Benzodiazepine Abuse and Addiction - Springer Link

Benzodiazepine Abuse and Addiction

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Annie Umbricht and Martha L. Velez

Contents 21.1 21.2 21.3 21.4 21.5 21.6 21.7 21.8 21.9 21.10 21.11 21.12 21.13 21.14 21.15 21.16

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacology of Benzodiazepine and Other BZD-Site Agonists . . . . . . . . . . . . . . . . . . . . Clinical Uses of BZDs and Z-Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacokinetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Problems Related to the Long-Term Use of BZDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BZDs Misuse, Abuse, and Dependence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recreational BZD Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BZD Withdrawal Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BZD Abuse in Specific Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adolescents and Young Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Polysubstance Users . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug-Facilitated Rape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of BZD Dependence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BZD Detoxification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.16.1 Gradual Tapering of the BZDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.16.2 Switching to an Equivalent Dose of a Long Half-Life BZD Before Tapering Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.16.3 Adjuvant Medication Treatment to Decrease BZD Withdrawal Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.16.4 Pharmacologic Treatment of Underlying Conditions . . . . . . . . . . . . . . . . . . . . . . 21.16.5 Non-pharmacologic Treatment of BZD Addiction . . . . . . . . . . . . . . . . . . . . . . . . .

345 346 347 348 348 350 350 351 352 353 354 354 355 355 356 356 356 357 358 358 358

A. Umbricht (*) Behavioral Pharmacology Research Unit, The Johns Hopkins University School of Medicine, Baltimore, MD, USA e-mail: [email protected] M.L. Velez Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA e-mail: [email protected] N. el-Guebaly et al. (eds.), Textbook of Addiction Treatment: International Perspectives, DOI 10.1007/978-88-470-5322-9_102, # Springer-Verlag Italia 2015

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A. Umbricht and M.L. Velez

Prevention of BZD Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.17.1 Awareness of Professional Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.17.2 Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.17.3 Patient Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.17.4 Monitoring of Patients Receiving Prescriptions of BZDs . . . . . . . . . . . . . . . . . 21.18 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Chlordiazepoxide’s sedative activity was serendipitously discovered by Sternbach in 1955 in Basel, Switzerland, and this first benzodiazepine (BZD) was introduced in 1960 for the treatment of anxiety and insomnia, followed shortly by diazepam in 1963. Given their lower toxicity, BZDs soon replaced barbiturates and other hypnotic drugs, and they became widely prescribed. Although generally considered effective and safe for short-term use for a wide range of conditions, the long-term use of BZDs is much more controversial as they lose efficacy and have been associated with adverse reactions. Problems associated with long-term use include rebound of the symptoms for which they were prescribed, alteration of sleep architecture with loss of sleep efficiency, nightmares, agitation, anterograde amnesia leading to cognitive impairment, confusion, depression, psychomotor compromise with increased risk of falls and motor vehicle accidents, withdrawal symptoms upon discontinuation, and risk of dependence and abuse in special populations. In the late 1980s and early 1990s, a new group of GABAA receptor agonists at the benzodiazepine receptor site, the Z-drugs, was introduced for the treatment of insomnia, the most common being zaleplon, zolpidem, zopiclone, and its s-enantiomer eszopiclone. Chemically distinct from the benzodiazepine group, they have been promoted to be safer than traditional BZDs and gained wide acceptance with the public and practitioners. However, given their site of action at the benzodiazepine site of the GABAAR, complications are expected to be similar. In fact, the FDA, on May 14, 2013, released a safety announcement recommending a dose reduction for zolpidem extended release as well as a warning not to operate a vehicle or machinery requiring complete mental alertness on the day following the use of zolpidem due to residual psychomotor impairment. Next day sedation, physical dependence and withdrawal, cognitive and psychomotor problems are found in patients receiving Z-drugs. Abuse of the Z-drugs is on the increase and studies suggest that Z-drugs may also increase the risk of depression. Clinicians prescribing sedatives should ensure short-term use to maximize benefit while minimizing misuse and diversion. They can play a critical role in identifying patients at risk to misuse or divert prescription drugs. Several studies demonstrate that BZD discontinuation in patients with long-term use and dependence is associated with improved quality of life. The management of the patients with BDZ abuse and/or dependence and interventions for BZD detoxification will be described.

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21.1

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Introduction

Benzodiazepine (BZD) and other BZD receptor agonists (so-called Z-drugs) remain among the most widely prescribed drugs, in spite of recommendations to prescribe SSRIs for long-term treatment of anxiety disorders and melatonin agonists for insomnia. Alprazolam, zolpidem, diazepam, clonazepam, and lorazepam are listed among the 200 most commonly prescribed medications in the United States (Tan et al. 2011). Alprazolam is the tenth most often prescribed medication in the United States, and the number of prescriptions increased from 41.4 million in 2007 to 49.1 million in 2011. Zolpidem follows as the 12th most prescribed drug with 34.5 million prescriptions in 2007 and increasing to 44.6 million prescriptions in 2011. The prevalence of regular BZD use is estimated between 2.2 % and 17.6 % in the general population (Donoghue and Lader 2010; Lader 2011), and 5.4 % of the population receive BZD agonist prescriptions for insomnia. Public health problems associated with BZDs are mainly due to chronic prescriptions for legitimate symptoms, diversion to other persons than the patients for whom the prescription was initially ordered, and broader illegal trade for nonmedical use. The nonmedical use of prescription drugs has soared in the last 20 years and become a major public health threat. Due to the heterogeneity in individuals classified as “misusers” or “abusers” of prescription medications, it is difficult to determine the true magnitude and clinical significance of problems associated with any particular form of inappropriate medication use (Barrett et al. 2008). However, sedatives are among the medications most frequently used without prescription in the United States (Manchikanti 2006). In one study, 84 % of 3,234 benzodiazepine users identified in a study of 15 general practices were still using them 8 months later, and in the 1996 Australian National Health Survey, 58 % of the 359,300 benzodiazepine users had been taking them for at least 6 months (Parr et al. 2009). Although misuse and abuse of BZDs can be found at any age, they disproportionately impact vulnerable populations, including the elderly, adolescents and young adults, pregnant women, individuals subject to sexual victimization or dating violence, those with a history of mental illness, and those with a history of substance abuse disorders. BZD misuse is among the most widespread forms of adolescent prescription drug misuse. In population-based national surveys, 9.3 % and 9.5 % of 12th grade students report lifetime sedative and anxiolytic use for recreational purpose (Johnston et al. 2009). In European countries, an average of 5.6 % of adolescents had used tranquilizers/sedatives with prevalences ranging from 1.5 % in Ukraine and the United Kingdom to about 13 % in Lithuania and France. In Brazil, adolescents have a 5 % lifetime use of sedatives or tranquilizers; females and students attending private schools are at increased risks of BZD use (Opaleye et al. 2013). Long-term use of BZDs is prevalent among seniors in North America, Australia, and Europe (Curran et al. 2003). Approximately 9–54 % of elderly adults have used benzodiazepines in a given year (Llorente et al. 2000), and two thirds of the prescriptions were inappropriate. People who are mentally or physically vulnerable are more likely to misuse these drugs. In 2009, at least 33 % of drug-related emergency department (ED) visits in

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the United States were related to CNS depressants. ED visits involving benzodiazepines more than doubled between 2004 and 2009. This demonstrates an alarming increase in the abuse of BZDs and other non-BZD hypnotics. In addition, there is a significant increase in the involvement of alprazolam, clonazepam, and zolpidem in drug-related suicide cases since 2004, with a 148 % increase for zolpidem and a 105 % increase for alprazolam. Substance abuse treatment programs and emergency departments’ data indicate that the combination of benzodiazepines and narcotic pain reliever abuse is common as 80 % of people who abused benzodiazepines also misused other drugs, most commonly opioids. An estimated 3–41 % of alcoholics abused benzodiazepines. The rehabilitation of patients who also abuse BZDs in combination to other drugs is very challenging as they represent a treatment-resistant population. The number of admissions to addiction treatment for abuse of BZDs nearly tripled in the United States between 1998 and 2008, compared to an 11 % increase in overall substance abuse admissions. The number of annual admissions for combined abuse of benzodiazepine and narcotic pain reliever increased by 570 % from 5,032 admissions in 2000 to 33,701 admissions in 2010. The majority of these admissions were non-Hispanic white males between 18 and 34 years of age. Most BZD abusers (95 %) reported abuse of another substance besides the BZD, with 82.1 % reporting primary abuse of another substance and 12.9 % reporting primary abuse of BZD (SAHMSA Treatment Episode Data Set 2011).

21.2

Pharmacology of Benzodiazepine and Other BZD-Site Agonists

BZDs and the Z-drugs are allosteric modulators on the gamma-aminobutyric A receptor (GABAAR). Gamma-aminobutyric acid (GABA) is the most important inhibitory-type neurotransmitter and its actions are mediated by ionotropic (GABAA)and metabotropic (GABAB)-type receptors, which are widely distributed throughout the central nervous system. The GABAAR are ligand-gated ion channels allowing influx of chloride (Cl-), causing hyperpolarization of the neuronal membrane, and inhibiting the firing of new action potentials. The GABAAR is a transmembrane receptor made of five subunits (2 a, 2 b, and 1 g) binding GABA on the extracellular side of the receptor. It takes two GABA molecules to activate GABAAR. Barbiturates bind between the g and b2 subunit, while BZD and the Z-drugs bind between a1 and g2 interface. Barbiturates, benzodiazepines, and ethanol are GABAA-positive allosteric modulators (i.e., their binding induces a neuronal response only in the presence of the actual agonist GABA), with two GABA molecules needed to open the chloride channel. BZDs and Z-drugs act as GABA potentiators by increasing the frequency with which the chlorine channel opens when two GABA molecules bind to GABAAR. The increase in intracellular chloride concentration hyperpolarizes the neuron which becomes less excitable (Heikkinen et al. 2009; Tan et al. 2010). It is through their ability to increase the potency of GABAAR that BZDs and Z-drugs produce a transient relaxation for patients with anxiety or insomnia disorders.

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The shorter the onset of action after drug taking, the more efficient is the learning of the subjective effect associated to the drug. With BZDs of short onset of action (30 min), the individual learns that relaxation, stress relief, or sleep is obtained by taking a pill rather than by learning more effective practices of stress reduction and a more structured lifestyle with regular sleep hygiene. Moreover, attempts to discontinue medications after several weeks of regular intake are met with resurgence or rebound of the primary symptom of anxiety or insomnia, frustrating the attempts, triggering further drug seeking, and leading to automatic and compulsive drug-taking behaviors or the cycle of addiction. With chronic intake, tolerance sets in to the effect and duration of the desired effect of the drug, requiring increases in doses and frequency of doses. Tolerance to chronic benzodiazepine use appears to result from neuroadaptive processes involving both desensitization of inhibitory gamma-aminobutyric acid (GABA) receptors and sensitization of excitatory glutaminergic receptors (Ashton 2005). When high-dose benzodiazepines or ethanol is abruptly discontinued, this “downregulated” state of inhibitory transmission is unmasked, leading to characteristic withdrawal symptoms of anxiety, insomnia, irritability, autonomic hyperactivity, sweats, and, possibly, seizures. Benzodiazepine drugs form a homogenous class of medications made of a benzene ring and a diazepine ring. The differences between the different benzodiazepine drugs are in their side chains. On the other hand, the non-benzodiazepine drugs (Z-drugs) bind specifically to and activate the benzodiazepine site of GABAA receptors but they are not chemically related to benzodiazepines. They are principally classified into three groups of chemicals: (1) imidazopyridines (zolpidem, alpidem, necopidem, saripidem), (2) pyrazolopyrimidines (zaleplon, divaplon, fasplon, indiplon, lorediplon, ociplon, panadiplon, taniplon), and (3) cyclopyrrolones (eszopiclone, zopiclone, pagoclone, pazinaclone, suproclone, suriclone). Given their specific binding and allosteric modulation of GABAA, these drugs have similar long-term negative effects to benzodiazepines including adverse cognitive (amnesia) and psychomotor effects, compromise in balance, standing steadiness, night falls, and motor incoordination leading to driving impairments. Due to their heterogeneous chemical classes, routine toxicology screens for drugs of abuse do not include the Z-drugs sedatives, so that the extent of their impact on emergency room visits and other societal costs remain underreported. In clinical trials, these sedative hypnotics were found to more than double the risk of depression compared to the groups taking placebo. Consequently, the long-term use of sedative hypnotic drugs increase the suicide risk as well as overall mortality risk (partially due to increase in risks of cancer and infections). The Z-drugs have similar risks of rebound and withdrawal effects as benzodiazepine drugs.

21.3

Clinical Uses of BZDs and Z-Drugs

In this section, we are first reviewing accepted indications for BZDs. BZDs and other BZD-site agonists are indicated for short-term use and at the lowest effective dose for these indications.

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Indications include panic disorders and phobias preventing specific functions or procedures (such as flying in an airplane, undergoing an MRI for patients with claustrophobia). They are also indicated for short-term management of anxiety disorders, such as caused by a sudden stressor such as grief, and the short-term management of insomnia associated with alcohol withdrawal, withdrawal from sedatives with short half-lives, emergency intervention for grand mal seizures, and muscle relaxant of severe muscle spasms. They are used in the treatment of acute paranoia or other psychotic state induced by cocaine or other drug toxicity, in shortterm intervention of psychiatric emergencies accompanied by psychosis or mania, and to induce sedation before the onset of action of lithium or other antipsychotic medications (neuroleptics). They are also used for premedication to relieve anxiety of an upcoming surgical procedure or dental intervention, in anesthesia induction, sedation for procedural medical interventions, and sedation in intensive care (to facilitate mechanical ventilation and/or sedate patients in distress).

21.4

Pharmacokinetic

BZDs are well absorbed by the gastrointestinal tract after oral administration. After intravenous administration, BZDs quickly distribute to the brain and central nervous system. Only midazolam has reliable absorption after intramuscular administration. The main difference between BZDs relates to the time to peak effect (onset of action) and duration of action, depending on the metabolic half-life and the presence or not of psychoactive metabolites. BZD characteristics predicting the severity of the benzodiazepine withdrawal syndrome are higher dose, longer duration of treatment, shorter half-life, and more rapid taper. Clinical variables of BZD withdrawal severity include severity of preexisting anxiety and/or depression, personality disorder, panic disorder, and history of or concurrent substance use disorder. Withdrawal from rapidly absorbed, short-acting drugs with no active metabolites (e.g., alprazolam, triazolam) can start within hours of the last dose; withdrawal from substances with long-acting metabolites (e.g., diazepam) may have gradual onset with a peak within 1–10 days after the last dose.

21.5

Problems Related to the Long-Term Use of BZDs

The long-term clinical use of BZDs is much more controversial. Advocates of longterm management with BZDs quote patients’ acceptability and widespread belief of safety and efficacy. However, several academic and public health policies strongly advise against long-term use of BZDs for PTSD, generalized anxiety, insomnia, depression, and panic attacks due to the lack of evidence of demonstrated long-term efficacy in the treatment of these conditions and their problematic effects (Table 21.1). Sedatives adversely affect cognitive (memory, attention) and psychomotor functioning impacting daily activities. BZD-associated impairments in reaction time,

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Table 21.1 Potential problems related with the use of BZDS Potential side-effects of BZDs Sedation, residual effects during day-time Cognitive effects, especially in mild cognitive impairment Amnesia, not remembering activities Impulsivity associated with poor working memory Impairment – implications while driving, operating machinery Potentiation of respiratory depression from other medications (opioids) Paradoxical reaction due to desinhibition Reinforcement of avoidance, inflexibility: prevents coping/learning of adaptive response Problems associated with long-term use of BZDs or Z-drugs Impairment, psychomotor deficits (cerebellar: unsteadiness, nystagmus, propensity to falls, poor coordination, slurred speech, disorientation). Increase risk of falls with injuries in elderly (falls at night with head injuries, hip fractures, etc.) Decrease in self-regulation and awareness (metacognition): decrease in ability to perform simple repetitive tasks (decrease in skills, including driving skills), increase in reaction time, decrease in accuracy of performance, decrease in performance in tasks of attention Decrease in cognition: decrease in memory consolidation and learning (anterograde amnesia). The memory impairment increases with tasks of increased complexity Acceleration of cognitive decline in elderly or potential for pseudodementia in elderly or other vulnerable patients. Cognitive failures Increase in the risk of motor vehicle accidents (60–80 % more accidents in drivers on BZDs or Z-drugs) Behavioral problems with forensic implications. Problems of disinhibition in persons with borderline personality disorders or impulse disorders. This can lead to paradoxical increase in anxiety, hyperactivity, and aggressive impulses. The person may not have any recollection of the incident (fugue states)

attention, and visuospatial skills increase vulnerability for motor vehicle accidents. There is also a clear association between the use of BZDs in aged people and increased risk of falls and fractures and of traffic accidents (Thomas 1998; Gunja 2013). Psychomotor impairment, falls, and hip fractures are more likely to occur with Z-drugs that have longer half-lives. Among war veterans, potential adverse consequences are BZD misuse and/or addiction, especially among those patients with an already established substance use disorder. Disinhibition has been described in patients with traumatic brain injury; these two conditions are common and often underdiagnosed among veterans with PTSD returning from Iraq and Afghanistan. In addition, it is becoming apparent that BZDs have the potential to reduce the effectiveness of exposurebased psychotherapy, which is considered a pillar in the treatment of veterans with PTSD and requires effective short-term memory, as the mechanism underlying effectiveness is a change in memory (Lund et al. 2013). Evidence-based guidelines insist on BZD’s liability for physical dependence which may occur even with appropriate therapeutic dose but for longer period of time. The risk for negative effects such as abuse and dependence is minimized when they are prescribed for short term (e.g., 2–4 weeks for intense grief reaction).

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As stated earlier, because of rebound, i.e., exacerbation of symptoms for which the medications were taken initially, a large proportion of BZD recipients become chronic users, with ensuing development of tolerance and the potential for physical and psychological dependence. The dilemma is the difficulty to prevent what is anticipated for short-term therapy to become long-term misuse with no established evidence of long-term benefit and the liability of dependence and negative psychomotor and cognitive side effects (Lader 2011).

21.6

BZDs Misuse, Abuse, and Dependence

Three different populations of patients with BZD dependence can be described (Lader 2011), and this classification is useful to guide the type of intervention: • Those who are prescribed benzodiazepine at constant dose for more than 3 months, i.e., they are at risk of negative cognitive consequences from BZDs. These may include patients on multiple psychoactive prescription medications for chronic pains (iatrogenic dependence). • Those who are prescribed BZDs for more than 3 months and are progressively increasing their doses. • Those who use BZDs both from legal and illegal sources in a pattern reminiscent of polysubstance abuse. Many people who take prescription sedatives take them responsibly and benefit from their use, especially if they are taken for short term (less than 6 weeks). Longer duration or high dose of benzodiazepine use, however, increases the odds for developing benzodiazepine dependence (Kan et al. 2004). Also, women and those who have preexisting cognitive impairment (elderly), panic disorders, or suicidal ideations have elevated odds of developing dependence on benzodiazepines (Voyer et al. 2009). If BZD doses are voluntarily or involuntarily reduced or stopped, withdrawal symptoms or resurgence of the initial symptom is likely to occur. This type of physiological dependence is the most common and it is believed that several millions worldwide have this type of BZD dependence.

21.7

Recreational BZD Abuse

Intentional abusers actively seek the sedatives because of their rewarding psychoactive properties. Sedatives can be abused due to their ability to relax anxious feelings and remove inhibitions (such as during social encounters), similar to the euphoric feelings induced by alcohol or illegal drugs (Yu 2012). The drugs are purchased from legal or illegal sources for recreational use or obtained from friends or family members who have prescriptions. Other sources include illicit sales of diverted supplies or the Internet. The modern everywhere technology, such as the easy access to Internet, plays a significant role in this regard by opening up a new source for access to drugs, explaining a portion of the increase in their abuse. Illegal online pharmacies sell controlled substances, including

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sedatives, over the Internet without regard for local laws, without a valid prescription, and without medical guidance and supervision (Forman et al. 2006). Direct marketing of medications to patients through media (especially television) may be related to changed attitudes toward ingestion of psychotherapeutic agents. Misuse of psychoactive medications, particularly in the case of individuals with prescribed BZDs, may not only stem from the individual factors but from a lack of quality health-care service. The fact that these drugs are considered “medication” and are endorsed by physicians may give a false sense of safety. Health-care providers may inadvertently play a role in misuse behaviors by failing to recognize a patient’s potential for developing a substance abuse/dependence disorder, misdiagnosing the patient, overprescribing the medication, or just due to time pressure on the physician: it takes more time to refuse a patient’s request and teach alternative behavioral strategies for anxiety or insomnia than to agree and write the requested prescription. Increased “medicalization” and pharmacotherapeutic management of common symptoms such as insomnia and subsequent increase in prescription of BZDs or Z-drugs have also led to more addiction and abuse problems. More worrisome, and by no means rare, are those who are on chronic prescription of opiates and sedatives for chronic pain, given the increased potential for respiratory depression and cardiac arrest especially with comorbid diagnoses of COPD or obstructive sleep apnea. Finally, while doctor shoppers, physicians, and the Internet receive much of the attention regarding diversion, data suggest that there are numerous active street markets involving patients, Medicaid recipients, and pharmacies as well. Diversion can occur in many ways, including the illegal sale of prescriptions by physicians and those who are referred to on the street as “loose” pharmacists; “doctor shopping” by individuals who visit numerous physicians to obtain multiple prescriptions; theft, forgery, or alteration of prescriptions by health-care workers and patients; robberies and thefts from manufacturers, distributors, and pharmacies; and thefts of institutional drug supplies. Many of these individuals have conditions that have been appropriately diagnosed and addressed with a proper course of treatment but are selling their prescription drugs for profit or exchanging them for illicit drugs. In addition, there are many individuals posing as legitimate patients for the purposes of scamming physicians and pharmacists or otherwise defrauding the system (Inciardi et al. 2007).

21.8

BZD Withdrawal Syndrome

Withdrawal symptoms can sometimes occur after as little as 4 weeks of daily use of BZDs but occur in about half of the patients treated daily for more than 4 months (el-Guebaly et al. 2010), and may last for 6–8 weeks. In some protracted cases, it can last for months. However, many patients will report more restorative sleep and improved quality of life after a few weeks off the medications, due to improved cognitive and psychomotor functioning (Salzman et al. 1992).

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The onset of withdrawal symptoms produces subjective “need” for BZDs (or craving) prolonging their use, often for years after the initial indication for the drug has passed. Many long-term users, aware that the drugs are no longer effective and are causing adverse effects, try to stop but are unsuccessful because of the emergence of withdrawal symptoms (Ashton 2005). The symptoms after discontinuation of BZDs have been described in different ways: Recurrence or relapse refers to reemergence of symptoms that existed prior to the treatment but at the same intensity. Rebound refers to symptoms similar to the symptoms the patient had before using BZDs but experienced with increased intensity. Withdrawal refers to a cluster of symptomatology due to autonomic hyperactivity. This is believed to be a hyperexcitability in the same physiological system that was initially modified by the drug, which meant to counteract the effects of the drug in an attempt to maintain homeostasis. As stated before, the symptoms of BZD withdrawal are a function of their pharmacokinetics, duration of use, the underlying diagnoses, or individual personality. Withdrawal symptoms include anxiety; irritability; agitation; tremulousness; increased sensory perception such as photophobia, hyperosmia, or altered taste; hyperacusis; paresthesia; and hypersensitivity to touch. Patients also can have allodynia, pain, sore eyes, myalgia, insomnia, fatigue, lethargy, lightheadedness, dizziness, tinnitus, depersonalization, derealization, poor concentration, poor memory, headaches, depressed mood, palpitations, nightmares, diaphoresis, muscle twitching, muscle ache, memory and concentration impairments, dizziness, feeling faint, and gastrointestinal symptoms such as anorexia and nausea (Peturson 1994). Occasionally, more severe symptoms such as seizures, psychotic reactions, or delirium and rarely death from complication of seizure can occur. Kindling is a neurologic sensitization phenomenon resulting from repeated sedative withdrawal episodes and leading to more severe withdrawal intensity upon successive episodes, including an increased propensity to seizures.

21.9

BZD Abuse in Specific Populations

While in the past sedative medications traditionally have been prescribed to women and older age groups, the growing problem of prescription drug abuse in the beginning of the twenty-first century affects individuals of both genders and of all ages, including middle school-aged children (ages 12–16) worldwide. For example, in Canada, a national health survey showed the use of sedatives doubled between 1994 and 2003 with particular increase among men, individuals under 60 years of age, and among obese men and underweight women (Vozoris and Leung 2011). Usually, high prevalences among specific populations reflect the presence of underlying conditions that can explain in part the known relationship between sedatives and morbidity/mortality. This is the case of the greater odds of sedative medication use found among morbidly obese men complicating obesity-related

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sleep disruption (obstructive sleep apnea) and the associated cardiac mortality risk that has been found to be increased in the presence of BZDs. The same is true with chronic obstructive pulmonary disease, when the anxiety triggered by shortness of breath is treated with BZDs.

21.10 Adolescents and Young Adults The lifetime prevalence of anxiety ranges between 15 % and 20 % and the median age of onset is 11 years of age, constituting one of the most common and earliest type of psychopathology among children and adolescents (Mohr and Schneider 2013). Anxiety disorders are found in 5–19 % of all children and adolescents, and in children younger than 12, prevalence ranges between 2.6 % and 5.2 %, with separation anxiety as the most common disorder (Costello et al. 2004; Ford et al. 2003). Children with an anxiety disorder are more likely to be engaged in drug abuse activities as young adults at follow-up (Beesdo et al. 2009). Sleep disorders are also very common in pediatric populations, with as many as 17 % of adolescents having unrestorative sleep (Roberts et al. 2002). However, sleep problems among children often go unrecognized in general practice, in part because of parents underreporting of sleep problems in their children or adolescents. Awareness of the importance and potential consequences of sleep problems on academic performance, neurocognitive function, and daytime behavioral problems has to be emphasized (Blunden et al. 2004). Children and adolescents are frequently sleeping less than 9 hours at night, the recognized minimum amount of sleep required in this age group. Intrinsic contributors to inadequate sleep patterns in children and adolescents include developmental changes causing a shift in circadian rhythm during puberty, delayed sleep phase syndrome (7 % of adolescents), sleep-disordered breathing, and insomniatype symptoms found in up to 34 % of adolescents. Extrinsic factors include early school start time and poor sleep habits (also called sleep hygiene) such as use of electronic devices near or during bedtime and caffeine consumption, especially problematic when undisclosed in soda or other foods (Tan et al. 2012). Anxiety, poor academic performance, behavioral problems, and sleep problems have been recognized as risk factors for substance use, abuse, and dependence. The nonprescribed use of sedatives among adolescents and young adults is a cause of concern in many countries. Fast brain development during this life stage, especially the development of executive function and learning acquisition, implies that exposure to amnesia-inducing drugs may stunt development and result in devastating neurobiological changes and behavioral consequences such as missed educational milestones, increased impulsivity (inversely correlated with short-term memory), and school dropouts. Young people report using sedatives to relieve anxiety symptoms and to sleep, with high percentage of teenagers and many of their parents believing that prescription drugs, even taken nonmedically, are more safe than illegal drugs. Uncharted societal changes exposing children and adolescents are increased exposure to direct-to-consumer advertisement of medications since 1992, rushed medical visits promoting fixing of problems via prescription while decreasing

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patient–clinician interaction, increased media distractions, and increased time competition for numerous activities all potentially resulting in increased anxiety.

21.11 Elderly Published guidelines advise against the use of benzodiazepines or Z-hypnotics (BZD-Z) in the elder. However, inappropriate use of BZDs and non-BZDs among this age group is widespread although the risk–benefit ratio is clearly greater than 1. Estimated prevalence rates of insomnia in older people is over 30 %, and studies report that a third to half of seniors in North America and the United Kingdom are prescribed either a Z-drug or benzodiazepine for sleep disturbance (Glass et al. 2005; Nubukpo and Clement 2013). These are concerning statistics given the risks of sedatives in this age group for adverse health consequences. Older adults experience high rates of illnesses and are exposed to numerous pharmacologic agents, decreased drug metabolism, and increased susceptibility to toxic effects and cognitive and motor impairment, including falls and injuries. These medications can interact with over-the-counter medicines and dietary supplements, consumed in significant quantities by seniors. Cognitive adverse events (memory loss, confusion, disorientation, pesudodementia), psychomotor-type adverse events (reports of dizziness, loss of balance, or falls), and morning impairment (residual morning sedation) can lead to accidents, including when operating vehicles. Patients over 65 are significantly less likely to stop BZDs than younger patients (Holden et al. 1994); however, drug dependence is often unrecognized among older adults.

21.12 Women Women are a vulnerable population for BZD drug abuse. First, women are more likely than men to suffer from depression, anxiety, trauma, and victimization, all of which are also associated with substance abuse. Second, women at different ages report using drugs to cope with stressful situations in their lives. Third, studies suggest that women are significantly more likely than men to be prescribed medications with high abuse liability such as narcotics and anxiolytics and not rarely in combination and for long periods of time. BZDs cross the placenta and have the potential to accumulate in the embryo/fetus and may consequently cause adverse problems (Iqbal et al. 2002). The general consensus is that BZDs have low teratogenic potential but may be associated with an increased risk of cleft palate. Current recommendations are that in order to minimize risk if BZDs are absolutely needed, they should be prescribed at the lowest effective dose for the shortest possible duration, avoiding use in the first trimester and avoiding poly-pharmacotherapy use (Dell’osso and Lader 2013). Pregnant women on BZDs are often tapered off their BZD treatment. However, there is a portion of BZD-dependent pregnant women who are unable to discontinue their BZDs in spite of knowing the associated risk of cleft palate and the potential harm of BZD on the developing brain.

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Pregnant women substance users with BZD dependence are in general very impaired, emotionally challenged with frequent relapses and issues of noncompliance with treatment recommendations possibly due to underlying trust issues. BZDs should never be used for pregnant women with other addictive disorders as they increase impulsivity and prevent learning more adaptive coping skills. Moreover, when BZDs are continued into the late pregnancy, neonatal abstinence syndrome may occur in the baby and can be prolonged. This additional stressor at the start of life is not only detrimental to the baby, as her irritability may jeopardize bonding between the mother and child dyad, which may be very significant given the preexisting vulnerabilities of the mother. Alternative approaches to treating anxiety and stress during pregnancy are “desperately” needed, and more should be done to validate the usefulness of integrative approaches to improve self-regulation during pregnancy.

21.13 Polysubstance Users The prevalence of benzodiazepine abuse reaches up to 50 % among opiatedependent individuals, including those on agonist maintenance treatment. BZD use in opioid-dependent populations is a predictor of overdose, lethality, and poor treatment outcome including cocaine and other drug use, self-harm behaviors, and poor psychosocial functioning. Methadone fatalities include benzodiazepines in 75 % of cases as do almost all buprenorphine fatalities. Benzodiazepines are frequently abused in combination with alcohol or other drugs (mainly opiates) to enhance the subjective reward of the primary substance, to offset their adverse effects (e.g., irritability induced by stimulants), or to alleviate withdrawal symptoms including insomnia due to a relative lack of access to the primary substance such as alcohol or opiates. The abuse of benzodiazepines in combination with other central nervous system depressants is particularly dangerous due to potentially fatal respiratory depression. The rehabilitation literature demonstrates that among illegal drug users, those who also abuse benzodiazepine have worse outcome. This phenomenon could have several explanations: the concurrent dependence on BZDs and opioid pain relievers could lead to more severe withdrawal symptoms than opioid withdrawal alone, resulting in higher treatment attrition rates. More anxious patients are more averse or avoidant of discomfort and resistant to alternative treatment modalities (BZDs decrease flexibility). The negative impact of BZDs on memory and cognition prevents learning coping strategies indispensible to achieve abstinence.

21.14 Drug-Facilitated Rape Ingestion of intoxicant during parties puts participants at risk for sexual assaults. Studies on the prevalence of drug-facilitated sexual assaults have been conducted in the United States. Of 1,179 urine samples from victims of sexual assault analyzed

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over a 29-month period, alcohol was found in 41 %, followed by cannabinoids in 18.5 %, benzodiazepines in 8 %, and benzoylecgonine (cocaine metabolite) in 8 % (ElSohly and Salamone 1999). A special case of BZD abuse is the surreptitious BZD administration to an unsuspecting victim by sexual predators. In addition to alcohol, the so-called date rape drugs most frequently used by rapists to sedate their victims are flunitrazepam (Rohypnol ®), a fast-acting benzodiazepine, ketamine, and gamma hydroxybutyrate (GHB) and its congeners. Perpetrators choose these drugs because they act rapidly, produce disinhibition and relaxation of voluntary muscles, and cause the victim to have lasting anterograde amnesia for events that occurred under the influence of the drug. Many drugs associated with rape are given via alcohol, and alcoholic beverages potentiate the drug effects.

21.15 Treatment of BZD Dependence The management of patients with BZD dependence includes three concurrent aspects: management of the acute withdrawal phase (Voshaar et al. 2006), developing strategies for addressing the underlying condition, as well as crisis management. Clinicians need to work closely with patients showing empathy in helping manage distress while providing menus of integrative or supportive therapies from which patients can choose from. Educational materials and tips regarding insomnia (sleep hygiene, sleep diary) and anxiety (cognitive behavioral programs, self-help materials, referrals to mindfulness resources, bibliographies) should be provided.

21.16 BZD Detoxification For some long-term BZD user patients, minimal interventions such as brief consultation or a letter with information about risks of long-term use of BZDs and the recommendation for their discontinuation can be effective and do not produce adverse effects (Cormack et al. 1994; Heather et al. 2004). The management of BZD withdrawal syndrome includes, either independently or in combination, (1) gradual tapering of the BZD, (2) switching to an equivalent dose of a long half-life BZD before gradual tapering of the latter (Lader et al. 2009), (3) the use of adjuvant medications, (4) treatment of the underlying conditions (i.e., SSRIs for anxiety) prior to detoxification and continuing these medications after BZD discontinuation (Rickels et al. 1990), and (5) non-pharmacologic treatments of underlying conditions (Table 21.4).

21.16.1 Gradual Tapering of the BZDs The rate of BZD taper is different for each patient and needs to be individualized, but there are some common recommendations depending on the type of BZD

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Table 21.2 Benzodiazepines in equivalent doses of diazepam* and half-life elimination Benzodiazepine Alprazolam Chlordiazepoxide Clonazepam Diazepam Flunitrazepam Flurazepam Loprazolam Lorazepam Lormetazepam Nitrazepam Oxazepam Temazepam

Equivalent dosage (mg) of *diazepam 10 mg is approximately equivalent to 0.5 mg 25 mg 0.5 mg 10 mg 1 mg 15–30 1 mg 1 mg 1 mg 10 mg 20 mg 20 mg

Half-life elimination (h) 6–12 5–30 18–50 20–100 18–26 25–100 6–12 10–20 10–12 15–38 4–15 8–22

Table 21.3 Z-drugs in equivalent doses of diazepam* and half-life elimination Z-drugs Zaleplon Zolpidem Zopiclone Eszopiclone

Equivalent dosage (mg) of *diazepam 5 mg is approximately equivalent to 10 mg 10 mg 7.5 mg

Half-life elimination (h) 1–2 2–4 4–8 4–8

pattern of use/misuse/dependence. A common recommendation is a reduction by 10–15 % every 1–2 weeks, leaving some empowerment to the patient for decisionmaking. Individualizing treatment seems to result in better treatment retention. There is evidence that most patients will be able to complete taper in 6–8 weeks, although some patients may need more time, including up to a year (Ashton 2005).

21.16.2 Switching to an Equivalent Dose of a Long Half-Life BZD Before Tapering Withdrawal For patients dependent on the more potent BZDs (lorazepam, clonazepam) or on those with short duration of action (alprazolam, triazolam, zaleplon, zolpidem), it is recommended to switch to a diazepam equivalent for a few days and then rapidly taper off diazepam. This ensures a smoother detoxification as the drug will continue to taper itself for another 3–4 weeks after it is discontinued (Tables 21.2 and 21.3). Dose equivalence to diazepam can also be found at http://www.benzo.org.uk/ bzequiv.htm. For heavy BZD-dependent polysubstance abusers, outpatient detoxification may have less chance of success due to the availability of BZD from illegal sources, and residential treatment may be necessary to complete the detoxification after

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diazepam substitution and taper over 2–3 weeks. Especially in this group, the use of adjuvant antiepileptic medications is indicated (see below).

21.16.3 Adjuvant Medication Treatment to Decrease BZD Withdrawal Symptoms Antiepileptic medications such as carbamazepine, its safer metabolite oxcarbazepine (Croissant et al. 2008), and valproic acid are useful adjunct medications for attenuating BZD withdrawal symptoms especially for those coming off higher BZD doses, such as more than 20 mg diazepam equivalent daily. The newer antiepileptic zonisamide, which acts as both GABA enhancer and glutamate inhibitor, should also be investigated as it was found superior to diazepam on symptoms of craving, withdrawal, and depression for alcohol withdrawal (Rubio et al. 2010). Other GABA medications have been evaluated for BZD detoxification such as pregabalin (Bobes et al. 2012) and gabapentin. However, all these antiepileptic medications should not be considered for long-term substitution to BZD because of their negative effects on cognition. Propranolol, captodiamine, and buspirone were not found to be effective in facilitating BZD withdrawal. Inpatient detoxification with the BZD antagonist flumazenil has been described, although patients in this study were then switched to and discharged on the long-acting BZD clonazepam at high doses (2–6 mg), so that the procedure cannot be considered a detoxification from BZD although the authors report that 53 % of their patients were BZD-free at 6 months (Quaglio et al. 2012). A double-blind evaluation of the procedure without substitution with a BZD, possibly under the protective effect of a non-BZD antiepileptic medication, has to be undertaken before the procedure can be recommended. The use of flumazenil in the setting of BZD dependence should be advocated with caution due to the high risk of seizures and aspiration.

21.16.4 Pharmacologic Treatment of Underlying Conditions It is important to treat any underlying condition before, during, and after BZD withdrawal treatment. SSRIs and other antidepressant with low stimulating potential (sertraline, paroxetine, citalopram, escitalopram, mirtazapine, trazodone) are recommended for anxiety disorders, especially with concurrent depressive symptoms. Melatonin is recommended for insomnia.

21.16.5 Non-pharmacologic Treatment of BZD Addiction Maximizing the use of non-pharmacologic interventions is critically important, and different types of health-care providers can play a significant role in providing these psychosocial interventions. We are briefly reviewing non-pharmacologic

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Table 21.4 Steps recommended for BDZ discontinuation after long-term use 1. Send a letter or have a conversation with the patient explaining the negative consequences of long-term use of BDZs. Explain the process of taper and the non-pharmacologic options to deal with the symptoms related to BDZ discontinuation and/or underlying problems 2. Change to longer-acting medication and taper over a period of 6–12 weeks 3. If step 2 fails or the patient has a severe dependence with risk of seizures, use a medication to suppress the withdrawal symptoms for several weeks before and after BDZ reduction 4. If step 3 fails or the patient is at risk for complications, use inpatient dose reduction of BDZ over a period of 1–3 weeks 5. Consider the need for psychiatric or hypnotic medication different than BDZ to treat underlying anxiety and/or insomnia 6. Refer for therapy (CBT, mindfulness-based therapy, support groups)

approaches to the treatment of anxiety and sleep disorders. Although the review of these strategies is beyond the scope of this chapter, clinicians will benefit their patients in developing familiarity with self-empowering strategies aimed at improving quality of life and health by reducing stress while minimizing risks associated with pharmacologic management. Historically, psychotherapy for anxiety disorders (panic, generalized anxiety, social anxiety, phobias) was the first available treatment to provide relief for anxiety symptoms. The initial long-term dynamic therapy has been replaced by short-term intensive dynamic psychotherapy, cognitive behavioral therapy, and other interventions such as exposure therapy and mindfulness-based therapies. There are several promising therapies that have been used recently to treat anxiety. Some of them are COPE (Creating Opportunities for Personal Empowerment) that is a brief-focused cognitive behavioral therapy-based intervention that can be delivered to teens in school settings using a group format. Adolescents who received this therapy reported significant decreases in depression and anxiety on the Beck Youth Inventory as well as increases in personal beliefs about managing negative emotions. Evaluations indicated that the group COPE intervention was a positive experience for the teens (Mazurek Melnyk et al. 2013) (Table 21.4). A 12-session program of mindfulness-based stress reduction (MBSR) in seventh and eighth graders at a small school for low-income urban boys resulted in less anxiety, improved coping, and a possible attenuation of cortisol response to academic stress, when compared with Health Education participants (Sibinga et al. 2013). Pathological worry is considered a central symptom of generalized anxiety disorder but can be seen in other types of anxiety (e.g., excessive worry over future panic attacks). For that reason, studies of interventions that reduce pathological worry are considered very important. Results from a meta-analysis performed by Covin et al. (2008) found that cognitive behavioral therapy (CBT) for GAD can be a highly effective treatment for reducing pathological worry, especially for younger adults. CBT was also effective for geriatric patients and the improvement was both for the short term and over time.

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Avoidance is another cardinal feature in patients with anxiety disorders and is a maladaptive learned behavior that may temporarily relieve anxiety symptoms but actually perpetuates the anxiety often causing significant impairments in functioning. Avoidance of the uncomfortable symptoms of the withdrawal or rebound reactions during BZD tapering is a major difficulty in interrupting the vicious cycle of using BZDs to combat painful subjective states during the recovery from BZD misuse and dependence. To break this cycle, it is essential for individuals with co-occurring disorders to learn strategies to self-regulate anxiety symptoms as well as alternative coping strategies. The psychological support is required during and after the withdrawal because patients remain extremely vulnerable for several months after discontinuation. Cognitive behavioral therapies (CBTs) are among the most efficacious psychosocial treatments that can be used to treat individuals with anxiety disorders and SUDs. Action commitment therapy (ACT, Blackledge and Hayes 2001) has also found wide acceptance as effective treatment for avoidance and anxiety disorders. CBT demonstrated efficacy in SUD across diverse populations (Carroll and Schottenfeld 1997). The CB model of relapse is based on linear progression of responses in high-risk situations. It believes that increase in self-efficacy leads to increased coping with anxiety and stress and less substance use. Combination of CBT with contingency management and relapse prevention combined with pharmacotherapy are among the most successful treatments (Epstein et al. 2003). Acceptance commitment therapy (Blackledge and Hayes 2001) is a third-wave cognitive behavioral therapy intervention focusing on methods such as acceptance, mindfulness, cognitive defusion, decentering, and metaphors meant to reduce the impact of negative thoughts and feelings. Although prolonged exposure therapy (Foa et al. 2007) has been deemed one of the treatments of choice for PTSD, there is limited research exploring its efficacy in substance-abusing populations because of the fear that exposure to trauma cues would precipitate relapse. Physical exercise may enhance sleep and contribute to an increased quality of life in older adults (Montgomery and Dennis 2002), and increased physical activity is favorably associated with restoring sleep (Lang et al. 2013). Cognitive behavioral therapy for insomnia is as effective for improving sleep quality while decreasing depression and improving mental health.

21.17 Prevention of BZD Abuse 21.17.1 Awareness of Professional Guidelines Countries have created guidelines aiming at reducing the chronic use of BZD and consequently the risks of misuse and abuse. Several academic (American Psychiatric Association (APA), the National Institute for Health and Care Excellence (NICE), Royal Australian and New Zealand College of Psychiatrists (RANZCP), the UK Committee on Safety of Medicines (1988)) and governmental agencies (U.S. Department of Veterans Affairs (VA) and the U.S. Department of Defense (DoD),

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the UK Department of Health via the Chief Medical Officer (2004)) have created evidence-based guidelines describing indications and recommended length of time for BZD use. Most of these guidelines emphasize selective serotonin reuptake inhibitors (SSRI) as first-line treatment for generalized anxiety, panic attacks, and post-traumatic stress disorder and generally discourage the use of BZDs. However, primary and mental health-care providers frequently continue prescribing BZDs in situations not included in the guidelines (Abrams et al. 2013).

21.17.2 Screening Due to the strong association between anxiety disorders and substance use, as well as the strong association between drug abuse and prescription drug misuse, it is imperative to include screening questions regarding alcohol, smoking, and substance use histories when pharmacologic options for treatment of anxiety or insomnia are considered. Identifying at-risk individuals, considering alternative treatments where appropriate, and education on the safe and effective use of BZDs or Z-drugs may all decrease BZD diversion and misuse (McLarnon 2011). Obtaining patient signature for a treatment contract and monitoring the duration of therapy to limit at 2–6 weeks maximum are another way of preventing BZD-related problems. In addition, a history of respiratory insufficiency such as chronic obstructive lung disease or obstructive sleep apnea should be a relative contraindication to BZDs due to increased lethality in this group.

21.17.3 Patient Education Education should highlight the side effects of BZDs, including their potential for physical dependence; rebound symptoms upon discontinuation; adverse effect on memory, cognition, and mood; the increased risk of falls; and accidents when operating vehicles or machinery within 24 h of taking the medication. Prescribers should educate patients and their guardians that a prescription is only for the person who received the prescription, and inform about the risks of diversion including making medications available to other persons living in the household. Education should be provided regarding safe storage of medications in locked cabinets or boxes. Leftover medications should be disposed appropriately and returned to the pharmacist for environmentally safe disposal. There is a need for widespread education regarding the importance of sleep in children and adolescents and the timely recognition of poor sleep habits and/or sleep problems (Blunden et al. 2004). Sleep hygiene interventions are beneficial in improving sleep quality in children, adolescents, and adults. Combination of sleep hygiene intervention, cognitive behavioral therapy (CBT), and stress reduction has been used to improve sleep and decrease the risk of relapse among adolescents with substance abuse problems (Bootzin and Stevens 2005).

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21.17.4 Monitoring of Patients Receiving Prescriptions of BZDs An office policy should be in place to prevent BZD or Z-drug medications refill beyond 4–6 weeks. Depression should be addressed with specific medications indicated for mood disorders or patients should be referred for mental health treatment. Pharmacies should be engaged in patient monitoring, especially when filling prescriptions from different practitioners, feeding back this information with the respective practitioners in writing. Inform patients in writing of the risks of benzodiazepine if prescriptions for benzodiazepine exceed 3 months, obtaining patient signature acknowledging reception of the information or via certified letter. Programs that offer opiate detoxification may need to screen for concurrent benzodiazepine dependence and modify the detoxification protocol accordingly and address underlying psychiatric issues given their high prevalence in this population. Clinicians should avoid prescribing sedatives to children, as studies have documented that adolescents who received a medical prescription for sedatives are more likely to use nonprescribed medications of this type. Receiving a prescription reinforces the belief among adolescents that sedatives are “low risk” and that medications are the answers to life’s challenges or unpleasant emotions.

21.18 Conclusion While the true extent of benzodiazepines abuse and diversion is unknown, it is well known that they are among the top most frequently prescribed medications in Western countries and they are used and misused regularly or continuously for insomnia and anxiety and as muscle relaxants. In addition, due to the adverse effects on memory and cognition, BZDs may affect daily activities such as driving or taking care of children. Benzodiazepine abuse leading to dependence is a common and costly comorbidity among substance abuse patients and one for which safe and effective treatments are greatly needed. BZD-related problems are also found among adolescents, seniors, war veterans, and women. Health-care providers and the society in general need to be aware not only of the large abuse liability of these substances but also of the importance of individual differences in risk for misuse and diversion. Detoxification from BDZs is usually a challenging process and needs to be closely monitored by experienced and compassionate providers due to the severe discomfort and the underlying problems that required the medications. Non-pharmacologic therapies such as sleep hygiene, exercise, outdoor activities, cognitive behavioral therapy, mindfulness skills training, or other relaxation interventions have been shown to be as efficacious as pharmacotherapy for insomnia and anxiety. These interventions have the benefits of longterm stress reduction, improvement of cognition and life satisfaction, and decrease in disease burden.

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