Benzodiazepines Overuse

1. Benzodiazepines Overuse Steve Jenkusky, MD January 29, 2017

2. Pharmacist Objectives • Participants will review the pharmacology of benzodiazepines and be able to identify how various benzodiazepines differ. • Participants will review how benzodiazepines are used clinically, including risks and benefits. • Participants will learn the patterns of use of benzodiazepines. • Participants will develop an understanding of the risks around prescribing benzodiazepines and opioids, including recent and relevant recommendations from the CDC around pain management.

3. Technician Objectives • Participants will review the mechanism of action of the benzodiazepine class and understand difference between drugs in this class. • Participants will review how and when benzodiazepines are used in specific disease states. • Participants will learn the patterns of use of benzodiazepines. • Participants will develop an understanding of the risks and benefits of benzodiazepines.

4. A Bit of History • Prior to discovery of benzodiazepines, included alcohol, opium derivatives, paraldehyde, chloral hydrate, bromides and especially, barbiturates. All had limited effectiveness and high lethality. • In 1950, meprobamate (Miltown) was discovered with the hope that it might be a safer alternative, but it was found not to be an anxiolytic, but caused sedation, tolerance, abuse and still could be highly lethal. The first benzodiazepine, chlordiazepoxide (Librium) was discovered in 1955, shortly followed by the development of diazepam (Valium). Benzodiazepines were found to not only be effective as anxiolytics, but were significantly safer than barbiturates and meprobamate.

5. A Bit More History In the 1980’s it was recommended that BZD’s be considered controlled substances, and the “triplicate prescription program” in New York State was started. • Once hitting the market, benzodiazepines became the most widely prescribed drugsin the world, and became known in the press as “happy pills”, and as “mother’s little helper” by the Rolling Stones. • Heavily marketed in the 1970’s, but then the risk of dependence, abuse and withdrawal syndromes became evident. After a period of controversy in the US and Great Britain, the rational use of BZD’s seemed to begin in the 1990’s, although controversy never fully abated, and, now we find BZD’s playing a role in the opioid epidemic (see new black box warning). Lopez-Munoz et al 2011

6. Benzodiazepines: Mechanism of Action • BZDsact at the level of the limbic, thalamic and hypothalamic regions of the CNS, although there are BZD receptors throughout the CNS. • BZDsact by enhancing the actions of GABA, the brain’s primary inhibitory neurotransmitter, at the GABA-BZD receptor complex. • There are two BZD receptor subtypes on the GABA-A receptor that mediate either sedation/sleep (type 1) or muscle relaxation, anticonvulsant activity, motor coordination and memory (type 2). • Essentially, BZDshave sedative, anti-anxiety, anticonvulsant and muscle relaxant properties Clinical Pharmacology 2017c

7. Currently Available Benzodiazepines Anxiolytics Hypnotics Estazolam (ProSom) Flurazepam (Dalmane) Midazolam (Versed)* Temazepam (Restoril) Triazolam (Halcion) • Alprazolam (Xanax) • Chlordiazepoxide (Librium) • Clonazepam (Klonopin) • Clorazepate (Tranxene) • Diazepam (Valium) • Lorazepam (Ativan) • Oxazepam (Serax) Clinical Pharmacology 2017c

8. How to Tell One BZD From Another? • Why so many forms when all BZDs do essentially the same thing in the brain, i.e., enhance GABA transmission?

9. Pharmacokinetics • BZDs are differentiated by their pharmacokinetic profiles, based on lipophilicity and metabolism: • Half-life (short, intermediate, slow) • Onset-of-action (rapid, intermediate, slow) • Metabolic pathways (with or without active metabolites, with or without P450 involvement) Clinical Pharmacology 2017

10. Pharmacokinetics • MEDIUM ACTING • Lorazepam(Ativan) • Oxazepam(Serax) • Temazepam(Restoril) • SHORT ACTING • Alprazolam(Xanax) • Triazolam(Halcion) • Midazolam(Versed) • LONGER ACTING • Chlordiazepoxide(Librium) • Diazepam(Valium) • Clonazepam(Klonopin)

11. Pharmacokinetics • Longer the half-life: more hang-over and delayed/attenuated withdrawal (Clonazepam) • Shorter half-life: greater withdrawal with interdose rebound (Alprazolam) • Hepatic impairment and elderly: shorter half-life, 3-hydroxy forms safer (Lorazepam, Oxazepamand Temazepam) • More lipophilic: rapid onset, produce euphoria, wears off quickly (Alprazolam) • Less lipophilic: slower onset, longer lasting, less euphoric (Clonazepam) • Diazepam is lipophilic but long half-life, so quick onset, short acting in single dose, but will provide steady state coverage with chronic, multiple dosing. Clinical Pharmacology 2017

12. Benzodiazepines Are Used for: Generalized anxiety disorder(and generic anxiety) Panic disorder Social phobia Catatonia Akathisia Manic agitation Alcohol withdrawal Muscle spasms, restless legs Seizures/epilepsy Insomnia (“hypnotics”) Sedation (procedures) Schatzberg AF, DeBattist, C 2015

13. Drug Interactions • Potentiates sedative effects of narcotics and alcohol, some P450 inhibitors could increase levels of BZDs metabolized by that system (e.g., CYP3A4 inhibitors and alprazolam). • BZDs alone are generally safe in overdose, but combined with other CNS depressants, will cause death. Clinical Pharmacology 2017

14. X X Side Effects • Tolerance to sedation occurs in 5-10 days, while anxiolytic effects can continue indefinitely. • Physical dependence occurs more quickly if used well above normal dose, but also can occur over months with normal dosing. Additional Side Effects: • Memory impairment: anterograde amnesia with shorter acting, higher doses, IV use (e.g., midazolam) • Cognitive impairment with long-term use- controversial: study showing 50% increase of dementia!* • Sedation and psychomotor impairment: risk of falls, motor vehicle accidents, fractures • “Beers Criteria for Potentially Inappropriate Medication Use in Older Adults” includes BZDs due to risks of mental decline, delirium, falls, fractures and car accidents in older adults** Baldwin et al 2013 | *Billot de Gage et al 2012 | **Markota 2016

15. Abuse and Withdrawal • Psychological risk increased with fast onset, short-acting or prn use (e.g., alprazolam) • Risk of abuse is relatively low except in those prone to substance use disorders and (I believe) borderline personality disorder • Rebound anxiety and insomnia can occur even with appropriate use when discontinued • If discontinued suddenly: • Hyperpyrexia • Seizures • Cognitive impairment • Hypertension • Muscle cramps • Anxiety, panic attacks • Insomnia • Perceptual disturbances (hallucinations, derealization) • Death Bisaga and Mariani 2015

16. Anxiety Acute onset Chronic Panic Attacks Short-term BZDs Buspirone or SSRI/Effexor SSRI A Very Simplified Approach to the Assessment and Treatment of Anxiety (and where BZDs fit in)

17. First Line Treatment of Anxiety Disorders • Posttraumatic Stress Disorder (PTSD) – SSRIs/ CBT, exposure therapy • Acute Stress Disorder – supportive therapy • Generalized Anxiety Disorder (GAD) – SSRIs/Effexor/Buspar, psychotherapy • Anxiety Disorder Due to Medical Condition – optimal treatment of medical condition • Substance-induced Anxiety Disorder – substance abuse treatment • Panic Disorder – SSRI/BZD, exposure therapy • Agoraphobia – exposure therapy • Specific Phobia – exposure therapy • Social Phobia – exposure/CBT therapy, SSRI/beta blockers • Obsessive-Compulsive Disorder – SSRI’s Schatzberg AF, DeBattist, C 2015

18. BZD Overuse and Consequences • Excessive and/or inappropriate prescribing? • Substance abuse? • Polysubstance abuse? • Polypharmacy? • Resulting in what seems to be a contribution to ED utilization and death rates

19. Top US Psychiatric Prescriptions for 2013 • 1 Alprazolam: 48,465,000 • 2 Sertraline: 41,416,000 • 3 Citalopram: 39,445,000 • 4 Fluoxetine: 28,258,000 • 5 Lorazepam: 27,920,000 • 6 Trazodone: 26,242,000 • 7 Escitalopram: 24,920,000 • 8 Duloxetine: 18,573,000 • 9 Bupropion XL: 16,053,000 • 10 Venlafaxine ER: 15,796,000 • 11Diazepam: 14,335,000 Grohol 2016

20. BZD Overuse and Consequences Annual increase of 2.5% in prescriptions but a 9%/yr increase in quantity. Overall death rate increased from0.58/100,000 to 3.07/100,000. • Between 1996 and 2013, the percentage of adults receiving BZD prescriptions increased from 4.1% to 5.6%. • Lorazepam equivalents went from 1.1 kg/100,000 adults to 3.6 kg/100,000 adults. Bachhuber et al, 2016

21. Emergency Department Visits • From 2005 to 2011, over 940,000 ED visits involved BZDs, with visits increasing from nearly 90,000 in 2005 to over 175,000 in 2011 (an increase of 94%). SAMHSA, DAWN Report, 12/18/2014

23. ED Visits: Risk of Serious Outcomes SAMHSA, DAWN Report, 12/18/2014

24. ED Visits: Risk of Serious Outcomes • SUMMARY: Combining benzodiazepines with opioids or alcohol significantly increases the risks of a serious outcome. The number of patients prescribed BZDs (as well as opioids) have been increasing. Not all visits involving BZDs are the result of prescribing practices. Non-prescribed use or use of amounts beyond what is prescribed can be due to patient efforts to control symptoms or for “enjoyment,” including to enhance the high from opioids.* *Jones et al 2012

25. Benzodiazepine Use by Age • 18-35: 2.6% • 36-50: 5.4% • 51-64: 7.4% • 65-89: 8.7% • Female:Male ratio: 2:1 • Lower % when managed by psychiatrists Olfson M and King M 2015

26. Study of 300 Unintentional Drug Deaths in NM, 2006-2008 • Increase risk of death (adjusted odds ratio): • Male sex: 2.4 • One or more sedatives: 3.0 • Increased age: 1.3 • # of prescriptions:1.1 for each added Rx Buprenorphine Rx: 9.5 Fentanyl: 3.5 Hydromorphone: 3.3 Methadone: 4.9 Oxycodone: 1.9 >40 MME: 12.2 Paulozzi LJ et al 2012

27. Study of 300 Unintentional Drug Deaths in NM, 2006-2008 “ • Having at least one prescription for a sedative/hypnotic was a stronger risk factor than having an opioid prescription. Overlapping opioid or sedative/hypnotic prescriptions were strongly associated with risk. • During the study period, 44% of New Mexicans over 10 years of age filled a prescription for a controlled substance. ” Paulozzi LJ et al 2012

28. Primary Benzodiazepine Abuse Risk factors for sedative SUD include: • Participation in SUD self-help groups • Younger age • Longer duration of BZD use • Higher dosages • Lower level of education • Non-native cultural origin • Outpatient treatment of SUD. • A relatively small number of individuals show problematic use of BZDs • Perhaps 1% of the population with non-medical use • In 2012, 478,000 with sedative SUD (> heroin or methamphetamine) Bisaga and Mariani 2015

29. Primary Benzodiazepine Abuse • Having another BH disorder increases risk: 50% have another psychiatric disorder. • BZD abuse is a common secondary drug of abuse in individual with opioid or alcohol SUDs. • 40-50% of those in methadone or buprenorphine treatment will test positive for BZDs. • BZDs may enhance an opioid high, are used when withdrawing, can cause a high used alone, or may be used to “self-medicate” a comorbid psychiatric disorder, so the causes of misuse can be complicated. Bisaga and Mariani 2015

30. FDA Requires Black Box Warning for Benzodiazepines - 2016 • Concomitant benzodiazepine use with opioids may result in profound sedation, respiratory depression, coma, and death: reserve concomitant use for patients with inadequate alternative treatment options: limit to minimum required dosage and duration; monitor patients for signs and symptoms of respiratory depression and sedation. “ ”

31. CDC Guidelines for Opioid Use 2016 • Give preference to nonpharmacologic therapy and nonopioid therapy for chronic pain. • Establish realistic goals for treatment of pain and improvement of functioning. • Opioid risks and benefits, provider and patient responsibilities should be discussed. Initial treatment should be with immediate-release opioids. Lowest effective doses should be used, extra care if prescribing > 50 MME/day, and avoiding using >90MME/day. For acute pain, use the lowest dose and shortest duration of opioids.

32. CDC Guidelines for Opioid Use 2016 Urine drug testing should be used. Prescribing the combination of opioid pain medication and benzodiazepines should be avoided. Substance abuse treatment (including MATs) should be offered for patients with opioid use disorder. • For chronic pain, opioid usage should be regularly evaluated for effectiveness. • Evaluate risk factors and use strategies to reduce risk (e.g., offer naloxone). • Prescription monitoring programs should be regularly utilized.

33. Summary • BZDsare useful treatment for a variety of illnesses, but may be over prescribed • BZDs generally are considered safe when not combined with other sedatives, but there are worrisome side effects especially with long-term use and in the elderly • BZDsmisuse mostly a risk for patients with SUDs • BZDsappear to significantly increase mortality when combined with opiates

34. References • López-Muñoz F, Alamo C, García-García P. J Anxiety Disord. 2011 The discovery of chlordiazepoxide and the clinical introduction of benzodiazepines: half a century of anxiolytic drugs. May;25(4):554-62. • Clinical Pharmacology (https://www-clinicalkey-com.libproxy.unm.edu/pharmacology/resources/overviews?id=1216715) • Schatzberg, Alan F., DeBattista, Charles. 2015. Manual of clinical psychopharmacology. Eighth edition. American Psychiatric Publishing. • Baldwin DS et al 2013. Benzodiazepine: Risks and benefits. A reconsideration. J of Psychophamacology. 27(11)967-971. • Billioti de Gage S et al 2012. Benzodiazepine use and risk of dementia: prospective population based study. BMJ 345:e6231

35. References • Markota M et al 2016. Benzodiazepine use in older adults: dangers, management, and alternative therapies. Mayo Clin Proc 91(11):1632-1639 • Bisaga A, Mariani JJ 2015. Chapter 17: Benzodiazepines and other sedatives and hypnotics IN The APP Textbook of Substance Abuse Treatment. Galanter M, Kleber HD, KT Brady, eds. American Psychiatric Publishing.. Citing the National Prescription Audit. • Bachhuber MA et al 2016. Increasing benzodiazepine prescriptions and overdose mortality in the United States, 1996-2013. AJPH 106:686-688. • SAMHSA, Center for Behavioral Health Statistics and Quality. (December 18, 2014) The DAWN Report: benzodiazepines in combination with opioid pain relievers or alcohol: greater risk of more serious ED visit outcomes. Rockville, MD.

36. References • Jones JD et al 2012. Polydrug abuse: a review of opioid and benzodiazepine combination use. Drug and Alcohol Dependence 125(2012)8-18. • Olfson M, King M, Schoenbaum M. 2015. Benzodiazepine Use in the United States. JAMA Psychiatry. 72(2):136-142. • Leonard J. Paulozzi et al. 2012. A History of Being Prescribed Controlled Substances and Risk of Drug Overdose Death. Pain Medicine 13:87-95. • Centers for Disease Control and Prevention 2016. Guideline for prescribing opioids for chronic pain. J Pain & Palliative Care Pharmacotherapy 30(2)138-140.