Drugs and Human Performance FACT SHEETS - Zolpidem (and Zaleplon, Zopiclone)

Source: Zolpidem is available b y prescription and is a Schedule IV controlled substance. Ambien® is available in strengths of 5 mg and 10 mg (white and pink oval tablets, respectively). Sonata® contains zaleplon. Imovane® contains zopiclone.

Drug Class: Non-benzodiazepine sedative-hypnotic, CNS depressant, sleep aid. .

Medical and Recreational Uses: Zolpidem is a non-benzodiazepine hypnotic used in short-term treatment (up to 4 weeks) of insomnia. Zaleplon and zopiclone also are indicated for the treatment of insomnia.

Potency, Purity and Dose: Recommended zolpidem dose is 10 mg immediately before bedtime (5 mg in the elderly). Recommended nighttime zaleplon and zopiclone doses are 5-20 mg and 7.5 mg, respectively. Patients treated with zolpidem often concurrently use other medications such as antidepressants, narcotic analgesics, and muscle relaxants

Route of Administration: Oral.

Pharmacodynamics: While zolpidem has a chemical structure unrelated to benzodiazepines, it is a GABA A receptor agonist and shares some of the pharmacological properties of benzodiazepines. Zolpidem p referentially binds to receptors containing an a 1 subunit (also known as BZ1 - or w 1-receptor subtype s). Zolpidem shortens sleep latency and prolongs total sleep time in patients with insomnia, but has little effect on the stages of sleep in normal subjects. It also has weak anticonvulsant properties. Zaleplon binds preferentially to BZ-1, but also to BZ-2 and BZ-3; while zopiclone binds equally to BZ-1 and BZ-2. .

Pharmacokinetics: Zolpidem is absorbed readily from the gastrointestinal tract. First-pass hepatic metabolism results in an oral bioavailability of 67%, and 92% is bound in plasma. Zolpidem has a short elimination half-life (2.2 + 0.4 hours), which is reduced in children (~ 1.4 hours) and increased in the elderly (~ 2.8 hours) and patients with hepatic cirrhosis (~ 9.9 hours) 6. Peak plasma concentrations are detected at 1.5-2.5 hours. Peak concentrations are decreased with food and increased in patients with hepatic insufficiency. Zaleplon has a bioavailability of 30% and has a shorter half-life (1.1 hours) compared to zolpidem.

Molecular Interactions / Receptor Chemistry: Zolpidem is converted to hydroxylated metabolites principally by cytochrome P450 3A4 isoenzymes, with minor contributions by 1A2 and 2C9 isoforms. Potential inhibitors of these isoenzymes could decrease the rate of zolpidem elimination if administered concurrently, while potential inducers could increase the rate of elimination

Blood to Plasma Concentration Ratio: Data not available.

Interpretation of Blood Concentrations: Single doses of 5 mg zolpidem resulted in average peak concentrations of 0.06 mg/L at 1.6 hours; 10 mg produced 0.12 mg/L at 1.6 hours; 15 mg produced 0.20 mg/L at 1.5 hours; and 20 mg produced 0.23 mg/L at 2.1 hours.

Interpretation of Urine Test Results: Urinary excretion of unchanged zolpidem is less than 1%.

Effects:

Psychological: Sleep induction, drowsiness, dizziness, lightheadedness, amnesia, confusion, concentration difficulties, and memory impairment .

Physiological: Nausea, ataxia, slow and slurred speech, slow reflexes, and difficulty with coordination.

Side Effect Profile: Somnolence, lightheadedness, vertigo, he a dache, nausea, fatigue, cognitive deficits, and impairment of consciousness ranging from somnolence to light coma, vertigo. Infrequently reported side effects include agitation, decreased cognition, depressive syndrome, detachment, concentration difficulties, nightmares, hallucination, leg cramp, paresthesia, somnolence, speech disorder, double vision, dry mouth, and diarrhea. Hangover effects are unlikely with zolpidem, although morning-after anterograde amnesia may occur. In overdose, patients mainly suffer somnolence and drowsiness, pinpoint pupils, respiratory depression, and in extreme cases, coma and respiratory failure.

Duration of Effects: Following 10-20 mg oral doses of zolpidem, - 15effects can last 4up to 4-5 hours (dose-dependent). There are generally no residual effects the morning after a nighttime dose of zolpidem. Sedation may extend for 8-16 hours following intoxication. Zaleplon has a more rapid onset and shorter duration of effects compared to zolpidem, while zopiclone has longer duration of effects.

Tolerance, Dependence and Withdrawal Effects: Tolerance and dependency are not typically detected after 4 weeks of therapeutic use; however, tolerance may develop with chronic use. There is some evidence of tolerance and physical dependency observed with chronic administration of zolpidem in animal models. Withdrawal following abrupt discontinuation may include mild dysphoria and insomnia, abdominal and muscle cramps, vomiting, sweating, tremors, convulsions, fatigue, flushing, lightheadedness, nervousness, and panic attacks.

Drug Interactions: Imipramine has an additive effect of decreased alertness; chlorpromazine has an additive effect of decreased alertness and decreased psychomotor performance; ritonavir decreases clearance though inhibiting CYP3A hydroxylation; ketoconazol also decreases clearance; and flumazenil is an effective and therapeutic pharmacodynamic antagonist. Alcohol increases the sedation and decreases psychomotor performance produced by zolpidem. Other CNS depressant drugs may potentiate the effects of zolpidem. Zopiclone has additional performance decrements when concurrently taken with alcohol, carbamazepine, and diazepam.

Performance Effects: Unsteady gait, confusion, disorientation, and significant cognitive and psychomotor impairment can be observed within 1-5 hours following zolpidem doses of 10-20 mg. Memory impairment (learning, recall and recognition of words, pictures recall, and numbers) digit entry and recall psychomotor slowing (digit symbol substitution task, circular light tasks), reduced attentional capacity (impaired divided and sustained attention), impaired balance (ataxia, dizziness), visual disturbances ( Ataxia, double vision ), dizziness, nausea, and, impaired time estimation have been recorded Psychomotor impairment can be found up to 5 hours after a single 15 mg oral dose and up to 8.25 hours after a 20 mg dose.

Memory and learning impairment can be found up to 8.25 hours following a 10- 20 mg dose . Impaired coordination, reactive and cognitive skills.There has been no significant residual effect on memory or actual driving when subjects have been tested the morning after a single 10 mg dose.

Following a single 10-20 mg dose of zaleplon, studies have shown no residual effects on actual driving (5-10 hours) or on body sway, reasoning, retrieval and spatial memory (4-9 hours); however, significant impairment has been reported within 1-3 hours of dosing. Minor impairment of delayed free recall has occurred 4 hours after 20 mg dose of zaleplon. For zopiclone, a single 7.5 mg dose can cause severe residual effects on actual driving at 5 and 10 hours, severe residual effects on body sway and memory at 4 hours, and minor impairment of delayed free recall 9 hours after dosing.

Effects on Driving: The drug manufacturer states that patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination such as driving a motor vehicle. Within the first 4-5 hours, zolpidem can produce significantly impaired coordinative, reactive and cognitive skills following single oral doses of 10-20 mg. However, n o significant adverse effects were observed during a 1.5 hour driving test on a rural road, 10-12 hours after drug administration. In five reported cases of driving impairment in which zolpidem was the only drug detected, blood concentrations of zolpidem ranged from 0.08 to 1.4 mg/L (mean 0.65 mg/L). Symptoms and observed behavior included erratic driving (weaving, lane travel), slow and slurred speech, slow reflexes, dazed appearance, disorientation, confusion, loss of balance and coordination, loss of short-term memory, blacking out, somnolence, dilated pupils, double vision, poor performance on field sobriety tests, poor attention, and an inability to stand or walk unassisted. In another six reported cases of driving under the influence of zolpidem, blood concentrations ranged from 0.1 to 0.73 mg/L (mean 0.31 mg/L). The subjects were involved in automobile accidents or were seen to drive erratically, and symptoms included slow and slurred speech, ataxia, unsteady gait, confusion and disorientation.

DEC Category: CNS depressant

DEC Profile: Horizontal gaze nystagmus present; vertical gaze nystagmus present for high doses; lack of convergence present; pupil size normal; reaction to light slow; pulse rate down; blood pressure down; body temperature normal. Other characteristic indicators may include slow and slurred speech, somnolence, and poor performance on field sobriety tests.

Panel’s Assessment of Driving Risks: Zolpidem causes significant effects when driving within 5 hours of use (10 mg dose). Zaleplon causes significant impairment within 3 hours of use (10 mg), but no significant impairment after 4 hours (10 mg) and 5 hours (20 mg). Zolpidem and zaleplon are relatively free of residual morning-after effects. Zopiclone causes severe impairment 1-5 hours after dosing (7.5 mg), with residual hangover effects up to 10-11 hours.

References and Recommended Reading:

Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster City, CA; pp 451-3, pp 456-9, pp 460-4;2001.

Mattila MJ, Vanakoski J, Kalska H, Seppälä T. Effects of alcohol, zolpidem, and some other sedatives and hypnotics on human performance and memory. Pharm Biochem Behav 1990;59(4):917-923.

DeClerk AC, Bissebe JC. Short-term safety profile of zolpidem. Objective measures of cognitive effects. Eur Psychiat 1997;12(Suppl 1):15S-20S.

Garnier R, Guerault E, Muzard D, Azoyan P, Chaumet-Riffaud AE, Efthymiou M-L. Acute zolpidem poisoning – Analysis of 344 cases. J Tox Clin Tox 1994;32(4):391-404.

Greenblatt DJ, von Moltke LL, Harmatz JS, Merzanis P, Graf JA, Durol AL Counihan M, Roth-Schecter B, Shader RI. Kinetic and dynamic interaction of zolpidem with ketoconazole, itraconazole, and fluconazole. Clin Pharmac Therap 1998;64(6):661-7.

Hindmarch I, Patat A, Stanley N, Paty N, Rigney I. Residual effects of zaleplon and zolpidem following middle of the night administration five hours to one hour before awakening. Human Psychopharmac 2001;16(2):159-67.

Holm KJ, Goa KL. Zolpidem: An update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia. Drugs 2000;59(4):865-89.

Isawa S, Susuki M, Uchiumi M, Murasaki M. The effect of zolpidem and zopiclone on memory. Jap J Psychopharmac 2000;20(2):61-9.

Langtry HD, Benfield P. Zolpidem: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 1990;40(2):291-313.

Lheureux P, Debailleul G, De Witte O, Askenasi R. Zolpidem intoxication mimicking narcotic overdose: Response to flumazenil. Hum Exp Tox 1990;9(2):105-7.

Logan BK, Couper FJ. Zolpidem and driving impairment. J Forensic Sci 2001;46(1):105-10.

Mattila MJ, Vanakoski J, Kalska H, Seppala T. Effects of alcohol, zolpidem, and some other sedatives and hypnotics on human performance and memory. Pharmacol Biochem Behav 1998;59(4):917-23.

Meeker JEWhat is MMUCC MMUCC Committee MMUCC Documents What is MMUCC? The Model Minimum Uniform Crash Criteria (MMUCC) is a minimum set of crash data elements with standardized definitions that are relevant to injury control, highway and traffic safety. Not all of the MMUCC data elements need to be collected by police at the scene. Instead, some can be created from other data elements, such as the Vehicle Identification Number, to identify a specific vehicle characteristic. Or they can be obtained after linkage to other traffic records, such as injury or roadway inventory data to describe injury outcome or a specific roadway characteristic. FOR MORE INFORMATION ON THE MMUCC, PLEASE CLICK ON www-nrd.nhtsa.dot.gov/departments/nrd-30/ncsa/MMUCC.html Top of Page MMUCC Committee Acknowledgements The development of the Guideline for Minimum Uniform Crash Criteria (MMUCC) is being sponsored by the National Association of Governors' Highway Safety Representatives, the National Highway Traffic Safety Administration, and the Federal Highway Administration. Numerous state and local agencies and organizations have contributed staff to its development. The participation of the following individuals is recognized: Frank Carlile David Dickens Doug Donscheski Scott Falb Rosa Gill Dick Harmon Don Hillis David Kleppe David Lawrence Lance Mathess Creighton Miller David Mosley Phil Salzberg Manu Shah James Templeton Robert Thompson John Watson Ralph Craft Dennis Flemons Carl Hayden Janet Johnson Sandy Johnson Janet Kumer Tina Morgan Ed Milton Jack Oates Barbara Rhea Jackie Schraf David Sleet Carol Tan Esse Dennis Utter David Bozak Noel Bufe Charles Compton Barbara Harsha Roy Lucke Gary March Matt Snyder Richard Pain Charles Peltier Patricia Waller Florida Department of Transportation Charleston West Virginia Police Nebraska State Patrol Iowa Department of Transportation North Carolina State Division of Motor Vehicles Iowa Bureau of Emergency Medical Services Missouri Department of Transportation North Dakota State Highway Patrol Louisiana Office of Public Health Ohio State Patrol South Dakota Office of Accident Records Virginia Department of Motor Vehicles Washington Traffic Safety Commission Maryland State Highway Administration Texas Department of Public Safety Iowa Governor's Traffic Safety Bureau New York State Department of Transportation Federal Highway Administration National Highway Traffic Safety Administration Federal Highway Administration National Highway Traffic Safety Administration National Highway Traffic Safety Administration Federal Highway Administration National Highway Traffic Safety Administration National Highway Traffic Safety Administration National Highway Traffic Safety Administration National Highway Traffic Safety Administration National Highway Traffic Safety Administration National Center for Injury Prevention and Control Federal Highway Administration National Highway Traffic Safety Administration InfoGroup, Inc. Northwestern University Traffic Institute University of Michigan Transportation Research Institute National Association of Governors' Highway Safety Reps Northwestern University Traffic Institute March & Associates International Association of Chiefs of Police Transportation Research Board International Association of Chiefs of Police University of Michigan Transportation Research Institute Top of Page MMUCC Documents To visit the MMUCC Homepage, please click on the following link: Model Minimum Uniform Crash Criteria--Improving Crash Data for Safer Roadways The following links will take you to several documents related to the MMUCC effort. Download a PDF of the Final Guidelines (522KB) for Minimum Standardized Crash Data Reporting , Baselt RC . Six Cases cases of Impaired impaired driving following recent use of the sleep inducer zolpidem (Ambien ®). Presented at the AAFS American Academy of Forensic Sciences annual m eeting, NashvilleWhat is MMUCC MMUCC Committee MMUCC Documents What is MMUCC? The Model Minimum Uniform Crash Criteria (MMUCC) is a minimum set of crash data elements with standardized definitions that are relevant to injury control, highway and traffic safety. Not all of the MMUCC data elements need to be collected by police at the scene. Instead, some can be created from other data elements, such as the Vehicle Identification Number, to identify a specific vehicle characteristic. Or they can be obtained after linkage to other traffic records, such as injury or roadway inventory data to describe injury outcome or a specific roadway characteristic. FOR MORE INFORMATION ON THE MMUCC, PLEASE CLICK ON www-nrd.nhtsa.dot.gov/departments/nrd-30/ncsa/MMUCC.html Top of Page MMUCC Committee Acknowledgements The development of the Guideline for Minimum Uniform Crash Criteria (MMUCC) is being sponsored by the National Association of Governors' Highway Safety Representatives, the National Highway Traffic Safety Administration, and the Federal Highway Administration. Numerous state and local agencies and organizations have contributed staff to its development. The participation of the following individuals is recognized: Frank Carlile David Dickens Doug Donscheski Scott Falb Rosa Gill Dick Harmon Don Hillis David Kleppe David Lawrence Lance Mathess Creighton Miller David Mosley Phil Salzberg Manu Shah James Templeton Robert Thompson John Watson Ralph Craft Dennis Flemons Carl Hayden Janet Johnson Sandy Johnson Janet Kumer Tina Morgan Ed Milton Jack Oates Barbara Rhea Jackie Schraf David Sleet Carol Tan Esse Dennis Utter David Bozak Noel Bufe Charles Compton Barbara Harsha Roy Lucke Gary March Matt Snyder Richard Pain Charles Peltier Patricia Waller Florida Department of Transportation Charleston West Virginia Police Nebraska State Patrol Iowa Department of Transportation North Carolina State Division of Motor Vehicles Iowa Bureau of Emergency Medical Services Missouri Department of Transportation North Dakota State Highway Patrol Louisiana Office of Public Health Ohio State Patrol South Dakota Office of Accident Records Virginia Department of Motor Vehicles Washington Traffic Safety Commission Maryland State Highway Administration Texas Department of Public Safety Iowa Governor's Traffic Safety Bureau New York State Department of Transportation Federal Highway Administration National Highway Traffic Safety Administration Federal Highway Administration National Highway Traffic Safety Administration National Highway Traffic Safety Administration Federal Highway Administration National Highway Traffic Safety Administration National Highway Traffic Safety Administration National Highway Traffic Safety Administration National Highway Traffic Safety Administration National Highway Traffic Safety Administration National Center for Injury Prevention and Control Federal Highway Administration National Highway Traffic Safety Administration InfoGroup, Inc. Northwestern University Traffic Institute University of Michigan Transportation Research Institute National Association of Governors' Highway Safety Reps Northwestern University Traffic Institute March & Associates International Association of Chiefs of Police Transportation Research Board International Association of Chiefs of Police University of Michigan Transportation Research Institute Top of Page MMUCC Documents To visit the MMUCC Homepage, please click on the following link: Model Minimum Uniform Crash Criteria--Improving Crash Data for Safer Roadways The following links will take you to several documents related to the MMUCC effort. Download a PDF of the Final Guidelines (522KB) for Minimum Standardized Crash Data Reporting , TNWhat is MMUCC MMUCC Committee MMUCC Documents What is MMUCC? The Model Minimum Uniform Crash Criteria (MMUCC) is a minimum set of crash data elements with standardized definitions that are relevant to injury control, highway and traffic safety. Not all of the MMUCC data elements need to be collected by police at the scene. Instead, some can be created from other data elements, such as the Vehicle Identification Number, to identify a specific vehicle characteristic. Or they can be obtained after linkage to other traffic records, such as injury or roadway inventory data to describe injury outcome or a specific roadway characteristic. FOR MORE INFORMATION ON THE MMUCC, PLEASE CLICK ON www-nrd.nhtsa.dot.gov/departments/nrd-30/ncsa/MMUCC.html Top of Page MMUCC Committee Acknowledgements The development of the Guideline for Minimum Uniform Crash Criteria (MMUCC) is being sponsored by the National Association of Governors' Highway Safety Representatives, the National Highway Traffic Safety Administration, and the Federal Highway Administration. Numerous state and local agencies and organizations have contributed staff to its development. The participation of the following individuals is recognized: Frank Carlile David Dickens Doug Donscheski Scott Falb Rosa Gill Dick Harmon Don Hillis David Kleppe David Lawrence Lance Mathess Creighton Miller David Mosley Phil Salzberg Manu Shah James Templeton Robert Thompson John Watson Ralph Craft Dennis Flemons Carl Hayden Janet Johnson Sandy Johnson Janet Kumer Tina Morgan Ed Milton Jack Oates Barbara Rhea Jackie Schraf David Sleet Carol Tan Esse Dennis Utter David Bozak Noel Bufe Charles Compton Barbara Harsha Roy Lucke Gary March Matt Snyder Richard Pain Charles Peltier Patricia Waller Florida Department of Transportation Charleston West Virginia Police Nebraska State Patrol Iowa Department of Transportation North Carolina State Division of Motor Vehicles Iowa Bureau of Emergency Medical Services Missouri Department of Transportation North Dakota State Highway Patrol Louisiana Office of Public Health Ohio State Patrol South Dakota Office of Accident Records Virginia Department of Motor Vehicles Washington Traffic Safety Commission Maryland State Highway Administration Texas Department of Public Safety Iowa Governor's Traffic Safety Bureau New York State Department of Transportation Federal Highway Administration National Highway Traffic Safety Administration Federal Highway Administration National Highway Traffic Safety Administration National Highway Traffic Safety Administration Federal Highway Administration National Highway Traffic Safety Administration National Highway Traffic Safety Administration National Highway Traffic Safety Administration National Highway Traffic Safety Administration National Highway Traffic Safety Administration National Center for Injury Prevention and Control Federal Highway Administration National Highway Traffic Safety Administration InfoGroup, Inc. Northwestern University Traffic Institute University of Michigan Transportation Research Institute National Association of Governors' Highway Safety Reps Northwestern University Traffic Institute March & Associates International Association of Chiefs of Police Transportation Research Board International Association of Chiefs of Police University of Michigan Transportation Research Institute Top of Page MMUCC Documents To visit the MMUCC Homepage, please click on the following link: Model Minimum Uniform Crash Criteria--Improving Crash Data for Safer Roadways The following links will take you to several documents related to the MMUCC effort. Download a PDF of the Final Guidelines (522KB) for Minimum Standardized Crash Data Reporting , February etc 1996.

Physicians’ Desk Reference, Medical Economics Company, Montvale, NJ, 2002.

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Troy SM, Lucki I, Unruh MA, Cevallos WH, Leister CA, Martin PT, Furlan PM, Mangano R. Comparison of the effects of zaleplon, zolpidem, and triazolam on memory, learning, and psychomotor performance. J Clin Psychopharmacol 2000;20(3):328-37.

Vermeeren A, O'Hanlon JF, Declerck AC, Kho L. Acute effects of zolpidem and flunitrazepam on sleep, memory and driving performance, compared to those of partial sleep deprivation and placebo. Acta Therapeutica 1995;21.

Volkerts ER, Verster JC, van Heuckelum JHG. The impact on car-driving performance of zaleplon or zolpidem administration during the night. Eur Neuropsychopharmacol 2000;10(Suppl 3):S395.

Wilkinson CJ. The abuse potential of zolpidem administered alone and with alcohol. Pharmacol Biochem Behav 1998;60(1):193-202.

Wilkinson CJ. The acute effects of zolpidem, administered alone and with alcohol, on cognitive and psychomotor function. J Clin Psychiatry 1995;56(7):309-18.