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Zolpidem and driving impairment

Barry K. Logan,1,2 Ph.D. and Fiona J. Couper,2 Ph.D. REFERENCE: Logan BK, Couper FJ. Zolpidem and driving im-
(10 ng/mL), propoxyphene (100 ng/mL), barbiturates (100 ng/mL), pairment. J Forensic Sci 2001;46(1):105–110.
benzodiazepines (50 ng/mL), and tricyclic antidepressants (100ng/mL). The GC/MS methods are described elsewhere (2,3).
ABSTRACT: Zolpidem, a non-benzodiazepine hypnotic, was
Zolpidem (Fig. 1) is isolated in the basic fraction of the drug screen, identified in the blood of 29 subjects arrested for impaired driving.
and appears in the chromatogram in the same region as quinine and Zolpidem concentrations ranged from 0.05 to 1.4 mg/L (mean 0.29mg/L, median 0.19 mg/L). In the subjects whose cases we reviewed alprazolam. It has the mass spectrum shown in Fig. 2. When iden- where zolpidem was present with other drugs and/or alcohol, symp- tified in a subject’s blood, zolpidem was quantitated using a five- toms reported were generally those of CNS depression. Symptoms point calibration curve (0.00, 0.10, 0.25, 0.50, 1.00 mg/L). Cali- included slow movements and reactions, slow and slurred speech, bration was determined to be linear over the range 0.05 to 2.00 poor coordination, lack of balance, flaccid muscle tone, and hori-zontal and vertical gaze nystagmus. In five separate cases, where mg/L, and the correlation coefficient was typically better than zolpidem was the only drug detected (0.08–1.40 mg/L, mean 0.65 0.990. The limit of quantitation (LOQ) was defined as 0.05 mg/L, mg/L, median 0.47 mg/L), signs of impairment included slow and the lowest concentration at which the assay was determined to be slurred speech, slow reflexes, disorientation, lack of balance and co- linear. Any peaks with the correct retention time, quantitating at ordination, and “blacking out.” Although no quantitative relation- less than 0.05 mg/L, but for which a mass spectrum of zolpidem ship between blood concentrations and degree of driving impair-ment is currently possible, it is reasonable to conclude that because was obtained, were reported as Ͻ0.05 mg/L.
of its specific activity as a sleep inducer, blood concentrations con- In cases where the drug was identified, the circumstances of the sistent with therapeutic doses of zolpidem have the potential to af- incident, including alcohol or other drugs detected, driving behav- fect driving in a negative way, and that concentrations above the ior, subjects’ appearance, statements, performance in field sobriety normal therapeutic range would further impair a person’s level ofconsciousness and driving ability.
tests, etc., were tabulated from the arrest report and are included inTable 1.
KEYWORDS: forensic science, zolpidem, driving, impairment
Results and Discussion
Other workers have previously reported that subjects taking the In total, 29 cases of suspected impaired driving in which zolpi- popular sleep inducer zolpidem (Ambien®) have been arrested for dem was identified were encountered between January 1997 and impaired driving (1), and in our own jurisdiction, we have encoun- December 1999. Concentrations ranged from Ͻ0.05 (LOQ) to 1.4 tered a number of cases with similar fact patterns. This prompted mg/L (mean 0–29 mg/L, median 0–19 mg/L). Zolpidem was usu- us to review the literature on the pharmacology and performance ally present with other drugs including alcohol (9 cases), antide- effects of this drug, and to document the circumstances, indicia of pressants (10 cases), narcotic analgesics (7 cases), muscle relaxants impairment, patterns of combined drug use, and driving behavior (5 cases), benzodiazepines (3 cases), and valproic acid (2 cases). In in these cases in order to assist with the evaluation of future cases.
five cases, however, zolpidem was the only drug detected. In thesecases the concentration range was 0.08 to 1.40 mg/L (mean 0.65 Structurally, zolpidem is an imidazopyridine (Fig. 1), and unre- Cases of suspected drug-impaired driving are referred to the lated to the benzodiazepines. It acts as a non-benzodiazepine ago- Washington State Toxicology Laboratory by law enforcement agencies for drug and alcohol testing. Cases where the alcohol con- A1 function, resulting in sedative/hypnotic effects, without significant anxiolysis, anticonvulsant, or muscle relaxation centration cannot reasonably account for the degree of impairment properties. It is prescribed for the short-term treatment of insomnia observed in the subject are tested by EMIT and gas chromatogra- and other sleep disorders. The drug is normally prescribed in 5 to phy/mass spectrometry (GC/MS) for drugs with weakly acidic and 20 mg doses, to be taken before going to bed. Its rapid absorption basic character. The enzyme multiplied immunoassay technique after oral ingestion (peak concentrations are achieved in 1 to 2 h), (EMIT) procedure screened for cocaine metabolites (cutoff limit and short half-life (~1 to 2 h) make it very effective as a sleep in- 100 ng/mL), opiates (10 ng/mL), amphetamines (100 ng/mL), ducer, promoting a short-lasting sleep with rapid onset, and limited cannabinoids (10 ng/mL), methadone (100 ng/mL), phencyclidine Following administration of a single 15 mg oral dose of zolpi- 1 State toxicologist, Bureau of Forensic Laboratory Services, Washington dem, Mattila et al. (4) reported blood zolpidem concentrations of State Patrol, 2203 Airport Way S., Seattle, WA.
Ϯ 0.045 mg/L at 1.5 h, declining to 0.065 Ϯ 0.013mg/L by Washington State Toxicology Laboratory, University of Washington, 2203 5.5 h. Following 10 and 20 mg doses, peak plasma concentrations Received 5 Jan. 2000; and in revised from 7 March 2000; accepted 7 March (Cmax) of 0.125 Ϯ 0.015 mg/L and 0.232 Ϯ 0.017 mg/L, respec- tively, have been reported by Greenblatt et al. (5). Time-to-peak and half-lives for both the 10 and 20 mg doses were 1.7 and 2 to 2.2 drugs subject to first-pass metabolism by P450 3A4 (11), and this h, respectively, and both doses effectively induced sleep. The phar- may increase bioavailability of zolpidem.
macokinetics appeared unchanged following 15 consecutive nights Although less than 1% of a dose of zolpidem is reportedly ex- of administration of 20 mg (6). A review of other studies shows that creted unchanged in the urine, Levine et al. (12) reported measur- Cmax normally achieved in subjects following a 20 mg oral dose able zolpidem concentrations in urine of deceased subjects both in have been reported as between 0.192 and 0.324 mg/L at 0.75 to 2.6 overdose and during therapeutic use. In the cases we reviewed, h post-dose, and dose proportionality with respect to AUC and urine was tested in only one case and found to be qualitatively pos- Cmax have been reported over the dosage range of 2.5 to 40 mg (7).
Concentrations of 0.05 mg/L or greater (the LOQ for this study) In the subjects whose cases we reviewed where zolpidem was would likely represent levels present in the blood no more than 6 to present with other drugs, symptoms reported were generally those 8 h after ingestion of a normal therapeutic dose, and would be on of CNS depression. Nine of these subjects were evaluated by drug the low end of concentrations associated with a therapeutic effect.
recognition (DRE) officers, who expressed the opinion that the No differences in pharmacokinetics have been noted between eth- subject was under the influence of a CNS depressant. Of these nine nic groups or gender (7,8). Bianchetti et al. (9) have reported that cases, five involved erratic driving causing near collisions while time-to-peak blood concentrations appear unaffected by the pres- the other four involved vehicle collisions. Signs of impairment in- cluded horizontal gaze nystagmus (HGN) (7 cases), vertical gaze Zolpidem is metabolized oxidatively to a series of inactive hy- nystagmus (5 cases), lack of balance and unsteady gait (8 cases), droxylated metabolites (10). Metabolism appears to be directed poor or slow coordination (7 cases), poor performance of standard- through CYP450 3A4, 1A2, and 2D6. This raises the possibility of ized field sobriety tests (8 cases), slow and/or slurred speech (5 longer half-lives and greater AUC for zolpidem in patients taking cases), muscle flaccidity (4 cases), and impaired or double vision medications with significant inhibitory effects on these P450 (3 cases). One driver refused to perform the standardized field so- isozymes. These include the SSRI drugs fluoxetine, paroxetine, briety tests. The drivers usually had the general appearance of venlafaxine, and sertraline, which are substrates for, and inhibitors drowsiness, tiredness, confusion, and disorientation. However, of, P450 2D6. Of potential significance is the observation that symptoms associated with individual drugs cannot readily be re- grapefruit juice ingestion appears to increase bioavailability of solved in poly-drug cases. Harvengt et al. (13) have reported someincrease of impairment in alertness when zolpidem is given withother drugs with CNS depressant properties, including chlorpro-mazine, imipramine, and haloperidol.
In five cases zolpidem was the only drug detected. Concentra- tions ranged from 0.08 to 1.40 mg/L, with a mean of 0.65 mg/L,and a median of 0.47 mg/L. (Note, however, that because of theshort half-life, any delay between the driving and the collection ofthe blood will result in a drop in the concentration.) Signs of im-pairment included slow and slurred speech, slow reflexes, disori-entation and confusion, lack of balance and coordination, loss ofshort-term memory, and “blacking out.” Horizontal gaze nystag-mus was present in every case in which it was evaluated. The fol-lowing histories are from these five DUI cases. All subjects under-went blood alcohol analysis, an EMIT screen for drugs of abuse and several prescription drug classes, and a GC/MS screen for acid, FIG. 2—Electron impact mass spectrum of zolpidem. LOGAN AND COUPER • ZOLPIDEM AND DRIVING IMPAIRMENT unsteady gait, HGN, VGN, impaired vision, slurred speech, of alcohol and drugs, slurred speech, slow movements, slow speech, muscle flaccidity, poor SFSTs, appeared tired lack of convergence, slow and slurred speech, muscle flaccidity, lack of balance, unsteady gait, HGN, VGN, slow speech, unsteady gait, HGN, VGN, lack of convergence, double VGN, lack of convergence, repetitive speech, muscle flaccidity, Collision-causing driver—poor coordination, lack of balance, Erratic driving, lack of balance, appeared under the influence Near collision—slow and unsteady coordination, lack of balance, Drove over curb, struck parked vehicle, appeared Erratic driving—poor coordination, HGN, double vision, Single-vehicle accident—lack of balance, slurred speech Collision-causing driver—erratic driving, poor coordination, Erratic driving—violent and combative, appeared Collision-causing driver—poor coordination, lack of balance, Collision-causing driver—unsteady gait, hand tremors, HGN, Involved in accident–appeared disorientated and confused Circumstances and driving behavior in 29 drivers testing positive for zolpidem. admitted taking a sleeping pill about an hour before required assistance to walk, HGN, VGN, muscle flaccidity, poor SFSTs, appeared disorientated and confused Minor multi-car collision—causing driver was staggering around, Erratic driving—collision-causing driver, lack of balance, HGN, Erratic driving, near collision–poor coordination, lack of balance, Single-vehicle accident—officer observed signs of impairment Collision-causing driver—HGN, poor SFSTs Erratic driving—lack of balance, slow reflexes, slow and slurred Collision-causing driver—unable to stand or walk, appeared dazed Erratic driving—hit parked car and red stop light, slurred speech, Erratic driving—HGN, VGN, poor SFSTs, slurred speech, lack Single-vehicle accident—drove through red light, blacked out, Cases which underwent drug recognition evaluation expert (DRE)/Standard field sobriety tests (SFSTs) (19).
* HGN–Horizontal gaze nystagmus; VGN–Vertical gaze nystagmus.
LOGAN AND COUPER • ZOLPIDEM AND DRIVING IMPAIRMENT neutral and basic compounds as indicated above. In each case, all In each case, in the absence of any other reasonable explanation tests were negative for alcohol or for drugs other than zolpidem.
for the impairment, it was attributed to the ingestion of zolpidem.
There was no apparent correlation between the stated time of zolpi- Case 1—A 17-year-old male was stopped by police for erratic dem ingestion and the corresponding blood concentration. Two lane travel. The subject’s speech was slow and slurred, his pupils separate subjects stated they had taken a single Ambien® tablet ap- were dilated, and he was experiencing double vision, lack of bal- proximately 12 h prior to being arrested. The corresponding zolpi- ance, and lack of coordination. The subject also performed several dem concentrations were 0.33 mg/L and Ͻ0.05 mg/L. In another field sobriety tests poorly (such as “finger dexterity” and “walk and subject, zolpidem was taken within 1 to 2 h prior to the arrest, and turn” tests). The subject admitted to taking two white pills half an the zolpidem blood concentration was 0.31 mg/L. In a similar case, hour prior to the DUI stop, but did not know what pills they were.
a subject ingested two Ambien® tablets 30 min prior to the arrest, Several hours after the arrest, the subject was suffering from am- with the corresponding zolpidem blood concentration being 0.43 nesia. Blood was drawn an hour and a half after driving, and the mg/L. Four or five 10 mg Ambien® tablets were allegedly ingested zolpidem concentration was 0.08 mg/L.
by another subject whose blood zolpidem concentration after fivehours was Ͻ0.05 mg/L. Roger et al. (14) have reported a poor cor- Case 2—A 59-year-old male was the causing driver in a two-car relation (r2 ϭ 0.21) between dose and blood concentration of zolpi- collision, having hit another vehicle at an intersection. The subject dem at ten hours post administration.
was unable to walk or stand without assistance and appeared dazed, During the same period a single case of a fatally injured driver lethargic, and disorientated. He had poor attention and was unable testing positive for zolpidem was identified. This was a 49-year- to perform any standardized field sobriety tests since he was unable old male who had multiple sclerosis and a seizure disorder. He to stand without support. He could not follow a stimulus for a test was the causing driver in a three-car accident, going through a red of nystagmus; however, his eyes showed a lack of smooth pursuit.
light, and striking two other vehicles. He had been observed driv- The subject had taken two Ambien® tablets 30 min before the col- ing in an erratic manner prior to the accident. This individual had lision. Blood was drawn about an hour after driving, and the zolpi- a blood drug concentration identified as follows: zolpidem 0.38 mg/L, carbamazepine 4.13 mg/L, hydroxyzine 0.36 mg/L, andpentazocine 0.18 mg/L. The other drug concentrations are in the Case 3—A 37-year-old female was stopped by police for erratic normal therapeutic range, while the zolpidem concentration is driving. The subject had hit a parked car, garbage cans, and a stop sufficient to result in sedation and sleepiness, and consistent with sign, and then continued driving. The subject’s speech was slow concentrations in drivers showing significant impairment (see and slurred, her actions were very slow and she was unaware of what had just happened. The subject was extremely disorientated Other instances of drivers apparently impaired by zolpidem have and had a marked upper body sway and lack of balance. She ap- been reported. Meeker (1) reported six cases of subjects driving un- peared very tired and fell asleep during the evaluation, and was suf- der the influence of zolpidem, four of whom were involved in au- fering from amnesia. The interval between blood draw and driving tomobile accidents, three of which were single-vehicle crashes.
was not known, but the blood zolpidem concentration was 0.47 Blood zolpidem concentrations in these cases ranged from 0.10 to 0.73 mg/L (mean 0.31 mg/L, median 0.17 mg/L), and symptomsincluded slow slurred speech, unsteady gait, confusion, and disori- Case 4—A 52-year-old female was stopped by police on the entation. This is consistent with observations in our subjects, in- freeway after drifting into the northbound lanes while driving cluding the overlap of the blood concentrations with the therapeu- south, where she then continued to drive. The subject was slow to respond to police, and was disoriented, confused, and dazed once For many drugs, there is justifiably some reluctance in equating stopped. Her speech was slurred and shaky. She was dressed only blood concentrations with a specific degree of impairment. We be- in her underwear and a shirt, and told the officer she was returning lieve in the case of zolpidem, however, that this issue is clearer than from the store. Several standardized field sobriety tests were per- for many other drugs, since the specific function of zolpidem is to formed and the subject showed all six clues of horizontal nystag- induce sleep. For many other drugs the sedative effects are merely mus, and displayed vertical nystagmus also. She had extremely an inconvenient and often infrequent side effect. Therefore, for the poor balance on the “one leg stand” and “walk and turn” tests, and purposes of determining whether the drug would affect a person, could not touch the tip of her nose. When asked to estimate 30 sec- we advocate collection and analysis of a blood sample, as opposed onds she stopped at 14. The subject could not remember her ad- to a urine sample. Because of its short half-life (~2 h), a morning dress and other details about herself, or her current circumstances.
urinary void would almost certainly test positive for zolpidem, Blood was drawn an hour and forty-five minutes after driving, and even though the blood concentrations have fallen below effective the zolpidem concentration was 0.88 mg/L.
levels. This short half-life also means that any delay between thetime of driving and the blood draw could result in an appreciable Case 5—A 44-year-old female was involved in a single-vehicle drop in the blood zolpidem concentration, which should be taken traffic accident. The subject had driven through a red traffic light, into consideration in interpretation.
blacked out, and then driven down an embankment; however, she Rush (15) has reviewed the performance impairing effects of had no recollection of the event. The subject admitted being pre- zolpidem and notes that the general consensus of these studies scribed Ambien® and Remeron® (temazepam) for depression. The was that zolpidem did cause significant psychomotor impairment, subject was alert but stated she must have blacked out. The officer equivalent to clinically effective doses of the sedative hypnotics did not detect any apparent signs of impairment; however, the sub- triazolam, temazepam, or midazolam. Specifically, the studies re- ject was in considerable pain and could not perform any field so- viewed found impairment in standard psychological tests such as briety tests. Blood was drawn an hour and twenty-five minutes af- picture recall, digit entry and recall, digit symbol substitution ter driving, and the zolpidem concentration was 1.40 mg/L.
tasks, circular lights task, balance, time estimation, trails making, and a variety of other tests of cognitive and psychomotor func- 6. Albin H, Vincon G, Vincon J, Hermann P, Thiercelin JF. Study of the tion. Tolerance to the sleep latency effects of the drug has been pharmacokinetics of zolpidem in healthy volunteers after repeated ad- documented, making it most effective for treatment periods of ministration: effect on antipyrene clearance. In: Sauvanet JP, Langer SZ,Morselli PL, editors. Imidazopyridines in sleep disorders: a novel exper- less than 28 days. Tolerance to the psychomotor impairing effect imental and therapeutic approach. New York: Raven Press, 1988; Information from the manufacturer (16) indicates that the drug 7. Salvá P, Costa J. Clinical pharmacokinetics and pharmacodynamics of should not be taken before driving, and in fact, that performance zolpidem. Therapeutic implications. Clin Pharmacokinet 1995;29(3):142–53.
decrements might persist into the next day following use of the 8. Vandel S, Vandel B, Joanne C, Trocherie S, Bechtel P, Larribaud J. In- drug. Only 1.1% of patients in pre-clinical trials reported daytime fluence of ethnic origin on the clinical pharmacology of zolpidem. In: drowsiness, however, and given the short half-life of the drug when Sauvanet JP, Langer SZ, Morselli PL, editors. Imidazopyridines in sleep properly managed hangover or residual effects should be unlikely, disorders: a novel experimental and therapeutic approach. New York: but risk of subjective feelings of sedation increases with an in- 9. Bianchetti G, Dubruc C, Thierclin JF, Bercoff E, Bouchet JL, Emiriau creasing dose (17). The Physicians Desk Reference (16) notes that JP, et al. Clinical pharmacokinetcs of zolpidem in various physiological patients taking zolpidem may experience effects similar to those and pathological conditions. In: Sauvanet JP, Langer SZ, Morselli PL, associated with alcohol, and recommends that zolpidem not be editors. Imidazopyridines in sleep disorders: a novel experimental and taken with alcohol, since the effects would be additive.
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10. Pichard L, Gillet G, Bonfils C, Domergue J, Thenot JP, Maurel P. Ox- Vermeeren et al. (18) have reported on the impairment of actual idative metbolism of zolpidem by human liver cytochrome P450S. Drug driving performance resulting from use of zopiclone and zaleplon, two other recently introduced hypnotic drugs used in the treatment 11. Singh BN Effects of food on clinical pharmacokinetics. Clin Pharma- of insomnia. They found that zopiclone (7.5 mg), with a half-life of 3.5 to 6 h administered within 10 h of the driving test, produced an 12. Levine B, Wu SC, Smialek JE. Zolpidem distribution in postmortem cases. J Forensic Sci 1999;44(2):369–71.
increase in lateral drift (weaving) equivalent to a blood alcohol 13. Harvengt C, Hulhoven R, Desager JP, Coupez JM, Guillet Ph, Fuscau E, concentration of 0.10 g/100 mL. Zaleplon, on the other hand, with et al. Drug interactions investigated with zolpidem. In: Sauvanet JP, a much shorter half-life of 0.9 to 1.1 h, produced less next-day se- Langer SZ, Morselli PL, editors. Imidazopyridines in sleep disorders: a dation, and no driving impairment when administered as little as 5 novel experimental and therapeutic approach. New York: Raven Press,1988;165–73.
h prior to the driving test. Zolpidem, with a half-life of around 2 h, 14. Roger M, Dallot JY, Salmon O, Neveux E, Gitton JP, Gerson M, et al.
could reasonably be expected to exhibit a potential for hangover ef- Hypnotic effect of zolpidem in geriatric patients: a dose finding study.
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