver Therapeutic doses of buprenorphine have been linked to acute hepatitis and renal failure [185A].

The authors highlighted the need for liver function monitoring in the first few weeks of buprenorphine treatment in susceptible patients, such as those with hepatitis, alcohol abuse, or concomitant use of drugs that cause mitochondrial toxicity. Two patients developed acute hepatitis that occurred after abuse of buprenorphine intravenously [186A]. Both were taking

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sublingual buprenorphine 8 mg/day and were hepatitis C virus carriers. The authors stressed that buprenorphine had been the probable cause of the acute hepatitis and that the main mechanism was mitochondrial toxicity, exacerbated by other factors, such as concomitant use of alcohol. In both cases, acute hepatitis was followed by disappearance of hepatitis C RNA, suggesting clearance of the virus. Death The susceptibility factors that are associated with mortality among opioiddependent people taking buprenorphine or methadone treatment have been explored in an epidemiological study [187C]. Drug overdose and trauma were the major contributors to increased mortality. Periods of higher risk included the induction period on to methadone (but not on to buprenorphine) and at times of treatment withdrawal, which tend to be associated with a risk of relapse and an increased risk of suicide. Buprenorphine and methadone have similar standardized mortality ratios. The authors postulated that although buprenorphine induction was not associated with an increased risk, treatment with buprenorphine was linked to shorter periods of treatment, balancing the increased mortality rate. During the study period (1985–2006), the treatment program reduced mortality by 29%. Drug dependence Buprenorphine is suitable for treating opioid withdrawal. In a systematic review, buprenorphine was associated with low rates of full abstinence from drugs after opioid detoxification, and although detoxification with buprenorphine occurred over a shorter period, this was not associated with shifts in abstinence rates [188M]. Drug withdrawal Withdrawal symptoms have been described in a 2-year-old girl, who had been given regular buprenorphine tablets by her mother [189A]. She developed irritability, agitation, crying, yawning, piloerection, dilated pupils, a high pulse

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A.H. Ghodse and S. Galea

rate, and a blood pressure of 89/43 mmHg. Her symptoms resolved over 5 weeks after administration of morphine and then methadone. Pregnancy The roles of buprenorphine and methadone in the clinical management of opioid dependence during pregnancy and breast feeding have been reviewed [190R]. The dosages must be tailored to the needs of each opioid-dependent pregnant woman. Drug formulations A novel implant of buprenorphine (ProbuphineÒ) with sustained-release technology has been evaluated in 12 subjects with opioid dependence maintained on sublingual buprenorphine [191c]. Most of them (92%) had at least one adverse event and 58% had events related to the insertion or removal of the implant. Other adverse events were experienced by 42% and included dizziness, constipation, abdominal pain, implant site reactions, flushing, and pallor. There were no serious events. Drug administration route Transdermal buprenorphine has been studied in children with cancer pain in three case studies. An adverse event occurred in only one case— erythema and pruritus at the patch site [192A]. In 30 elderly patients over the age of 65 adverse events were comparable to those experienced by younger patients; however, 23% of elderly patients withdrew prematurely from the study owing to adverse events [193c]. In 30 adults, transdermal buprenorphine 35 micrograms/hour produced adequate pain relief, but there was a high incidence of adverse events: patients developed constipation (n ¼ 3), hypotension (3), urinary retention (2), or paradoxical hyperalgia (1); nine discontinued treatment mostly because of nausea and daytime sleepiness [194c]. Drug overdose During November 2002 to December 2005 there were 96 reports of unintentional buprenorphine overdose in children under 6 years of age from US

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Chapter 8

poison centers to the Research Abuse, Diversion & Addiction-Related Surveillance System; 10 patients were excluded because they did not meet the inclusion criteria—seven were lost to follow-up and three had taken multiple substances [195c]. Of the others, 32 had no symptoms after overdose, 48 had minor reactions, and six had severe reactions. The mean time of onset of the adverse reactions was 64 minutes and they lasted 2–8 hours in most cases. There was significant central nervous system and respiratory depression in 7%. The clinical implications of this are that generally buprenorphine overdose is well tolerated, but any child under 2 years of age and any child who has taken more than 2 mg would require observation for a minimum of 6 hours.

Butorphanol [SED-15, 582; SEDA-31, 172; SEDA-32, 210] Comparative studies When patients with suspected biliary colic were randomized to intravenous ketorolac 30 mg (n ¼ 21) or intravenous butorphanol 1 mg (n ¼ 25), the former had more nausea (24% versus 4%) and vomiting (5% versus none); the latter had more sedation (36% versus 5%), dizziness (28% versus none), and rashes (4% versus none) [196c]. When butorphanol 4 micrograms/kg/hour was compared with fentanyl 0.4 micrograms/ kg/hour as intravenous patient-controlled analgesia for postoperative pain after abdominal hysterectomy in 100 patients, there were few adverse reactions [197c]. Respiratory rate was reduced by butorphanol 1 hour after the start of treatment. Drug withdrawal A 58-year-old man, who took midazolam 1.2 mg and butorphanol 0.12 mg/hour for 12 hours for insomnia over 2 weeks, had an acute withdrawal syndrome during tracheotomy; accumulation of butorphanol triggered withdrawal when remifentanil was used during the operation [198A].

227

OPIOID RECEPTOR ANTAGONISTS Methylnaltrexone

[SED-15, 2307;

SEDA-32, 211] Methylnaltrexone has been widely used to manage opioid induced constipation and acts by blocking the entry of opioids into cells [199r]. The common adverse effects include abdominal pain, gas, nausea, dizziness, and diarrhea. The FDA has recommended that patients should stop taking methylnaltrexone if it causes severe diarrhea, vomiting, nausea, or abdominal pain. Placebo-controlled studies In a doubleblind, randomized, placebo-controlled trial in 154 patients with advanced illness and opioid induced constipation a single subcutaneous injection of methylnaltrexone 0.15 or 0.3 mg/kg was compared with placebo [200C]. The most common adverse events were abdominal pain and flatulence, and three patients had serious adverse events attributed to methylnaltrexone.

Nalmefene

[SED-15, 2420; SEDA-30, 119; SEDA-32, 211]

Placebo-controlled studies The effect of nalmefene on gambling symptoms and urges has been investigated using three doses of nalmefene (25, 50, and 100 mg) [201R]. Those who took 25 mg improved overall; those who took 50 and 100 mg did not, perhaps because of the frequency of adverse effects.

Naloxone

[SED-15, 2421; SEDA-30, 119; SEDA-31, 172] Cardiovascular Cardiac arrest occurred in a preterm neonate (gestation 27 weeks) after a bolus of naloxone (100 micrograms/kg) for the treatment of a 10-fold morphine

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overdose [202A]. Profound bradycardia and asystole occurred immediately after naloxone administration, the immediacy suggesting a causal relationship. Biliary tract Pruritus due to cholestasis in a 73-year-old man was treated with naloxone 2 nanograms/kg/minute, doubled every 12 hours up to 200 nanograms/kg/minute [203A]. The pruritus improved after 2 days but on the third day he had pain from metastases. The authors suggested caution in using opioid antagonists for pruritus, because of the possibility of unmasking pain.

Naltrexone

[SED-15, 2423; SEDA-30, 120; SEDA-31, 172; SEDA-32, 211]

The adverse reactions associated with the use of naltrexone in patients with alcohol dependence tend to be mild gastrointestinal reactions (nausea, vomiting, and abdominal pain or discomfort) and they occur early in treatment [204R]. Hepatotoxicity has been reported with high doses (100–300 mg/ day) and especially in obese individuals. Naltrexone can also precipitate opioid withdrawal and may not be suitable for those requiring future opioids, such as those requiring surgery. In 12 subjects with kleptomania the most common adverse reaction to naltrexone 50–150 mg/day was nausea (in five subjects, one of whom withdrew as a result) [205c]. Other events included dry mouth and

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insomnia. The events were mild to moderate and usually occurred in the first week of treatment. Observational studies In 30 drinkers the magnitude of naltrexone-induced aversion correlated with the amount of ethanol consumed during naltrexone treatment [206c]. The level of aversion also predicts future reduction in consumption. Placebo-controlled studies In a doubleblind, randomized, placebo-controlled trial in 80 patients with amfetamine dependence, naltrexone 50 mg/day was given for 12 weeks [207C]. There were adverse reactions in 14 patients and they were rated as mild. The most frequent reactions were nausea, gastrointestinal discomfort, headache, and fatigue. Drug–drug interactions Sertraline The combination of naltrexone 50 mg and sertraline 100 mg has been studied in patients with alcohol dependence in rural settings [208c]. The combination did not result in improved abstinence rates. Adverse events were more common in those who took naltrexone and sertraline (n ¼ 33) than those who took naltrexone alone (n ¼ 34) or placebo (n ¼ 34). There was nausea in 78% (compared with 59% and 47% respectively); dry mouth in 72% (47% and 47%); sleepiness in 69% (35% and 26%); and dizziness in 47% (24% and 21%).

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