Other psychomotor effects, such as problems with coordination and delayed
reaction time, can also occur during benzodiazepine treatment.
also dose-related, but usually subside within a few weeks of continued treatment.
Long-acting benzodiazepines taken the previous night may cause residual daytime
effects, which can result in car accidents and hospitalization in older individuals
The link between benzodiazepine use and falls, especially in the elderly, is well
63 Rapid dosage escalation and use of high doses have been identified as
major risk factors, but even use of low doses of short-acting agents greatly increases
the risk of falling in the elderly.
Respiratory depression is another potential adverse effect of benzodiazepines, but
it is usually clinically relevant only in patients with severe respiratory disease, in
overdose situations (see Case 83-5, Question 1), or when combined with alcohol or
substances that depress breathing, like opioids. It is recommended that
benzodiazepines be avoided in patients with sleep apnea.
Respiratory complications are encountered most often with IV administration.
Severe respiratory depression has also occurred with the concurrent use of
benzodiazepines and olanzapine IM (Zyprexa), loxapine (Loxitane), or clozapine
(Clozaril). Further, it should be noted benzodiazepines increase the risk of death in
prescription drug overdoses, typically in combination with other medications or
Paradoxical disinhibition, with increased anxiety, irritability, and agitation, can
occur infrequently with benzodiazepines,
23 primarily in elderly or developmentally
67 Other unusual behaviors, such as increased anger, hostility,
depression, suicidal ideation, and rage, have been attributed to benzodiazepine use in
23,68 Most of these reports were anecdotal and involved
patients with preexisting psychiatric disorders such as bipolar disorder or
schizophrenia. Overall, there is no convincing evidence that benzodiazepines actually
cause violent or suicidal behaviors, but there is some evidence to the contrary.
In summary, L.V. should be told he may experience sedation and difficulties in
thinking, concentration, or memory during the first week or so of therapy, but these
side effects should resolve once he experiences some tolerance to the drug. He
should be extremely careful while driving or performing other tasks requiring
psychomotor skills, especially during the first week, and he should avoid the use of
alcohol while he is taking benzodiazepines.
BENZODIAZEPINE ABUSE AND DEPENDENCE
CASE 83-2, QUESTION 5: Two weeks later, L.V. contacts his clinician to discuss a medication concern.
be counseled regarding “becoming addicted” to alprazolam?
Concerns related to abuse and dependence are one major drawback to the clinical
use of benzodiazepines. These agents are classified as schedule IV controlled
substances. Diazepam, alprazolam, and lorazepam are more likely to be abused than
are oxazepam and chlordiazepoxide.
69 This difference is commonly attributed to the
quicker onset of effect and high potency which may be associated with a subjective
euphoric sensation. The XR alprazolam formulation is reported to have a lower
abuse potential than immediate-release alprazolam because of its slower onset of
effect smaller peak to trough ratio and lower maximal plasma concentrations.
Patients without a history of substance abuse who take benzodiazepines for
therapeutic purposes are unlikely to escalate doses or use them in ways characteristic
The potential problems with benzodiazepine abuse and dependence can be
avoided or minimized in several ways. First is the identification of patients who have
a history of alcohol or substance abuse and using nonbenzodiazepine treatments in
69 Second, patients should be counseled about the anticipated duration of
benzodiazepine use, the possibility of withdrawal symptoms, and the importance of
gradual drug tapering when therapy is discontinued. The distinction between
“addiction” and appropriate therapeutic use, which may be accompanied by some
degree of physical dependence, should be explained.
L.V. should be advised that as long as the medication is helping his anxiety and he
is taking it according to his physician’s instructions, his use of alprazolam does not
constitute addiction. However, his body may develop some physiologic dependence
to the drug, so if he stops taking alprazolam abruptly, he could experience increased
anxiety and other withdrawal symptoms. When alprazolam is to be discontinued, the
dose should be decreased gradually for a sufficient period to minimize withdrawal
GAD is a chronic disorder fluctuating in severity and often requires long-term
treatment. Although long-term use of benzodiazepines can be safe and effective, it is
desirable to limit treatment to the shortest duration necessary.
benzodiazepines are used for acute anxiolytic effects during initiation of
antidepressant treatment for GAD, they are commonly limited to short-term (2–6
weeks) therapy. L.V. has demonstrated good response after 1 month of combined
alprazolam and paroxetine therapy. Because the anxiolytic effects of paroxetine
usually occur between 2 and 4 weeks of therapy and he is taking a therapeutic
paroxetine dose, it is appropriate to start discontinuing alprazolam at this time. While
it is unlikely, L.V. may experience significant withdrawal symptoms even after only 1
month of treatment; thus, the dose should be gradually decreased for several weeks,
according to tolerability of the taper.
In patients who are treated with short-acting
There is no consensus about the optimal duration of drug therapy for GAD.
However, recent recommendations suggest effective medication treatment be
continued for at least 6 to 12 months after response.
22,72 Continuation treatment with
antidepressants significantly reduces the risk of GAD relapse in 6 months.
Therefore, paroxetine therapy should be continued for another 5 to 11 months in
L.V.’s case. After that time, gradual paroxetine discontinuation may be considered,
and reinstitution of treatment is warranted if relapse occurs.
SYMPTOMS AND MANAGEMENT OF BENZODIAZEPINE WITHDRAWAL
tobacco, alcohol, or other drugs of abuse. How should T.B. be treated?
Because T.B. has not taken her prescribed diazepam for five days, it is likely she
is experiencing a withdrawal syndrome from long-term benzodiazepine use. Her
mental and physical symptoms are consistent with benzodiazepine withdrawal. The
benzodiazepine withdrawal syndrome implies some degree of physical dependence,
and its onset, duration, and severity can vary according to dose, duration of treatment,
speed of withdrawal, and elimination half-life of the agent used.
symptoms that follow discontinuation of agents with short half-lives usually appear
within 1 to 2 days and may be more intense and short-lived than after discontinuation
of long-acting benzodiazepines. Withdrawal symptoms usually appear 4 to 7 days
after discontinuation of long-acting agents and may last several weeks. Symptoms of
benzodiazepine withdrawal, which are listed in Table 83-7, are generally mild when
the drug is tapered gradually during discontinuation.
70 Rarely, serious symptoms such
as seizures or psychosis may occur during benzodiazepine withdrawal. Risk factors
for seizures include head injury, alcohol dependence, electroencephalogram
abnormalities, and use of other drugs that lower the seizure threshold.
Symptoms of Benzodiazepine Withdrawal
Muscle aches or weakness Hyperreflexia Seizures
Tremor Blurred vision Catatonia
Diazepam 10 to 20 mg orally should be administered and repeated within 1 to 2
hours if needed. Resumption of her previous diazepam dosage of 40 mg/day should
effectively treat her withdrawal symptoms. However, because her acute injury
occurred 7 months ago, it may be desirable to begin tapering diazepam.
Various dosage reduction regimens have been proposed for benzodiazepine
discontinuation. Even when managing withdrawal from low-dose benzodiazepine
use, doses should be reduced slowly for 4 to 16 weeks.
should be individualized to the patient, but a general recommendation is a 10% to
25% decrease in the dosage every 1 to 2 weeks. The first half of the benzodiazepine
taper (down to 50% of the original dose) is generally easier and can proceed more
quickly than the last half of the taper.
In T.B.’s case, the discontinuation period may
In general, the same benzodiazepine the patient has been taking should be used to
manage withdrawal. However, because withdrawal symptoms are more severe
during discontinuation of short-acting compared with long-acting benzodiazepines, a
long-acting agent can be substituted at an equivalent dosage and then tapered.
difficult cases, adjunctive medications, such as anticonvulsants, like carbamazepine
or phenobarbital, or propranolol, have been used to ease tolerability of the gradual
withdrawal, though the latter does not affect the associated anxiety or decrease the
BENZODIAZEPINE DRUG INTERACTIONS
QUESTION 1: N.P., a 20-year-old female college student, has been taking alprazolam 1 mg TID PRN for
treatment of GAD for the past 2 months. She states alprazolam has been very helpful for her GAD, but
The most significant pharmacodynamic drug interactions involve other CNS
depressants such as alcohol or barbiturates. These combinations can lead to additive
CNS and respiratory depressant effects that can be deadly. Important
pharmacokinetic drug interactions mainly involve agents that either inhibit or induce
75 One clinically significant drug interaction occurs with
the use of azole antifungals in combination with benzodiazepines. Azole antifungals
are potent CYP3A4 inhibitors that can cause a 170% increase in the area under the
76 Therefore, the dosage of alprazolam should be reduced by
about one-third in patients receiving this combination. Since benzodiazepines have a
relatively wide margin of safety, elevated plasma levels or prolonged elimination
half-lives are unlikely to cause serious toxicity. However, they can lead to increased
sedative and psychomotor effects, which may be clinically significant in certain
cases. Conversely, increased benzodiazepine metabolism by hepatic enzyme inducers
may result in medication ineffectiveness. Most pharmacokinetic drug interactions
with benzodiazepines involve CYP3A4- or CYP2C19-mediated mechanisms. Please
refer to a drug interactions database, such as Facts & Comparisons
(http://www.wolterskluwercdi.com/) for additional information.
In N.P.’s case, the most important drug interaction is between alprazolam and the
newly prescribed oral contraceptive, Yaz. Estrogen-containing oral contraceptives
can inhibit the CYP3A4 metabolism of benzodiazepines such as alprazolam,
potentially resulting in increased side effects.
77,78 Thus, a reduction in the
benzodiazepine dosage may be needed when oral contraceptives are added to
ongoing benzodiazepine therapy, as in N.P.’s case. The clearance of benzodiazepines
that undergo glucuronidation (lorazepam, oxazepam, and temazepam) can be
accelerated by oral contraceptives, but this interaction is probably clinically
Cigarette smoking increases the clearance of some benzodiazepines (clorazepate,
lorazepam, oxazepam), but has no effect on others (diazepam, midazolam,
79 Overall, the effect of smoking is unpredictable and is most
likely to be important in patients who either stop or start smoking while taking a
benzodiazepine. N.P. should be urged to quit smoking for the sake of her general
health and to prevent substantial risks for serious cardiovascular events occurring in
smokers taking oral contraceptives. If N.P. does quit, careful monitoring will be
needed to determine whether any alprazolam dosage reduction is necessary.
N.P. should also be encouraged to decrease her soda consumption because
caffeine can increase anxiety, thus decreasing the effectiveness of alprazolam.
Caffeine has been shown to decrease diazepam concentrations by approximately
22%, but studies with other benzodiazepines are lacking.
BENZODIAZEPINE USE IN PREGNANCY AND LACTATION
her oral contraceptive in hopes of becoming pregnant soon and has successfully quit smoking. N.P.
alternative treatments are available for the management of N.P.’s anxiety?
Early reports implicated diazepam in causing several birth deformities, including
cleft lip or cleft palate and limb and digit malformations, but later studies failed to
80–84 Most benzodiazepine anxiolytics are classified as
pregnancy category D (however, this language will be modified once the FDA
labeling changes for pregnancy and lactation go into effect), indicating there is some
evidence of fetal risk but the benefits of the medication may outweigh these risks in
80,82 Available evidence suggests benzodiazepine use during the first
trimester increases the risk for oral clefts by approximately 2.4-fold, but the absolute
risk is increased only 0.01%. Benzodiazepines have not exhibited strong teratogenic
effects, but it is always advisable to avoid drug use during pregnancy when possible,
especially in the first trimester.
In patients such as N.P., the benzodiazepine
should be tapered and discontinued before she becomes pregnant. Nondrug treatments
for her GAD such as relaxation therapy, meditation, biofeedback, or cognitive
therapy may be helpful. If necessary, single or repeated small doses of
benzodiazepines during the second and third trimesters are unlikely to have important
adverse effects on the fetus. In these instances, an agent with a short half-life, such as
lorazepam, should be considered.
84 Chronic or large doses, especially of long-acting
agents, should be avoided because they may accumulate in the fetus. Perinatal
sequelae in newborns of mothers who took benzodiazepines during pregnancy
include withdrawal symptoms, sedation, muscle weakness, hypotonia, apnea, poor
feeding, low birth weight, and increased risk for preterm birth.
The clinical situation of unexpected pregnancy in a woman maintained on
benzodiazepines can also arise. The general course of action in such cases is often to
discontinue all medications immediately. However, it is unwise to abruptly stop
benzodiazepine treatment in someone who has been receiving chronic therapy
because the resultant withdrawal syndromes can be detrimental to both mother and
child. Benzodiazepine dosages should be tapered as quickly as possible to the lowest
dosage necessary and discontinued if possible. The postpartum period is a time of
heightened risk for recurrence of anxiety disorders, and new mothers should be
monitored carefully for signs of relapse.
86 Benzodiazepines are excreted readily in
breast milk, and they should be avoided by nursing mothers, when possible, but use is
not absolutely contraindicated.
If benzodiazepines are used, short-acting agents with
no active metabolites are recommended to avoid sedation, poor feeding, withdrawal,
and other effects in the infant.
BENZODIAZEPINE OVERDOSE AND USE OF FLUMAZENIL
symptoms are consistent with benzodiazepine overdose? Why is it inappropriate to administer the
benzodiazepine antagonist, flumazenil, in this case?
Benzodiazepine overdose is characterized by respiratory and CNS depression,
both of which are evident in this case (S.P. is almost unconscious, with slow and
shallow breathing). Overdose with benzodiazepines as the sole ingested agent is
rarely life-threatening, and full recovery is the usual outcome.
benzodiazepine receptor antagonist effective in reversing sedation associated with
benzodiazepine intoxication. Its effects on respiratory depression are inconsistent,
but improved breathing may occur secondarily to increased consciousness.
The primary use of flumazenil is in reversing benzodiazepine-induced conscious
sedation (primarily with midazolam) in patients who have been sedated for minor
surgical or diagnostic procedures. Flumazenil is also approved for treating
benzodiazepine overdose, but this use is controversial because of potentially serious
complications (e.g., supraventricular arrhythmia and seizure), and questions about its
90,91 Flumazenil administration does not appear to decrease
mortality or length of hospital stay in cases of benzodiazepine overdose; therefore, its
use for this purpose has become limited.
Flumazenil is contraindicated in overdoses of any agent that decreases the seizure
threshold, such as TCAs. Toxicology screening and an electrocardiogram (ECG)
should be performed before flumazenil is administered. Because of a risk of seizures,
flumazenil should also be avoided in patients with increased intracranial pressure or
a known history of seizures or head injury, in those who have been receiving chronic
benzodiazepine therapy, and in patients with a history of recent illicit drug abuse
(cocaine, heroin). Administration of flumazenil should occur only when acute seizure
management measures are available.
Flumazenil reverses benzodiazepine-induced sedation or coma within 1 to 2
minutes after IV administration. The most common side effects include agitation,
dizziness, nausea, general discomfort, tearfulness, anxiety, and a sensation of
89 Rapid or excessive infusion has been associated with tachycardia and
hypertension. The elimination half-life of flumazenil is 41 to 79 minutes, and sedation
may recur after 1 to 2 hours, especially when large doses of long-acting
benzodiazepines are involved. Repeated flumazenil doses or an IV infusion may be
indicated in these cases. Full recovery should be verified (3–4 hours of stable
alertness) before patients are discharged after flumazenil administration, and they
should be advised to avoid driving or performing other potentially hazardous
activities for 24 hours. Flumazenil undergoes extensive hepatic metabolism to its
glucuronide conjugate and de-ethylated free acid. Dosage reductions are
recommended in patients with liver dysfunction.
Flumazenil is not appropriate in S.P.’s case because of his history of head injury
and risk of post-traumatic seizures. Instead, management should involve general
supportive measures and mechanical ventilation, if indicated. A psychiatric
evaluation is also indicated in this case to identify and address the reasons for S.P.’s
PHYSIOLOGIC VARIABLES INFLUENCING BENZODIAZEPINES
Physiologic Factors Influencing Benzodiazepine Pharmacokinetics
Factor Physiologic and Pharmacokinetic Effects Clinical Significance or Comments
Aging Increased elimination half-life as a result of
increased Vd of all benzodiazepines
Lower benzodiazepine dosages, and possibly less
frequent dosing intervals, recommended in the
Decreased clearance of benzodiazepines that
undergo oxidative hepatic metabolism (Table 83-
Benzodiazepines that undergo glucuronidation
(lorazepam, oxazepam) preferred in the elderly
Decreased plasma proteins may lead to increased
free fraction of highly protein-bound
Possible increased clinical effects
Decreased gastric acidity may lead to increased
rate of benzodiazepine absorption
Possible faster onset of clinical effects
Sex Age-related decrease in hepatic oxidative
metabolism of benzodiazepines more pronounced
Elderly men may require especially low
Increased CYP 3A4 and CYP 2C19 activity in
premenopausal women may result in higher
clearance of drugs that undergo oxidative
Possible decreased plasma benzodiazepine
concentrations and shorter duration of clinical
effects of oxidatively metabolized agents in
Decreased glucuronidation in women may result
in slower clearance of benzodiazepines
Women may have longer elimination half-lives of
lorazepam and temazepam and may require lessfrequent dosing
Increased Vd in women owing to lower lean body
mass and increased adipose tissue
Possible longer elimination half-lives in women,
especially the elderly, and greater drug
Lower plasma protein binding in women
77 Clinicalsignificance unknown
Obesity Increased benzodiazepine elimination half-lives
Increased chance of drug accumulation in obese
patients; dosage reductions may be indicated
Decreased clearance and increased elimination
half-lives of long-acting benzodiazepines and
alprazolam in cirrhosis and hepatitis; no changes
Avoid long-acting benzodiazepines, or use
significantly lower doses to avoid drug
Increased elimination half-life of lorazepam in
cirrhosis but not acute hepatitis
Decreased lorazepam dose or increased dosing
interval recommended in cirrhosis
Decreased plasma protein binding may lead to
increased free fraction of highly protein-bound
Dosage reductions may be necessary
Ethnicity Decreased oxidative metabolism (via CYP 2C19)
of diazepam and alprazolam in Asians
Asians may require lower doses of diazepam,
alprazolam, and possibly other benzodiazepines
CYP, cytochrome P-450; Vd, volume of distribution.
Benzodiazepine pharmacokinetics can be affected by various physiologic factors,
57,77,92–95 Several of these factors are present in this case and may
have contributed to the accumulation of clonazepam with resulting adverse
B.G.’s age may influence clonazepam disposition. Reductions in both CYP3A4
and CYP2C19 activity have been reported to occur with aging. The glucuronidation
metabolic pathways are minimally affected with age, so no such effect is seen with
57 Other factors contributing to longer benzodiazepine half-
lives in the elderly include decreased hepatic blood flow and increased volumes of
distribution of lipid-soluble compounds (owing to decreased muscle mass and
increased fat); the latter can increase a drug’s half-life in the absence of any
clearance changes. As described in Case 83-3, Question 4, older patients are more
sensitive to the sedative and psychomotor and especially cognitive impairing effects
of benzodiazepines. For these reasons, benzodiazepines should be avoided in the
elderly but if necessary, then the recommended benzodiazepine dosages for patients
older than 65 years are generally one-third to one-half of those used in healthy adults
Sex also may influence benzodiazepine clearance, but studies yield mixed
77,96,97 Women have been reported to have higher CYP3A4 and CYP2C19
activities than men, which may partially explain these findings. Increased CYP3A4
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