- Email: [email protected]
Hypnotics and sedatives
T.C. Jerram
5
Hypnotics and sedatives
B E N Z O D I A Z E P I N E S ( S E D A - 1 7 , 42) General Further information, although not necessarily comprehensive, continues to appear on the mechanisms by which benzodiazepines exert their effects. Doble and Martin (1 R) have reviewed the pharmacology and distribution of benzodiazepine receptors; they report that differences between receptors are probably related to variations in the sub-unit, 6 such variations having been identified. As yet no clear correlation with pharmacological effects has been demonstrated. Turning to clinical practice, further comments have been published on short-acting benzodiazepines and on their epidemiology. O'Donovan and McGuffin (2 R) take up the issues of rebound insomnia (SEDA-17; 42) and of memory impairment and are adamant that the former is most common and severe for those compounds with short half-lives. However, they then argue that memory difficulties and other psychological symptoms such as anxiety and depression are commoner with triazolam than with other similar drugs and that it has 'no compelling singular benefit.' There have been 2 studies of how benzodiazepines are actually used in general practice. A Dutch study was part of a year long project involving 45 practitioners in the late 1980s (3c). The main finding was that middle-aged females (45 64 years) were almost twice as likely to receive a prescription than males: a worrying finding was that part of this discrepancy was accounted for by the fact that benzodiazepines were regularly prescribed for symptoms such as headache and lethargy which are not generally accepted as indications for their use. A smaller U K study concentrated on day-time use in one general practice (4r In all, 0.5% of the population had been taking the drugs for more than one year; of those about two-thirds ~:3 1995 Elsevier Science B.V. All rights reserved. Side Effects of Drugs Annual 18 J.K. Aronson and C.J. van Boxtel, eds.
thought the treatment was beneficial. About one-half of the group wished to stop their drugs and they tended to be younger than those who did not. An accompanying leader gives a useful summary of how to reduce inappropriate long-term use (5R): and a small study in London showed that a significant reduction in benzodiazepine use can be achieved by using simple information sheets and regular consultations (6c). Benzodiazepine use has declined by about a third from its peak in the mid-1980s, most of the reduction being due to decreased use of anxiolytics rather than of hypnotics. In the future, relatively few new long-term prescriptions should be written and the total number of users should continue to decline gradually. Two possible side effects have been reported, both in rare conditions. Joseph and Wroblewski report four episodes of akathisia which occurred in three patients with traumatic brain injury and seizure disorder (7c). The benzodiazepines involved were clonazepam, clorazepate and lorazepam and it was suggested that the akathisia may be similar to benzodiazepine-induced disinhibition. Nikoskelainen et al. describe a patient with Leber's hereditary optic neuropathy (LHON). After a complicated medical history including alcoholism, seizures and syphilis, he was admitted in a state of delirium (8c). He developed an episode of severe hypoventilation after being treated with oxazepam. Patients with LHON are known to be sensitive to drugs that usually have little respiratory effect - such as mild analgesics - and these now include benzodiazepines. Two possible interactions have been recorded, both in elderly patients. In the first a 78 year old male patient was prescribed amiodarone amongst other preparations. He was subsequently prescribed clonazepam for nocturnal myo-clonus but some weeks later developed the clinical picture of benzodiazepine toxicity. This resolved spontaneously when the clonazepam was withdrawn (9c). Ataxia oc43
44 curred in two men who were prescribed omeprazole, one with triazolam and lorazepam and the other with flurazepam (10c). It was suggested that omeprazole may act in a similar way to cimetidine by impairing the oxidative metabolism of benzodiazepines.
INDIVIDUAL BENZODIAZEPINES
Bromazepam ( SED-12, 98) 'A 41-year-old male was prescribed bromazepam 9 mg tid. After 2 days treatment he suddenly developed a dystonic spasm of the jaw and tongue. These symptoms remitted rapidly following intravenous administration of an anti-cholinergic drug. No other cause for the dystonia could be established ...' (11c) While benzodiazepines have been associated with the development of parkinsonian symptoms, only diazepam has previously been reported as causing dystonia. The mechanism for this remains unclear.
Clonazepam ( SED-12, 98) This is an unusual benzodiazepine which is mainly used as an anti-convulsant, especially in children and those with mental handicap. Two problems which affect its use are that it may lose its effect after a time and that discontinuation seizures or exacerbation can occur. These are particularly troublesome if the clonazepam has to be withdrawn rapidly because of other adverse effects. In a large personal series of children Sugai identified 17 such cases and compared them to 23 patients who did not react in this way. He then devised a carefully controlled regime and withdrew a further 54 patients with no ill effects (12").
Flunitrazepam ( SED-12, 99) An Austrian group investigated possible treatments for alcohol withdrawal delirium (13"). They identified good control, flexibility of dosage and rapid reversibility of action as necessary features and concluded that flunitrazepam given in an intra-venous infusion was an appropriate drug. They carried out an open study in 25 patients and reported few signifi-
Chapter 5 T.C Jerram cant adverse effects even though many of the patients had concomitant diseases. One case of respiratory depression occurred but this was rapidly reversed with flumazenil.
Midazolam (SED-12, 99; SEDA-17, 44) Midazolam is used primarily for endoscopy and dental procedures. A relatively frequent occurrence is paradoxical disinhibition sometimes combined with allegations of sexual assault and two brief reports are of interest. In the first a 70 year old male who was undergoing gastroscopy alleged that he had been assaulted by two female nurses, thus demonstrating that such allegations are not restricted to females (14c). The second report is particularly valuable in that although the disinhibition was typical, the patient was taking part in a large multi-site study, and a large amount of pre-event data was recorded and the events were videotaped (15c). One particular fact came to light subsequently and that was a previous problem with alcohol dependence which had not been revealed beforehand. The authors suggest that alcohol may have altered the receptor system in some way.
Temazepam (SEDA-17, 45) The most significant adverse effects of this compound are frc;m the results of injection by drug addicts. The effects of intra-arterial injections have been described in previous editions but two rarer events have been reported. Vella and Edwards carried out a post-mortem on a 31 year old female who had crushed temazepam and injected the solution into the femoral vein. At necropsy, small pulmonary vessels were occluded with fibrillary foreign material and the cause of death was given as pulmonary micro-embolisation (16c). A 40 year old male, also a drug misuser, attempted to inject temazepam, in the gel formulation, into the inner canthus. Bilateral blindness resulted (17c).
Triazolam (SED-12, 99; SEDA-17, 45) The role and safety of this drug continue to generate controversy (1R), with continuing correspondence between those who think it should be withdrawn and those who feel it an effective drug if used properly (18r). However, even the
Hypnotics and sedatives Chapter 5
45
most supportive authors argue only that it is as safe as the other benzodiazepines and do not claim that it has any particular benefits.
BENZODIAZEPINE ANTAGONISTS (SED-12, 100; SEDA-1L 46) Flumazenil is now widely used and its use has been approved by the US Food and Drug Administration. It is used to reverse conscious sedation, to counteract the effects of midazolam when used as an induction agent and, occasionally, in the assessment of suspected benzodiazepine overdosage. It has some side effects which include nausea, dizziness, blurring of vision, anxiety and headache: it may also induce panic attacks in some patients. Particular difficulties may occur if it is used unwittingly in patients already taking benzodiazepines: convulsions have occurred and Sleth and Duhamel described such a patient who became tetraplegic for some hours after colonoscopy (19c).
NON-BENZODIAZEPINE
DRUGS
Alpidem (SED-12, 99; SEDA-17, 46) The effects of this drug were studied in an 8-week open trial in 13 patients with panic disorder (20c). Although side effects were reported as being generally mild, seven patients noted drowsiness. Other effects observed were dizziness, influenzal symptoms, headache, skin rash, dyspepsia and altered bowel habits. Baelofen (SEDA-1Z 155; SED-12, 288) Krupitsky et al. discussed the treatment of affective symptoms in recovering alcoholics
(21c). They noted that benzodiazepines were not usually used as cross-tolerance and dependence may occur and that tricyclic antidepressants may have more side effects because of associated liver and CNS damage: they argued that as baclofen is a selective ligand of GABAB receptors and does not act on the benzodiazepine/GABA receptor complex it may be an effective drug in such patients. In a preliminary study involving ninety patients they found no side-effects specific to baclofen. Buspirone (SED-12, 100) Two further cases of movement disorders possibly associated with buspirone have been reported (22cr). One of the patients had received neuroleptics some time previously and it is possible that this may be a predisposing factor. A related drug is ipsapirone for which a dose-finding study has been published (23c). Hydroxyzine ( SEDA-17, 199) As the benzodiazepines fall into disfavor, some older drugs have been revived, of which hydroxyzine is one. There are no recent studies of its effects but an earlier report suggested that there are few specific or serious adverse effects other than sedation (24c). Zolpidem (SED-12, 99; SEDA-17, 46) Individual case reports have been published of possible idiosyncratic effects of this hypnotic. Iruela et al. described a female patient who developed complex and terrifying visual hallucinations (25c). CavaUaro et al. described two patients who appeared to develop intolerance to zolpidem with escalating doses which resulted in a withdrawal syndrome (26c).
REFERENCES 1. Doble A, Martin IL (1992) Trends PharmacoL Sci., 13, 7681. 2. O'Donovan MC, McGuffin P (1993) Short acting benzodiazepines:dream drugs or nightmare? Br Meal J., 306, 945-946. 3. Van der Waals FW, Mohrs J, Foets M (1993) Sex differencesamong recipients of benzodiazepines
in Dutch general practice. Br. Med. J., 307, 363366. 4. Wright N, Caplan R, Payne S (1994) Community survey of long term daytime use of benzodiazepines. Br. Meal J., 309, 27-28. 5. Tiller JW (1994) Reducing the use of benzodiazepines in general practice. Br. Med. J., 309, 34.
46 6. Morrice AAG, Iliffe S (1992) Reducing benzodiazepine use in patients requesting repeat prescriptions in general practice. Med. Sci. Res., 20, 535536. 7. Joseph AB, Wroblewski BA (1993) Paradoxical akathisia cause by clonazepam, clorazepate and lorazepam in patients with traumatic encephalopathy and seizure disorders: a subtype of benzodiazepine-induced disinhibition? Behav. NeuroL, 6, 221-223. 8. Nikoskelainen E, Asola M, Kalimo H, Savontau M-L, Majander A (1992) Benzo-diazepine sensitivity in Leber's hereditary optic neuroretinopathy. Lancet, 340, 1223-1224. 9. Witt DM, Ellsworth A,I, Leversee JH (1993) Amiodarone-clonazepam interaction. Ann. Pharmacother., 27, 1463-1464. 10. Marti-Masso .IF, De Munain A, De Dicastillo G (1992) Ataxia following gastric bleeding due to omeprazole-benzodiazepine interaction. Ann. Pharmacother., 26, 429-430. 11. Perez Trullen JM, Modrego Pardo P J, Vazquez Andre M, Lopez Lozano JJ (1992) Bromazepaminduced dystonia. Biomed. Pharmacother., 46, 375376. 12. Sugai K (1993) Seizures with clonazepam: discontinuation and suggestions for safe discontinuation rates in children. Epilepsia, 34, 1089- 1097. 13. Pycha R, Miller C, Barnas C, Hummer M, Stuppack C, Whitworth A, Fleischhacker, WW (1993) Intravenous flunitrazepam in the treatment of alcohol withdrawal delirium. Alcohol Clin. Exp. Res., 17, 753-757. 14. Playford RJ (1993) Allegations of sexual assault following midazolam sedation in a man. Anaesthesia, 47, 818. 15. Fiset L, Milgrom P, Beirne O, Roy-Byrne P (1992) Disinhibition of behaviors with midazolam. J. Oral Maxillofac. Surg.. 50, 645~a49. 16. Vella EJ, Edwards CW (1993) Death from
Chapter 5
T.C. Jerram
pulmonary microembolisation after intravenous injection of temazepam. Br. Med. J., 307, 26. 17. Thompson ,IL, Ferner RE (1993) Br. Med. J., 307, 1434. 18. Dinan TG, Leonard BE (1993) Triazolam: As safe as other benzodiazepines. B~ Med. Z, 306, 1475. 19. Sleth JC, Duhamel O (1993) Tetraplegia after colonoscopy: benzodiazepine withdrawal syndrome due to flumazenil? Ann. Fr Anesth. Reanim., 12, 434-436. 20. Schneier FR, Carrasco ,IL, Hollander E, Campeas R, Fallon B, Saoud JB, Feerick J, Liebowitz MR (1993) Alpidem in the treatment of panic disorder. J. Clin. P~ychopharmacol., 13, 150-153. 21. Krupitsky EM, Burakov AM, Ivanov VB, Krandashova GF, Lapin IP, Ja Grinenko A, Borodkin YS (1993) Baclofen administration for the treatment of affective disorders in alcoholic patients. Drug Alcohol Depend., 33, 157-163. 22. LeWitt PA, Walter A, Hening W, McHale D (1993) Persistent movement disorders induced by buspirone. Mov. Disord., 3, 331-334. 23. Boyer WF, Feighner ,IP (1993) A placebocontrolled double-blind multicenter trial of two doses of ipsapirone versus diazepam in generalized anxiety disorder. Int. Clin. PsychopharmacoL, 8, 173-176. 24. Rickels K, Gordon PE, Zamostien BB, Case W, Hutchison K, Chung H (1970) Hydroxyzine and chlordiazepoxide in anxious neurotic outpatients: a collaborative controlled study. Compr. Psychiatry, 11,457-474. 25. Iruela LM, Ibanez-Rojo V, Baca E (1993) Zolpidem macropsia in anorexic woman. Lancet, 342, 443-444. 26. Cavallaro R, Regazzetti M, Covelli G, Smeraldi E (1993) Tolerance and withdrawal with zolpidem. Lancet, 342, 374-375.
5
Hypnotics and sedatives
B E N Z O D I A Z E P I N E S ( S E D A - 1 7 , 42) General Further information, although not necessarily comprehensive, continues to appear on the mechanisms by which benzodiazepines exert their effects. Doble and Martin (1 R) have reviewed the pharmacology and distribution of benzodiazepine receptors; they report that differences between receptors are probably related to variations in the sub-unit, 6 such variations having been identified. As yet no clear correlation with pharmacological effects has been demonstrated. Turning to clinical practice, further comments have been published on short-acting benzodiazepines and on their epidemiology. O'Donovan and McGuffin (2 R) take up the issues of rebound insomnia (SEDA-17; 42) and of memory impairment and are adamant that the former is most common and severe for those compounds with short half-lives. However, they then argue that memory difficulties and other psychological symptoms such as anxiety and depression are commoner with triazolam than with other similar drugs and that it has 'no compelling singular benefit.' There have been 2 studies of how benzodiazepines are actually used in general practice. A Dutch study was part of a year long project involving 45 practitioners in the late 1980s (3c). The main finding was that middle-aged females (45 64 years) were almost twice as likely to receive a prescription than males: a worrying finding was that part of this discrepancy was accounted for by the fact that benzodiazepines were regularly prescribed for symptoms such as headache and lethargy which are not generally accepted as indications for their use. A smaller U K study concentrated on day-time use in one general practice (4r In all, 0.5% of the population had been taking the drugs for more than one year; of those about two-thirds ~:3 1995 Elsevier Science B.V. All rights reserved. Side Effects of Drugs Annual 18 J.K. Aronson and C.J. van Boxtel, eds.
thought the treatment was beneficial. About one-half of the group wished to stop their drugs and they tended to be younger than those who did not. An accompanying leader gives a useful summary of how to reduce inappropriate long-term use (5R): and a small study in London showed that a significant reduction in benzodiazepine use can be achieved by using simple information sheets and regular consultations (6c). Benzodiazepine use has declined by about a third from its peak in the mid-1980s, most of the reduction being due to decreased use of anxiolytics rather than of hypnotics. In the future, relatively few new long-term prescriptions should be written and the total number of users should continue to decline gradually. Two possible side effects have been reported, both in rare conditions. Joseph and Wroblewski report four episodes of akathisia which occurred in three patients with traumatic brain injury and seizure disorder (7c). The benzodiazepines involved were clonazepam, clorazepate and lorazepam and it was suggested that the akathisia may be similar to benzodiazepine-induced disinhibition. Nikoskelainen et al. describe a patient with Leber's hereditary optic neuropathy (LHON). After a complicated medical history including alcoholism, seizures and syphilis, he was admitted in a state of delirium (8c). He developed an episode of severe hypoventilation after being treated with oxazepam. Patients with LHON are known to be sensitive to drugs that usually have little respiratory effect - such as mild analgesics - and these now include benzodiazepines. Two possible interactions have been recorded, both in elderly patients. In the first a 78 year old male patient was prescribed amiodarone amongst other preparations. He was subsequently prescribed clonazepam for nocturnal myo-clonus but some weeks later developed the clinical picture of benzodiazepine toxicity. This resolved spontaneously when the clonazepam was withdrawn (9c). Ataxia oc43
44 curred in two men who were prescribed omeprazole, one with triazolam and lorazepam and the other with flurazepam (10c). It was suggested that omeprazole may act in a similar way to cimetidine by impairing the oxidative metabolism of benzodiazepines.
INDIVIDUAL BENZODIAZEPINES
Bromazepam ( SED-12, 98) 'A 41-year-old male was prescribed bromazepam 9 mg tid. After 2 days treatment he suddenly developed a dystonic spasm of the jaw and tongue. These symptoms remitted rapidly following intravenous administration of an anti-cholinergic drug. No other cause for the dystonia could be established ...' (11c) While benzodiazepines have been associated with the development of parkinsonian symptoms, only diazepam has previously been reported as causing dystonia. The mechanism for this remains unclear.
Clonazepam ( SED-12, 98) This is an unusual benzodiazepine which is mainly used as an anti-convulsant, especially in children and those with mental handicap. Two problems which affect its use are that it may lose its effect after a time and that discontinuation seizures or exacerbation can occur. These are particularly troublesome if the clonazepam has to be withdrawn rapidly because of other adverse effects. In a large personal series of children Sugai identified 17 such cases and compared them to 23 patients who did not react in this way. He then devised a carefully controlled regime and withdrew a further 54 patients with no ill effects (12").
Flunitrazepam ( SED-12, 99) An Austrian group investigated possible treatments for alcohol withdrawal delirium (13"). They identified good control, flexibility of dosage and rapid reversibility of action as necessary features and concluded that flunitrazepam given in an intra-venous infusion was an appropriate drug. They carried out an open study in 25 patients and reported few signifi-
Chapter 5 T.C Jerram cant adverse effects even though many of the patients had concomitant diseases. One case of respiratory depression occurred but this was rapidly reversed with flumazenil.
Midazolam (SED-12, 99; SEDA-17, 44) Midazolam is used primarily for endoscopy and dental procedures. A relatively frequent occurrence is paradoxical disinhibition sometimes combined with allegations of sexual assault and two brief reports are of interest. In the first a 70 year old male who was undergoing gastroscopy alleged that he had been assaulted by two female nurses, thus demonstrating that such allegations are not restricted to females (14c). The second report is particularly valuable in that although the disinhibition was typical, the patient was taking part in a large multi-site study, and a large amount of pre-event data was recorded and the events were videotaped (15c). One particular fact came to light subsequently and that was a previous problem with alcohol dependence which had not been revealed beforehand. The authors suggest that alcohol may have altered the receptor system in some way.
Temazepam (SEDA-17, 45) The most significant adverse effects of this compound are frc;m the results of injection by drug addicts. The effects of intra-arterial injections have been described in previous editions but two rarer events have been reported. Vella and Edwards carried out a post-mortem on a 31 year old female who had crushed temazepam and injected the solution into the femoral vein. At necropsy, small pulmonary vessels were occluded with fibrillary foreign material and the cause of death was given as pulmonary micro-embolisation (16c). A 40 year old male, also a drug misuser, attempted to inject temazepam, in the gel formulation, into the inner canthus. Bilateral blindness resulted (17c).
Triazolam (SED-12, 99; SEDA-17, 45) The role and safety of this drug continue to generate controversy (1R), with continuing correspondence between those who think it should be withdrawn and those who feel it an effective drug if used properly (18r). However, even the
Hypnotics and sedatives Chapter 5
45
most supportive authors argue only that it is as safe as the other benzodiazepines and do not claim that it has any particular benefits.
BENZODIAZEPINE ANTAGONISTS (SED-12, 100; SEDA-1L 46) Flumazenil is now widely used and its use has been approved by the US Food and Drug Administration. It is used to reverse conscious sedation, to counteract the effects of midazolam when used as an induction agent and, occasionally, in the assessment of suspected benzodiazepine overdosage. It has some side effects which include nausea, dizziness, blurring of vision, anxiety and headache: it may also induce panic attacks in some patients. Particular difficulties may occur if it is used unwittingly in patients already taking benzodiazepines: convulsions have occurred and Sleth and Duhamel described such a patient who became tetraplegic for some hours after colonoscopy (19c).
NON-BENZODIAZEPINE
DRUGS
Alpidem (SED-12, 99; SEDA-17, 46) The effects of this drug were studied in an 8-week open trial in 13 patients with panic disorder (20c). Although side effects were reported as being generally mild, seven patients noted drowsiness. Other effects observed were dizziness, influenzal symptoms, headache, skin rash, dyspepsia and altered bowel habits. Baelofen (SEDA-1Z 155; SED-12, 288) Krupitsky et al. discussed the treatment of affective symptoms in recovering alcoholics
(21c). They noted that benzodiazepines were not usually used as cross-tolerance and dependence may occur and that tricyclic antidepressants may have more side effects because of associated liver and CNS damage: they argued that as baclofen is a selective ligand of GABAB receptors and does not act on the benzodiazepine/GABA receptor complex it may be an effective drug in such patients. In a preliminary study involving ninety patients they found no side-effects specific to baclofen. Buspirone (SED-12, 100) Two further cases of movement disorders possibly associated with buspirone have been reported (22cr). One of the patients had received neuroleptics some time previously and it is possible that this may be a predisposing factor. A related drug is ipsapirone for which a dose-finding study has been published (23c). Hydroxyzine ( SEDA-17, 199) As the benzodiazepines fall into disfavor, some older drugs have been revived, of which hydroxyzine is one. There are no recent studies of its effects but an earlier report suggested that there are few specific or serious adverse effects other than sedation (24c). Zolpidem (SED-12, 99; SEDA-17, 46) Individual case reports have been published of possible idiosyncratic effects of this hypnotic. Iruela et al. described a female patient who developed complex and terrifying visual hallucinations (25c). CavaUaro et al. described two patients who appeared to develop intolerance to zolpidem with escalating doses which resulted in a withdrawal syndrome (26c).
REFERENCES 1. Doble A, Martin IL (1992) Trends PharmacoL Sci., 13, 7681. 2. O'Donovan MC, McGuffin P (1993) Short acting benzodiazepines:dream drugs or nightmare? Br Meal J., 306, 945-946. 3. Van der Waals FW, Mohrs J, Foets M (1993) Sex differencesamong recipients of benzodiazepines
in Dutch general practice. Br. Med. J., 307, 363366. 4. Wright N, Caplan R, Payne S (1994) Community survey of long term daytime use of benzodiazepines. Br. Meal J., 309, 27-28. 5. Tiller JW (1994) Reducing the use of benzodiazepines in general practice. Br. Med. J., 309, 34.
46 6. Morrice AAG, Iliffe S (1992) Reducing benzodiazepine use in patients requesting repeat prescriptions in general practice. Med. Sci. Res., 20, 535536. 7. Joseph AB, Wroblewski BA (1993) Paradoxical akathisia cause by clonazepam, clorazepate and lorazepam in patients with traumatic encephalopathy and seizure disorders: a subtype of benzodiazepine-induced disinhibition? Behav. NeuroL, 6, 221-223. 8. Nikoskelainen E, Asola M, Kalimo H, Savontau M-L, Majander A (1992) Benzo-diazepine sensitivity in Leber's hereditary optic neuroretinopathy. Lancet, 340, 1223-1224. 9. Witt DM, Ellsworth A,I, Leversee JH (1993) Amiodarone-clonazepam interaction. Ann. Pharmacother., 27, 1463-1464. 10. Marti-Masso .IF, De Munain A, De Dicastillo G (1992) Ataxia following gastric bleeding due to omeprazole-benzodiazepine interaction. Ann. Pharmacother., 26, 429-430. 11. Perez Trullen JM, Modrego Pardo P J, Vazquez Andre M, Lopez Lozano JJ (1992) Bromazepaminduced dystonia. Biomed. Pharmacother., 46, 375376. 12. Sugai K (1993) Seizures with clonazepam: discontinuation and suggestions for safe discontinuation rates in children. Epilepsia, 34, 1089- 1097. 13. Pycha R, Miller C, Barnas C, Hummer M, Stuppack C, Whitworth A, Fleischhacker, WW (1993) Intravenous flunitrazepam in the treatment of alcohol withdrawal delirium. Alcohol Clin. Exp. Res., 17, 753-757. 14. Playford RJ (1993) Allegations of sexual assault following midazolam sedation in a man. Anaesthesia, 47, 818. 15. Fiset L, Milgrom P, Beirne O, Roy-Byrne P (1992) Disinhibition of behaviors with midazolam. J. Oral Maxillofac. Surg.. 50, 645~a49. 16. Vella EJ, Edwards CW (1993) Death from
Chapter 5
T.C. Jerram
pulmonary microembolisation after intravenous injection of temazepam. Br. Med. J., 307, 26. 17. Thompson ,IL, Ferner RE (1993) Br. Med. J., 307, 1434. 18. Dinan TG, Leonard BE (1993) Triazolam: As safe as other benzodiazepines. B~ Med. Z, 306, 1475. 19. Sleth JC, Duhamel O (1993) Tetraplegia after colonoscopy: benzodiazepine withdrawal syndrome due to flumazenil? Ann. Fr Anesth. Reanim., 12, 434-436. 20. Schneier FR, Carrasco ,IL, Hollander E, Campeas R, Fallon B, Saoud JB, Feerick J, Liebowitz MR (1993) Alpidem in the treatment of panic disorder. J. Clin. P~ychopharmacol., 13, 150-153. 21. Krupitsky EM, Burakov AM, Ivanov VB, Krandashova GF, Lapin IP, Ja Grinenko A, Borodkin YS (1993) Baclofen administration for the treatment of affective disorders in alcoholic patients. Drug Alcohol Depend., 33, 157-163. 22. LeWitt PA, Walter A, Hening W, McHale D (1993) Persistent movement disorders induced by buspirone. Mov. Disord., 3, 331-334. 23. Boyer WF, Feighner ,IP (1993) A placebocontrolled double-blind multicenter trial of two doses of ipsapirone versus diazepam in generalized anxiety disorder. Int. Clin. PsychopharmacoL, 8, 173-176. 24. Rickels K, Gordon PE, Zamostien BB, Case W, Hutchison K, Chung H (1970) Hydroxyzine and chlordiazepoxide in anxious neurotic outpatients: a collaborative controlled study. Compr. Psychiatry, 11,457-474. 25. Iruela LM, Ibanez-Rojo V, Baca E (1993) Zolpidem macropsia in anorexic woman. Lancet, 342, 443-444. 26. Cavallaro R, Regazzetti M, Covelli G, Smeraldi E (1993) Tolerance and withdrawal with zolpidem. Lancet, 342, 374-375.