1 A review on Benzos Gilles Fleury, MD, FRCPC PsychiatristMontfort Hospital Assistant Professor Education Director – Division of addiction and mental health Department of Psychiatry University of Ottawa October 2016

2 Disclosure No conflict of interest

3 Acknowledgements Ralph Dell’Aquila MDCM, CCFP, MRO, ABAM and other presenters Christine Landry, Pharmacist, Montfort Hospital, Ottawa, ON

4 Objectives Why can BZD use be problematic ?When is BZD use problematic ? What can we do about problematic BDZ use? Describe detoxification approache Detox 101: How to Get Patients Off Benzo's and Alcohol  Idenfify whether your pafient is dependent on alcohol or benzo; Detox 101: How to Get Patients Off Benzo's and Alcohol  Develop a plan to help pafients taper and stop drinking;  Idenfify whether your pafient is dependent on alcohol or benzo; Detox 101: How to Get Patients Off Benzo's and Alcohol  Develop an approach to detox;  Develop a plan to help pafients taper and stop drinking;  Idenfify whether your pafient is dependent on alcohol or benzo;  Idenfify available resources for dependent pafients  Develop an approach to detox;  Develop a plan to help pafients taper and stop drinking;  Idenfify available resources for dependent pafients  Develop an approach to detox;  Idenfify available resources for dependent pafients

5 Benzodiazepines (BZD): mechanism of actionEnhance GABA activity GABA is the major inhibitory neurotransmitter of the CNS, it decreases neuronal excitation GABAA : depressant effect Benzodiazepine (Bz) receptors: Bz1: Sleep-inducing effect Site of action of zolpidem Bz2 and Bz3 : antiseizure, antianxiety and muscle relaxation effects

6 BZD - Therapeutic uses Anticonvulsant Muscle RelaxantCerebral palsy, dystonia Amnesia with Sedation Peri-operative or medical procedures Alcohol withdrawal Insomnia Acute agitation Anticonvulsant action. Diazepam is used in the treatment of status epilepticus, and clonazepam is used in the treatment of myoclonic, petit mal and absence seizures. Tolerance builds up to the anticonvulsant effects of benzodiazepines so they are usually not used for long-term treatment. Muscle relaxation. Benzodiazepines reduce skeletal muscle tone, and have been used in the treatment of neuromuscular disorders such as cerebral palsy. Their effectiveness in the treatment of backache and other common conditions is not proven. Hypnotic. Benzodiazepines induce sleep, increase total sleep time, and suppress rapid eye movement sleep. Short-acting benzodiazepines are used to treat transient insomnia. It is recommended that they be prescribed at the lowest effective dose for a limited time, typically three weeks or less. Benzodiazepines are also used in the treatment of parasomnias including periodic restless leg movements, sleepwalking and night terrors. Careful diagnostic evaluation is needed since treatment is usually long-term. Amnesia with sedation. Benzodiazepines such as midazolam and intravenous diazepam induce sedation and amnesia for procedures such as endoscopy.

7 BZD - Therapeutic uses - PsychiatricSevere acute anxiety * Not first line treatment for any chronic anxiety disorder Severe generalized anxiety disorder unresponsive to other treatments Panic disorder, social phobia Adjunctive treatment of depression, bipolar affective disorder and schizophrenia Anxiety Disorders. Benzodiazepines are anxiolytic, with less sedation than other drugs such as barbiturates or alcohol. Panic disorder may respond to short-term treatment with short-acting benzodiazepines such as clonazepam and alprazolam, although long-term use may result in problems with dependence and difficulty with discontinuation. Similarly, benzodiazepines are used to treat acute and chronic generalized anxiety disorder. Benzodiazepines are best used intermittently during periods of severe anxiety symptoms and at the lowest possible dose for the shortest possible time. Some of these patients may have other underlying psychiatric disorders or personality disorders and may be at risk for benzodiazepine addiction. Adjunctive treatment of depression, bipolar affective disorder and schizophrenia. Benzodiazepines are often combined with antidepressants in patients with depression and prominent anxiety symptoms, and are also used as an adjunct to lithium in bipolar affective disorder when anxiety symptoms are prominent. However, caution is warranted in the use of benzodiazepines with depressed patients (see adverse effects). Benzodiazepines may be used as adjuncts to neuroleptics in treating patients with schizophrenia who do not respond to neuroleptics alone.

8 Benzodiazepines: Why taper?Usually not because patient “addicted” Possible benefits of tapering: more alert, energetic better able to make positive life changes not need drug anymore avoid future adverse effects High risk if concomitant use of other depressants Need to be aware of comorbid medical conditions and consider physiological stress to patients of tapering, patients with chronic medical conditions experience withdrawal more severely For patients on therapeutic doses of benzodiazepines with no obvious adverse effects, tapering should be viewed as a therapeutic trial to establish the ongoing need for benzodiazepines, to determine the lowest effective dose, and to determine if the patient actually feels and functions better without the medication. Even if patients do not notice adverse effects they often feel more alert and energetic when the benzodiazepine dose has been reduced or discontinued. Tapering should not begin until the patient is ready and a plan for supportive counselling is in place. Close and consistent follow-up is required to ensure success. Patients should be encouraged to note positive effects of the taper, such as feeling more alert and energetic. Stress management techniques and cognitive-behavioral therapy are often helpful. Underlying psychosocial causes of anxiety, such as marital discord, should be identified and the patient and physician should negotiate a strategy and timetable for dealing with them. If the patient becomes much more symptomatic during the taper, it should be halted or reversed. For example, benzodiazepines can exacerbate depression and a trial of tapering is often indicated in depressed patients. However, patients with mixed anxiety and depression may become more depressed, even suicidal if their benzodiazepine dose is abruptly stopped or tapered too quickly. Such patients require careful tapering and close support and monitoring.

9 Benzodiazepines: Adverse EffectsACUTE Sedation (depressant) Decreased respiratory drive Overdose (with other drugs - esp. alcohol and opioids) Disinhibition CHRONIC Decreased Neurocognition Physiologic Dependency: Tolerance, Withdrawal Addiction (Intoxication Syndromes) Depression. In common with other sedatives such as alcohol and barbiturates, benzodiazepines may cause or exacerbate symptoms of depression, particularly in higher doses over a prolonged period. Falls and Confusion. Epidemiological studies indicate an increased risk of falls and hip fractures in seniors taking benzodiazepines, particularly long-acting benzodiazepines such as diazepam and chlordiazepoxide. Benzodiazepines alone may contribute to risk, but those patients at greatest risk are more likely to be taking other psychoactive drugs and to have significant co-existing medical illness. Elderly benzodiazepine users are also at increased risk for confusion and impaired recall. Motor Vehicle Accidents. Recent evidence suggests that long-acting benzodiazepine use in the elderly increases the risk of motor vehicle accidents. Risk is probably greatest in the first few days or weeks of treatment, and when benzodiazepines are used in combination with alcohol or other psychoactive agents. Decreased Respiratory Drive. Benzodiazepines can decrease respiratory drive and cause potentially fatal hypoxia in patients with sleep apnea or chronic obstructive lung disease. Reproductive Effects. It is not clear whether benzodiazepines are teratogenic or have an adverse effect on outcomes during pregnancy. Teratogenicity, after heavy maternal benzodiazepine use, occurs with multiple alcohol and substance abuse exposure. Heavy use of benzodiazepines during or just prior to labor may result in “floppy baby syndrome” (poor muscle tone, less alert). Disinhibition. Benzodiazepines sometimes cause paradoxical excitement in psychotic patients or in patients with personality disorders. Rebound Insomnia. Benzodiazepines suppress the REM and deep stages of sleep. Patients who stop their night-time benzodiazepine use after several weeks of daily use may experience intense, prolonged REM sleep, causing vivid dreams with frequent awakening. References:1) Ray W.A., Griffin M.R., Downey W. Benzodiazepines of long and short elimination half-life and the risk of hip fracture. JAMA 1989; 262 (23), ) Hemmelgran B, Suissa S, Huang A et al. Benzodiazepine use and the risk of motor vehicle crash in the elderly. JAMA 1997; 278: ) Lyznicki JM, Doege TC, Davis RM et al. Sleepiness, driving, and motor vehicle crashes. JAMA 1998; 279:

10 When is BZD use problematic?Risk Factors for BZD abuse Comorbid substance use disorders 80% of BZD abuse part of polydrug abuse 40% of alcohol abuse Psychiatric comorbidities: (PD, chemical coping) Genetic vulnerability (tolerance) Environmental factors Pharmacodynamics of BZD (most reinforcing BZD)

11 Risk Evaluation & Management StrategiesAssessment of Risk Factors Treatment Goals Treatment Agreement Care Plan Medical Monitoring: Reassess comorbidites & Diagnoses How is Functional Status Progressing? Progress in Behavioural Therapies ? Management: Have a Plan to manage Complications Patients with a prior or current history of drug and/or alcohol problems are at highest risk of benzodiazepine misuse. In such patients, buspirone or SSRIs are the agents of choice. If benzodiazepines are used, those with a lower dependence liability (such as oxazepam or chlordiazepoxide) should be chosen over benzodiazepines with a higher dependence liability (such as alprazolam or lorazepam). Treatment contracts are helpful in minimizing abuse and preventing behaviours such as running out early and double-doctoring. Other safeguards include dispensing of medications for short periods only, careful monitoring of amounts dispensed over time and avoidance of phone repeats. Benzodiazepines should be avoided or prescribed with considerable caution with patients at high risk for adverse effects, such as patients with COPD, sleep apnea, (decreased respiratory drive), psychosis and personality disorders (excitement, disinhibition). Benzodiazepines can exacerbate depression, and they are not recommended during pregnancy. Reference:Juergens SM. Sedative-hypnotics. American Society of Addiction Medicine 1994. Benzodiazepines—Side Effects, Abuse Risk and Alternatives Longo et al. Am Fam Physician. 2000 Apr 1;61(7):

12 Addressing problematic bdz use: Implement rems & safe prescribing guidelinesOther sedating drugs COPD, sleep disorders Elderly (esp long acting) Liver dysfunction Comorbidities are the rule, not the exception If prescribing: careful assessment, care plan, Rx goals medical monitoring management: Have a plan to reassess ++ & manage complications Should clearly state intended short term nature and dependence potential Patients with a prior or current history of drug and/or alcohol problems are at highest risk of benzodiazepine misuse. In such patients, buspirone or SSRIs are the agents of choice. If benzodiazepines are used, those with a lower dependence liability (such as oxazepam or chlordiazepoxide) should be chosen over benzodiazepines with a higher dependence liability (such as alprazolam or lorazepam). Treatment contracts are helpful in minimizing abuse and preventing behaviours such as running out early and double-doctoring. Other safeguards include dispensing of medications for short periods only, careful monitoring of amounts dispensed over time and avoidance of phone repeats. Benzodiazepines should be avoided or prescribed with considerable caution with patients at high risk for adverse effects, such as patients with COPD, sleep apnea, (decreased respiratory drive), psychosis and personality disorders (excitement, disinhibition). Benzodiazepines can exacerbate depression, and they are not recommended during pregnancy. Reference:Juergens SM. Sedative-hypnotics. American Society of Addiction Medicine 1994.

13 Benzodiazepine withdrawalThe clinical picture looks like a rebound hyperexcitability with: body changes in a direction opposite to that seen with the first administration of the drug Time course: Acute syndrome: For Short-acting BZDs (lorazepam, oxazepam), 3 to 7 days Longer for longer acting drugs (e.g. diazepam) Protracted withdrawal: less intense symptoms for 3-6 months

14 Benzodiazepine withdrawalSymptoms are likely to include: Headaches and anxiety (80%) Insomnia (70%) Tremors (60%) Fatigue (60%) Perceptual changes Tinnitus Sweating Decrease concentration Abrupt abstinence after higher doses could cause delirium and seizures

15 Benzodiazepine (BDZ) WithdrawalSYMPTOMS Anxiety-related (irritability, insomnia, panic attacks, hypersensitivity (photo/phono,touch) Neurologic (tinnitus, distorted vision, dysperceptions, tremor) Muscle twitching, insomnia, irritability, decreased concentration SIGNS / COMPLICATIONS Autonomic hyperactivity (diaphoresis, tremor, tachycardia, HTN) Hyperreflexia, Mydriasis Seizures, Arrythmias Psychosis, Delirium Suicidal Ideation Acute Sedative-hypnotic Withdrawal. Withdrawal can occur with both therapeutic and high doses of benzodiazepines. Dependence and withdrawal symptoms can occur after as little as two weeks on high doses, and two months at therapeutic doses. For those taking short-acting benzodiazepines (SABs), the onset of withdrawal symptoms is within one or two days of cessation, whereas onset is within two to four days for those taking long-acting benzodiazepines (LABs). In either case, symptoms peak within five to seven days of cessation and may last several weeks. Subacute, Prolonged Withdrawal. This is seen with both therapeutic and high doses of benzodiazepines. For both SABs and LABs the duration of symptoms may vary from several weeks up to one year (possibly longer). There is controversy as to whether prolonged symptoms represent withdrawal or re-emergence of anxiety symptoms. Patients with this pattern should be assessed in more detail with respect to the possibility of an underlying anxiety disorder.

16 BZD withdrawal Factors influencing severity: Duration of drug useDoses used Drug half-life Individual personality style Expections from patient and physician Khong E, Sim MG, Hulse G.Benzodiazepine Dependence. Aust Fam Physician. 2004 Nov;33(11):923-6

17 Treatment of BZD withdrawalGood physical exam / screening investigations Consider inpatient detoxification (hospital setting) If using diazepam ≥ 60 mg / day OR unknown dosage If outpatient, taper BZDs over 1 to 6 month-duration On average, taper over 8 to 12 weeks If too long, withdrawal becomes ‘the morbid focus of the patient’s existence’ Either use the same BZD for taper or convert to long-acting (e.g. diazepam or chlordiazepoxide)

18 Long >24h Short <12h Medium (10-15h) BDZ (Duration Action)Onset of effect Equivalence to 5 mg diazepam Elimination t1/2 Active Metabolites Short <12h Alprazolam (Xanax) fast 6-14 Yes Triazolam (Halcion) h No Oxazepam (Serax) slow 8-12 6-12h Medium (10-15h) Lorazepam (Ativan) 0.5-1 10-20h Temazepam (Restoril intermediate 5-17 6-24 Long >24h Flurazepam (Dalmane) 7.5-15 50-100h Diazepam (Lorazepam) 5 mg 20-100h Clonazepam (Rivotril) 17-50h Chlordiazepoxide (Librium) 10-25 7-25h

19 Treatment of BZD withdrawalConverting to diazepam

20 Treatment of BZD withdrawalTreatment agreement on schedule and process « we agree that the goal is zero BZD » Weekly dispensing of medication if necessary No BZD PRN during the taper Close monitoring of the patient during the taper Monitor increase alcohol consumtion / other drug use Non-pharmacological intervention for anxiety Patient to keep a diary of symptoms and triggers CBT (targeting underlying condition) Physical exercise Relaxation techniques Sleep hygiene

21 BZD withdrawal - schedule

22 Basic principles in primary carePsychoeducation Techniques to deal with anxiety and insomnia Letter from the GP suggesting ↓ in the use of BZD Acknowledge that withdrawal could be stressful Advise changes in lifestyle such as physical activity Avoid stimulants and alcohol Refer to support group Refer to specialized program / agency

23 Treatment of BZD withdrawalPotential pharmacological agents to consider: Carbamazepine: some evidence, but not enough to systematically recommend 200 to 800 mg / day Valproic acid (250 mg TID) / Gabapentin / Trazodone SSRIs: if there is an underlying untreated anxiety / mood disorder Was the patient depressed or anxious before the dependence? Remember: There is no medication approved for chronic insomnia

24 Discontinuation Symptom Recurence/Relapse Common Anxiety or InsomniaCan present rapidly or slowly Consider alternative treatment Rebound Occurs within hours-days Qualitatively more intense Transiently worse than before benzo initiation Short duration and self limited Pseudowithdrawal Overinterpretation of symptoms Expectation of withdrawal leads to experiencing abstinence symptoms Expectation created by physicians and media True Withdrawal Symptoms and signs related to physiological dependence Results from a reversal of neuroadaptive changes in the CNS that were induced by chronic Benzo use 4 categories of discontinuation discontinuation syndromes, can be considerable over lap between the two. Pseudo with drawal- effect observed in study patients who discontinued placebo

25 Resources benzo.org.uk by Professor Heather Ashtoninformation about the effects that BZDs have on the brain and body and how these actions are exerted Detailed suggestions on how to withdraw after long-term use and individual tapering schedules for different BZDs are provided Deprescribing algorithm Deprescribing.org

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28 Are z drugs addictive? Z drugs: Zoplicone (Imovane), zolpidem (Ambien)Non-BDZ Onset: T1/2 Abuse potential: lower than BDZ ; incr risk in SUD & Psych Abuse and dependence of zopidem and zoplicone. Hajak et al. Addiction : Zoplicone: Is it a pharmacolgic agent for abuse? Cimolai, N. Cdn Family Physician Dec 2007:53(12)

29 Questions / DiscussionThank you!

30 Thank you

31 References Denis et al. Pharmacological interventions for benzodiazepine mono-dependence management in outpatient settings. Cochrane Database Syst Rev Jul 19;(3) Gould RL et al. Interventions for reducing benzodiazepine use in older people: meta-analysis of randomised controlled trials. Br J Psychiatry Feb;204(2):98-107 Khong E, Sim MG, Hulse G.Benzodiazepine Dependence. Aust Fam Physician. 2004 Nov;33(11):923-6 Lader M1, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. Expert Opin Investig Drugs Jul;21(7):