Evidence Table 10

Case Reports

DrugSub-groupAdverse EventsStudy# of casesCase CharacteristicsEffects during treatmentEffects during treatment reduction or discontinuation
EszopicloneAdultvisual and auditory hallucinations(Duggal, 2007)145-year old male night shift worker, had to wake up only a few hours after taking medication and falling asleep no history of psychiatric illness negative drug screen taking several other medications (doses unchanged)difficulty sleeping erratic sleep pattern visual and auditory hallucinations after waking up a few hours after taking medication (lasting several minutes)Hallucinations subsided after taking medication and sleeping for the recommended 8 hours
ZaleplonAdultCNS side effect(Stillwell, 2003)1drug abuse concurrent use of other drugsCNS depression including slow movements and reactions, poor coordination, lack of balance, and poor attentionnot reported
ZaleplonAdulthallucination
illusions
depersonalization
(Bhatia, Arora, & Bhatia, 2001)1healthy female nonsmoker, occasional drinkerlightheaded
illusion
visual hallucinations
not reported
ZaleplonPediatricssomnambulism(Liskow & Pikalov, 2004)1major depressive disorder, moderate
no history of sleep deprivation
somnambulism with complex behaviornot reported
ZolpidemAdultanterograde amnesia compulsive repetitive behaviors(Tsai, 2007)3adult womencompulsive repetitive behaviors (eating, shopping, and cleaning)
combined with anterograde amnesia (no recollection of behaviors)
adverse events stopped after discontinuation of zolpidem
ZolpidemAdultCNS side effect(Canaday, 1996)2not reportedamnesianot reported
ZolpidemAdultCNS side effect(Markowitz & Brewerton, 1996)2depression
no history of drug abuse concurrent use of antidepressants, serotonin-reuptake inhibitors
visual hallucination
auditory hallucination
confusion difficulties at work and marital
hallucination ceased
ZolpidemAdultCNS side effect(Toner, 1999)3motor vehicle accident or psychiatric historynightmare
hallucination
visual illusion
difficulty in concentration
nightmares, hallucination and visual illusion ceased
ZolpidemAdultCNS side effect(Tripodina kis, 2003)1no epileptic seizure nor drug abuse historythe patients increased the dose to 600mg per day
epigastric pain, nausea, epileptic seizures and depression
not reported
ZolpidemAdultdelirium hallucination(Freudenre ich & Menza, 2000)1depressionagitated and confused disorganized
visual hallucinations
not reported
ZolpidemAdultdependence(Aragona, 2000)1history of drug abuse seizure history after benzodiazepine discontinuationthe patient increased the dose up to 450–600mg per day for anxiolytic effect.
dependence and tolerance
epileptic seizure
ZolpidemAdultdependence(Bottlender, 1996)1history of drug abusethe patient increased the dose up to 140mg per day for well-being and reduction of tremor caused by parkinsonism, and also took five other drugs for Parkinson disease delusion disorder at the same time. dependence and tolerancedisturbed sleep, restlessness, sweating, tachycardia and hypertension.
ZolpidemAdultdependence(Liappas et al., 2002)1history of abuse and dependence on cocaineconsumed up to 200–300 mg/day for progressive reduction of his cocaine craving.
more excited, hyperactive and euphoric, often exhibiting childish behavior, logorrhea and memory blanks.
not reported
ZolpidemAdultdependence(Liappas, 2003)3history of drug abusepatients increased the dose up to 300–600mg for sedation, reduction of cocaine craving, stimulation, or euphoria.
dependence and tolerance childish behavior, confusion, memory blank or amnesia
confusion, amnesia or epileptic seizure
ZolpidemAdultdependence(Ravishan kar 1998)2depressionthe patient increased the dose up to 200mg per daytachycardia, confusion, anxiety, panic attacks and fear of ongoing outside
ZolpidemAdultdependence(Sakkas 1999)1depression history of drug abusethe patient increased the dose up to 300mg per day for stimulation dependence and tolerance
depression
mood disorders
suicidality
visual hallucinations
not reported
ZolpidemAdultdependence(Vartzopou los, Bozikas, Phocas, Karavatos, & Kaprinis, 2000)4history of drug abuse patients with borderline personality disorderpatients increased the dose up to 500mg daily to enhance the experienced relieving effect on their dysphoric states. dependence and tolerance
Mild to severe withdrawal syndrome after discontinuation.
confusion, anxiety, irritability, nausea, vomiting or psychomotor agitation.
ZolpidemAdult Elderlydependence delirium(Sharan, 2007)5history of drug/alcohol dependence and/or mental illness (depression, bipolar disorder, late-onset psychosis)
elderly patients (3) all taking 10mg zolpidem (recommended dose for the elderly is 5 mg)
dependence (including symptoms of withdrawal, cravings, apprehension/anxiety, restlessness, irritability, insomnia, palpitations)
delirium (agitation, talking irrelevantly, unable to recognize relatives, disorientation, auditory/visual/tactile hallucinations, restlessness, violent behavior)
2 patients diagnosed with zolpidem dependence: both successfully detoxified with clonazepam (8 mg/day), with one of the two relapsing after 3 months 3 patients diagnosed with delirium induced by zolpidem: symptoms subsided after zolpidem was discontinued
ZolpidemAdultdependence tolerance(Kao, 2004)1history of substance abuseIV administration for stimulant effect and euphoria and increased up to 300–400 mg/dayyawning, rhinorrhea and lacrimation
ZolpidemAdultdependence tolerance(Quaglio et al., 2005)2no common characteristicsincreasing toleranceno withdrawal disturbances during detoxification with flumazenil infusion
ZolpidemAdultgeneralized seizure(Cubala, 2007)1female
history of psychiatric hospitalization for organic dissociative disorder history of depression
Zolpidem dependence
Zolpidem tolerance, abuse and dependence
major depression
generalized tonic clonic seizures and a prolonged post convulsion period following sudden zolpidem withdrawal subsequent to drug dependence
ZolpidemAdulthallucination(Elko, Burgess, & Robertson, 1998)5concurrent use of serotonin- reuptake inhibition depressionhallucinationnot reported
ZolpidemAdulthallucination(Ginsberg, 2003), (Huang, 2003)1concurrent use of other drugs for hormone replacement, osteoporosis and insomniaheadache
spotty memory
hallucination
visual perception distortion
not reported
ZolpidemAdulthallucination(Tsai, 2003)1not reportedvisual illusions, confusion and hallucination especially reusing after rapid withdrawals.insomnia
ZolpidemAdulthallucination amnesia(Van Puijenbroe k, Egberts, & Krom, 1996)2one without history of psychiatric disorders, the other with major depressive disorder for 6 monthhallucination
amnesia
not reported
ZolpidemAdulthallucination CNS side effect(Hoyler, Tekell, & Silva, 1996)1history of pothyroidism, mild vascular dementia, and auditory hallucinationsagitated and disoriented to time and place
hallucination and increased psychomotor activity
regained her orientation, responded to redirection, was able to communicate at her usual level of efficiency, and her bizarre behavior was resolved
ZolpidemAdultHepatic problem(Clark, 1999)1liver transplantationdecline in mentality hepatic encephalopathy abdominal pain
awoke in a stupor and was disoriented to place and time
not reported
ZolpidemAdulthepatic problem(Karsenti, Blanc, Bacq, & Melman, 1999)1cholecystectomyabdominal pain
hepatotoxicity
not reported
ZolpidemAdultothers- drug interaction(Ortega 1996)1long term benzodiazepine user
no psychiatric history
nervousness, irritability, fainting, asthenia, muscular cramps, excessive hear and sweating occasional febrile episodes, weight loss, and a surprising sweet taste in the mouthall symptoms disappeared
ZolpidemAdultseizure dependence tolerance(Gericke & Ludolph, 1994)1depression
no seizure history
consumed 150–280 mg/day for stimulant effectrecurrence of depressive mood with apathy and drug carving
ZolpidemAdultsensory distortions tolerance(Pies, 1995)1no history of psychosis or substance abusesensory distortionsnot reported
ZolpidemAdultsleep related eating disorder(Najjar, 2007)146-year old female
history of depression, hypothyroidism, hypertension and insomnia
sleep related eating disorder starting 3 weeks after starting zolpidem, resulting in weight gain (50 pounds over a one-year period) and the development of obstructive sleep apneacomplete recovery after zolpidem was discontinued
ZolpidemAdultsomnambulism(Harazin & Berigan, 1999)1depressionsomnambulismsomnambulism stopped
ZolpidemAdultsomnambulism(Sattar, Ramaswa my, Bhatia, & Petty, 2003)1bipolar disorder
history of drug abuse
history of alcohol dependence mania
taking valproic at the same time
somnambulism
difficulty in concentration
insomnia
ZolpidemAdultsomnambulism(Yang, 2005)1Heavy alcohol consumption with questionable delitium tremens but had stopped drinking alcohol 20 years ago
Traumatic head injury
somnambulism
agitated and confused but had no psychotic experiences
no additional episodes of sleepwalking
ZolpidemAdulttolerance(Cavallaro, 1993)2psychiatric disordersincrease dosage because of tolerance with awakening after 2–3 h. abstinence phenomena during the day and increased dosage again to control those symptoms.not reported
ZolpidemAdultabruption vaginal spotting periorbital headache abdominal pain respiratory problems trouble sleeping withdrawal-like symptoms (nervousness, anxiety)(Askew, 2007)1pregnant female
history of zolpidem abuse (10–15 tablets/night)
cord blood testing resulted in measurable zolpidem levels (possibly as high as peak plasma
concentrations after a 5-mg dose of the drug), but no withdrawal symptoms noted in the neonate
withdrawal-like symptoms (nervousness, anxiety), complained of headaches and inability to sleep after treatment reduction
ZolpidemAdultvisual hallucinations
sleepiness
nausea
dizziness
diplopia
(de Haas, 2007)132-year old male
negative psychiatric personal or family history
no concomitant medication or illicit drugs
visual hallucinations starting 20 minutes after drug intake and lasting 2 hours
sleepiness, nausea, dizziness, diplopia, and dysphasia (present for 3.5 hours)
adverse events subsided after a few hours of taking the medication
ZolpidemAdult ElderlyCNS side effect(Logan & Couper, 2001)29no common characteristicsdriving impairment because of slow movements and reactions visual distortionsnot reported
ZolpidemAdult Elderlydependence(Liappas, 2003)8minor psychiatric disorderspatients increased the dose up to 150–600mg for stimulation, sedation, improving mood, relax, coping or sleep better.
dependence and tolerance
several traffic accidents
memory impairment
confusion
4 without withdrawal symptoms
1 with discomfort, irritability, and agitation
1 with epileptic seizure
1 with instability, dizziness and a craving for other psychotropic substances
1 not reported
ZolpidemAdult Elderlyothers(Morgenth aler & Silber, 2002)5no history of eating disorders concurrent use of other drugsamnestic sleep-related eating disorder
restless legs syndrome
no nocturnal eating
ZolpidemElderlyCNS side effect(Brodeur & Stirling, 2001)1Extensive medical historydelirium
psychosis
restless
amnesia
not reported
ZolpidemElderlydelirium mania(Hill, Oberstar, & Dunn, 2004)1no significant psychiatric history
family history of mild depression
no hallucination
no suicidal or homicidal ideation
mania
not reported
ZolpidemElderlydependence(Madrak & Rosenberg, 2001)1history of alcohol and drug abuseuse up to 100mg/day for the last 1.5 years
psychomotor agitation; tremor; facial flushing; anxiety
not reported
ZolpidemElderlyhallucination(Markowitz, Rames, Reeves, & Thomas, 1997)1no substance abuse depressionhallucinationno further episodes after discontinuation
ZolpidemElderlyhallucination(Pitner, Gardner, Neville, & Mintzer, 1997)1no psychiatric historyhallucination
delusion
psychomotor agitation
irritable and difficult to redirect
not reported
ZolpidemElderlypalpitations Torsades de Pointes (TdP) ventricular tachycardia degenerated to ventricular fibrillation QTc interval prolongation(Letsas, 2006)167-year-old woman
history of prosthetic mitral valve and congestive heart failure (NYHA II)
3 weeks after starting zolpidem, complained of palpitations Potential drug interaction with amiodarone, causing TdP ventricular tachycardia degenerated to ventricular fibrillation and a QTc interval prolongationafter zolpidem and amiodarone were withdrawn, patient’s QTc interval gradually decreased to its initial value
ZolpidemElderlyvisual hallucinations amnesia(Kito, 2006)182-year-old Asian woman being treated with fluvoxamine an d zolpidem for major depressive disorder and insomnia no prior psychiatric treatment and no history of alcohol or substance abusevisual hallucinations (lasting several minutes to half an hour) and amnesia 30 minutes after taking zolpidem starting on the third day of being given an increased dose of fluvoxamine – researchers postulated a possible fluvoxaminezolpidem interactionnightly visual hallucinations and amnesia disappeared after discontinuing zolpidem
ZolpidemPediatricshallucination(Andrade, 2002)1history of vascular headachedrowsiness, confusion, unsteadiness and hallucination vascular
headache and the use of zolpidem in children may increase the hallucination
not reported
ZolpidemPediatricssomnambulism(Lange, 2005)1depressive disorder
history of somnambulism
family history of somnambulism
no epileptiform activity
somnambulismchange to citalopram without incident
ZopicloneAdultdependence(Aranko, Henriksso n, Hublin, & Seppalain en, 1991)1depression
compulsive personality disorder
history of drug abuse
concurrent use of antidepressants
the patient increase the dose up to 90mg per day for uninterrupted sleep. Memory difficulties cognitive impairments dependencegrand-mal-type convulsion
ZopicloneAdultdependence(Haasen, Mueller- Thomsen, Fink, Bussopulo s, & Reimer, 2005)1no history of benzodiazepine or other psychotropic substance use and only very in frequently drank a glass of winedependence
daily dosage of 37.5mg
Remain symptom:
dystonia

symptoms peaked 8 days after initiating the reduction and 3 days after discontinuation, and then gradually remitted: torticollis such as tremulousness, sympathetic autonomic hyperactivity, including anxiety, arousal, sweating, tachycardia, facial flushing and mild hypertension

Reappeared insomnia
ZopicloneAdultdependence(Jones, 2005)4no common characteristicsdependencesevere anxiety with tachycardia, tremor, sweating, rebound insomnia, flushes, palpitations, and derealization.
ZopicloneAdultdependence(Thakore & Dinan, 1992)1depression
history of alcohol dependency
history of flurazepam addiction take zopiclone more due to anxiety and agoraphobia
dependencetachycardia
hand tremor
weakness
panic attack
ZopicloneAdultextreme agitation(Moloney, 2007)23-month history of depression concomitant alprazolam and antidepressant medicationone patient developed insomnia, restlessness, agitation, and a complete inability to relax 3 weeks after starting zopiclone
Another patient became extremely agitated, developed forgetfulness, inability to sit still, insomnia, nocturnal wandering, and racing thoughts one week after starting zopiclone
after zopiclone was withdrawn, adverse events resolved within 24–48 hours
ZopicloneAdultglobal amnesia(Fava, 1996)1no current psychiatric
symptomatology
no drinking history
no other medication
global amnesiano further episodes of global amnesia were observed during a 6- month period
ZopicloneAdultincidence of cancer(Stebbing et al., 2005)32not reported2 weeks of zopiclone. 32 (5.3%) patients have subsequently been diagnosed with cancer at least 3 months after exposure to zopiclone The label for eszopiclone contains significant warnings regarding carcinogenicity and mutagenesisnot reported
ZopicloneElderlydependence(Bramness, Arnestad, Karinen, & Hilberg, 2001)1smoker
respiratory problems
anxiety
difficulty in breathing
death caused by 337.5mg overdose
not reported
ZopicloneElderlydependence(Kuntze, Bullinger, & Mueller- Spahn, 2002)1depressive disorder
no use of psychotropic
tolerance to 337.5mg/day
dependence
not reported
ZopicloneElderlydependence delirium(Wong, 2005)174-year old woman with congestive heart failure
taking several concomitant medications
habit of using high-dose zopiclone (112.5 mg) daily for 20+ years
dependence
delirium (including confusion, disorientation) caused by abrupt zopiclone withdrawal
after zopiclone was resumed at a lower dose, delirium resolved completely after a few days
ZopicloneElderlyothers- drug interaction(Alderman, Gebauer, Gilbert, & Condon, 2001)1depression
concurrent use of antidepressants
morning drowsiness
increased plasma concentrations
zopiclone plasma concentrations back to normal after nefazodone discontinuation
ZopicloneElderlyrespiratory depression(Vogal, 1998)1COPD
ex-smoker with a history of ethanol abuse
drowsy
respiratory acidosis
not reported
ZopiclonePediatricsothers(Sullivan, McBride, & Clee, 1995)3history of drug abuse
alcohol abuse
no evidence of dependencenot reported

Alderman, C. P., Gebauer, M. G., Gilbert, A. L., & Condon, J. T. (2001). Possible interaction of zopiclone and nefazodone. Annals of Pharmacotherapy, 35(11), 1378–1380.

Aragona, M. (2000). Abuse, dependence, and epileptic seizures after zolpidem withdrawal: Review and case report. Clinical Neuropharmacology, 23(5), 281–283.

Aranko, K., Henriksson, M., Hublin, C., & Seppalainen, A. M. (1991). Misuse of zopiclone and convulsions during withdrawal. Pharmacopsychiatry, 24(4), 138–140.

Bhatia, S. C., Arora, M., & Bhatia, S. K. (2001). Perceptual disturbances with zaleplon. Psychiatric Services, 52(1), 109–110.

Bramness, J. G., Arnestad, M., Karinen, R., & Hilberg, T. (2001). Fatal overdose of zopiclone in an elderly woman with bronchogenic carcinoma. Journal of Forensic Sciences, 46(5), 1247–1249.

Brodeur, M. R., & Stirling, A. L. (2001). Delirium associated with zolpidem. Annals of Pharmacotherapy, 35(12), 1562–1564.

Canaday, B. R. (1996). Amnesia possibly associated with zolpidem administration. Pharmacotherapy, 16(4), 687–689.

Clark, A. (1999). Worsening hepatic encephalopathy secondary to zolpidem. Journal of Pharmacy Technology, 15(4), 139–141.

Elko, C. J., Burgess, J. L., & Robertson, W. O. (1998). Zolpidem-associated hallucinations and serotonin reuptake inhibition: a possible interaction. Journal of Toxicology - Clinical Toxicology, 36(3), 195–203.

Fava, G. A. (1996). Amnestic syndrome induced by zopiclone European Journal of Clinical Pharmacology, 50(6), 509.

Freudenreich, O., & Menza, M. (2000). Zolpidem-related delirium: A case report Journal of Clinical Psychiatry, 61(6), 449–450.

Gericke, C. A., & Ludolph, A. C. (1994). Chronic abuse of zolpidem. Journal of the American Medical Association, 272(22), 1721–1722.

Haasen, C., Mueller-Thomsen, T., Fink, T., Bussopulos, A., & Reimer, J. (2005). Zopiclone dependence after insomnia related to torticollis. International Journal of Neuropsychopharmacology, 8(2), 309–310.

Harazin, J., & Berigan, T. R. (1999). Zolpidem tartrate and somnambulism. Military Medicine, 164(9), 669–670.

Hill, K. P., Oberstar, J. V., & Dunn, E. R. (2004). Zolpidem-Induced Delirium with Mania in an Elderly Woman. Psychosomatics, 45(1), 88–89.

Hoyler, C. L., Tekell, J. L., & Silva, J. A. (1996). Zolpidem-induced agitation and disorganization. General Hospital Psychiatry, 18(6), 452–453.

Karsenti, D., Blanc, P., Bacq, Y., & Melman, E.-H. (1999). Hepatotoxicity associated with zolpidem treatment. British Medical Journal, 318, 1179%N 7192.

Kuntze, M. F., Bullinger, A. H., & Mueller-Spahn, F. (2002). Excessive use of zopiclone: A case report. Swiss Medical Weekly, 132, 35–36.

Lange, C. L. (2005). Medication-Associated Somnambulism. Journal of the American Academy of Child & Adolescent Psychiatry, 44(3), 211–212.

Liappas, I. A., Malitas, P. N., Dimopoulos, N. P., Gitsa, O. E., Liappas, A. I., Nikolaou, C. H. K., et al. (2002). A zolpidem and cocaine abuse case report. International Journal of Psychiatry in Clinical Practice, 6(4), 217–219.

Liskow, B., & Pikalov, A. (2004). Zaleplon overdose associated with sleepwalking and complex behavior. Journal of the American Academy of Child and Adolescent Psychiatry, 43(8), 927–928.

Logan, B. K., & Couper, F. J. (2001). Zolpidem and driving impairment. Journal of Forensic Sciences, 46(1), 105–110.

Madrak, L. N., & Rosenberg, M. (2001). Zolpidem abuse American Journal of Psychiatry, 158(8), 1330–1331.

Markowitz, J. S., & Brewerton, T. D. (1996). Zolpidem-induced psychosis. Annals of Clinical Psychiatry, 8(2), 89–91.

Markowitz, J. S., Rames, L. J., Reeves, N., & Thomas, S. G. (1997). Zolpidem and hallucinations Annals of Emergency Medicine, 29(2), 300–301.

Morgenthaler, T. I., & Silber, M. H. (2002). Amnestic sleep-related eating disorder associated with zolpidem. Sleep Medicine, 3(4), 323–327.

Pitner, J. K., Gardner, M., Neville, M., & Mintzer, J. (1997). Zolpidem-induced psychosis in an older woman Journal of the American Geriatrics Society, 45(4), 533–534.

Quaglio, G., Lugoboni, F., Fornasiero, A., Lechi, A., Gerra, G., & Mezzelani, P. (2005). Dependence on zolpidem: Two case reports of detoxification with flumazenil infusion. International Clinical Psychopharmacology, 20(5), 285–287.

Sattar, S. P., Ramaswamy, S., Bhatia, S. C., & Petty, F. (2003). Somnambulism due to probable interaction of valproic acid and zolpidem. Annals of Pharmacotherapy, 37(10), 1429–1433.

Stebbing, J., Waters, L., Davies, L., Mandalia, S., Nelson, M., Gazzard, B., et al. (2005). Incidence of cancer in individuals receiving chronic zopiclone or eszopiclone requires prospective study. Journal of Clinical Oncology, 23(31), 8134–8136.

Stillwell, M. E. (2003). Zaleplon and driving impairment. Journal of Forensic Sciences, 48(3), 677–679.

Sullivan, G., McBride, A. J., & Clee, W. B. (1995). Zopiclone abuse in South Wales: Three case reports. Human Psychopharmacology, 10(4), 351–352.

Thakore, J., & Dinan, T. G. (1992). Physical dependence following zopiclone usage: A case report. Human Psychopharmacology, 7(2), 143–145.

Van Puijenbroek, E. P., Egberts, A. C. G., & Krom, H. J. (1996). Visual hallucinations and amnesia associated with the use of zolpidem International Journal of Clinical Pharmacology and Therapeutics, 34, 318%N 317.

Vartzopoulos, D., Bozikas, V., Phocas, C., Karavatos, A., & Kaprinis, G. (2000). Dependence on zolpidem in high dose. International Clinical Psychopharmacology, 15(3), 181–182.

From: Evidence Tables

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Drug Class Review: Newer Drugs for Insomnia: Final Report Update 2 [Internet].
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