Dr. Choy is in private practice and works as a staff psychiatrist at the Student Health Center of the University of California, Irvine.

Disclosure: Dr. Choy reports no affiliation with or financial interest in any orgnization that may pose a conflict of interest.
Acknowledgments: Dr. Choy would like to thank Franklin R. Schneier, MD, for his review of this manuscript.

Please direct all correspondence to: Yujuan Choy, MD, 4199 Campus Dr, Suite 550, Irvine, CA 92612; Tel: 949-725-2951; E-mail: choyMD@gmail.com


 

Abstract

Side effects from effective medications can lead to non-adherence, medication discontinuation, or suboptimal therapeutic dose. This article discusses the common side effects of benzodiazepines and other anxiolytic agents in the treatment of anxiety disorders. Drug-drug interactions, drug dependence, and pregnancy risks of benzodiazepines are also discussed. Sedation and cognitive impairment are the most bothersome side effects of benzodiazepines, but these can be minimized by observing basic treatment principles. Although concerns about benzodiazepine dependence and withdrawal have been raised, most discontinuation symptoms can be avoided with proper education and a gradual taper schedule. The non-benzodiazepine anxiolytics, including buspirone, propranolol, hydroxyzine, and gabapentin, have specific and limited roles in the treatment of anxiety, but their side-effect profiles are fairly benign.

 

Introduction

Although selective serotonin reuptake inhibitors (SSRIs) and psychotherapy are now considered first-line treatments for most anxiety disorders, benzodiazepines remain an important class of medication for the treatment of anxiety disorders.1 Benzodiazepines are much safer than older anxiolytics such as barbiturates or meprobamate, because of a higher therapeutic index and lower propensity to cause respiratory depression, coma, and death in overdoses.2 Benzodiazepines also work rapidly, alleviating anxiety within a few days. This is an advantage over the SSRIs, which have a delayed onset-of-action and often cause initial worsening of anxiety.3

As a class, benzodiazepines are effective and generally well tolerated, but not side-effect free. Typical side effects and associated risks include drug-drug interactions, safety during pregnancy, psychomotor impairment, memory problems, and physiologic dependence and withdrawal. This article focuses on the management of common side effects and risks associated with the use of benzodiazepines in the treatment of anxiety. Although an exhaustive review of non-benzodiazepine anxiolytics is not possible, a brief discussion of several of these agents (buspirone, β-blockers, hydroxyzine, and gabapentin) is provided.

 

Benzodiazepines

To date, more than two dozen benzodiazepine derivatives exist, but only 13 are approved by the Food and Drug Administration for psychiatric indications—eight for anxiety and five for insomnia (Table 1).2,4 All benzodiazepines have the same mechanism of action and are equally effective in alleviating anxiety.5 Benzodiazepines exert their anxiolytic effect by binding to the γ-aminobutyric acid (GABA)A receptor complex and enhancing the inhibitory action of GABA in the central nervous system (CNS).3

 

 

Most benzodiazepines undergo Phase I (oxidation) and Phase II (conjugation) metabolism.5 The majority of benzodiazepine Phase I metabolism involves cytochrome P450 (CYP) 3A4. The exception is diazepam, which is mainly metabolized by CYP 2C19.6 Several derivatives (lorazepam, oxazepam, and temazepam) require only conjugation for elimination,6 so they may be better tolerated in the elderly and patients with liver impairment.5 Most benzodiazepines do not affect plasma levels of other drugs,7 with exception of alprazolam, which may be associated with increased digoxin levels in the elderly.6

However, drugs that inhibit or induce hepatic enzyme activity can influence benzodiazepine plasma levels (Table 2).7 Dosages should be adjusted accordingly when benzodiazepines are combined with these other medications. Combination of benzodiazepines with other sedating agents, such as alcohol, can enhance CNS depression (Table 2).1,7

 

 

 

Acute Central Nervous System Side Effects

The acute administration of benzodiazepines is most commonly associated with cognitive side effects, including sedation, impairment in attention, delay in psychomotor performance, and memory deficits.8-10 CNS adverse effects are observed across all benzodiazepines and most severe within the first few hours after administration in a dose-dependent manner.8 With the exception of memory impairment, tolerance to side effects generally develops after repeated dose administration.8

Sedation is manifested by subjective feelings of drowsiness and decrease in alertness. It is often unwanted in the treatment of anxiety, but even in cases where sedation is desired (eg, treatment of insomnia), residual daytime sedation can be problematic. Problems in attention include inability to sustain focus on task or shift attention from one task to another.10 There are also measurable impairments in coordination and psychomotor speed as well as delay in reaction time.10 Thus, it is not surprising that benzodiazepines have been associated with traffic accidents and workplace injuries.8 One study reported that even a one-time dose of a short-acting benzodiazepine can significantly impair driving ability and psychomotor performance.11 Ataxia and postural instability are particularly problematic in the elderly, and benzodiazepines have been associated with an increased risk of falls and hip fractures in this group.12

Benzodiazepines may cause memory problems in the form of anterograde amnesia, independent of their effects on attention and alertness. Previously learned memory is not affected, but ability to assimilate new information into long-term memory10 and recall recently learned information13 are impaired.

 

Chronic Central Nervous System Side Effects

Chronic treatment with benzodiazepines has raised concerns about potential cognitive impairments. One meta-analysis of 13 studies concluded that chronic benzodiazepines can impair many cognitive processes.14 Compared to healthy normal controls, patients who took benzodiazepines for at least 1 year performed worst in almost all domains of cognitive function, most notably in sensory processing, psychomotor speed, nonverbal memory, and visual-spatial processing (weighted effect size was approximately 0.4). Some of these changes (eg, attention) appear to be reversible within 6 months of medication discontinuation.15 However, patients still functioned below that of normal healthy controls in almost all other domains, including verbal memory, psychomotor speed, speed of cognitive processing, and motor control performance (overall weighted effect size was approximately .48).

Nonetheless, critics have cautioned against accepting these findings because of the many limitations of the studies in the analysis, including a lack of baseline assessment of cognitive function and inappropriate comparison to normal healthy controls.16 Moreover, some of the studies (3 out of 13) did not exclude patients with a history of alcohol or substance use, and most studies (12 out of 13) did not evaluate or exclude patients with underlying cognitive deficits or dementia (age range was 21–75 years). The length of benzodiazepine use was also quite variable (1–29 years) and the patient sample was heterogeneous, which included patients with anxiety, depression, and insomnia. These study limitations make interpretation of the results difficult. Regardless, physicians would need to take these potential cognitive effects into consideration when weighing the risks and benefits of long-term benzodiazepine use.

 

Other Central Nervous System Side Effects

Other reported CNS side effects include depression, delirium, and paradoxical reactions. Treatment-emergent depressive symptoms have been reported with both acute and chronic benzodiazepine use,17 but some have argued that there is insufficient evidence for a cause-and-effect relationship.18 Incidences of confusion and disorientation are rare and generally exhibited only in the elderly or critically ill patients.19,20 Similarly, paradoxical reactions occur infrequently.5,9 Case reports have included symptoms of insomnia, anxiety, and behavioral disinhibition such as hostility, rage, emotional release, and manic-like symptoms (eg, irritability, excitability, hyperactivity, and increased talkativeness).21 A majority of these cases occur during intravenous sedation with midazolam or in the treatment of insomnia in the elderly, and very rarely, with other benzodiazepines in the treatment of anxiety. Individuals with mental retardation may also be more sensitive to benzodiazepine-induced behavioral disturbances.22 However, others have found no association between benzodiazepines and aggressive behaviors in patients hospitalized in an inpatient psychiatric unit.23 There was no difference in the rates of self-injurious acts, physical assaults, or requirements for seclusion or restraints between benzodiazepine (n=219) and non-benzodiazepine patients (n=109) in a retrospective review of medical records.23 Based on the limited data, it appears that occurrence of negative behavioral outcomes are uncommon in healthy individuals but may be a concern in the elderly or individuals with underlying cognitive deficits.

 

Management of Central Nervous Side Effects

Evaluation Process
The first and most important consideration in managing benzodiazepine-induced side effects is to establish a clear indication for their use. Although benzodiazepines are effective and fast-acting in alleviating anxiety, clinicians must also explore other treatment options, including SSRIs and psychotherapy. It is also important to evaluate baseline cognitive status, substance use history, and the presence of any chronic conditions that can affect gait and balance.12 A regular review of the benzodiazepine regimen and discussion of discontinuation should be ongoing during treatment.24

Psychoeducation
Once the decision to prescribe a benzodiazepine has been determined, patients must be thoroughly educated about the potential side effects and goals of treatment.24 Patients will be less distressed if side effects are anticipated and more likely to be adherent if treatment goals are collaborative. In addition, patients are often comforted by the knowledge that many of the side effects will resolve within 2 weeks when tolerance develops.5,8 Dosage can be increased to maximize anxiolytic effects if anxiety persists after sedation and other transient side effects resolve. Patients should be informed that there may be several rounds of dose increase with interruption to allow tolerance to develop. Patients should also be warned against driving or participating in other dangerous activities that require alertness and psychomotor skills. They should be warned against taking other drugs or substances with similar sedative effects or those that interact negatively with benzodiazepines (Table 2).7 Elderly patients should be educated on prevention of falls, and this may include directing them to install a nightlight or handrails or to remove slippery rugs in the bedroom.12

During titration and dose adjustment, it is very important to maintain close contact with patients and to encourage them to call with any problems. This will prevent self-discontinuation or unnecessary side effects.

Use Lowest Effective Dose and Avoid Drug-Drug Interactions
Dosage should be individualized and flexible, with the goal of remission of anxiety symptoms and minimal side effects.5 Clinicians should use the lowest effective dose for the shortest possible duration.24 This is especially important in benzodiazepine-naïve patients, the elderly, or the medically ill. The elderly are more sensitive to drug effects because of decreased metabolism and clearance of benzodiazepines as a result of age-related physiologic changes.25 They are also more likely to suffer adverse effects because of a greater chance of polypharmacy as well as increased risks of cognitive impairments and medical conditions. In patients with liver failure, clinicians should choose an agent that only requires Phase II metabolism and that is, therefore, less affected by liver impairment. Concomitant use of other psychotropics and sedatives with similar pharmacologic effects should be avoided. Patients should be instructed to inform clinicians of concomitant drugs in order to avoid any drug-drug interactions. The dosage should be adjusted appropriately if benzodiazepines have to be combined with other medically necessary drugs.

Managing Central Nervous System Side Effects: Lowering Dosage/Switching/Discontinuation
If patients develop severe sedation or psychomotor impairment, dosages can be lowered to aim for minimal side effects while still maintaining efficacy. Another strategy is to shift most of the dosage to nighttime so that most side effects will wear off during sleep; however, this may decrease daytime coverage of anxiety symptoms. A third option is to switch to a different benzodiazepine. Switching is most helpful with residual daytime sedation when benzodiazepines are taken as a hypnotic.5 In anxiety treatment, switching from a long-acting to a short-acting agent may be more tolerable, but the trade off is less anxiety coverage and possible discontinuation symptoms between doses. If none of these strategies work, the last option would be discontinuation of the offending agent.

Management of Depression, Delirium, and Paradoxical Reactions
If patients develop depressive symptoms as a result of benzodiazepine treatment (and depression is clearly not pre-existing), lowering the dosage or discontinuing the drug is recommended. If symptoms do not resolve after discontinuation, treatment with an antidepressant should be considered.17

As noted above, delirium and paradoxical reactions are rare. When they occur, the benzodiazepine should be discontinued immediately. These reactions usually resolve within a few hours after the discontinuation of the offending agent. When immediate reversal of the adverse effect is necessary, such as in the midst of a surgical procedure, treatment with an antipsychotic (eg, halperidol) or flumazenil is an option.21

 

Dependence/Discontinuation/Withdrawal

Similar to the unsubstantiated fear of addiction to analgesic medications in patients with terminal illness,26 concerns of abuse and addiction have also been raised in chronic benzodiazepine treatment.27 Benzodiazepines are typically used in maintenance pharmacotherapy for patients with chronic anxiety, and long-term use may lead to a physiologic dependence as manifested by tolerance and withdrawal.

However, pharmacologic dependence is a natural physiologic adaptation and does not imply addiction or substance abuse or dependence.27 Addiction is characterized by the deliberate, inappropriate use of drugs for recreational purposes, and requires evidence of drug-seeking behavior or loss of control over use.28 In patients with an anxiety disorder, the risk of abuse and addiction to benzodiazepines is rare and there is little evidence of dose escalation over time.29,30 Most follow-up studies showed that, on average, >50% of patients actually require a lower benzodiazepine dosage in the long term.16 The risk of addiction may be limited to patients with a personal history of substance dependence (alcohol, opiates, and other sedative hypnotics).24,29,30

Discontinuation of a benzodiazepine after prolonged use may lead to one of three types of discontinuation symptoms; namely, relapse, rebound, and withdrawal.31 Relapse is the return of original symptoms at the same intensity as before treatment. Symptoms of relapse may include return of anxiety or insomnia. In one study, relapse occurred in 27% of patients receiving long half-life benzodiazepines and in 57% of patients receiving short half-life benzodiazepines.32 Rebound is the occurrence of original symptoms but at more severe intensity. Withdrawal is the occurrence of new symptoms as a result of medication discontinuation, and may occur in 60% to 100% of patients depending on the outcome criteria used, with a peak severity at 2 days for short half-life and 4–7 days for long half-life benzodiazepines.32 Common symptoms of withdrawal include anxiety, insomnia, restlessness, agitation, gastrointestinal distress, tremor, muscle tension, and sweating.31 These symptoms may be difficult to differentiate from relapse of anxiety since both can include anxiety and insomnia. However, the time course and specific symptoms of withdrawal may be helpful in differentiating the two.27 Relapse of anxiety will persist and worsen over time whereas symptoms of withdrawal are usually time-limited, depending on the dosage, duration of action, and length of use. Symptoms that are specific to withdrawal but not to relapse include sensitivity to light and sound, tinnitus, tremors, myoclonic jerks, perceptual changes, and seizures.

 

Managing Discontinuation and Withdrawal

Since most patients will develop physiologic dependence with prolonged use, it is important to minimize discontinuation symptoms. Patients must be educated about not missing doses or abruptly stopping the medication. If a dose is missed, they should take the missed dose as soon as they remember unless it is close to the time of the next scheduled dose.

Several patient variables affect the severity of withdrawal symptoms and tolerability of discontinuation, and effective strategies for a planned medication discontinuation must address these patient variables.29,33 Patients who tend to have difficulty tolerating medication tapers include those with panic disorder, pre-existing history of alcohol or substance use, and higher levels of anxiety and depression prior to taper. Thus, any residual anxiety or depressive symptoms should be aggressively treated prior to any taper attempts. In addition, patients with higher personality psychopathology such as dependency, neuroticism, and passivity traits are more sensitive to minor withdrawal symptoms and tend to drop out of taper early in the process.34 Given these known predictors, it is important to establish a good alliance and trusting relationship with patients to ensure that they are on board with the goals of discontinuation.29 This includes a thorough discussion of the risk and benefits of medication discontinuation and education of what to expect during the taper process. Clinicians also need to be available to patients between visits to provide reassurance.

Many known drug factors also affect the severity of withdrawal. Withdrawal is more severe with higher daily doses, short-acting benzodiazepines, longer duration of use, and abrupt discontinuation or rapid tapers.34 One strategy in minimizing symptoms is to switch patients from a short-acting to a long-acting benzodiazepine.27 A well-tolerated switching protocol is outlined in one study.35  For example, in a switch from alprazolam to clonazepam, the standing alprazolam dose is discontinued and clonazepam is started at a dose that is equal in potency to that of the baseline alprazolam dose. During the first 5–7 days of the switch (the length of time to achieve steady state for clonazepam), alprazolam can be taken as needed, up to the full dosage as before the switch, to cover residual anxiety. After 7 days, additional coverage should be obtained by taking additional clonazepam but not alprazolam. Once the switch is completed, then taper can begin.

The most effective discontinuation strategy is a very gradual taper schedule.29 A maximum of 25% of the daily benzodiazepine dose should be reduced per week.27 Others have recommended that taper not to exceed 10% per week.31 An even more conservative approach, particularly in those who are very anxious about discontinuation, is to taper the first 50% of benzodiazepine dosage in 2–4 weeks. Once the patient reaches 50% of the baseline dose, that dosage should be maintained for over several months before proceeding with further taper.29 Regardless of the taper schedule, patients should be monitored closely and rates should be adjusted as tolerated. Patients should know that they can temporarily increase their dose to the previous taper level if unacceptable symptoms emerge. Adjunctive agents, such as carbamazepine, valproate, clonidine, or propranolol, can facilitate the taper process by treating the withdrawal symptoms. However, these agents have not been shown to improve taper outcome or reduce the severity of withdrawal symptoms.29

There is also good evidence that cognitive-behavioral therapy (CBT) during or immediately after medication discontinuation decreases the chance of relapse of anxiety, particularly in patients with panic disorder.36,37 During medication taper, CBT helps patients to better cope with the withdrawal and anxiety symptoms related to the taper process as well as apprehension regarding stopping a medication that they believe is the reason for their treatment success.37 CBT gives patients confidence in dealing with the anxiety symptoms and enables them to attribute therapeutic gains to their own efforts.37

If all of the above strategies fail, the remaining options include continuing with the lowest possible dose of benzodiazepine27 or discontinuation in an inpatient unit where withdrawal is closely monitored and treated.38

 

Benzodiazepines and Pregnancy

Most benzodiazepines are rated with FDA pregnancy risk category D, which indicates positive evidence of human fetal risk, and benefit of benzodiazepine must be clearly outweighed by the risk. Several agents (ie, flurazepam, temazepam, triazolam, and quazepam) are placed in category X in which risk outweighs any possible benefit, and are thus contraindicated in women who are or may become pregnant.

A comprehensive review of studies in 1996 concluded that first-trimester exposure of benzodiazepines may be associated with a relative increased risk of oral cleft defect, but the absolute risk appears to be low.39 In infants exposed to alprazolam in utero, the risk was increased 12-fold, from baseline rate of 6 in 10,000 (0.06%) to 7 in 1,000 (0.7%). However, it is not clear if these rates differ among the benzodiazepines. Data from later studies are quite limited and report contradictory results. Several studies have found no increased risk of congenital malformations, including a case series of 38 women exposed to benzodiazepines40 and a population-based, case-controlled study that included 132 women exposed to benzodiazepines.41 Another small survey that included 43 infants exposed to clonazepam found one infant (3%) with congenital defect,42 but this is consistent with the rate of congenital malformation in the general population. In contrast, another study of 262 women exposed to benzodiazepines found a strong association between lorazepam and anal atresia, although risks of other types of congenital defects were not increased.43 These studies suggest that there are some risks of anal atresia and oral cleft defect in infants exposed to benzodiazepines during the first trimester.

In infants exposed to benzodiazepines either in the last trimester of pregnancy or at the time of parturition, there have also been reports of neonatal toxicity, including symptoms of muscular hypotonicity, failure to feed, impaired temperature regulation, apnea, and low Apgar scores.39

Given the limited safety data during pregnancy, women of child-bearing age should be educated about the risks of congenital defects and neonatal toxicity with benzodiazepine treatment, and advised to use contraception during the course of treatment. If at all possible, female patients who wish to conceive should consider CBT treatment before resorting to medication treatment. If they are already on a benzodiazepine, they should be advised to taper benzodiazepines in conjunction with CBT.39 If tapering is unsuccessful, it may be necessary to reinstitute the benzodiazepine or switch to another agent with efficacy for anxiety but lower risk for congenital defects, such as fluoxetine.39

Non-Benzodiazepine Anxiolytics

Buspirone

Buspirone is a non-benzodiazepine anxiolytic approved for the treatment of anxiety, with efficacy primarily limited to generalized anxiety disorder (GAD).44 Unlike benzodiazepines, buspirone has a delayed onset of action of up to 4 weeks.44,45 Its mechanism of action is complex, but is believed to be linked to its full agonist activity at the serotonin (5-HT)1A pre-synaptic receptors and partial agonist activity at the post-synaptic 5-HT1A receptors.46

Buspirone is considered one of the safest psychotropics available, and has a very benign side-effect profile.47 One of the major advantages over benzodiazepines is its lack of dependence/withdrawal symptoms or drug-abuse potential.44,45 It also has a lower incidence of sedation and drowsiness.48-51 The most commonly reported side effects include dizziness, headache, nervousness, light-headedness, diarrhea, nausea, paresthesia, excitement,49 and insomnia.52 Since most of these studies used a relatively low dose of buspirone (average=20 mg) and relied on spontaneous self-report of side effects, one would expect a higher incidence of adverse effects in clinical practice, particularly at higher doses. Indeed, side effects are more frequent at higher starting doses,47 so initiating treatment gradually can minimize side effects. For example, treatment can be started at 5 mg three times a day, and increased by 5 mg every few days as tolerated to a maximum dose of 60 mg/day. If side effects develop and do not resolve spontaneously, lowering the dose can help. Buspirone is usually taken in divided doses of two to three times a day because of its short elimination half-life (2–11 hours).53

In addition to a benign side-effect profile, buspirone also lacks significant drug-drug interactions. Buspirone is eliminated primarily by oxidative metabolism,53 but does not affect CYP enzyme activity.45 Although it is highly protein bound (95%), it does not displace other drugs (ie, dilantin, propranolol, phenytoin, and warfarin) from protein-binding sites.53 Buspirone is also well-tolerated in the elderly, without a need for dose adjustment.52,54 However, clearance is reduced in patients with hepatic cirrhosis and renal impairment,54 so dosage should be adjusted in these cases.

 

Propranolol

Propranolol is not FDA-approved for anxiety, but it is commonly used off-label for the as-needed treatment of performance anxiety. Advantages of propranolol over benzodiazepines include propranolol’s lack of abuse potential and minimal CNS effects on alertness and psychomotor performance. Several studies suggest that a one-time dose of propranolol 30–60 minutes prior to a performance reduces anxiety.55 Propranolol is a β-blocker, and its anxiolytic effect is attributed to its ability to block the autonomic arousal experienced during stress and anxiety.55 Peak blood levels occur approximately 1 hour after an acute dose. Studies of performance anxiety that have shown efficacy have used dosages from 40–80 mg, but the Physician’s Desk Reference suggests a dose of 10 mg of immediate-release form 1 hour prior to the event.4

β-adrenergic receptors mediate heart rate and bronchial smooth muscle function. Thus, dangerous side effects can include hypotension, bradycardia, and increased airway resistance.56 Propranolol should not be given to people with bradycardia, heart block, or heart failure, or to those with respiratory problems such as bronchial asthma, chronic obstructive pulmonary disease, or bronchospasm.55 In addition, β-blockers can cause hypoglycemia,56 so it must be monitored carefully in patients with diabetes.

Overall, propranolol is well tolerated. The most commonly experienced side effects include lightheadedness, dizziness, fatigue, and insomnia.55,56 gastrointestinal effects such as nausea and diarrhea are also common. Less common is dose-related sexual dysfunction.56 Side effects can be minimized by giving the dose early in the day and reducing the dose when side effects appear.55 It may also be helpful to give a test dose days prior so patients know how the medication may affect them during the actual performance. However, most patients do not experience any side effects, particularly when propranolol is used on an as-needed basis.

 

Hydroxyzine

Hydroxyzine is an antihistamine that has FDA approval for the treatment of anxiety. Several placebo-controlled clinical trials reported that hydroxyzine at dosages between 25 and 50 mg/day decreased anxiety symptoms in patients with GAD,57-59 but the overall anxiolytic effect was modest at best. For example, only approximately 40% of the patients responded to treatment in two of the studies.57,58 The most frequently reported side effect is sedation, which occurs in approximately 33% of patients, but this effect is generally transient.57,59 Other reported side effects include colitis, depression, agitation,59 weight gain, dry mouth, loss of concentration, and insomnia.58

Although hydroxyzine has fewer cholinergic effects than the other classic antihistamines, precaution should be taken when administering to the elderly, who are more prone to anticholinergic side effects such as impaired cognitive function, confusion, blurred vision, and urinary retention.60 Clearance of the drug is also significantly impaired in the elderly60 and in patients with hepatic dysfunction.61 Hydroxyzine is metabolized by the liver to an active metabolite, cetirizine, which is subsequently excreted by the kidney in unchanged forms.61 The drug can be taken once or twice a day as the elimination half-life is approximately 20 hours for the parent compound and 11.4 hours for the active metabolite.60

 

Gabapentin

Gabapentin is an anticonvulsant that is used off label for the treatment of social anxiety disorder. It was shown to reduce social anxiety symptoms in one placebo-controlled trial, but only 33% of gabapentin-treated patients (versus 19% of placebo) were considered responders after 14 weeks.62 Gabapentin is a structural analog of GABA that inhibits neurotransmission by binding to the α2δ subunit of voltage-sensitive calcium channels.63 Gabapentin is essentially free of drug-drug interactions. It is not protein bound or metabolized by the liver, and has no effects on hepatic enzyme activity. It is predominantly excreted unchanged by the kidney, so dose adjustment is recommended in patients with renal impairment. It is generally well tolerated, and the most common side effects in order of decreasing frequency are somnolence, dizziness, ataxia, fatigue, nystagmus, tremor, and diplopia.64 The recommended dose range is between 900 and 3,600 mg/day, given in three divided doses because of its short elimination half-life (5–7 hours). Side effects are dose-dependent and usually dissipate after the first few weeks. Slow titration can help minimize side effects. For example, clinicians should start 300 mg QD for day 1, 300 mg BID for day 2, and 300 mg TID for day 3. The dose should be adjusted based on clinical response, but it is not necessary to monitor plasma levels. Discontinuation of gabapentin should also be done gradually over a 1-week period to avoid seizures.

 

Conclusion

Benzodiazepines are very good anxiolytics for the treatment of anxiety, but care must be taken to avoid adverse effects. The most common side effects of benzodiazepine are CNS effects such as sedation, problems with attention and memory, and psychomotor impairments (Table 3).4 Adverse effects can be minimized when benzodiazepines are used at the lowest effective dose for the shortest period of time, particularly in the elderly and patients with liver dysfunction. Patients should be evaluated appropriately and educated about side-effect potentials, including the common side effects, drug-drug interactions, and pregnancy risks such as oral cleft palate and anal atresia in infants exposed to benzodiazepines. Most side effects are transient when tolerance develops. If side effects are not tolerable, lowering the dosage, switching agents, discontinuation of the medication, or considering alternative forms of treatment such as CBT may be helpful. Physiologic dependence and withdrawal symptoms are very common during abrupt discontinuation of benzodiazepines after prolonged use. Patients should be educated about the importance of not missing doses. If a planned discontinuation is expected, taper should be conducted very gradually and patients should be monitored closely for withdrawal symptoms. In addition, there is very low abuse potential in patients with anxiety disorders, but benzodiazepines should be avoided in patients with alcohol or active substance abuse.

 

 

Other non-benzodiazepine agents have mild anxiolytic effects with limited indications. The established efficacy of buspirone and hydroxyzine is limited to patients with GAD, propranolol to patients with performance anxiety, and gabapentin to patients with social anxiety disorder. However, these agents are fairly benign with tolerable side effects (Table 3).4 Side effects of buspirone and gabapentin can be minimized by a slow dose titration. Hydroxyzine should be administered carefully in the elderly and patients with liver impairment. Propranolol should be avoided in patients with cardiac or obstructive lung disease and monitored carefully in patients with diabetes. PP

 

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