Benzodiazepine Use and Discontinuation in Patients with Psychiatric Disorders

Transcription

1 M ATERIA EDICA Volume 1, Issue 11 April 2013 Benzodiazepine Use and Discontinuation in Patients with Psychiatric Disorders Alex Bolser, PharmD Candidate and older age. This article examines the role of BZDs for the treatment of anxiety disorders, discusses some of the dangers associated with use, and reviews methods of discontinuing BZDs in patients who have been taking BZDs for an extended period of time. GENERALIZED ANXIETY DISORDER B enzodiazepines (BZDs) have been used since the early 1960s and are still the most common class of drugs prescribed for anxiety. 1 BZDs exhibit their anxiolytic effect by binding to A- type GABA receptors, thereby increasing the affinity of GABA for its own binding site. GABA is an inhibitory neurotransmitter and one of the most abundant within the central nervous system. The American Psychiatric Association (APA) and the World Federation of Societies of Biological Psychiatry (WFSBP) recommend antidepressants such as selective serotonin reuptake inhibits (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) as first line therapy, ahead of BZDs, for the treatment of most anxiety disorders. 2,3 Despite these recommendations, BZDs continue to be used to treat anxiety, in part because these agents are generally considered safe and effective with a rapid onset of action. However, unlike the SSRIs and SNRIs, BZDs do not have antidepressant effects and many patients with anxiety disorders also suffer from concomitant depression. 4 Furthermore, BZDs have a high abuse potential and can cause sedation, cognitive and coordination problems, memory and psychomotor impairment (particularly in the elderly), as well as physiological dependence. 4 The risk of adverse effects increases with duration of use INSIDE THIS ISSUE: BENZODIAZEPINE USE AND DISCONTINUATION IN PATIENTS WITH PSYCHIATRIC DISORDERS INSOMNIA MANAGEMENT WITH NON- BENZODIAZEPINE SEDATIVE HYPNOTICS IN THE PRIMARY CARE SETTING Scheduled BZDs, along with pregabalin, tricyclic antidepressants, and buspirone are recommended as second-line agents for long-term treatment of generalized anxiety disorder (GAD) per current WFSBP guidelines. 3 However, evidence supporting the use of BZDs for long term treatment of GAD are lacking and the risk of adverse effects may outweigh the benefits in many cases. BZDs should be avoided in patients with GAD characterized by substantial hostility, impatience, irritability and impulsivity because BZDs can worsen these symptoms. 8 BZDs can also be used short term while initiating an antidepressant to avoid increased anxiety that can occur on starting serotonergic antidepressants and to provide relief of anxiety symptoms while waiting for the antidepressant s onset of efficacy. 8 When an antidepressant is initiated, a BZD may be considered for two to four weeks, and possibly longer, if needed, given the onset of efficacy of serotonergic agents in the setting of GAD is typically 4-6 weeks. 8 When the BZD bridge therapy is no longer needed, a gradual taper should be started with decreasing doses over the course of a couple weeks to avoid withdrawal and break-through anxiety symptoms. Of the BZDs, only alprazolam, diazepam and lorazepam are supported by evidence from randomized controlled trials for use in GAD. 5-7 However, in the setting of GAD, BZDs with longer durations of action such as clonazepam and diazepam may be preferred as they carry a lower risk of inter-dose rebound anxiety and help to curb abuse potential because of their long half-lives. BZDs with longer half-lives prevent the fluctuating blood concentrations that can lead to a high. BZD pharmacokinetic and pharmacodynamic 1

2 characteristics are summarized in Table 1. Example dosing regimens include clonazepam mg once to twice daily, titrated up to 1 mg two to three times daily based on response, and diazepam mg once or twice daily, titrated up to 10 mg two to three times daily based on response. BZDs should be prescribed on a scheduled basis for GAD to prevent the symptoms of GAD and to avoid fluctuating blood concentrations. SOCIAL ANXIETY DISORDER As in GAD, BZDs are recommended as secondline options for chronic treatment of generalized social anxiety disorder (SAD). 3 However, whether adding a BZD on to an antidepressant contributes additional benefit is not known, and the addition of a BZD to an antidepressant for chronic management is not currently recommended. 3 In contrast, BZDs can be used in the setting of SAD as a bridge when initiating an antidepressant, which may take 8-12 weeks to reduce SAD symptoms. 3 Generally, using a BZD bridge is only recommended if the patient will not be able to manage their symptoms while waiting for the antidepressant to take effect. When using BZDs for generalized SAD, BZDs with longer half-lives are preferred. For non-generalized SAD, in which anxiety is limited to social performance, beta-blockers and BZDs are recommended as first-line agents. 9 For patients who experience tachycardia or tremor, beta-blockers are preferred; a typical regimen in this patient population is propranolol mg taken minutes prior to performance. BZDs should be reserved for patients with severe performance anxiety and used, as needed, minutes prior to performance. 9 Typically, a BZD with a fast or intermediate onset is chosen, such as lorazepam or diazepam, and depending on the performance length, an agent with a long or short half-life may be preferred. OBSESSIVE COMPULSIVE DISORDER BZD use in obsessive compulsive disorder (OCD) is poorly supported by the available literature and is not currently recommended. Double-blind studies comparing BZDs to placebo have demonstrated that BZDs, whether as monotherapy or adjunctive therapy to SSRIs, are not beneficial for patients with OCD. 10,11 POST-TRAUMATIC STRESS DISORDER Currently, data do not support the use of BZDs in the treatment of post-traumatic stress disorder (PTSD) and they are not recommended for use in PTSD. 3 However, these agents are commonly prescribed to treat symptoms of anxiety and hyperarousal in patients with PTSD. 12 Prescribing BZDs for PTSD can be potentially problematic given the high prevalence of substance abuse within the PTSD population and because BZDs should be avoided in patients with a history of substance abuse. Based on the available evidence, BZDs do not currently have a role in the treatment of PTSD outside of severe symptoms in an emergent situation. SPECIFIC PHOBIAS Limited published data support the use of BZDs for the treatment of specific phobias as first-line pharmacotherapy after cognitive behavior therapy (CBT) has failed. 13 After attempting CBT, pharmacotherapy targeting the anticipated event or encounter with a BZD is recommended as first-line therapy. For example, a BZD can be considered if the specific phobia is infrequently encountered and unavoidable, such as flying. 13 BZDs such as lorazepam or alprazolam are preferred because of their intermediate onset and intermediate duration of action. Patients should be instructed to take the BZD 30 minutes prior to the encounter. To minimize the risk of abuse, a small quantity for infrequent use is advised. In cases where a BZD has failed or repeated exposure to the phobic stimulus is anticipated over a prolonged time period, chronic SSRI or SNRI therapy may be considered. PANIC DISORDER Of all the anxiety subtypes, panic disorder (PD) has the most data supporting the use of BZDs for shortterm management. BZDs have been shown to improve the three main components of panic disorder, including reducing attack frequency, anticipatory anxiety, and phobic avoidance. Alprazolam and clonazepam have FDA-labeled indications for the treatment of acute episodes of PD (panic attacks). When treating panic attacks, BZDs with short to intermediate onset and intermediate duration are preferred, because they provide fast relief and generally last for the duration of the attack. BZDs are considered second-line options for the chronic treatment of PD after failing an SSRI or SNRI. 2,3 However, it is reasonable to consider a BZD bridge while waiting for the onset of the antidepressant, which may take 6-12 weeks. When used as a 2

3 Table 1 Pharmacokinetic and pharmacodynamic properties of benzodiazepines. Peak (hr) Active Metabolite Extensive Hepatic Metabolism CYP450 Interactions Anxiolytic Sedative/ Hypnotic Anti- Convulsant PO Dose Range (mg/d) b Drug Onset Duration (hr) Lorazepam Intermed Intermed No No No Alprazolam Intermed Intermed No Yes 3A4, 1A Oxazepam Short Intermed No No No Clonazepam Short Long No Yes 3A Diazepam Long Long Yes a Yes 3A4, 2C9/ Clorazepate Long Long 1-2 n/a c Yes a Yes No Estazolam Long Intermed No Yes 3A Halazepam Intermed Intermed Yes a Yes No Chlordiazepoxide Intermed Long Yes a Yes No Midazolam Short Intermed No Yes 3A n/a (IV) Temazepam Short Intermed No No No Triazolam Intermed Short No Yes 3A Flurazepam Long Long Yes a Yes 2C, 2D Quazepam Long Long Yes a Yes 2D These data should be used as a guide; data may vary between references. bridge, a long-acting BZD such as clonazepam or diazepam is recommended. The APA treatment guidelines for panic disorder recommend against using BZDs on an as needed basis outside of the setting of panic attacks, and instead using them scheduled to prevent panic attacks. 2 A recent randomized trial showed that augmenting with a BZD is as effective as augmenting with CBT in non-remitting PD after 12 weeks of therapy with an SSRI, suggesting that both BZDs and CBT are potential second-line options. 14 t1/2 a Active metabolite t 1/2 may be 40 hrs; many are >100 hours. b Lower doses for elderly and certain populations. c Clorazepate is a prodrug. CAUTIONS WITH BENZODIAZEPINE USE BZDs have a very low risk of toxicity when used alone and are often well-tolerated due to their relatively low side effect profile. However, these agents are associated with some serious adverse effects. Specifically, short-term BZD use is associated with dizziness, poor concentration, somnolence, ataxia and fatigue. 15 In addition, major drug interactions (e.g., with opioids, alcohol) can cause severe toxicity such as respiratory depression. 16 Furthermore, psychomotor slowing (e.g., poor concentration, lack of motor coordination, and mental confusion) can be experienced when initiating or increasing the dose of a BZD. 17 Studies have shown the psychomotor deficits can lead to increased rates of motor vehicle accidents in patients taking these agents, especially with use of longer-acting BZDs, when used in the elderly, and within the first few weeks of therapy. 18 Impaired memory, learning and other cognitive effects show persistent impairment during long term use and may persist after discontinuation. 4 Paradoxical excitement is another adverse effect of BZDs that is characterized by increased excitement, aggression, irritability, hostility and impulsivity. These disinhibitory effects can lead to criminal acts or other negative outcomes. High-risk patients for paradoxical excitement include those with borderline personality disorder, impulse control disorders and those with a history of alcohol abuse. 4 Another concern is the use of BZDs during pregnancy, as they cross the placenta. BZDs are considered category D because they have been associated with preterm deliveries and low birth weights in infants of women taking BZDs during pregnancy. If BZDs cannot be entirely avoided during pregnancy, they should at least be avoided during the first trimester and the lowest dose should be used for the shortest duration possible. 19 If used during pregnancy, the neonate must also be monitored carefully for life threatening withdrawal. Caution should also be exercised during lactation as there is evidence of diazepam causing lethargy, sedation and weight loss in infants. 19 3

4 Tolerance, dependence and withdrawal are important considerations with long-term BZD use. Fortunately, although tolerance develops to many of the BZD effects, it does not appear to develop with their anxiolytic properties. 20 As doses are escalated, patients experience proportional improvements in anxiety, but no proportional increases in hypnotic and other potential adverse effects. Approximately 15-30% of patients taking BZDs for 4-6 weeks will become dependent; 4 this percentage may be higher as the dose and duration of BZD use increases. By definition, persons who are dependent on BZDs, will experience withdrawal symptoms upon rapid discontinuation. Rebound anxiety is the mildest form of withdrawal and consists of a temporary increase in anxiety above baseline following discontinuation of BZDs. 21 Withdrawal symptoms (Box) generally subside in 2-4 weeks, but can be prolonged and life-threatening. Importantly, BZD withdrawal symptoms do not always occur immediately after discontinuation and some patients may not exhibit any significant withdrawal symptoms. 22 BZD abuse can occur as well and is characterized by failure to fulfill major obligations, continued use despite causing harm, use resulting in recurrent legal problems. 24 BZDs with a more rapid onset of action, such as diazepam, alprazolam and lorazepam, are more likely to be abused due to their rapid penetration into the blood brain barrier. 23 Further, BZDs with shorter half-lives have greater abuse potential because they allow for more frequent fluctuations in serum concentrations. Although the risk of BZD abuse in the general population is very low (~ <1%), BZD abusers can concurrently abuse other substances, such as opioids and alcohol. 24 Moreover, BZDs are frequently taken with alcohol because the combination results in increased feelings of intoxication. 4 For patients with a history of substance abuse, the decision to prescribe a BZD should be made on a case-by-case basis, including the patient in this decision as appropriate. For some patients with a history of substance abuse, BZD treatment for a given indication may prevent self treatment with alcohol or other substances. ELDERLY Estimates vary, but up to 32% of elderly individuals may be prescribed BZDs every year, 25 and these patients are reported to be at an increased risk for the development of adverse effects such as cognitive or psychomotor impairment, falls and fractures, motor vehicle accidents, and incident loss of physical function. 26 Long-term BZD use in elderly men may also associated with an increased risk of incident dementia. 27 These increased risks associated with BZD use are likely due to alterations in pharmacokinetics and pharmacodynamics in the elderly. 15 Lower doses are advised in elderly patients in part because they have decreased renal and hepatic function resulting in accumulation, as well as their increased risk of adverse effects. Often times, adverse effects of BZDs such as sedation, unsteadiness, confusion, memory loss and disinhibition can be difficult to separate from symptoms related to the natural aging process. These symptoms can come on gradually and overlap with age related changes, making it difficult to realize the patient is experiencing an adverse drug event. Consequently, BZDs should be prescribed with caution and in small doses for short periods of time in elderly patients. Intermediate acting BZDs, such as oxazepam, lorazepam and alprazolam are usually recommended because these agents do not accumulate in the blood, are rapidly cleared and offer greater dosage flexibility. 15 Discontinuation of BZDs in the elderly is usually beneficial and followed by improved psychomotor and cognitive functioning. 28 Box Withdrawal symptoms of benzodiazepines. 22 Common Anxiety Impaired concentration Nightmares Perspiration Muscle cramps Aches and pains Blurred vision Weight loss Tachycardia Flu-like symptoms Metallic taste Agitation Insomnia Impaired memory Headache Fatigue Nausea and vomiting Dizziness Severe Delirium tremens Convulsions, status epilepticus Catatonia Severe depression Suicidal ideation Homicidal thoughts Delusions Psychosis Confusion 4

5 TITRATING OFF BENZODIAZEPINES Most guidelines recommend switching the patient from their BZD to diazepam prior to beginning the withdrawal process because diazepam can be administered less frequently, it is available in multiple tablet strengths and in liquid form which can be ideal for titration schedules. Equipotent doses of common BZDs are summarized in Table 2. The rate of down titration is often determined by the patient s ability to tolerate symptoms. For most patients, tapers can be completed in 8-12 weeks; if they have failed a taper in the past a longer taper of closer to 6 months or longer may be required. 28 Generally, initial reductions can be quicker than reductions towards the end of the taper. 22 It is reasonable to aim for a 25% reduction in the first two weeks and 12.5% the following 4-6 weeks (Table 3). The exact taper rate is patient specific and should be adjusted based on each individual patient s symptoms. CONCLUSION Significant evidence supports the use of BZDs in GAD, SAD, PD and specific phobias. However, currently little evidence supports the use of BZDs in PTSD and OCD. In GAD, SAD and PD, BZDs can be considered first-line for bridging and second-line for treatment resistant cases. BZDs and beta-blockers, used on an as needed basis, are considered first line in non-generalized SAD, in which anxiety is limited to social performance, and can be used minutes prior to the performance. For specific phobias, after failing CBT, BZDs can be used as needed 30 minutes prior to the encounter. BZDs are not recommended in Table 2 Benzodiazepine equivalent doses. Drug Dose Alprazolam 1 mg Chlordiazepoxide 15 mg Diazepam 5 mg Lorazepam 0.5 mg Nitrazepam 5 mg Oxazepam 15 mg Temazepam 10 mg PTSD and OCD. Even though BZDs are used as long -term treatment in many patients with anxiety disorders, there is little evidence to support this practice. There are two patient populations in which BZDs should be used with extreme caution: the elderly and patients with a history of substance abuse. The elderly are more likely to experience adverse effects such as cognitive impairment and falls, and possibly even dementia. In patients with a history of substance abuse, BZDs should be reserved as a last-line option. The choice of BZD should be tailored according to the patient s concomitant diseases and medications, as well as the duration of anxiety (acute vs. chronic). When BZDs are being discontinued a slow taper should be used to avoid serious withdrawal symptoms such as delirium tremens, seizures and possible psychosis. REFERENCES 1. Paulose-Ram R, Jonas BS, Orwig D, Safran MA. Pre- Table 3 Example benzodiazepine tapering schedules. Normal Titration Schedule (8 weeks) Extended titration schedule (24 weeks) Week Dose Week Dose 0 (starting dose) 20 mg three times daily 0 (starting dose) 15 mg once daily 1 15 mg three times daily 1 11 mg once daily 2 10 mg three times daily mg once daily mg three times daily 4 6 mg once daily 4 5 mg three times daily mg once daily 5 3 mg three times daily mg once daily 6 2 mg three times daily mg once daily 7 1 mg three times daily 12 2 mg once daily 8 1 mg once or twice daily mg once daily 9 D/C if tolerated 16 1 mg once daily mg once daily mg once daily mg once daily 24 D/C if tolerated 5

6 scription psychotropic medication use among the U.S. adult population: results from the third National Health and Nutrition Examination Survey, J Clin Epidemiol 2004;57: American Psychiatric Association (APA). Practice guideline for the treatment of patients with panic disorder. 2nd ed. Washington (DC): American Psychiatric Association (APA); 2009 Jan. 90 p. 3. Bandelow B, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders first revision. World J Biol Psychiatry 2008;9: Dell'osso B, Lader M. Do benzodiazepines still deserve a major role in the treatment of psychiatric disorders? A critical reappraisal. Eur Psychiatry 2012;28: Rickels K, Downing R, Schweizer E, Hassman H. Antidepressants for the treatment of generalized anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam. Arch Gen Psychiatry 1993;50: Ansseau M, Olie JP, von Frenckell R, et al. Controlled comparison of the efficacy and safety of four doses of suriclone, diazepam, and placebo in generalized anxiety disorder. Psychopharmacology 1991;104: Elie R, Lamontagne Y. Alprazolam and diazepam in the treatment of generalized anxiety. J Clin Psychopharmacol 1984;4: Davidson JR, et al. A psychopharmacological treatment algorithm for generalised anxiety disorder. J Psychopharmacol 2010;24: Schneier FR. Clinical practice. Social anxiety disorder. N Engl J Med 2006;355: Crockett BA, Churchill E, Davidson JR. A double-blind combination study of clonazepam with sertraline in obsessive-compulsive disorder. Ann Clin Psychiatry 2004;16: Hollander E, Kaplan A, Stahl SM. A double-blind, placebo-controlled trial of clonazepam in obsessivecompulsive disorder. World J Biol Psychiatry 2003;4: Mohamed S, Rosenheck RA. Pharmacotherapy of PTSD in the U.S. Department of Veterans Affairs: diagnostic- and symptom-guided drug selection. J Clin Psychiatry 2008;69: Barlow DH, Allen LB, Basden SL. Psychological treatments for panic disorders, phobias, and generalized anxiety disorder. In: A Guide to Treatments That Work, 3rd ed., Nathan PE, Gorman JM. (Eds), Oxford University Press, New York p Simon NM, et al. Next-step strategies for panic disorder refractory to initial pharmacotherapy: A 3-phase randomized clinical trial. J Clin Psychiatry 2009;70: Madhusoodanan S, Bogunovic OJ. Safety of benzodiazepines in the geriatric population. Expert Opin Drug Saf 2004;3: Lader M. Benzodiazepines revisited will we ever learn? Addiction 2011;106: Lader M. Long-term benzodiazepine use and psychological functioning. In: Freeman HL, Rue Y, eds. The benzodiazepines in current clinical practice. International congress and symposium series: Proceedings of a symposium sponsored by Wyeth Laboratories. London: Royal Society of Medicine Services, 1987: Luijendijk HJ, Tiemeler H, Hofman A, et al. Determinants of chronic benzodiazepine use in the elderly: A longitudinal study. Br J Clin Pharmacol 2008;65: Ashton H. Guidelines for the rational use of benzodiazepines: When and what to use. Drugs 1994;48: Schwiezer E, Rickels K, Weiss S, Zavodnick S. Maintenance drug treatment of panic disorder: I. Results of a prospective, placebo-controlled comparison of alprazolam and imipramine. Arch Gen Psychiatry 1993;50: Rickels K, Schweizer E, Weiss S, Zavodnick S. Maintenance drug treatment for panic disorder, II. Short- and long-term outcome after drug taper. Arch Gen Psychiatry 1993;50: Department of Health UK, the devolved administrations. Drug misuse and dependence: UK guidelines on clinical management. London: Department of Health; Griffiths RR, Weerts EM. Benzodiazepine selfadministration in humans and laboratory animalsimplications for problems of long-term use and abuse. Psychopharmacology 1997;134: Posternak MA, Mueller TI. Assessing the risks and benefits of benzodiazepines for anxiety disorders in patients with a history of substance abuse or dependence. Am J Addict 2001;10: Llorente M, et al. Defining patterns of benzodiazepine use in older adults. J Geriatr Psychiatry Neurol 2000;13: Assem-Hilger E, et al. Benzodiazepine use in the elderly: an indicator for inappropriately treated geriatric depression? Int J Geriatr Psychiatry 2009;24: Gallacher J, et al. Benzodiazepine use and risk of dementia: evidence from the Caerphilly Prospective. J Epidemiol Community Health 2012;66: Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs 2009;23:

7 Insomnia Management with Non- Benzodiazepine Sedative Hypnotics in the Primary Care Setting Stephanie Kling, PharmD Candidate A ccording to the National Center for Sleep Disorders Research at the National Institutes of Health, about 30-40% of adults report having symptoms of insomnia within a given year, and 10-15% of adults say they suffer from chronic insomnia. 1 Insomnia is the leading cause of sleep disturbance in primary care practice. 2 Furthermore, insomnia is associated with increased incidence of motor vehicle accidents, and a reduction in overall quality of life and cognitive functioning of the patient. 3-5 The America Insomnia Survey, a national survey of patients enrolled in a large US national health plan assessed the effects of insomnia on work performance of over 7,400 health plan subscribers. The survey found that insomnia significantly decreased work performance and if the decreased productivity found in the study is generalized to the total US workforce, the cost is estimated at $63.2 billion annually. 6 Management of all patients with insomnia should include identifying the cause of insomnia, education on sleep hygiene, and stress management. 7 Pharmacologic treatment is recommended in conjunction with nonpharmacologic management when insomnia has a significant impact on sleep, health, and daytime function. 8 The National Sleep Foundation estimates that one of every four adult Americans takes sleep medication at some point during the year. 8 Non-benzodiazepine sedative hypnotics, antihistamines, benzodiazepines, and trazodone are used to treat insomnia because of their sedating properties. Of these, the most commonly used agents are the non-benzodiazepine sedative hypnotics, including zolpidem (Ambien ), eszopiclone (Lunesta ), and Zaleplon (Sonata ). 7 In fact, about 39 million prescriptions for zolpidem products were dispensed in 2011 alone. 9 The objectives of this article are to discuss the pharmacology, pharmacokinetics, role in therapy, dosing recommendations, and safety of the nonbenzodiazepine sedative hypnotics. This article will also discuss the comparative effectiveness of nonbenzodiazepine sedative hypnotics and highlight recently updated FDA dosing recommendations for zolpidem. PHARMACOLOGY To better understand the pharmacology of nonbenzodiazepine sedative hypnotics, it is important to understand the pharmacology of benzodiazepines, as they are the prototypical class of hypnotics. 8 Benzodiazepines modulate GABA A receptors, which are gated ion channels that mediate the effects of GABA (the major inhibitory neurotransmitter in the brain). Benzodiazepines bind to the benzodiazepine receptor on GABA A so that the inhibitory action of GABA is allosterically enhanced (Figure 1). 8 In contrast to traditional benzodiazepines, the nonbenzodiazepine sedative hypnotics selectively bind to the α-1 subunit of the GABA A receptor. This increased selectivity results in more targeted hypnotic action compared with traditional benzodiazepines. 8 Nonbenzodiazepine sedative hypnotics have similar hypnotic action as traditional benzodiazepines and an improved safety profile due to fewer anxiolytic and myorelaxant properties. 8 PHARMACOKINETICS The choice of a specific non-benzodiazepine sedative hypnotic is based, in part, on its pharmacokinetic profile. In particular, the decision is based on the onset and duration of action of the agent. T max is a useful indicator of onset of action, whereas the duration of action is affected by the elimination half-life and rate of metabolism. Half-life is the parameter most predictive of the agent s ability to improve sleep maintenance. 8 Zolpidem is available in five dosage forms: immediate-release (IR) oral tablets, controlled-release (CR) oral tablets, an oromucosal spray (Zolpimist ), and Figure 1 The non-benzodiazepine sedative hypnotics selectively bind to the α-1 subunit of the GABA A receptor. 10 7

8 Table 1 Pharmacokinetic parameters of the non-benzodiazepine sedative hypnotics. 7,12-20 Drug Product T max (hrs) Half-life (hrs) Metabolism Elimination Zolpidem IR Zolpidem CR Zolpimist to 3 Edluar to 2.85 Intermezzo 0.5 to Zaleplon 1 1 Eszopiclone 1 to to 6 Zolpimist = zolpidem oromucosal spray. Edluar = zolpidem sublingual tablet. Intermezzo = zolpidem sublingual tablet. In the liver, principally by CYP3A4 (and to a lesser extent by CYP 1A2 and 2D6) In the liver, principally by aldehyde oxidase (and to a lesser extent by CYP 3A4) In the liver, principally by CYP3A4 and 2E1 Excreted principally in urine as inactive metabolites Excreted principally in urine as inactive metabolites Excreted principally in urine as inactive metabolites sublingual tablets (Edluar and Intermezzo ). The pharmacokinetic properties of zolpidem CR are similar to zolpidem IR. 11 Controlled-release zolpidem was developed as a two-layered biphasic release tablet to maintain effective plasma concentrations during the 3- to 6-hour post-dosage interval. 11 Zolpidem oromucosal spray and sublingual tablets are bioequivalent to zolpidem IR oral tablets with respect to C max and AUC, and are rapidly absorbed The pharmacokinetic parameters of the five zolpidem products, zaleplon, and eszopiclone are described in Table 1. ROLE IN THERAPY The predominant driver(s) of insomnia that is, failure to achieve sleep onset or inadequate sleep maintenance should be considered when selecting a specific non-benzodiazepine sedative hypnotic agent (Box). A short acting sedative hypnotic is preferred for patients who have difficulty achieving sleep onset. A sedative hypnotic with a long half-life is preferable for patients who have difficulty maintaining sleep. In cases in which a patient has both difficulty in achieving sleep onset and an adequate duration of uninterrupted sleep, an agent with a reasonably short T max and longer halflife should be considered. Eszopiclone has a quick onset of action and long half-life, and is effective at reducing time to sleep onset and maintenance of sleep. 17 Eszopiclone is the only non-benzodiazepine sedative hypnotic that is FDA approved for long-term use (6 months). 17 Clinical trials have shown no evidence of tolerance when taking eszopiclone nightly for up to 12 months. 21,22 Zaleplon may be best-suited for inducing sleep onset due to the rapid onset of action and short duration of action. 23 This agent can also be used as a sleep aid for middle-of-the-night awakenings. 24 Zaleplon has not been shown to increase total sleep time. 23 Zolpidem IR is used primarily to induce sleep. Due to the controlled release of zolpidem CR, it may be preferential for patients with both sleep onset and maintenance difficulty. 15 Zolpimist and Edluar are indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. 12,13 Intermezzo is indicated for use as needed for the treatment of insomnia when a middle-of-the-night awakening is followed by difficulty returning to sleep. 14 However, Intermezzo is not indicated for the treatment of middle-of-the night awakening when the patient has fewer than 4 hours of bedtime remaining before the planned time of waking. 14 COMPARATIVE EFFECTIVENESS Compared with placebo, non-benzodiazepine sedative hypnotics produce improvements in subjective and polysomnographic sleep latency. However, few clinical trials have been performed to evaluate the comparative effectiveness of the non-benzodiazepine sedative hypnotics. Specific clinical trials are outlined in Table 2. Of the clinical trials that have compared zolpidem with zaleplon, results have been inconclusive. Box Role in therapy of the non-benzodiazepine sedative hypnotic agents. Sleep Induction Sleep Maintenance Sleep Induction and Maintenance Eszopiclone Eszopiclone Eszopiclone Zaleplon Zolpidem CR Zolpidem CR Zolpidem CR Zolpidem IR Zolpimist Edluar Intermezzo 8

9 Table 2 Comparative effectiveness trials comparing zolpidem with zaleplon or escopiclone Study Methods Primary Objective Interventions Outcome Conclusion Ancoli-Israel et al. 25 (1999) Allain et al. 26 (2003) Huang et al. 27 (2011) Erman et al. 28 (2008) placebo-controlled, parallel-group study 549 pts 65 years old Randomized, double- Patient s prefer- blind, single dose, crossover study with zolpidem 10 mg and zaleplon 10 mg in 53 patients Randomized, double- 45 pts completed study Multicenter, randomized, blind, active-controlled, double-dummy comparative study 6-way crossover study sleep latency ence for reducing sleep latency and improving quality of sleep latency from baseline induction and duration included as an active control Zaleplon 5 mg and 10 mg compared to zolpidem 5 mg for 14 nights Single dose zolpidem 10 mg versus zaleplon 10 mg on two consecutive nights (no washout period) zaleplon 10 mg or zolpidem 10 mg for 14 day treatment period Eszopiclone 1, 2, 2.5, or 3 mg or Zolpidem 10 mg for 2 consecutive nights Zaleplon and zolpidem significantly reduced sleep latency 62% of patients preferred zolpidem, 38% preferred zaleplon on the basis of quality of sleep and sleep latency (no significant difference) No statistically significant difference was observed between the zaleplon group and zolpidem group in sleep latency (p=0.084 at day 14) Compared to placebo, all active treatments produced statistical improvements in measures of sleep induction and duration Zaleplon is effective in reducing latency to sleep, but no more effective than zolpidem Zolpidem preferred over zaleplon based on quality of sleep and sleep latency Patients receiving zaleplon exhibited a marginally (but not statistically significant) greater reduction in sleep latency than those who received zolpidem Eszopiclone 2 mg and 3 mg are effective in improving sleep induction and increasing sleep duration, but no more effective than zolpidem 10 mg (study not powered to detect differences between active drugs) Ancoli-Israel and colleagues demonstrated significantly reduced sleep latency in the zaleplon group, whereas Allain and colleagues concluded that patients prefer zolpidem based on the subjective outcomes of quality of sleep and sleep latency. 25,26 Another study found no statistically significant difference between zaleplon and zolpidem in the efficacy of reducing sleep latency or the occurrence of adverse effects. 27 Erman, et al. compared zolpidem with eszopiclone, but their study was not powered to detect a significant difference between the two drugs. 28 No clinical trials have compared the efficacy of zaleplon with eszopiclone. DOSING AND ADMINISTRATION Zolpidem, zaleplon, and eszopiclone should be taken immediately before bedtime. Taking any of these medications with or immediately after a heavy, high-fat meal results in slower absorption and reduces the effect on sleep latency ,17-20 Edluar and Intermezzo should be placed under the tongue and allowed to disintegrate completely before swallowing. 13,14 The sublingual tablet should not be swallowed whole or taken with water. 13,14 Each metered actuation (one spray) of Zolpimist delivers 5 mg zolpidem tartrate. Zolpimist should be sprayed directly into the mouth over the tongue. 12 Table 3 summarizes the FDA dosing recommendations for each non-benzodiazepine sedative hypnotic product. On January 10, 2013, the FDA issued a safety announcement about the risk of next-morning impairment after use of insomnia drugs and lowered the recommended doses of medications containing zolpidem for women. Women appear to be more susceptible to the risk of next-morning impairment because they eliminate zolpidem from their bodies more slowly than men. 9 Post-marketing data showed that blood levels in some patients may be high enough to impair driving eight hours or more after use. The risk for nextmorning impairment is highest for women and patients taking the controlled-release form of zolpidem. 9 The FDA recommends physicians prescribe the lowest dose of zolpidem necessary and is requiring manufacturers of the drugs to lower the recommended doses that appear on the drug s label. SAFETY Multicenter, randomized, Reduction of Change in sleep Improved sleep 65 patients enrolled Zolpidem was While the FDA did not decrease the dose recommendations for zaleplon or eszopiclone, as they did for zolpidem, it is important to remind patients that all medications taken for insomnia can impair driving and 9

10 Table 3 FDA dosing recommendations for non-benzodiazepine sedative hypnotic products. 9,12-14,17-20 Patient Population Product Non-elderly Men Women Elderly a Hepatic Impairment b Other Zolpidem IR 10 mg (5 mg can be 5 mg 5 mg 5 mg None considered in men) Zolpidem CR 12.5 mg (6.25 mg can be considered in men) 6.25 mg 6.25 mg 6.25 mg none Zolpimist 10 mg 5 mg 5 mg 5 mg none Edluar 10 mg 5 mg 5 mg 5 mg none Intermezzo 3.5 mg 1.75 mg 1.75 mg 1.75 mg Zaleplon Eszopiclone 10 mg (20 mg maximum c ) 5 mg for low weight individuals d 2 mg initial dose Can be initiated at or raised to 3 mg if clinically indicated No dose adjustment necessary No dose adjustment necessary 5 mg (doses over 10 mg are not recommended) 1 mg for sleep onset; increased to 2 mg if clinically indicated 2 mg for sleep maintenance 5 mg for mildmoderate impairment Not recommended in severe impairment Initial dose 1 mg in severe hepatic impairment. Use with caution 1.75 mg when coadministered with CNS depressants 5 mg initially in patients concomitantly taking cimetidine Initial dose should not exceed 1 mg when used with 3A4 inhibitors. Dose may be increased to 2 mg No dose adjustments are needed in patients with renal insufficiency. a Age 65. b Mild-to-moderate hepatic impairment is classified as Child-Pugh class A and B; severe hepatic impairment is classified as Child-Pugh class C. c 20 mg has been shown to be adequately tolerated and may be considered for the occasional patient who does not benefit from a trial of a lower dose. d Low weight individuals defined by a BMI <18.5. activities that require alertness in the morning after use. Patients who take insomnia drugs can experience impairment of mental alertness the morning after use, even if they feel fully awake. 9 Patients should also be educated on the risk of bizarre sleep-related behaviors such as sleep walking, hallucinations, and even eating and driving, that have been associated with the use of non-benzodiazepine sedative hypnotics, particularly zolpidem. 15 Non-benzodiazepine sedative hypnotics should be used with caution with other CNS depressants, as they may cause additive effects. Patients who are pregnant or who have a history of substance abuse should not use non-benzodiazepine sedative hypnotics ,17-20 TOLERABILITY The non-benzodiazepine sedative hypnotics appear to be well-tolerated overall in clinical trials. The incidence of GI symptoms and dizziness were low for patients taking non-benzodiazepine sedative hypnotics, as indicated in Table 4. However, patients did report next-day residual effects, memory problems, and confusion ,17-20 CONCLUSION Non-benzodiazepine sedative hypnotics are the most commonly used treatments for insomnia in the United States. These agents have similar hypnotic action as traditional benzodiazepines, but an improved safety profile with fewer anxiolytic and myorelaxant properties. Zolpidem, zaleplon, and eszopiclone can all be used for sleep onset. Agents with longer half-lives such as zolpidem CR and eszopiclone are preferred for sleep maintenance. Eszopiclone is the only nonbenzodiazepine hypnotic sedative FDA approved for use for up to 6 months. All insomnia drugs can cause next-morning impairment and patients should be educated to use caution, particularly early in therapy. The FDA lowered the recommended doses for drugs containing zolpidem in January 2013 for women, and has 10

11 Table 4 Common adverse effects of non-benzodiazepine sedative hypnotics from clinical trials ,17-20 Adverse Effect CR IR Zolpimist Edluar Intermezzo Zaleplon Eszopiclone Dizziness 12% a 1% b (5% c ) 1% b (5% c ) 1% b (5% c ) 1-4% c 7-9% c 5-7% c Headache 19% a 7% b 7% b 7% b 3% c 30-42% c 17-21% c Nausea 7% a NR NR NR 4% c 6-8 % c 4-5% c Diarrhea 1% a 1% b (3% c ) 1% b (3% c ) 1% b (3% c ) NR NR 2-4% d Drugged Feeling NR 3% c 3% c 3% c NR NR NR Dry Mouth NR 3% c 3% c 3% c NR NR 3-7% d CR = controlled-release; IR = immediate-release; NR = not reported. a Reported with 3 weeks of use. b Reported after short term use (<10 nights). c Reported after long term use (28-35 nights). d Reported with 2 weeks of use. Zolpidem suggested lowering the recommended dose for men as well. REFERENCES 1. National Sleep Foundation. Can't Sleep? What To Know About Insomnia. < Accessed 1/22/ Hilty D, Young J, Bourgeois JA, et al. Algorithms for the assessment and management of insomnia in primary care. Patient Prefer Adherence 2009;3: Chiang YY, Tsai PY, Chen PC, et al. Sleep disorders and traffic accidents. Epidemiology 2012;23(4): Ishak WW, Bagot K, Thomas S, et al. Quality of life in patients suffering from insomnia. Innov Clin Neurosci 2012;9(10): Cricco M, Simonsick EM, Foley DJ. The impact of insomnia on cognitive functioning in older adults. J Am Geriatr Soc 2001;49: Kessler RC, Berglund PA, Coulouvrat C, et al. Insomnia and the performance of US workers: Results from the America insomnia survey. Sleep 2011;34(9): Dopp J, Phillips B. Sleep Disorders. In: DiPiro et al. Pharmacotherapy: A Pathophysiologic Approach. 8 th Edition. Printed in China: McGraw-Hill Education, LLC; Sullivan SS. Insomnia Pharmacology. Med Clin N Am 2010;94: U.S. Food and Drug Administration. FDA Drug Safety Communications. FDA Drug Safety Communication: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem. < Accessed 1/11/ Costa E. GABA A receptors and benzodiazepines: a role for dendritic resident subunit mrnas. Neuropharmacology 2002;43(6): Greenblatt D. Dynamics and kinetics of a modifiedrelease formulation of zolpidem: comparison with immediate-release standard zolpidem and placebo. J Clin Pharmacol 2006;46: Zolpimist [Package Insert]. Richmond, VA: ECR Pharmaceuticals Edluar [Package Insert]. Somerset, NJ: Meda Pharmaceuticals, Inc.; Intermezzo [Package Insert]. Stamford, CT: Purdue Pharma L.P.; Dang A, Garg A, Rataboli P. Role of Zolpidem in the Management of Insomnia. CNS Neurosci Ther 2011;17: Morin A, Willet K. The Role of Eszopiclone in the Treatment of Insomnia. Adv Ther 2009;26(5): Lunesta [Package Insert]. Marlborough, MA: Sunovion Pharmaceuticals, Inc Sonata [Package Insert]. Bristol, TN: King Pharmaceuticals, Inc.; Ambien [Package Insert]. Bridgewater, NJ: Sanofi- Aventis U.S. LLC; Ambien CR [Package Insert]. Bridgewater, NJ: Sanofi -Aventis U.S. LLC; Krystal AD, Walsh JK, Laska E, et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 2003;26 (7): Roth T, Walsh J, Krystal A, et al. An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia. Sleep Medicine 2005;6: Elie R, Ruther E, Farr I, et al. Sleep latency is shortened during 4 weeks of treatment with zaleplon, a novel nonbenzodiazepine hypnotic. J Clin Psychiatry 1999;60: Zammit GK, Corser B, Doghramji K, et al. Sleep and residual sedation after administration of zaleplon, 11

12 zolpidem, and placebo during experimental middle-ofthe-night awakening. J Clin Sleep Med 2006;2(4): Ancoli-Israel S, Walsh J, Mangano R, Fujimori M. Zaleplon, a novel nonbenzodiazepine hypnotic, effectively treats insomnia in elderly patients without causing rebound effects. Prim Care Companion J Clin Psychiatry 1999;1: Allain H, Bentue-Ferrer D, Le Brenton S, et al. Preference of insomniac patients between a single dose of zolpidem 10 mg versus zaleplon 10 mg. Hum Psychopharmacol Clin Exp 2003;18: Huang YS, Hsu SC, Liu SI, Chen CK. A double-blind, randomized, comparative study to evaluate the efficacy and safety of zaleplon versus zolpidem in shortening sleep latency in primary insomnia. Chang Gung Med J 2011;34: Erman MK, Zammit G, Rubens R, et al. A polysomnographic placebo-controlled evaluation of the efficacy and safety of eszopiclone relative to placebo and zolpidem in the treatment of primary insomnia. J Clin Sleep Med 2008;4(3): MATERIA MEDICA A publication of the Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Editor Steven M. Smith, PharmD, MPH, BCPS Associate Editor Katy E. Trinkley, PharmD, BCACP The material contained in this newsletter has been prepared by the Skaggs School of Pharmacy for informational purposes only. The articles are the work product of the individual authors to whom each article is attributed. The articles contained herein should not be used without proper permission or citation. Should you have questions about any of the content in this newsletter please contact the Editor. 12