- Email: [email protected]
Hypnosedatives and anxiolytics
Stephen Curran and Shabir Musa
5
Hypnosedatives and anxiolytics
Insomnia is a common disorder and has a number of physiological, physical, and psychological causes. Jet lag, excessive physical exercise, and caffeine-containing drinks are common causes. Psychiatric conditions, such as depression and anxiety, are also frequent causes. Hypnotics have a role to play in the management of insomnia, but initially the underlying cause should be treated and sleep hygiene should be tried, for example, by making sure that the room is not too warm, cold, noisy, etc; a regular sleep pattern and modest exercise can be very helpful.
(SED-14, 133; SEDA-22, 39; SEDA-23, 45; SEDA-26, 49) AZASPIRONES
Buspirone Drug interactions
Clinicians should inform their patients about the risks associated with taking St John's won if they are taking psychotropic drugs that can cause the serotonin syndrome. 9 A 27-year-old married woman developed symptoms of generalized anxiety disorder and was given buspirone 30 mg/day ( 1A) . During treatment she felt depressed and decided to take St John's wort. Two months later she started to have nervousness, aggressiveness, hyperactivity, insomnia, blurred vision, and very short periods of confusion and disorientation. The symptoms were consistent with serotonin syndrome. St John's wort was withdrawn and her symptoms resolved after 1 week. Buspirone is a partial agonist at 5HTIA receptors; St John's wort is a non-selective inhibitor of 5HT reuptake and also upregulates postsynaptic 5HTIA and 5HT2A receptors; it therefore causes overstimulation of 5HTIA receptors, leading to the serotonin syndrome.
9 2004 Published by Elsevier B.V.
Side Effects of Drugs, Annual27 J.K. Aronson, ed.
BENZODIAZEPINES (SED-14, 122; SEDA-24, 46; SEDA-25, 47; SEDA-26, 46) Psychological In a prospective study, 1389 people aged 60-70 years were recruited from the electoral rolls of the city of Nantes (Epidemiology of Vascular Aging Study) (2c). A range of symptoms was examined, including cognitive functioning and symptoms of depressive anxiety, and data were also collected on psychotropic and other drugs, as well as tobacco use and alcohol consumption at baseline and thereafter at 2 years and 4 years. Users of benzodiazepines were divided into episodic users, recurrent users, and chronic users. Chronic users of benzodiazepines had a significantly higher risk of cognitive decline in the global cognitive test and two attention tests than non-users. Overall, episodic and recurrent users had lower cognitive scores compared with non-users, but the differences were not statistically significant. These findings suggest that long-term use of benzodiazepines is a risk factor for increased cognitive decline in elderly people.
Drug overdose Overdosage of benzodiazepines alone is generally thought to be safe, but deaths have occasionally been reported (3 A, 4 c, 5A). Death has again been reported, attributed to an overdose of triazolam (6A). 9 A 77-year-old woman was found dead in her bathtub. She had a history of depression, liver disease, spinal stenosis, and diabetes mellitus. An empty bottle of triazotam was found in the bin. At autopsy there was no injury or evidence of drowning. There was triazolam 0.12 mg/1 in the heart blood. In 204 consecutive suicides seen by the San Diego County Coroner during 1981-2, drugs were detected in 68%, and anxiolytics and hypnotics in 11% and t2% respectively; although benzodiazepines were found in under 10% of the group as a whole, they were found in onethird of those who died by overdose (7c). In a 43
44 retrospective analysis of 352 consecutive cases of fatal overdose, temazepam accounted for 65% of all deaths from benzodiazepine overdose (8 c). In one series of 2827 intentional cases of poisoning, in which there were ten deaths, three were associated with benzodiazepines; death was related to a delay between ingestion and medical intervention (9c), and advanced age has also been described as a risk factor (10c). In other cases death has been attributed to combined overdose with other drugs, such as alcohol (4c), oxycodone (11 A, 12A), tramadol (13A), and amitriptyline (14A). Concomitant benzodiazepine overdose has also been reported to be an independent risk factor in the development of hepatic encephalopathy (OR = 1.91; CI = 1.00, 3.65) and renal dysfunction (OR = 1.81; CI = 1.00, 3.22) in patients who take a paracetamol overdose (15c).
Chapter 5
Stephen Curran and Shabir Musa
This case illustrates the potential severity of alprazolam rebound and how its long-term use can exacerbate the symptoms for which it was originally administered. D r u g w i t h d r a w a l A 39-year-old woman had withdrawal symptoms after her dose of alprazolam was reduced (18A). Cognitive symptoms made it almost impossible for her to stop taking alprazolam or to continue psychotherapeutic treatment. The medication was stopped by means of a behavioral experiment, in which both patient and therapist were unaware of the way in which the medication was reduced, after which continuation of treatment became possible.
Bromazepam
Drug interactions The question of whether starting a benzodiazepine in patients taking levodopa is followed by a faster increase in antiparkinsonian drug requirements has been studied using drug dispensing data for all the residents in six Dutch cities (16c). All were 55 years old or older and had used levodopa for at least 360 days. There were 45 benzodiazepine starters and 169 controls. Antiparkinsonian drug doses increased faster in the benzodiazepine group, but the difference was not significant (RR = 1.44; 95% CI = 0.89, 2.59).
Alprazolam Psychiatric Alprazolam is a recognized treatment for panic disorder, and abrupt withdrawal from prolonged treatment is associated with panic attacks. 9 A 77-year-old married woman with panic attacks did not experience them while she took alprazolain 0.5 mg bd for 5 months; however, the attacks recurred after an increase in dose to 0.5 mg qds (17A). The authors suggested that the duration of action of alprazolam is too brief to prevent rebound anxiety with administration four times a day, but this explanation is highly speculative.
Drug interactions The interaction of bromazepam with fluconazole has been studied in 12 healthy men in a randomized, double-blind, four-way crossover study (19c). The subjects took a single oral or rectal dose of bromazepam (3 mg) after pretreatment for 4 days with oral fluconazole 100 mg/day or placebo. Pharmacodynamic effects of bromazepam were assessed using self-rated drowsiness, the continuous number addition test, and electroencephalography. After rectal administration there was a higher AUC (1.7-fold) and a higher Cmax (1.6-fold) than after oral administration; there were electroencephalographic effects and subjective drowsiness after rectal hromazepam, and the electroencephalographic effects correlated closely with mean plasma bromazepam concentrations. However, fluconazole caused no significant changes in the pharmacokinetics or pharmacodynamics of oral or rectal bromazepam.
Diazepam Immunologic Diazepam hypersensitivity is probably very rare: a MEDLINE search showed no reports between 1982 and 2002, but a case has now been reported (20 A).
l-lypnosedatives and anxiolytics
Chapter 5
45
9 A 28-year-old nurse had generalized urticaria and collapsed while she was undergoing a gastroscopy for suspected Helicobacter pylori infection. Before the start of the procedure she was given lidocaine oral spray and intravenous diazepam 10 mg, and at the end intravenous flumazenil 1 mg. Skin prick tests and intradermal tests with diazepam 5 mg/ml produced a weal-and-flare reaction; flumazenil 0.1 mg/ml and lidocaine 2% had no effect. Although for safety reasons a challenge test was not performed, the author suggested that the reaction had been IgE-mediated.
Lormetazepam Psychiatric Auditory hallucinations been attributed to lormetazepam (21A).
have
9 A 45-year-old woman with moderate depression and anxiety took tormetazepam 4 rag/day. After a few days, she noticed musical auditory hallucinations like children's songs. There were no neurological, otological, or psychiatric causes for the hallucinations. When the dose of lormetazepam was reduced to 2 mg the auditory experience changed to "classic tinnitus". The lorrnetazepam was eventually withdrawn, but a slight degree of tinnitus remained.
Quazepam Drug-food interactions The disposition of quazepam 20 mg, fasted and 30 minutes after the consumption of meals containing different amounts of dietary fat, has been studied in a three-arm, randomized, crossover study in nine healthy men (22c). Plasma concentrations of quazepam and its metabolite, 2 oxoquazepam, were measured for up to 48 hours after dosing. The peak concentrations of quazepam 30 minutes after low-fat and high-fat meals were 243% and 272% respectively of those in the fasted state. The A U C s of quazepam from 0 to 8 hours and from 0 to 48 hours were increased by both the low-fat and highfat meals by 1.4-2 fold times. Quazepam was well tolerated, with no significant difference in the Stanford Sleepiness Scale between fasted and fed conditions. Thus, food significantly increased the absorption of quazepam but did not prolong the half-life. Quazepam is lipophilic; it would therefore be more highly dissolved in a fatty meal and more available for absorption.
Temazepam D r u g abuse Inadvertent intra-arterial injection of temazepam can cause tissue damage. 9 A 29-year-old unemployed man developed pain and swelling of the right hand following inadvertent intra-arterial injection of temazepam capsules (23A). Over 10 days, necrotic areas involving the index, middle, and little fingers developed and the fingers had to be amputated. He reported episodes of intravenous drug use during the previous 3 days--a single heroin dose followed by temazepam four times (10 mg gel capsules dissolved in hot water). He had injected the drugs into a superficial blood vessel on the back of the right hand. D r u g dosage regimens Benzodiazepine prescribing for sleep induction in an elderly medical in-patient population has been examined, to determine if hospital prescribing increases the use of benzodiazepines after discharge (24c). The secondary objectives included monitoring for adverse effects and assessment of the quality of sleep in hospital compared with the quality of sleep at home. In-patient and out-patient prescribing of benzodiazepines used for insomnia was recorded over 3 months. Benzodiazepines were prescribed for 20% of patients, and 94% of the prescriptions were for temazepam. O f the 57 patients who were given benzodiazepines during a hospital admission, 57% had not taken a benzodiazepine at home before admission. Benzodiazepines were effective in the short-term for inducing sleep in hospital, with little evidence of adverse effects.
Triazolam Liver Liver damage has been attributed to triazolam (25A). A 64-year-old woman developed anorexia, fatigue, and jaundice. She had occasionally taken triazolain 0.25 mg for insomnia, and her liver function tests had been normal 5 months before. There was no history of liver disease or alcohol misuse or other serious medical history. She was jaundiced, with spider angiomata, and gradually deteriorated over the next 16 days, finally losing consciousness. Liver histology was consistent with submassive necrosis, extensive coagulation necrosis, and marked inflammation secondary to triazolam. She had a liver transplant 31 days after the initial presentation and 2 years later was in good health.
46
OTHER HYPNOTICS AND SEDATIVES
Chapter 5
StephenCurran and Shabir Musa
neuropsychological tests scores. Thus, clomethiazole did not improve or worsen cerebral outcome after coronary artery bypass surgery.
Chloral hydrate (SED-14,133; SEDA-24, 49; SEDA-25, 49)
Immunologic Several reports have highlighted the importance of gelatin allergy in young children, with some deaths due to anaphylaxis. A 2-year-old boy and a 4-year-old boy developed anaphylactic symptoms after being given a chloral hydrate suppository, which contained gelatin, for sedation before electroencephalography (26A). Chloral hydrate suppositories are often used to sedate children during various examinations and the authors suggested using gelatin-free formulations.
Zaleplon
(SEDA-24, 49; SEDA-25, 50;
SEDA-26, 49) A review of published studies of zaleplon has shown that it has a quick onset of action and undergoes rapid elimination, which results in a better safety profile than previously available agents (29R). In additional, rebound insomnia and other withdrawal effects have not been demonstrated with zaleplon, and it is well tolerated in both young and older patients. These characteristics may be clinically advantageous for patients who should not receive benzodiazepines.
Clomethiazole (SED-14, 133; SEDA-24, 49; SEDA-25, 49; SEDA-26, 49) Nervous system In a double-blind, doubledurnrny, placebo-controlled comparison of clomethiazole and gamma-hydroxybutyrate in ameliorating the symptoms of alcohol withdrawal, alcohol-dependent patients were randomized to receive either clomethiazole 1000 mg or gamma-hydroxybutyrate 50 mg/kg (27c). There was no difference between the three treatments in ratings of alcohol withdrawal symptoms or requests for additional medication. After tapering the active medication, there was no increase in withdrawal symptoms, suggesting that physical tolerance did not develop to either clomethiazole or gamma-hydroxybutyrate during the 5-day treatment period. The most frequently reported adverse effect of gammahydroxybutyrate was transient vertigo, particularly after the evening double dose. The effect of clomethiazole on cerebral outcome in patients undergoing coronary artery bypass surgery has been investigated in 245 patients, who were randomized double-blind to placebo or clomethiazole (1800 mg over 45 minutes followed by 800 mg/hour until the end of surgery) (28r A battery of eight neuropsychological tests was administered preoperatively and repeated 4-7 weeks after surgery. There were no differences between the clomethiazole and placebo groups in postoperative
Zolpidem (SED-14, 132; SEDA-24, 50; SEDA-25, 50; SEDA-26, 50) Nervous system Three patients had improvements in dystonia and parkinsonism after taking zolpidem 10 mg (30c). The improvement in dystonia began at 15-45 minutes and optimal benefits were observed alter 1-2 hours. The mean duration of action was 4.5 hours initially, falling to 2-3 hours with chronic use. This is similar to that reported in patients with progressive supranuclear palsy, and corresponds to the drug's half-life (2.5 hours). Sleepiness was noted at doses over 10 mg bd.
Psychiatric
Delirium has been attributed to
zolpidem (31 g). 9 Zolpidem 5 mg caused temporary delirium in an 86-year-old woman after 5 hours, when she became very restless and would not follow the directions of the nursing staff. She climbed out of bed over the rails and began to walk with an unsteady gait. She knew her name but was not oriented in time or place. Her symptoms resolved 2 days later with haloperidol. The zolpidem was withdrawn without recurrence of the delirium. ACT scan a few days later showed no significant changes. Improvement in cognitive function has been attributed to zolpidem (32A).
Hypnosedatives and anxiolytics
Chapter5
9 A recovering 60-year-old alcoholic woman developed reduced cognitive function, including considerable memory loss, praxis disorders, and an inability to join in conversation. A C T scan showed non-specific cerebral atrophy. She was given zolpidem 10 mg for insonmia, which she took at first at 2200 hours, but then earlier, at 1900 hours. After starting to take it at the earlier time she talked more easily and could wash the dishes and do the housework, things that she had lost the ability to do. This beneficial effect was detectable 45~60 minutes after the dose of zolpidem, lasted for 3 hours after each administration, and then abated. The subjective improvement in cognitive function was confirmed several times by her general practitioner.
47
Zopiclone
(SED-14, 132; SEDA-24, 50;
SEDA-26, 51) N e r v o u s s y s t e m In a two-part, placebo-controlled, crossover comparison of the effects of zopiclone and zaleplon on car driving, memory, and psychomotor performance, zaleplon l 0 mg had no residual effect on driving when taken at bedtime, 10 hours before driving (33c). In contrast, zopiclone 7.5 mg caused marked residual impairment. Patients should be advised to avoid driving the morning after taking zopiclone.
REFERENCES
1. Dannawi M. Possible serotonin syndrome after combination of buspirone and St John's wort. J Psychopharmacol 2002; 16: 401. 2. Pateruiti S, Dufouil C, Alperovitch A. Long-term benzodiazepine use and cognitive decline in the elderly: the Epidemiology of Vascular Aging Study. J Clin Psychopharmacol 2002; 22: 285-93. 3. Michalodimitrakis M, Christodoulou P, Tsatsakis AM, Askoxilakis I, Stiakakis I, Mouzas I. Death related to midazolam overdose during endoscopic retrograde cholangiopancreatography. Am J Forensic Med Pathol 1999; 20: 93-7. 4. Drummer OH, Syrjanen ML, Cordner SM. Deaths involving the benzodiazepine flunitrazepam. Am J Forensic Med Pathol 1993; 14: 238-43. 5. Aderjan R, Mattern R. Eine todlich verlaufene Monointoxikation mit Flurazepam (Dalamadorm). Probleme bei der toxikologischen Beurteilung. Arch Toxicol 1979; 43: 69-75. 6. Levine B, Grieshaber A, Pestaner J, Moore KA, Smialek JE. Distribution of triazolam and a-hydroxytriazolam in a fatal intoxication case. J Anal Toxicol 2002; 26: 52-4. 7. Mendelson WB, Rich CL. Sedatives and suicide: the San Diego study. Acta Psychiatr Scand 1993; 88: 337-41. 8. Obafunwa JO, Busuttil A. Deaths from substance overdose in the Lothian and Borders region of Scotland (1983-1991). Hum Exp Toxicol 1994; 13: 401-6. 9. Bruyndonckx RB, Meulemans AI, Sabbe MB, Kumar AA, Delooz HH. Fatal intentional poisoning cases admitted to the University Hospitals of Leuven, Belgium from 1993 to 1996. Eur J Emerg Med 2002; 9: 238-43. 10. Shah R, Uren Z, Baker A, Majeed A. Trends in suicide from drug overdose in the elderly in England and Wales, 1993-1999. Int J Geriatr Psychiatry 2002; 17: 416-21.
11. Burrows DL, Hagardorn AN, Harlan GC, Wallen ED, Ferslew KE. A fatal drug interaction between oxycodone and clonazepam. J Forensic Sci 2003; 48: 683~5. 12. Drummer OH, Syrjanen ML, Phelan M, Cordner SM. A study of deaths involving oxycodone. J Forensic Sci 1994; 39: 1069-75. 13. Michaud K, Augsburger M, Romain N, Giroud C, Mangin IF'.Fatal overdose of tramadol and alprazolam. Forensic Sci lnt 1999; 105: 185-9. 14. Kudo K, Imamura T, Jitsufuchi N, Zhang X-X, Tokunaga H, Nagata T. Death attributed to the toxic interaction of triazolam, amitriptyline and other psychotropic drugs. Forensic Sci Int 1997; 86: 3541. 15. Schmidt LE, Dalhoff K. Concomitant overdosing of other drugs in patients with paracetamol poisoning. Br J Clin Pharmacol 2002; 53: 535-41. 16. Van de Vijver DAMC, Roose RAC, Jansen PAF, Porsius A J, De Boer A. Influence of benzodiazepines on antiparkinsonian drug treatment in levodopa users. Acta Neurol Scand 2002; 105: 8-12. 17. Bashir A, Swartz C. Alprazolam-induced panic disorder. J Am Board Fam Pract 2002; 15: 69-72. 18. Meesters Y, Van Velzen CJM, Horwitz EH. A cognitive aspect related to the withdrawal of alprazolam; a case study [in Dutch]. Tijdschr Psychiatrie 2002; 44: 199-203. 19. Ohtani Y, Kotegawa T, Tsutsumi K, Morimoto T, Hirose Y, Nakano S. Effect of ftuconazole on the pharmacokinetics and pharmacodynamics of oral and rectal bromazepam; an application ofelectroencephalography as the pharmacodynamic method. J Clin Pharmacol 2002; 42: 183-91. 20. Asero R. Hypersensitivity to diazepam. Allergy Eur J Allergy Clin Immunol 2002; 57: 1209. 21. Curtin E Remund C. Musical hallucinations during a treatment with benzodiazepine: case report. Can J Psychiatry 2002; 47: 789-90.
48 22. Yasui-Furukori N, Kondo T, Takahata T, Mihara K, Ono S, Kaneko S, Tateishi T. Effect of dietary fat content in meals on pharmacokinetics of quazepam. J Clin Pharmacol 2002; 42: 1335-40. 23. Feeney GFX, Gibbs HH. Digit loss following misuse of temazepam. Med J Aust 2002; 176: 380. 24. Ramesh M, Roberts G. Use of night-time benzodiazepines in an elderly inpatient population. J Clin Pharm Ther 2002; 27: 93-7. 25. Kanda T, Yokosuka O, Fujiwara K, Saisho H, Shiga H, Oda S, Okuda K, Sugawara Y, Makuuchi M, Hirasawa H. Fulminant hepatic failure associated with triazolam. Dig Dis Sci 2002; 47: 1111-14. 26. Yamada A, Ohshima Y, Tsukahara H, Hiraoka M, Kimura I, Kawamitsu T, Kimura K, Mayumi M. Two cases of anaphylactic reaction to gelatin induced by a chloral hydrate suppository. Pediatr Int 2002; 44: 87-9. 27. Nimmerrichter AA, Walter H, Gutierrez-Lobos KE, Lesch OM. Double-blind controlled trial of gamma-hydroxybutyrate and clomethiazole in the
Chapter 5
Stephen Curran and Shabir Musa
treatment of alcohol withdrawal. Alcohol Alcohol 2002; 37: 67-73. 28. Kong RS, Butterworth J, Aveling W, Stump DA, Harrison MJG, Hammon J, Stygall J, Rorie KD, Newman SP. Clinical trial of the neuroprotectant ctomethiazole in coronary artery bypass graft surgery. Anaesthesiology 2002; 7: 585-91. 29. Israel AG, Kramer JA. Safety of zaleplon in the treatment of insomnia. Ann Pharmacother 2002; 36: 852-9. 30. Evidente VGH. Zolpidem improves dystonia in "Lubag" or X-linked dystonia-parkinsonism syndrome. Neurology 2002; 58: 662-3. 31. Shuster J. ISMP adverse drug reactions. Hosp Pharm 2002; 37: 242-9, 333. 32. Jarry C. Beneficial effect of zolpidem for dementia. Ann Pharmacother 2002; 36: 1808. 33. Vermeeren A, Riedel WJ, Van Boxtel MPJ, Darwish M, Paty I, Patat A. Differential residual effects of zaleplon and zopictone on actual driving: a comparison with a low dose of alcohol. Sleep 2002; 25: 224-31.
5
Hypnosedatives and anxiolytics
Insomnia is a common disorder and has a number of physiological, physical, and psychological causes. Jet lag, excessive physical exercise, and caffeine-containing drinks are common causes. Psychiatric conditions, such as depression and anxiety, are also frequent causes. Hypnotics have a role to play in the management of insomnia, but initially the underlying cause should be treated and sleep hygiene should be tried, for example, by making sure that the room is not too warm, cold, noisy, etc; a regular sleep pattern and modest exercise can be very helpful.
(SED-14, 133; SEDA-22, 39; SEDA-23, 45; SEDA-26, 49) AZASPIRONES
Buspirone Drug interactions
Clinicians should inform their patients about the risks associated with taking St John's won if they are taking psychotropic drugs that can cause the serotonin syndrome. 9 A 27-year-old married woman developed symptoms of generalized anxiety disorder and was given buspirone 30 mg/day ( 1A) . During treatment she felt depressed and decided to take St John's wort. Two months later she started to have nervousness, aggressiveness, hyperactivity, insomnia, blurred vision, and very short periods of confusion and disorientation. The symptoms were consistent with serotonin syndrome. St John's wort was withdrawn and her symptoms resolved after 1 week. Buspirone is a partial agonist at 5HTIA receptors; St John's wort is a non-selective inhibitor of 5HT reuptake and also upregulates postsynaptic 5HTIA and 5HT2A receptors; it therefore causes overstimulation of 5HTIA receptors, leading to the serotonin syndrome.
9 2004 Published by Elsevier B.V.
Side Effects of Drugs, Annual27 J.K. Aronson, ed.
BENZODIAZEPINES (SED-14, 122; SEDA-24, 46; SEDA-25, 47; SEDA-26, 46) Psychological In a prospective study, 1389 people aged 60-70 years were recruited from the electoral rolls of the city of Nantes (Epidemiology of Vascular Aging Study) (2c). A range of symptoms was examined, including cognitive functioning and symptoms of depressive anxiety, and data were also collected on psychotropic and other drugs, as well as tobacco use and alcohol consumption at baseline and thereafter at 2 years and 4 years. Users of benzodiazepines were divided into episodic users, recurrent users, and chronic users. Chronic users of benzodiazepines had a significantly higher risk of cognitive decline in the global cognitive test and two attention tests than non-users. Overall, episodic and recurrent users had lower cognitive scores compared with non-users, but the differences were not statistically significant. These findings suggest that long-term use of benzodiazepines is a risk factor for increased cognitive decline in elderly people.
Drug overdose Overdosage of benzodiazepines alone is generally thought to be safe, but deaths have occasionally been reported (3 A, 4 c, 5A). Death has again been reported, attributed to an overdose of triazolam (6A). 9 A 77-year-old woman was found dead in her bathtub. She had a history of depression, liver disease, spinal stenosis, and diabetes mellitus. An empty bottle of triazotam was found in the bin. At autopsy there was no injury or evidence of drowning. There was triazolam 0.12 mg/1 in the heart blood. In 204 consecutive suicides seen by the San Diego County Coroner during 1981-2, drugs were detected in 68%, and anxiolytics and hypnotics in 11% and t2% respectively; although benzodiazepines were found in under 10% of the group as a whole, they were found in onethird of those who died by overdose (7c). In a 43
44 retrospective analysis of 352 consecutive cases of fatal overdose, temazepam accounted for 65% of all deaths from benzodiazepine overdose (8 c). In one series of 2827 intentional cases of poisoning, in which there were ten deaths, three were associated with benzodiazepines; death was related to a delay between ingestion and medical intervention (9c), and advanced age has also been described as a risk factor (10c). In other cases death has been attributed to combined overdose with other drugs, such as alcohol (4c), oxycodone (11 A, 12A), tramadol (13A), and amitriptyline (14A). Concomitant benzodiazepine overdose has also been reported to be an independent risk factor in the development of hepatic encephalopathy (OR = 1.91; CI = 1.00, 3.65) and renal dysfunction (OR = 1.81; CI = 1.00, 3.22) in patients who take a paracetamol overdose (15c).
Chapter 5
Stephen Curran and Shabir Musa
This case illustrates the potential severity of alprazolam rebound and how its long-term use can exacerbate the symptoms for which it was originally administered. D r u g w i t h d r a w a l A 39-year-old woman had withdrawal symptoms after her dose of alprazolam was reduced (18A). Cognitive symptoms made it almost impossible for her to stop taking alprazolam or to continue psychotherapeutic treatment. The medication was stopped by means of a behavioral experiment, in which both patient and therapist were unaware of the way in which the medication was reduced, after which continuation of treatment became possible.
Bromazepam
Drug interactions The question of whether starting a benzodiazepine in patients taking levodopa is followed by a faster increase in antiparkinsonian drug requirements has been studied using drug dispensing data for all the residents in six Dutch cities (16c). All were 55 years old or older and had used levodopa for at least 360 days. There were 45 benzodiazepine starters and 169 controls. Antiparkinsonian drug doses increased faster in the benzodiazepine group, but the difference was not significant (RR = 1.44; 95% CI = 0.89, 2.59).
Alprazolam Psychiatric Alprazolam is a recognized treatment for panic disorder, and abrupt withdrawal from prolonged treatment is associated with panic attacks. 9 A 77-year-old married woman with panic attacks did not experience them while she took alprazolain 0.5 mg bd for 5 months; however, the attacks recurred after an increase in dose to 0.5 mg qds (17A). The authors suggested that the duration of action of alprazolam is too brief to prevent rebound anxiety with administration four times a day, but this explanation is highly speculative.
Drug interactions The interaction of bromazepam with fluconazole has been studied in 12 healthy men in a randomized, double-blind, four-way crossover study (19c). The subjects took a single oral or rectal dose of bromazepam (3 mg) after pretreatment for 4 days with oral fluconazole 100 mg/day or placebo. Pharmacodynamic effects of bromazepam were assessed using self-rated drowsiness, the continuous number addition test, and electroencephalography. After rectal administration there was a higher AUC (1.7-fold) and a higher Cmax (1.6-fold) than after oral administration; there were electroencephalographic effects and subjective drowsiness after rectal hromazepam, and the electroencephalographic effects correlated closely with mean plasma bromazepam concentrations. However, fluconazole caused no significant changes in the pharmacokinetics or pharmacodynamics of oral or rectal bromazepam.
Diazepam Immunologic Diazepam hypersensitivity is probably very rare: a MEDLINE search showed no reports between 1982 and 2002, but a case has now been reported (20 A).
l-lypnosedatives and anxiolytics
Chapter 5
45
9 A 28-year-old nurse had generalized urticaria and collapsed while she was undergoing a gastroscopy for suspected Helicobacter pylori infection. Before the start of the procedure she was given lidocaine oral spray and intravenous diazepam 10 mg, and at the end intravenous flumazenil 1 mg. Skin prick tests and intradermal tests with diazepam 5 mg/ml produced a weal-and-flare reaction; flumazenil 0.1 mg/ml and lidocaine 2% had no effect. Although for safety reasons a challenge test was not performed, the author suggested that the reaction had been IgE-mediated.
Lormetazepam Psychiatric Auditory hallucinations been attributed to lormetazepam (21A).
have
9 A 45-year-old woman with moderate depression and anxiety took tormetazepam 4 rag/day. After a few days, she noticed musical auditory hallucinations like children's songs. There were no neurological, otological, or psychiatric causes for the hallucinations. When the dose of lormetazepam was reduced to 2 mg the auditory experience changed to "classic tinnitus". The lorrnetazepam was eventually withdrawn, but a slight degree of tinnitus remained.
Quazepam Drug-food interactions The disposition of quazepam 20 mg, fasted and 30 minutes after the consumption of meals containing different amounts of dietary fat, has been studied in a three-arm, randomized, crossover study in nine healthy men (22c). Plasma concentrations of quazepam and its metabolite, 2 oxoquazepam, were measured for up to 48 hours after dosing. The peak concentrations of quazepam 30 minutes after low-fat and high-fat meals were 243% and 272% respectively of those in the fasted state. The A U C s of quazepam from 0 to 8 hours and from 0 to 48 hours were increased by both the low-fat and highfat meals by 1.4-2 fold times. Quazepam was well tolerated, with no significant difference in the Stanford Sleepiness Scale between fasted and fed conditions. Thus, food significantly increased the absorption of quazepam but did not prolong the half-life. Quazepam is lipophilic; it would therefore be more highly dissolved in a fatty meal and more available for absorption.
Temazepam D r u g abuse Inadvertent intra-arterial injection of temazepam can cause tissue damage. 9 A 29-year-old unemployed man developed pain and swelling of the right hand following inadvertent intra-arterial injection of temazepam capsules (23A). Over 10 days, necrotic areas involving the index, middle, and little fingers developed and the fingers had to be amputated. He reported episodes of intravenous drug use during the previous 3 days--a single heroin dose followed by temazepam four times (10 mg gel capsules dissolved in hot water). He had injected the drugs into a superficial blood vessel on the back of the right hand. D r u g dosage regimens Benzodiazepine prescribing for sleep induction in an elderly medical in-patient population has been examined, to determine if hospital prescribing increases the use of benzodiazepines after discharge (24c). The secondary objectives included monitoring for adverse effects and assessment of the quality of sleep in hospital compared with the quality of sleep at home. In-patient and out-patient prescribing of benzodiazepines used for insomnia was recorded over 3 months. Benzodiazepines were prescribed for 20% of patients, and 94% of the prescriptions were for temazepam. O f the 57 patients who were given benzodiazepines during a hospital admission, 57% had not taken a benzodiazepine at home before admission. Benzodiazepines were effective in the short-term for inducing sleep in hospital, with little evidence of adverse effects.
Triazolam Liver Liver damage has been attributed to triazolam (25A). A 64-year-old woman developed anorexia, fatigue, and jaundice. She had occasionally taken triazolain 0.25 mg for insomnia, and her liver function tests had been normal 5 months before. There was no history of liver disease or alcohol misuse or other serious medical history. She was jaundiced, with spider angiomata, and gradually deteriorated over the next 16 days, finally losing consciousness. Liver histology was consistent with submassive necrosis, extensive coagulation necrosis, and marked inflammation secondary to triazolam. She had a liver transplant 31 days after the initial presentation and 2 years later was in good health.
46
OTHER HYPNOTICS AND SEDATIVES
Chapter 5
StephenCurran and Shabir Musa
neuropsychological tests scores. Thus, clomethiazole did not improve or worsen cerebral outcome after coronary artery bypass surgery.
Chloral hydrate (SED-14,133; SEDA-24, 49; SEDA-25, 49)
Immunologic Several reports have highlighted the importance of gelatin allergy in young children, with some deaths due to anaphylaxis. A 2-year-old boy and a 4-year-old boy developed anaphylactic symptoms after being given a chloral hydrate suppository, which contained gelatin, for sedation before electroencephalography (26A). Chloral hydrate suppositories are often used to sedate children during various examinations and the authors suggested using gelatin-free formulations.
Zaleplon
(SEDA-24, 49; SEDA-25, 50;
SEDA-26, 49) A review of published studies of zaleplon has shown that it has a quick onset of action and undergoes rapid elimination, which results in a better safety profile than previously available agents (29R). In additional, rebound insomnia and other withdrawal effects have not been demonstrated with zaleplon, and it is well tolerated in both young and older patients. These characteristics may be clinically advantageous for patients who should not receive benzodiazepines.
Clomethiazole (SED-14, 133; SEDA-24, 49; SEDA-25, 49; SEDA-26, 49) Nervous system In a double-blind, doubledurnrny, placebo-controlled comparison of clomethiazole and gamma-hydroxybutyrate in ameliorating the symptoms of alcohol withdrawal, alcohol-dependent patients were randomized to receive either clomethiazole 1000 mg or gamma-hydroxybutyrate 50 mg/kg (27c). There was no difference between the three treatments in ratings of alcohol withdrawal symptoms or requests for additional medication. After tapering the active medication, there was no increase in withdrawal symptoms, suggesting that physical tolerance did not develop to either clomethiazole or gamma-hydroxybutyrate during the 5-day treatment period. The most frequently reported adverse effect of gammahydroxybutyrate was transient vertigo, particularly after the evening double dose. The effect of clomethiazole on cerebral outcome in patients undergoing coronary artery bypass surgery has been investigated in 245 patients, who were randomized double-blind to placebo or clomethiazole (1800 mg over 45 minutes followed by 800 mg/hour until the end of surgery) (28r A battery of eight neuropsychological tests was administered preoperatively and repeated 4-7 weeks after surgery. There were no differences between the clomethiazole and placebo groups in postoperative
Zolpidem (SED-14, 132; SEDA-24, 50; SEDA-25, 50; SEDA-26, 50) Nervous system Three patients had improvements in dystonia and parkinsonism after taking zolpidem 10 mg (30c). The improvement in dystonia began at 15-45 minutes and optimal benefits were observed alter 1-2 hours. The mean duration of action was 4.5 hours initially, falling to 2-3 hours with chronic use. This is similar to that reported in patients with progressive supranuclear palsy, and corresponds to the drug's half-life (2.5 hours). Sleepiness was noted at doses over 10 mg bd.
Psychiatric
Delirium has been attributed to
zolpidem (31 g). 9 Zolpidem 5 mg caused temporary delirium in an 86-year-old woman after 5 hours, when she became very restless and would not follow the directions of the nursing staff. She climbed out of bed over the rails and began to walk with an unsteady gait. She knew her name but was not oriented in time or place. Her symptoms resolved 2 days later with haloperidol. The zolpidem was withdrawn without recurrence of the delirium. ACT scan a few days later showed no significant changes. Improvement in cognitive function has been attributed to zolpidem (32A).
Hypnosedatives and anxiolytics
Chapter5
9 A recovering 60-year-old alcoholic woman developed reduced cognitive function, including considerable memory loss, praxis disorders, and an inability to join in conversation. A C T scan showed non-specific cerebral atrophy. She was given zolpidem 10 mg for insonmia, which she took at first at 2200 hours, but then earlier, at 1900 hours. After starting to take it at the earlier time she talked more easily and could wash the dishes and do the housework, things that she had lost the ability to do. This beneficial effect was detectable 45~60 minutes after the dose of zolpidem, lasted for 3 hours after each administration, and then abated. The subjective improvement in cognitive function was confirmed several times by her general practitioner.
47
Zopiclone
(SED-14, 132; SEDA-24, 50;
SEDA-26, 51) N e r v o u s s y s t e m In a two-part, placebo-controlled, crossover comparison of the effects of zopiclone and zaleplon on car driving, memory, and psychomotor performance, zaleplon l 0 mg had no residual effect on driving when taken at bedtime, 10 hours before driving (33c). In contrast, zopiclone 7.5 mg caused marked residual impairment. Patients should be advised to avoid driving the morning after taking zopiclone.
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