BENZODIAZEPINES

THE 30,000 FOOT VIEW

The International Benzodiazepine Symposium September 16, 2017Bend, OR Steven Wright, MD

Family MedicineAddiction Medicine

Medical Pain Management

Disclosures

Astra Zeneca – Daiichi Sankyo Movantik, Morphabond

Cordant Health Solutions Drug testing, Pharmacogenetics

Collegium Pharmaceuticals Xtampza ER

Depomed Opioids in Chronc Pain

Indivior Suboxone, Opioid Addiction

Objectives

1) Describe the basics of medical decision-making

2) Describe the risks, benefits, and alternatives to benzodiazepines

3) Outline the goals of the symposium

Medication Principles

• Does it work ?

• Does it work without side effects ?

• If side effects, are they managable ?

How Do We Know ?

• Anecdotes

• Evidence Based Medicine (EBM)

• Personalized Medicine Study Length for FDA Approval12 week Estazolam9 week Clonazepam4 week Flurazepam, Alprazolam2 week Temazepam, Triazolam

How Do We Decide to Prescribe ?

• Risks

• Benefits

• Alternatives

Balanced Medical Decision Making

• Sedation Dizziness Vertigo Fatigue 1-3

• Dyscognition 1-4

Confusion ↓memory Anterograde amnesia ↓attention

• Psychomotor impairment 1-3,5-9

Incoordination Ataxia Slurred speech Diplopia MVAs Injury Falls Fractures

• Disinihibition 1 Often referred to as paradoxicalExcitement Irritability Aggression Hostility Impulsivity Violence

1 Longo. BZ side effects, abuse risk & alternatives. Am Fam Phys. 2000;61(7):2121-82 Salzman. BZ in panic, agoraphobia. J Psych Res. 1993;27 Suppl 1:97-1103 Noyes. Alprazolam in panic, agoraphobia. Arch Gen Psych. 1988;45(5):423-8 4 Giersch. Lorazepam atypical behavioral effects. Pharmacol Ther. 2010;126(1):94-1085 Uzun. Side effects of BZs. Psychiatr Danub. 2010;22(1):90-3

6 Aizenberg. Elderly psychotropics, falls, hip fractures. Exp Aging Res. 2015;41(5):546-557 Bakken. Anxiolytic-hypnotics & elderly hip fractures. Eur J Clin Pharmacol. 2014;70(7):873-808 Passaro. BZs with different half-life and falls. J Clin Epidemiol. 2000;53(12):1222-99 Price. BZs & workplace safety. J Addict Med. 2014;0(0):1-510 van der Bijl. Disinhibitory reactions to BZs. J Oral Maxillofac Surg. 1991;49(5):519-23

What are Benzodiazepine Potential Risks ?

• Other Adverse Mood Effects 1-6

Emotional blunting Mania Depression Suicidality

• Tolerance Physical dependence Intoxication Addiction 1-3,7-12

• Discontinuation problems 1,11-16

Relapse Rebound Withdrawal syndrome

• Respiratory depression Overdose Overdose death 17-23

• ↑ Overall mortality 24

1 Longo. BZ side effects, abuse risk & alternatives. Am Fam Phys. 2000;61(7):2121-8 2 Noyes. Alprazolam in panic, agoraphobia. Arch Gen Psych. 1988;45(5):423-8 3 Uzun. Side effects of BZs. Psychiatr Danub. 2010;22(1):90-3 4 Dodds. Prescribed BZs & and suicide risk. Prim Care Companion CNS Disord. 2017;19(2)5 McCall. Hypnotics & suicide. Am J Psych. 2017;174(1):18-256 Pae. Sedative-hypnotics & suicidality. Expert Rev Neurother. 2011;11(3):345-97 Lader. Anxiolytic dependence, addiction, abuse. Eur Neuropsychopharm. 1994;4(2):85-918 Shukla. BZ, Z-Drug dependence. Prim Care Companion CNS Disord. 2017;19(1)

9 Griffiths. Relative abuse liability of BZs. J Clin Psychopharm. 1990;10(4):237-4310 Pradel. BZ abuse potential. CNS Drugs. 2010;24(7):611-2011 Wolf. BZ physical dependence differences. Drug Alc Dep. 1991;29(2):153-612 DuPont. Approach BZ discontinuation. J Psychiatr Res. 1990;24 Suppl 2:81-9013 Ashton H. The Ashton Manual. 200214 DuPont. Physician guide to BZ discontinuation. West J Med. 1990;152(5):600-315 Higgitt. Prolonged BZ WD. Acta Psychiatr Scand. 1990;82(2):165-816 Guaiana. Discontinuing BZs best practices. Epidemiol Psych Sci. 2016;25(3):214-6

17 Denaut. Lorazepam, diazepam effects in COPD. Curr Med Res Opin. 1975;2:611-518 Delpierre. Anxiolytic effects on respiration in lung disease. Respiration. 1981;42(1):15-2019 MasonI. Sedating med effects on OSA. Cochrane Rev. 2015;7:CD01109020 Bachhuber. ↑ BZ Rx & OD mortality. Am J Pub Health. 2016;106(4):686-821 Warner. Drugs most frequently involved in drug OD. Natl Vital Stat Rep. 2016;65(10):1-1522 Weich. Anxiolytic-hypnotic mortality hazards. BMJ. 2014;348:g199623 Isbister. Alprazolam more toxic v other BZs in OD. Br J Clin Pharm. 2004;58(1):88-9524 Parsaik. Anxiolytic-hypnotic mortality meta-analysis. Aust N Z J Psych. 2016;50(6):520-33

What are Benzodiazepine Potential Risks ?

What are Benzodiazepine Potential Risks ?Paradigm Shift

Adverse Events Evolving Over Time

• Depression • Dyscognition• Dementia 1-7

• Addiction 8-10

Sensitization Kindling Wind-up 11,12

• ↓ Anxiolysis → ↑ Anxiety 11-13

• Neurologic symptoms 14,15

• ↑ Protracted withdrawal 14-20

1 Barbui. BZ dementia risk. Epidemiol Psychiatr Sci. 2013;22(4):307-82 Billioti de Gage. BZ Alzheimer risk. BMJ. 2014;349:g52053 Gallacher. BZ dementia risk. J Epidemiol Community Health. 2012;66(10):869-734 Gomm. BZ, Z-substance & dementia risk. J Alzheimer’s Dis. 2016;54(3):801-85 Pariente. BZ-dementia disorders link. CNS Drugs. 2016;30(1):1-76 Takada. BZ & dementia. Int J Med Sci. 2016;13(11):825-34 7 Zhong. BZ & dementia meta-analysis. PLoS One. 2015;10(5):e0127836 8 Lader. Anxiolytic dependence, addiction, abuse. Eur Neuropsychopharm. 1994;4(2):85-91 9 Griffiths. BZ relative abuse liability. J Clin Psychopharm. 1990;10(4):237-43 10 Kurtz. BZ dependence among multidrug users. Drug Alc Dep. 2011;119(1-2):99-105

11 Song. BZ WD-induced up-regulation of GluR1receptors. J Pharm Exp Ther. 2007;322(2):569-8112 Stephens. Glutamatergic drug dependence hypothesis. Behav Pharm. 1995;6(5 And 6):425-4613 Barthelmé. Anxiety, addiction to anxiolytics. Presse Med. 2008;37(11):1555-6014 Luderer. LT BZs. Psychiatr Prax. 1995;22(6):231-415 Pélissolo. Anxiety, depressive disorders in LT BZ users. Encephale. 2007;33(1):32-8 16 Pelissolo. Dependence on BZs. Encephale.1994;20(2):147-5717 Rickels. LT diazepam therapy clinical outcome. JAMA. 1983;250(6):767-7118 Higgitt. Plonged BZ WD: anxiety or hysteria? Acta Psych Scand. 1990;82(2):165-819 Landry. BZ dependence & WD. J Am Board Fam Pract. 1992;5(2):167-7520 Lapierre, BZ WD. Can J Psych. 1981;26(2):93-5 21 Iqbal. Is LT BZ risk for cancer? Medicine (Baltimore). 2015; 94(6): e483

Clonazepam and cancer risk ? 21

• ↑ benzodiazepine-associated deaths • 23-31% of all opioid-associated deaths

1 CDC. Multiple Cause of Death, 1999-2015. CDC WONDER Online Database2 Denaut. Lorazepam, diazepam effects in COPD. Curr Med Res Opin. 1975;2:611-53 Delpierre. Anxiolytic effects on respiration in lung disease. Respiration. 1981;42(1):15-204 MasonI. Sedating med effects on OSA. Cochrane Rev. 2015;7:CD011090 5 Bachhuber. ↑ BZ Rx & OD mortality. Am J Pub Health. 2016;106(4):686-86 Warner. Drugs most frequently involved in drug OD. Natl Vital Stat Rep. 2016;65(10):1-157 Weich. Anxiolytic-hypnotic mortality hazards. BMJ. 2014;348:g19968 Isbister. Alprazolam more toxic v other BZs in OD. Br J Clin Pharm. 2004;58(1):88-95 9 Chen. Opioid OD deaths US 1999-2011. Center for Health Statistics. 2014.

What are Benzodiazepine Potential Benefits ?

• Anxiety States 1,2

• Insomnia 3

• Pain (weak evidence) 4-10

• Muscle relaxation 11,12

• Seizures 13,14

• Procedure amnestic 15

• Alcohol withdrawal 16,17

• Movement disorders 18-20

1 Starcevic. Reappraisal of BZs in anxiety. Expert Rev Neurother. 2014;14(11):1275-862 Baldwin. British Assoc Psychopharm guidelines anxiety. J Psychopharm. 2005;19(6):567-963 Sateia. Med guideline for chronic insomnia. J Clin Sleep Med. 2017;13(2):307-494 Chou. Medications for LBP review. Ann Int Med. 2007;147(7):505-14 5 Manfredini. Muscle relaxants in myofascial face pain. Minerva Stomatol. 2004;53(6):305-13 6 Brötz. BZs in lumbar disc prolapse with acute sciatica? Pain. 2010;149(3):470-57 Chou. Pharmacological management of LBP. Drugs. 2010;70(4):387-4028 McCarberg. Acute back pain Rx. Curr Med Res Opin. 2010;26(1):179-909 Strumpf. Treatment of LBP. Schmerz. 2001;15(6):453-60 10 Enna. GABA role in pain perception. Adv Pharmacol. 2006;54:1-27

11 Am Acad Neurology 2010 guide: Meds for CP spasticity 12 Ntl Guideline Alliance 2012: Spasticity in Youth with Non-Progressive Brain Disorders13 NICE Guidance: Epilepsy Pharmacological Update. 2012 14 Prasad. Anticonvulsants for status epilepticus. Cochrane Rev. 2014;(9):CD00372315 Devabhakthuni. Analgosedation. Ann Pharmacother. 2012;46(4):530-40 16 Amato. BZs for alcohol WD. Cochrane Rev. 2010;(3):CD005063 17 Ilomäki. Alcohol + sedative-hypnotics. Ann Psharmacother. 2013;47(2):257-68 18 Am Acad Neurology 2013 Guide: Treatment of Tardive Syndromes 19 Am Acad Neurology 2005 Guide: Treatment of Essential Tremor 20 Am Acad Sleep Medicine 2012: RLS, PLMD Treatment in Adults

What are Benzodiazepine AlternativesFor Anxiety ?

• Mindfulness Based Stress Reduction (MBSR) 10-14

• Religious / Spiritual Interventions 15

• Relaxation / Breathing Interventions 16,17

• Biofeedback 17,18

1 Ravindran. CAM as add-on to meds for mood disorders. J Affect Disord. 2013;150(3):707-192 Hale. Anxiety responses to exercise over 8w. J Sports Med Phys Fitness. 2002;42(1):108-123 Stonerock. Exercise as anxiety Rx. Ann Behav Med. 2015;49(4):542-564 Strickland. Anxiolytic effects of resistance exercise. Front Psychol. 2014;5:753 5 Rogers. Tai chi, qigong in elderly. West J Nurs Res. 2009;31(2):245-796 Wang. Tai chi effects on depression, anxiety, psych well-being. Int J Behav Med. 2014;21(4):605-177 Marc I. Mind-body Rx for anxiety in pregnancy. Cochrane Rev. 2011;(7):CD0075598 McKinney. Imagery, music Rx effect on mood, cortisol. Health Psychol. 1997;16(4):390-4009 McKinney. Guided Imagery, music Rx outcomes. J Music Ther. 2017;54(1):1-34

10 Goldin. MBSR effect on SAD. Emotion. 2010;10(1):83-9111 Hofmann. Mindfulness Rx effect on anxiety, depression. J Consult Clin Psych. 2010;78(2):169-8312 Marchand. Mindfulness as adjunct for psych disorders. Psych Clin North Am. 2013;36(1):141-5213 Piet. Mindfulness Rx effect on anxiety, depression in cancer. J Consult Clin Psych. 2012;80(6):1007-2014 Strauss. Mindfulness for current anxiety, depressive disorder. PLoS One. 2014;9(4):e9611015 Gonçalves. Religious / spiritual interventions in mental health. Psychol Med. 2015;45(14):2937-4916 Jerath. Breathing self-regulation for anxiety. Appl Psychophysiol Biofeedback. 2015;40(2):107-1517 Biondi. Relaxation, biofeedback for anxiety, stress-related disorders. Riv Psychiatr. 2014;49(5):217-2618 Schoenberg. Biofeedback for psych disorders. Appl Psychophysiol Biofeedback. 2014;39(2):109-35

• Exercise 1-4

• Movement Meditation 5,6

• Imagery 7-9

• Music therapy 8,9

Self - Directed After Training

What are Benzodiazepine AlternativesFor Anxiety ?

• Cognitive Behavioral Therapy (CBT) 1-15

At least as good as BZs 9-15

• Acceptance and Commitment Therapy (ACT) 16-19

Outcomes similar to CBT 16

• Acupuncture (weak evidence) 20

• Massage 21

1 Craske. CBT for panic disorder. Behav Res Ther. 2007;45(6):1095-1092 Durham. CBT for anxiety disorders LT outcomes. J Affect Disord. 2012;136(3):875-813 Erickson. CBT group for anxiety disorders. Psychiatr Serv. 2007;58(9):1205-114 Hofmann. CBT for anxiety disorders effect on QOL. J Consult Clin Psych. 2014;82(3):375-915 Hofmann. CBT for adult anxiety disorders meta-analysis. J Clin Psych. 2008;69(4):621-326 Kaczkurkin. CBT for anxiety disorders update. Dialogues Clin Neurosci. 2015;17(3):337-467 Olthuis. Therapist-supported internet CBT for anxiety. Cochrane Rev. 2016;3:CD0115658 Olatunji. CBT efficacy for anxiety meta-analysis. Psych Clin North Am. 2010;33(3):557-779 Westra. BZ use & CBT outcome in panic disorder. J Anxiety Disord. 2002;16(3):233-4610 Pull. Pharmacotherapy of panic disorder. Neuropsychiatr Dis Treat. 2008;4(4):779-95

CollaborationImprovesResults 25-27

Professionally - Directed

11 Otto. BZ & CBT for anxiety disorders. J Clin Psych. 2005;66 Suppl 2:34-812 Heuzenroeder. GAD, panic psych & med cost-effectiveness. Aust N Z J Psych. 2004;38(8):602-1213 Imai. Psych v med Rx for panic disorder. Cochrane Rev. 2016;10:CD011170 14 van Balkom. Panic disorder: med v CBT v combination. J Nerv Ment Dis. 1997;185(8):510-6 15 Heuzenroeder. Psych, med cost-effectiveness in GAD, PD. Aust N Z J Psych. 2004;38(8):602-12 16 Bluett . ACT for anxiety, OCD spectrum disorders. J Anxiety Disord. 2014;28(6):612-2417 Ducasse . Acceptance and commitment therapy. Encephale. 2015;41(1):1-918 Eilenberg. Group ACt for health anxiety. Dan Med J. 2016;63(10). pii: B529419 Swain. ACT for anxiety systematic review. Clin Psychol Rev. 2013;33(8):965-7820 Pilkington. Acupuncture for anxiety, anxiety disorders. Acupunct Med. 2007;25(1-2):1-1021 Chen. Back massage for anxiety. J Altern Complement Med. 2013;19(5):464-7022 Field. Massage therapy research review. Complement Ther Clin Pract. 2014;20(4):224-923 Moyle. Massage effect on agitation in demented elderlyi. J Clin Nurs. 2013;22(5-6):601-1024 Pinar. Back massage for anxiety, sleep in caregivers. Asian Pac J CA Prev. 2015;16(18):8127-3325 Archer. Collaboration for depression, anxiety. Cochrane Rev. 2012;10:CD00652526 Fjorback. Mindfulness and bodily distress. Dan Med J. 2012;59(11):B454727 Hofmann. Adding meds to CBT for anxiety disorders. Int J Cogn Ther. 2009;2(2):160-75

What are Benzodiazepine Alternatives ?

Non – Benzodiazepine Pharmacologics

• Adrenergic inhibiting agents• Mono-amine regulatory agents• Serotonin receptor agents• Anti-psychotic medications • Sodium channel blockers

• Calcium channel modulators • Glutamine system agents • Hormones • Plant-based medicines

Where are we Headed ?Next Step Strategies

Improving Benzodiazepine Prescribing

• Legal / Regulatory

• Prescriber focused *

• Behavioral Health focused *

• Pharmacist focused *

• Pharmaceutical Industry focused

• Affected persons, networks focused

• Treatment / Treatment system

• Peer Support / Coaching

• Public focused

• Research needs

* Education Guidelines Workforce adequacy

We don’t see things as they are,

we see themas we are.

- Anais Nin