Download LITERATURE REVIEW Drug Review

LITERATURE REVIEW
Drug Review
Document ID: N04-023
Author: Julie Qidwai
Date: December 2004
National Advanced Driving
Simulator
2401 Oakdale Blvd.
Iowa City, IA 52242-5003
Fax (319) 335-4658
TABLE OF CONTENTS
1
Introduction ............................................................................................................................ 1
2
Alprazolam.............................................................................................................................. 1
3
Amitriptyline........................................................................................................................... 2
4
Biperiden ................................................................................................................................. 2
5
Brompheniramine .................................................................................................................. 2
6
Butorphanol ............................................................................................................................ 2
7
Cetirizine ................................................................................................................................. 3
8
Chloroquine ............................................................................................................................ 3
9
Chlorpheniramine .................................................................................................................. 4
10 Clemastine............................................................................................................................... 4
11 Diazepam................................................................................................................................. 4
12 Flurazepam ............................................................................................................................. 5
13 Hydroxyzine............................................................................................................................ 5
14 Imipramine ............................................................................................................................. 6
15 Lithium.................................................................................................................................... 6
16 Lorazepam .............................................................................................................................. 6
17 Methamphetamine ................................................................................................................. 7
18 Morphine................................................................................................................................. 8
19 Oxybutynin ............................................................................................................................. 8
20 Promethazine .......................................................................................................................... 9
21 Secobarbital ............................................................................................................................ 9
22 Temazepam ........................................................................................................................... 10
23 Triazolam .............................................................................................................................. 10
24 Trihexyphenidyl ................................................................................................................... 10
i
25 Tripelennamine..................................................................................................................... 10
26 Triprolidine........................................................................................................................... 11
27 Zolpidem ............................................................................................................................... 11
References.................................................................................................................................... 12
ii
1 INTRODUCTION
This review describes the performance-impairing effects of twenty-six commonly used
drugs. It is not intended to list comprehensively all drugs that may affect driving
performance. However, it does list and describe several drugs that have been the topic of
intense research scrutiny.
2 ALPRAZOLAM
Alprazolam (Xanax) is the most frequently-used benzodiazepine and is one of the 10
most-prescribed drugs in the US. It has a short half-life and is generally prescribed in
divided doses from 0.5-10 mg/day. It is used to treat anxiety and panic disorders.
In a crossover study, Verster, Volkerts and Verbaten (2002) dosed 20 healthy participants
with 1 mg alprazolam and placebo on 2 days of testing (separated by a 14-day washout
period). This study involved acute testing only; there was no testing at steady state. In the
standard on-the-road Dutch test, alprazolam was associated with a larger SDLP than
placebo. This 9-cm increase in SDLP was likened to the increase that might be seen with
a BAC of 0.15%. Speed variability also increased significantly with alprazolam
compared to placebo. When participants took alprazolam, they also exhibited
significantly more right and left lane excursions than they did with placebo. Participants
rated their own driving performance and alertness as significantly worse/greater with
alprazolam than with placebo. RMS error in tracking ability (in a computerized task) was
significantly impaired by alprazolam. Alprazolam also increased reaction time
significantly in the Sternberg memory scanning task. After taking alprazolam, six of the
twenty participants fell asleep while attempting to complete the on-road driving task. No
participants fell asleep after taking placebo.
Fourteen participants took part in a crossover study comparing the effects of 0.5, 1 and 2
mg alprazolam with placebo (Evans, Troisi and Griffiths, 1994). All alprazolam doses
significantly impaired participants’ ability to balance on one foot. All doses were also
associated with poor performance on the DSST compared to placebo and slower choice
reaction time. Performance on immediate and delayed recall memory tasks was also
impaired by all doses of alprazolam, and participants felt significantly more drowsy after
taking alprazolam than after placebo. In comparison with pre-drug baseline testing in 12
female volunteers, a single 0.5-mg dose of alprazolam significantly reduced critical
flicker fusion threshold (CFFT; Subhan, Harrison and Hindmarch, 1986), as do most
sedating drugs (stimulants increase CFFT). After repeated dosing for one week with 0.5
mg tid, however, this effect was no longer observed. Neither the acute nor the more
chronic administration led to impairment in reaction times or divided attention
performance, but participants did report significant subjective sedation at both times.
In a visual search task, 1 mg alprazolam increased reaction times and decreased hit rate in
comparison with placebo (Munte, Gehde, Johannes, Seewald and Heinze, 1996). Twelve
male participants completed this crossover study.
1
3 AMITRIPTYLINE
Amitriptyline (Elavil, Endep) is a tricyclic antidepressant. Typical doses run from 75-200
mg/day.
An acute dose of 50 mg amtriptyline significantly reduces critical flicker fusion threshold
(Curran, 1990). Similar effects were found in a different study with 9 healthy female
volunteers; CFFT was significantly reduced by an acute dose of 50 mg amtriptyline
compared with placebo (Hindmarch, Harrison and Shillingford, 1988). In this study, too,
choice reaction time was significantly increased by 50 mg amitriptyline and produced
more errors on the Stroop test. Subjective drowsiness was also significantly higher with
amitriptyline than with placebo.
In another study, participants taking fluoxetine rated themselves as significantly less
drowsy than participants taking amitriptyline 75 mg. This difference was significant for
the first two weeks of treatment with the drugs and was observable (but not significant)
during the third week of treatment (Evans et al., 1994).
4 BIPERIDEN
Biperiden is an anticholinergic drug sometimes used to combat the extrapyramidal
symptoms created by the administration of antipsychotic drugs.
Fourteen healthy volunteers were dosed twice in one day with 4 mg biperiden, placebo
and another drug in a crossover study (Guthrie, Manzey, Scott, Giordani and Tandon,
2000). Subjective sedation (VAS) was significantly greater with biperiden than with
placebo or the other drug. Backwards digit span was impaired by biperiden, along with
performance on a number of memory tasks.
5 BROMPHENIRAMINE
Brompheniramine is an extremely sedating first-generation antihistamine. It is often
combined with other drugs in OTC allergy and cold preparations. Since its sedative
properties are no longer in question, it is not studied very often.
The effects of a combination of 12 mg brompheniramine, 15 mg phenylephrine and 15
mg phenylpropanolamine (commonly found in Dimetapp) were compared in a betweensubjects study with the effects of placebo. Four-choice reaction time increased at 2.75
and 5.5 hours post-dose (Millar and Standen, 1982).
6 BUTORPHANOL
Butorphanol is a narcotic analgesic that can be administered transnasally for relief of
migraine headaches and postoperative pain.
In a crossover study with 10 healthy participants, 2 mg butorphanol administered
transnasally significantly impaired DSST performance for 120 minutes following dosing
(Zacny, Lichtor, Klafta, Alessi and Apfelbaum, 1996). There were no significant effects
on two other measures of cognitive performance. Subjective sedation, sleepiness and
stimulation were also increased by the same dose, compared to placebo. A 1-mg dose had
no significant effects compared to placebo. The authors state that “Certainly, child care,
2
operating machinery and driving an automobile would be contraindicated at this dose, at
least when administered acutely” (p. 934).
7 CETIRIZINE
Cetirizine (Zyrtec) is generally classified as a second-generation antihistamine. However,
it is the most “controversial” of the antihistamines in the sense that some studies indicate
that it causes sedation and performance impairment; some do not show these effects.
Ten and twenty mg cetirizine did not cause subjective drowsiness (VAS) in a small
sample of 4 allergic volunteers, whose ratings were compared to those of 4 other
volunteers who took placebo (Gengo and Gabos, 1987). There was also no significant
effect of cetirizine on Stroop test performance, and it did not cause changes in CFFT
performance. Digit symbol substitution was unaffected by cetirizine at 5, 10 and 20 mg in
another study, when compared with placebo (Gengo, Gabos and Mechtler, 1990).
Ten mg cetirizine did not cause changes in lateral position in on-the-road driving (the
standard, 100-km driving test) when compared with placebo (Patat, Stubbs, Dunmore,
Ulliac, Sexton, Zieleniuk, Irving and Jones, 1995). This dose did, however, cause slight
but significant impairments in adaptive tracking and divided attention (tracking and
vigilance) performance. In another study (Volkerts, van Willigenburg, van Laar and
Maes, 1992), 10 mg was not associated with elevated SDLP after acute dosing or after 4
days of dosing. Cetirizine did not affect reaction time or memory performance in this
study, either. Van Cauwenberge (1992), however, reported significant elevations in
SDLP with 10 mg cetirizine that were comparable to the effects of a 0.1% BAC, in a
crossover study with 16 participants. Cetirizine also seemed to potentiate the effects of
alcohol when the two were administered together. Significantly more allergy patients
reported sedation as a side effect with 10 mg cetirizine than with placebo in a study with
278 participants, involving an allergy challenge situation. Ten mg cetirizine did cause
significant increases in subjective sedation in 15 participants in a crossover study
(comparison with placebo; Simons, Fraser, Reggin and Simons, 1996).
Walsh, Muehlbach and Schweitzer (1992) took the novel approach of asking participants
to complete a simulated assembly line task. The task was essentially a vigilance task,
with participants being asked to accept or reject simulated computer parts coming off of a
simulated assembly line. However, the task lasted for the duration of a regular work day,
8 hours. This study had a between-subjects design with four participants each receiving
10 mg cetirizine, 25 mg hydroxyzine or placebo. Cetirizine did not affect the number of
correct responses or the number of correct rejections of the simulated computer parts.
Similar results were found in a second study using the simulated assembly line task and
three-day administration of 10 mg cetirizine (Schweitzer, Muehlbach and Walsh, 1994).
In this study, cetirizine also did not produce subjective sedation when compared to
placebo.
8 CHLOROQUINE
Chloroquine is a drug used for malaria prophylaxis. Unfortunately, it is stored in the
retinal pigment epithelium for several years after it is taken, which can lead to
irreversible blurred vision, visual field losses and color vision defects.
3
In twenty-eight patients shown to have chloroquine retinopathy (defined by bilateral
scotomas), 26 failed more than one color vision test, while only 5 out of 25 patients who
were taking chloroquine but had no retinopathy failed even one of the tests (Vu,
Easterbrook and Hovis, 1999). The primary color defect in patients with chloroquine
retinopathy is difficulty distinguishing blue, a defect that may not be picked up in
standard red-green color blindness testing.
9 CHLORPHENIRAMINE
Chlorpheniramine (Chlor-Trimeton) is a heavily sedating first-generation antihistamine.
After four days of dosing with four mg chlorpheniramine tid, CFFT decreased, compared
with placebo, in a between-subjects study with 10 participants per group (Hindmarch and
Parrott, 1978). In another study, the same acute dose caused significantly increased
scores on the Stanford Sleepiness Scale at three hours post-dose, compared with placebo,
and choice reaction time was significantly longer with chlorpheniramine at 1 and 3 hours
post-dose (Witek, Canestrari, Miller, Yang and Riker, 1995).
10 CLEMASTINE
Clemastine (Tavist) is a first-generation antihistamine.
Two mg (acute) clemastine significantly increased SDLP compared with placebo in the
standard 100-km on-road test (Vuurman, Uiterwijk, Rosenzweig and O'Hanlon, 1994).
This study was conducted with 24 participants in a crossover design. Clemastine also
increased subjective drowsiness ratings, reduced CFFT and impaired tracking
performance and both parts of a divided attention test consisting of a tracking and a
reaction time task. One and two mg clemastine also impaired auditory reaction time at 2.5
hours post-dose in a crossover study with acute dosing (Peck, Fowle and Bye, 1975).
Two mg still slowed reaction time at 5 hours post-dose and impaired DSST performance
at 2.25 and 4.75 hours post-dose.
11 DIAZEPAM
Diazepam (Valium) is a very commonly-used anxiolytic with significant CNS depressant
properties.
In a between-subjects comparison, eight participants who took 10 mg diazepam
performed significantly worse in a low-fidelity driving simulation than eight others who
took placebo. Additional deficits were noted in participants’ divided attention
performance—they exhibited longer reaction times to targets at one hour post-dose, but
not at three or five hours post-dose (Moskowitz and Smiley, 1982). After continuous
diazepam dosing (15 mg/day) for eight days, when participants were dosed on the eighth
day, performance was similarly affected; tolerance to the drug’s effects on performance
did not appear to have developed.
Twelve anxious patients were dosed with 5 mg diazepam tid for one week before
completing the standard 100-km on-road driving test (van Laar, Volkerts and van
Willigenburg, 1992). One participant asked to stop driving due to the sedative effects of
the drug in the first week of testing, and another participant asked to stop during the
4
driving test in the second week of dosing. Diazepam significantly increased SDLP after
one, two and three weeks (but not four weeks) of dosing (in comparison to a pre-drug
baseline). In an epidemiological study of all motor vehicle fatalities in one Texas county
over 18 months (Garriott, DiMaio, Zumwalt and Petty, 1977), diazepam was the drug
most commonly detected in blood and urine tests. It was present in 56.5% of samples that
were positive for any drug.
Acute doses of 10 mg diazepam decreased CFFT in crossover studies with men in
different age groups (compared with placebo; Palva, Linnoila, Routledge and Seppälä,
1982). Moser, Huether, Koch-Weser and Lundt (1978) made a similar finding in 20
healthy male participants.
12 FLURAZEPAM
Flurazepam (Dalmane), a benzodiazepine derivative, is a hypnotic sleep aid.
Moskowitz and Chen (1990) reported on a study in which they administered 45 mg
flurazepam to 30 healthy adult males in a crossover study. Forty-five mg is more than the
recommended prescription dose of 15-30 mg. Testing was conducted 9 hours post-dose,
after participants had a full night’s sleep. Flurazepam 45 mg was associated with
significant increases in choice (but not simple) reaction time when compared with
placebo. In divided attention testing, tracking error and mean reaction time increased with
flurazepam. Reaction time and number of misses in a vigilance task also increased with
flurazepam.
In another study of residual impairment with flurazepam (Warburton and Wesnes, 1984),
six participants were given 30 mg flurazepam and tested 10 hours post-dose. Each drug
treatment was examined twice in this study. Flurazepam significantly reduced the number
of correct detections participants made in a vigilance task (compared with placebo) as
well as slowing reaction times.
13 HYDROXYZINE
Hydroxyzine (Atarax) is a heavily sedating first-generation antihistamine. It is also used
for anxiety reduction and as a sleep aid.
In a crossover study with 12 male allergy patients, 25 mg hydroxyzine (acute) decreased
CFFT and impaired Stroop test scores at 2 and 4 hours post-dose (Gengo, Dabronzo,
Yurchak, Love and Miller, 1987). The same dose of hydroxyzine also slowed reaction
time performance in a 30-minute vigilance test (Seidel, Cohen, Bliwise, Dement, 1987).
This was a between-groups comparison between hydroxyzine and placebo with 15
participants per group. Performance impairment was no longer evident 6 hours post-dose.
In another crossover study with 16 healthy participants, the effects of 25 mg hydroxyzine
were compared with those of a placebo after 2 and 5 days of twice-daily dosing. Simple
and choice reaction times were significantly longer with hydroxyzine than with placebo
after 2 days of dosing, and this effect was still present and significant after 5 days of
treatment with hydroxyzine (Goetz, Jacobson, Murnane, Reid, Repperger, Goodyear and
Martin, 1989). Subjective drowsiness, measured on a 4-point scale, was also significantly
greater on both test days with hydroxyzine than with placebo.
5
In the simulated assembly line study described above (Walsh et al., 1992), 25 mg
hydroxyzine given acutely in a between-subjects design had several effects on
performance. Participants made significantly fewer correct responses and fewer correct
rejections with hydroxyzine than participants who took placebo. There was a significant
interaction between time of day and drug administered, in that performance was
significantly worse at 9:30 AM and 2 PM with hydroxyzine than with placebo.
Participants also rated their own performance as significantly worse with hydroxyzine
than with placebo and felt significantly sleepier (VAS).
14 IMIPRAMINE
Imipramine (Tofranil) is a tricyclic antidepressant with significant anticholinergic
properties.
Van Laar, van Willigenbrg and Volkerts (1995) conducted research with 12 healthy
young adults and 12 elderly adults to determine the effects of 50 mg imipramine given
twice daily on driving performance. In this crossover study, after acute dosing,
imipramine produced a significantly elevated SDLP in the young adults but not in the
elderly adults (compared to placebo). The effect in the young adults was still observable
and significant but small on the 7th day of dosing. Both groups of participants were
significantly sleepier with imipramine than with placebo after acute dosing, but the article
did not report on the incidence of subjective sleepiness after 7 days of dosing.
15 LITHIUM
Lithium is a drug given primarily to treat bipolar disorder.
In one study (Hatcher, Sims and Thompson, 1990), 16 patients who had been taking
lithium for at least three months were compared in their choice reaction time performance
with 22 healthy drug-free controls. Reaction times in the patients were significantly
longer than in the controls. The patients were taking different doses of lithium, which had
been titrated to meet their treatment needs. However, lithium dosage was not significantly
related to reaction time. The authors commented that lithium does not cause subjective
sedation but appears to interfere with at least one aspect of psychomotor performance.
Lithium also significantly impaired long-term retrieval measures of memory in 22 bipolar
patients treated with different doses (Shaw, Stokes, Mann and Manevitz, 1987).
16 LORAZEPAM
Lorazepam (Ativan) is an anxiolytic. Its relatively long duration of action makes it useful
as a hypnotic and a surgical pre-medication as well.
Two mg lorazepam significantly reduced CFF threshold in acute dosing of twelve female
volunteers, but there was no effect after seven days of dosing at 2 mg tid (Subhan et al.,
1986). This dose did, however, increase choice reaction times and impair performance in
both aspects of a divided attention task (tracking and reaction time) both acutely and after
repeated dosing. Subjective sedation was reported by the participants acutely but not after
repeated dosing. These comparisons are all in reference to pre-drug baseline testing and
ratings.
6
With acute dosing of 2 mg lorazepam, experienced users of CNS depressants exhibited
impaired tracking performance and standing steadiness (balance) for 4 hours following
dosing (Sellers, Schneiderman, Romach, Kaplan and Somer, 1992). Memory
performance was also impaired; however, none of the tasks completed by participants are
described particularly well in the publication. The drug effects are with reference to the
effects of placebo in this crossover study.
Mean tracking speed in an adaptive tracking task and divided attention performance were
significantly impaired by acute dosing with 0.5 mg lorazepam (Irving and Jones, 1992).
Two mg impaired performance on those tasks as well as reaction time to hazards and
lateral deviation in curves in a closed-course driving task. The participants were twelve
45-55-year-old female volunteers.
In a parallel groups study with 9 participants per group, 2 mg lorazepam given acutely
impaired response time on the Baddeley task, prose recall, digit cancellation, DSST and
pursuit rotor when compared to placebo (Curran, Schifano and Lader, 1991). Subjective
sedation was also significantly greater with lorazepam than with placebo. Sedation scores
were more closely related to psychomotor testing scores than to the scores from memory
tasks, and the authors speculated that any amnestic effect of lorazepam was not secondary
to the drug’s sedative effects.
In another parallel groups study with 12 participants per group, 2.5 mg lorazepam given
acutely impaired performance on a number of measures, including number cancellation,
symbol copying, simple reaction time and memory for images (File, 1992). A crossover
study with 12 healthy participants found that 1 mg lorazepam impaired simple reaction
time 1 and 2 hours post-dose and choice reaction time, word and picture recognition
speed 1-6 hours post-dose (Hanks, O’Neill, Simpson and Wesnes, 1995). Subjective
sedation was not significantly greater with lorazepam than with placebo.
One mg of lorazepam three times daily was given to 12 female participants in a study of
cognitive and driving performance (Hindmarch and Gudgeon, 1980). Dosing continued
for three days before participants were tested. Lorazepam caused significant subjective
sedation compared to placebo, and it impaired mental arithmetic and letter cancellation
performance as well. Car driving ability was rated by driving instructors on the following
tasks: reverse parking, a three-point turn, a slalom around cones and brake reaction test.
These abilities were all significantly impaired by lorazepam compared with placebo.
17 METHAMPHETAMINE
Methamphetamine is a stimulant drug of abuse; it also has limited therapeutic
applicability use in weight control.
Chronic users of methamphetamine (who did not, however, abuse other drugs)
demonstrated memory impairment and had difficulty with the DSST and Trails B tests
compared to drug-free controls (Simon, Domier, Carnell, Brethen, Rawson and Ling,
2000). The pattern of results exhibited by the drug users in Stroop testing was similar to
that exhibited by people with “isolated pre-frontal [brain] injuries” (p. 226).
7
18 MORPHINE
Morphine is a strong opioid analgesic often used to treat cancer pain.
In a crossover study of 12 participants, 10- and 15-mg doses of morphine were associated
with significant memory impairment at one hour post-dose (Hanks et al., 1995).
Subjective alertness was not altered by morphine, but the participants’ critical flicker
fusion threshold was significantly reduced by both morphine doses.
19 OXYBUTYNIN
Oxybutynin (Ditropan) is a tertiary amine ester with anticholinergic/antimuscarinic,
spasmolytic and local anesthetic properties. It is commonly used to treat urinary
frequency and urgency, nocturia and urge incontinence arising from overactive detrusor
function or instability. The recommended dose is 5 mg BID or TID with a maximum dose
of 5 mg QD.
The most common side effect of anticholinergic drugs is dry mouth; this effect has been
reported by 50% of patients taking oxybutynin in some studies (Pietzko, Dimpfel,
Schwantes and Topfmeier, 1994). Blurred vision and constipation are also reported, but
less frequently (Davila, Daugherty and Sanders, 2001).
Cognitive impairment as a possible adverse effect of oxybutynin has been investigated in
only a few studies. In one such study (Katz, Sands, Bilker, DiFilippo, Boyce and
D’Angelo, 1998), oxybutynin was associated with reduced performance on certain
cognitive measures. Twelve normal individuals (7 men and 5 women) aged 65-76 were
given placebo, 5 mg oxybutynin, 10 mg oxybutynin, or 50 mg diphenhydramine across
four separate visits before completing a series of cognitive tests. These tests included the
Buschke Selective Reminding Test, Digit Span, Verbal Fluency - Letters, Trailmaking
Parts A and B, and Digit Symbol Substitution administered by an interviewer, and several
tests from the Neurobehavioral Evaluation System administered by computer.
The results of the study indicated that oxybutynin (dose not identified) resulted in a
statistically significant reduction in performance on 7 of 15 cognitive measures. The
effects of oxybutynin were at least as great as those produced by diphenhydramine. Two
tests, the Buschke Selective Reminding Test and the Reaction Time Test (part of the
Neurobehavioral Evaluation System), were especially sensitive to performance
decrements caused by oxybutynin. The authors encouraged caution in interpreting the
results due to the small sample used but encouraged physicians to monitor patients on
oxybutynin for possible cognitive effects.
Elsewhere, oxybutynin was compared to trospium chloride (a drug similar to oxybutynin
that is not available in the United States) to evaluate central nervous system effects
(Pietzko et al., 1994). The participants, 12 healthy males, were randomly assigned to one
of three treatments: oxybutynin (20 mg), trospium chloride i.v. (1.2 mg), or trospium
chloride p.o. (45 mg). Oxybutynin was found to lower heart rate and affect EEG results.
Another study compared immediate-release oxybutynin administered orally to that
administered via a transdermal patch (Davila et al., 2001). In this study, 76 older patients
(70 women and 6 men) were randomly assigned to receive either the oral medication or
8
the transdermal patch. Adverse effects related to the central nervous system for
transdermal and oral medication, respectively, included: drowsiness (18% vs. 37%),
dizziness (16% vs. 26%), and blurred vision (18% vs. 24%).
One review of the effectiveness and adverse effects of extended-release oxybutynin
(Goldenberg, 1999) has been published. One of the studies reviewed examined
oxybutynin in 257 patients and found that dry mouth was reported by 57% of
participants, constipation by 10% of participants and drowsiness by 7% of participants.
Across the studies reviewed, dosages of oxybutynin ranging from 5 to 30 mg resulted in
the following reports of adverse effects: dry mouth (61%), constipation (13%),
drowsiness (12%), headache (10%), blurred vision (8%), and dizziness (6%). No
information was provided regarding sample sizes or the comparison treatments (e.g.,
active drug or placebo) used in these clinical trials.
The elderly are more sensitive to the adverse effects of anticholinergic drugs than the
younger population (Feinberg, 1993). Older people are also likely to suffer from multiple
chronic conditions requiring treatment. When multiple drugs are prescribed for multiple
conditions (one of which, in the elderly, is likely to be overactive bladder), the side
effects can be additive, leading to behavioral or pharmacologic toxicity. For this reason, it
is particularly important to understand the effects of all of the anticholinergic drugs.
20 PROMETHAZINE
Promethazine (Phenergan) is a sedating, first-generation antihistamine that is also used as
an anti-emetic. In a crossover study with 6 participants, 10 mg promethazine given
acutely impaired visual vigilance performance and reaction time compared with placebo
(Nicholson and Turner, 1998). It also increased subjective sleepiness and decreased sleep
latency from 1.5-5.5 hours post-dose. Another crossover study with 24 participants
showed that 30 mg promethazine given acutely significantly decreased CFFT 3-9 hours
post-dose(Hindmarch, Shamsi, Stanley and Fairweather, 1999).
21 SECOBARBITAL
Secobarbital is a barbiturate, used to treat insomnia and sometimes given before surgery
to relieve anxiety.
In a study of the effects of secobarbital on reactions to letter stimuli presented with
different levels of visual masking or degradation, secobarbital, at doses of 2 and 2.9
mg/kg body weight, was associated with increased recognition reaction time and a
significant drug x visual degradation interaction, in comparison with placebo (Logsdon,
Hochhaus, Williams, Rundell and Maxwell, 1984). Secobarbital had greater negative
effects on recognition reaction time as stimuli were more heavily masked. Secobarbital
was also associated with significantly more recognition errors than placebo, and a drug x
visual degradation interaction similar to the one mentioned previously was also found.
This study was conducted with 18 male participants in a crossover design.
Another study reported on the administration of 100 mg secobarbital to 30 male
participants in a between-groups study comparing secobarbital, d-amphetamine and
placebo (Schroeder, Collins and Elam, 1974). Participants were asked to perform a
9
compensatory tracking task while stationary and while undergoing angular acceleration.
There were no between-group differences in tracking accuracy while participants were
stationary, but tracking accuracy was significantly worse in the secobarbital group than in
the placebo group in the angular acceleration condition.
22 TEMAZEPAM
Temazepam is a benzodiazepine with a moderate half-life of approximately 12 hours.
Ten to twenty mg of temazepam is a typical dose for the treatment of insomnia.
Van Steveninck, Schoemaker, Pieters, Kroon, Breimer and Cohen (1991) published a
study comparing the effects of 5, 10 and 20 mg temazepam with placebo. All of the
temazepam doses slowed saccadic eye movements; the 10- and 20-mg doses increased
subjective drowsiness compared to placebo. The accuracy of saccades to a rank of LEDs
was also significantly diminished by all 3 temazepam doses. The 20-mg dose also
impaired adaptive tracking performance compared to placebo.
23 TRIAZOLAM
Triazolam (Halcion) is a benzodiazepine hypnotic with a very short half-life of only
about 3 hours.
In a crossover study comparing 0.25 mg triazolam with placebo, triazolam significantly
decreased immediate and delayed recall at 1.25 and 8.25 hours post-dose (Troy, Lucki,
Unruh, Cevallos, Leister, Martin, Furlan and Mangano, 2000). This study employed 24
participants and also showed that 0.25 mg triazolam impaired performance on the DSST
at both testing times.
In a between-subjects study with 10 participants per group, two doses (0.25 and 0.5 mg)
of triazolam were compared with placebo (Wesensten, Balkin and Belenky, 1996). The
larger drug dose was associated with the completion of fewer logical reasoning trials than
placebo, and decision time in the logical reasoning task increased with this dosage as
well. Similar effects of the drug were seen on a mental arithmetic task, in which the
percentage of trials completed was significantly lower with 0.5 mg triazolam than with
placebo, and significantly more errors were made. Additionally, two participants who
received the larger triazolam dose were too sedated to complete the test battery.
24 TRIHEXYPHENIDYL
Trihexyphenidyl (Artane) is an anticholinergic drug used to treat the extra-pyramidal
symptoms caused by antipsychotic drugs.
In a crossover study of 14 healthy volunteers given 5 mg trihexyphenidyl and placebo,
the drug was associated with significant decreases in digit span performance and memory
impairment on the Buschke selective reminding task (Guthrie et al., 2000).
25 TRIPELENNAMINE
Tripelennamine (PBZ) is a widely-abused antihistamine. A 50-mg dose was administered
to 18 adult volunteers in a crossover study and compared with placebo (Stern, Chait and
10
Johanson, 1989). Tripelennamine was associated with significantly higher subjective
ratings of fatigue, confusion and sedation than placebo. A 25-mg dose did not
significantly elevate subjective ratings on these scales.
26 TRIPROLIDINE
Triprolidine is a first-generation antihistamine and is very sedating. It is commonly
combined with pseudoephedrine in OTC allergy medications.
Triprolidine was shown to impair performance in a number of domains in a study
conducted by Volkerts et al. (1992). Performance testing was conducted on days 1 and 4
of dosing, when the drug had been administered at 5 mg bid. SDLP increased
significantly on days 1 and 4 compared with placebo in the standard 100-km test.
Subjective driving performance was significantly worse with triprolidine on day 1 but not
on day 4. Triprolidine prolonged reaction time significantly on day 1 in two out of three
choice reaction time tasks; no significant impact of triprolidine on reaction time was
observable on day 4. In a similar study (O’Hanlon, 1988), 10 mg triprolidine caused
significant increases in SDLP 1 and 3 hours post-dose, but participants stopped reporting
subjective sedation prior to the test session at 3 hours post-dose. The author compared the
SDLP impairment with a 0.05% BAC.
Three acute doses of triprolidine (1.25, 2.5 and 5 mg) were associated with decreased
vigilance performance in an hour-long task; fewer signals were detected with triprolidine
than with placebo in a crossover study with 24 participants (Peck et al., 1975). All of
these doses also impaired auditory reaction time at 2.5 hours post-dose, but only the two
higher doses were still impairing 5 hours post-dose. The highest dose impaired DSST
performance at 2.25 and 4.75 hours post-dose. Five mg also caused subjective sedation in
a placebo-controlled crossover study 1.5 hours post-dose (Alford, Bhatti, Rombaut,
Curran and Hindmarch, 1989).
In a crossover study with 7 female participants, 10 mg triprolidine was associated with
impaired visual-motor coordination and dynamic visual acuity (Bradley and Nicholson,
1987). It also decreased the number of correct substitutions in the DSST and significantly
increased CFFT when compared with placebo. Subjective drowsiness was also
significantly higher after dosing with triprolidine than with placebo.
27 ZOLPIDEM
Zolpidem (Ambien) is a hypnotic drug used to treat insomnia. It is rapidly absorbed
(Tmax 1-2 hours) and has a short half-life of only 1-2 hours.
In a crossover study comparing 10 and 20 mg zolpidem with placebo, zolpidem
significantly decreased immediate and delayed recall at 1.25 and 8.25 hours post-dose
(Troy et al., 2000). The 20-mg dose significantly decreased digit span length at 1.25
hours post-dose and impaired DSST performance at both testing sessions. The 10-mg
dose impaired DSST performance only at 1.25 hours post-dose. Both doses significantly
impaired divided attention performance (in terms of tracking, variability and reaction
time) at 1.25 but not 8.25 hours post-dose. This study employed 24 participants.
11
A second study, employing 18 adult volunteers, dosed participants with 5, 10 and 20
mg/70 kg of zolpidem and tested them in a negative priming task (Mintzer and Griffiths,
1999). The two higher doses were associated with significant memory impairment
compared to placebo; correct responses in a recognition task were also decreased to a
significant extent by the highest dose.
REFERENCES
Alford, C., Bhatti, J. Z., Rombaut, N. E. I., Curran, S., & Hindmarch, I. (1989). A
comparison of antihistamines using EEG and questionnaire-based assessments.
Medical Science Research, 17, 421-423.
Bradley, C. M., & Nicholson, A. N. (1987). Studies on performance with aspirin and
paracetamol and with the centrally acting analgesics meptazinol and pentazocine.
European Journal of Clinical Pharmacology, 32, 135-139.
Curran, H. V., Schifano, F., & Lader, M. (1991). Models of memory dysfunction? A
comparison of the effects of scopolamine and lorazepam on memory, psychomotor
performance and mood. Psychopharmacology, 103, 83-90.
Curran, S. (1990). Critical flicker fusion techniques in psychopharmacology. In I.
Hindmarch & P. D. Stonier (Eds.), Human Psychopharmacology: Measures and
Methods (Vol. 3, pp. 21-38): John Wiley and Sons, Limited.
Davila, G. W., Daughtery, C. A., & Sanders, S. W. (2001). A short-term, multicenter,
randomized double-blind dose titration study of the efficacy and anticholinergic side
effects of transdermal compared to immediate release oral oxybutynin treatment of
patients with urge urinary incontinence. The Journal of Urology, 166, 140-145.
Evans, S. M., Troisi, J. R., II, & Griffiths, R. R. (1994). Tandospirone and alprazolam:
Comparison of behavioral effects and abuse liability in humans. The Journal of
Pharmacology and Experimental Therapeutics, 271, 683-694.
Fairweather, D. B., Kerr, J. S., Harrison, D. A., Moon, C. A., & Hindmarch, I. (1993). A
double blind comparison of the effects of fluoxetine and amitriptyline on cognitive
function in elderly depressed patients. Human Psychopharmacology, 8, 41-47.
Feinberg, M. (1993). The problems of anticholinergic adverse effects in older patients.
Drugs and Aging, 3(4), 335-348.
File, S. E. (1992). Effects of lorazepam on psychomotor performance: A comparison of
independent-groups and repeated-measures designs. Pharmacology Biochemistry and
Behavior, 42, 761-764.
Garriott, J. C., DiMaio, V. J. M., Zumwalt, R. E., & Petty, C. S. (1977). Incidence of
drugs and alcohol in fatally-injured motor vehicle drivers. Journal of Forensic
Sciences, 22(2), 383-389
Gengo, F. M., Dabronzo, J., Yurchak, A., Love, S., & Miller, J. K. (1987). The relative
antihistaminic and psychomotor effects of hydroxyzine and cetirizine. Clinical
Pharmacology and Therapeutics, 42, 265-272.
12
Gengo, F. M., & Gabos, C. (1987). Antihistamines, drowsiness, and psychomotor
impairment: Central nervous system effect of cetirizine. Annals of Allergy, 59 (II),
53-57.
Gengo, F. M., Gabos, C., & Mechtler, L. (1990). Quantitative effects of cetirizine and
diphenhydramine on mental performance measured using an automobile driving
simulator. Annals of Allergy, 64, 520-526.
Goetz, D. W., Jacobson, J. M., Murnane, J. E., Reid, M. J., Repperger, D. W., Goodyear,
C., & Martin, M. E. (1989). Prolongation of simple and choice reaction times in a
double-blind comparison of twice-daily hydroxyzine and terfenadine. Journal of
Allergy and Clinical Immunology, 84, 316-322.
Goldenberg, M. M. (1999). An extended-release formulation of oxybutynin chloride for
the treatment of overactive urinary bladder. Clinical Therapeutics, 21(4), 634-642.
Guthrie, S. K., Manzey, L., Scott, D., Giordani, B., & Tandon, R. (2000). Comparison of
central and peripheral pharmacologic effects of biperiden and trihexyphenidyl in
human volunteers. Journal of Clinical Pharmacology, 20(1), 77-83.
Hanks, G. W., O'Neill, W. M., Simpson, P., & Wesnes, K. (1995). The cognitive and
psychomotor effects of opioid analgesics: II. A randomized controlled trial of single
doses of morphine, lorazepam and placebo in healthy subjects. European Journal of
Clinical Pharmacology, 48, 455-460.
Hatcher, S., Sims, R., & Thompson, D. (1990). The effects of chronic lithium treatment
on psychomotor performance related to driving. British Journal of Psychiatry, 157,
257-278.
Hindmarch, I., & Gudgeon, A. C. (1980). The effects of clobazam and lorazepam on
aspects of psychomotor performance and car-handling ability. British Journal of
Clinical Pharmacology, 10, 145-150.
Hindmarch, I., Harrison, C., & Shillingford, C. A. (1988). An investigation of the effects
of lofepramine, nomifensine, amitriptyline and placebo on aspects of memory and
psychomotor performance related to car driving. International Clinical
Psychopharmacology, 3, 157-165.
Hindmarch, I., & Parrott, A. C. (1978). A repeated dose comparison of the side effects of
five antihistamines on objective assessments of psychomotor performance, central
nervous system arousal and subjective appraisals of sleep and early morning
behaviour. Drug Research, 28(1), 483-486.
Hindmarch, I., Shamsi, N. S., & Fairweather, D. B. (1999). A double-blind, placebocontrolled investigation fo the effects of fexofenadine, loratadine and promethazine
on cognitive and psychomotor function. British Journal of Clinical Pharmacology,
48, 200-206.
Irving, A., & Jones, W. (1992). Methods for testing impairment of driving due to drugs.
European Journal of Clinical Pharmacology, 43, 61-66.
13
Katz, I. R., Sands, L. P., Bilker, W., DiFilippo, S., Boyce, A., & D'Angelo, K. (1998).
Identification of medications that cause cognitive impairment in older people: The
case of oxybutynin chloride. Journal of the American Geriatrics Society, 46, 8-13.
Logsdon, R., Hochhaus, L., Williams, H. L., Rundell, O. H., & Maxwell, D. (1984).
Secobarbital and perceptual processing. Acta Psychologica, 55, 179-193.
Millar, K., & Standen, P. J. (1982). Differences in performance impairment due to
brompheniramine maleate as a function of the sustained-release system. British
Journal of Clinical Pharmacology, 14, 49-55.
Mintzer, M. Z., & Griffiths, R. R. (1999). Triazolam and zolpidem: Effects on human
memory and attentional processes. Psychopharmacology, 144, 8-19.
Moser, L., Huether, K. J., Koch-Weser, J., & Lundt, P. V. (1978). Effects of terfenadine
and diphenhydramine alone or in combination with diazepam or alcohol on
psychomotor performance and subjective feelings. European Journal of Clinical
Pharmacology, 14, 417-423.
Moskowitz, H., & Chen, D. (1990). Drug performance sensitivity: A pilot study. Journal
of Clinical Psychopharmacology, 10(4S), 20S-23S.
Moskowitz, H., & Smiley, A. (1982). Effects of chronically administered buspirone and
diazepam on driving-related skills performance. Journal of Clinical Psychiatry,
43(12), 45-55.
Munte, T. F., Gehde, E., Johannes, S., Seewald, M., & Heinze, H.-J. (1996). Effects of
alprazolam and bromazepam on visual search and verbal recognition memory in
humans: A study with event-related brain potentials. Neuropsychobiology, 34(1), 4956.
Nicholson, A. N., & Turner, C. (1998). Central effects of the H1 antihistamine cetirizine.
Aviation, Space and Environmental Medicine, 69(2), 166-171.
O'Hanlon, J. F. (1988). Antihistamines and driving safety. CUTIS, 42, 10-13.
Palva, E. S., Linnoila, M., Routledge, P., & Seppälä, T. (1982). Actions and interactions
of diazepam and alcohol on psychomotor skills in young and middle-aged subjects.
Acta Pharmacologica et Toxicologica, 50, 363-369.
Patat, A., Stubbs, D., Dunmore, C., Ulliac, N., Sexton, B., Zieleniuk, I., Irving, A., &
Jones, W. (1995). Lack of interaction between two antihistamines, mizolastine and
cetirizine, and ethanol in psychomotor and driving performance in healthy subjects.
European Journal of Clinical Pharmacology, 48, 143-150.
Peck, A. W., Fowle, A. S. E., & Bye, C. (1975). A comparison of triprolidine and
clemastine antagonism and performance tests in man: Implications for the mechanism
of drug-induced drowsiness. European Journal of Clinical Pharmacology, 8, 455463.
Pietzko, A., Dimpfel, W., Schwantes, U., & Topfmeier, P. (1994). Influences of trospium
chloride and oxybutynin on quantitative EEG in health volunteers. European Journal
of Clinical Pharmacology, 47, 337-343.
14
Schroeder, D. J., Collins, W. E., & Elam, G. W. (1974). Effects of secobarbital and damphetamine on tracking performance during angular acceleration. Ergonomics,
17(5), 613-621.
Schweitzer, P. K., Muehlbach, M. J., & Walsh, J. K. (1994). Sleepiness and performance
during three-day administration of cetirizine or diphenhydramine. Journal of Allergy
and Clinical Immunology, 94, 716-724.
Sellers, E. M., Schneiderman, J. F., Romach, M. K., Kaplan, H. L., & Somer, G. R.
(1992). Comparative drug effects and abuse liability of lorazepam, buspirone and
secobarbital in nondependent subjects. Journal of Clinical Psychopharmacology,
12(2), 79-85.
Seidel, W. F., Cohen, S., Bliwise, N. G., & Dement, W. C. (1987). Cetirizine effects on
objective measures of daytime sleepiness and performance. Annals of Allergy, 59 (II),
58-62.
Shaw, E. D., Stokes, P. E., Mann, J. J., & Manevitz, A. Z. A. (1987). Effects of lithium
carbonate on the memory and motor speed of bipolar outpatients. Journal of
Abnormal Psychology, 96(1), 64-69.
Simon, S. L., Domier, C., Carnell, J., Brethen, P., Rawson, R., & Ling, W. (2000).
Cognitive impairment in individuals currently using methamphetamine. The
American Journal on Addictions, 9, 222-231.
Simons, F. E. R., Fraser, T. G., Reggin, J. D., & Simons, K. J. (1996). Comparison of the
central nervous system effects produced by six H1-receptor antagonists. Clinical and
Experimental Allergy, 26, 1092-1097.
Stern, K. N., Chait, L. D., & Johanson, C. E. (1989). Reinforcing and subjective effects
of oral tripelennamine in normal human volunteers. Behavioural Pharmacology, 1,
161-167.
Subhan, Z., Harrison, C., & Hindmarch, I. (1986). Alprazolam and lorazepam single and
multiple-dose effects on psychomotor skills and sleep. European Journal of Clinical
Pharmacology, 29(6), 709-712.
Troy, S. M., Lucki, I., Unruh, M. A., Cevallos, W. H., Leister, C. A., Martin, P. T.,
Furlan, P. M. B., & Mangano, R. (2000). Comparison of the effects of zaleplon,
zolpidem and triazolam on memory, learning and psychomotor performance. Journal
of Clinical Psychopharmacology, 20, 328-337.
Van Cauwenberge, P. B. (1992). New data on the safety of loratadine. Drug
Investigations, 4(4), 283-291.
van Laar, M. W., van Willigenburg, A. P. P., & Volkerts, E. R. (1995). Acute and
subchronic effects of nefazodone and imipramine on highway driving, cognitive
functions and daytime sleepiness in healthy adult and elderly subjects. Journal of
Clinical Psychopharmacology, 15(1), 30-40.
van Laar, M. W., Volkerts, E. R., & van Willigenburg, A. P. P. (1992). Therapeutic
effects and effects on actual driving performance of chronically administered
15
buspirone and diazepam in anxious outpatients. Journal of Clinical
Psychopharmacology, 12(2), 86-95.
van Steveninck, A. L., Schoemaker, H., Pieters, M. S. M., Kroon, R., Breimer, D. D., &
Cohen, A. F. (1991). A comparison of the sensitivities of adaptive tracking, eye
movement analysis and visual analog lines to the effects of incremental doses of
temazepam in healthy volunteers. Clinical Pharmacology and Therapeutics, 50, 172180.
Verster, J. C., Volkerts, E. R., & Verbaten, M. N. (2002). Effects of alprazolam on
driving ability, memory functioning and psychomotor performance: A randomized,
placebo-controlled study. Neuropsychopharmacology, 27(2), 260-269.
Volkerts, E. R., van Willigenburg, A. P. P., van Laar, M. W., & Maes, R. A. A. (1992).
Does cetirizine belong to the new generation of antihistamines? An investigation into
its acute and subchronic effects on highway driving, psychometric test performance
and daytime sleepiness. Human Psychopharmacology, 7, 227-238.
Vu, B. L. L., Easterbrook, M., & Hovis, J. K. (1999). Detection of color vision defects in
chloroquine retinopathy. Ophthalmology, 106, 1799-1804.
Vuurman, E. F. P. M., Uiterwijk, M. M. C., Rosenzweig, P., & O'Hanlon, J. F. (1994).
Effects of mizolastine and clemastine on actual driving and psychomotor performance
in healthy volunteers. European Journal of Clinical Pharmacology, 47, 253-259.
Walsh, J. K., Muehlbach, M. J., & Schweitzer, P. K. (1992). Simulated assembly line
performance following ingestion of cetirizine or hydroxyzine. Annals of Allergy, 69,
195-200.
Warburton, D. M., & Wesnes, K. (1984). A comparison of temazepam and flurazepam in
terms of sleep quality and residual changes in activation and performance. Drug
Research, 34(11), 1601-1604.
Wesensten, N. J., Balkin, T. J., & Belenky, G. L. (1996). Effects of daytime
administration of zolpidem and triazolam on performance. Aviation, Space and
Environmental Medicine, 67, 115-120.
Witek, T. J., Canestrari, D. A., Miller, R. D., Yang, J. Y., & Riker, D. K. (1995).
Characterization of daytime sleepiness and psychomotor performance following H1
receptor antagonists. Annals of Allergy, Asthma and Immunology, 74, 419-426.
Zacny, J. P., Lichtor, J. L., Klafta, J. M., Alessi, R., & Apfelbaum, J. L. (1996). The
effects of transnasal butorphanol on mood and psychomotor functioning in healthy
volunteers. Anesthesia and Analgesia, 82, 931-935.
16