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Home , Marilyn Monroe, Quazepam

Benzodiazepines: Risks, Benefits and Accidental Deaths

Chris Aiken, MD Instructor, Wake Forest U. Dept of Psychiatry Director, Mood Treatment Center, Winston-Salem, Greenboro, Boone Editor-in-Chief, The Carlat Psychiatry Report

NCPA Annual Meeting, September, 2018 Disclosures

Sub-Investigator, Janssen Objectives

To understand… 1. Benefits of 2. Short and long-term risks with benzodiazepines 3. The role of benzodiazepines in unintended overdose History Benzodiazepines Part I Before Benzos

1903 seen as a safer replacement for , , and hydrate 1940-60 use peaks, 24 pills per U.S. citizen; overdoses rise

Deaths from barbiturate overdose

Judy Garland Monroe Jimi Hendrix Bruce Lee Benzos 1960-1980

1960 (Librium) released, followed by (Valium) in 1963 1963 withdrawal identified 1970-4 Usage peaks: 10-20% of US adults take benzos 1975-9 Abuse recognized, moved to schedule-IV 1981 (Xanax) released

1977 Accidental overdose on: Diazepam, Opioids (Codeine, , Meperidine), Barbiturates (, ), Other Sedatives (, , , ),

His physician’s medical license was suspended for 3 months and later revoked in 1995 for overprescribing to Jerry Lee Lewis and others. , Singer Benzos 1980-present

1980-90s Use in the elderly rises 1989 Triplicate scripts required in NY 2003 Medicare withdraws, then reinstates (2013) coverage of benzos 2000-10 Rate of accidental death triples from sedatives 2007 Controlled Substance Reporting System in NC

1983 Admitted to a 35-year addiction to: Diazepam and .

Her physicians were reprimanded in 1994.

Elizabeth Taylor, Actress Benzo Use Increases with Age (U.S., 2008)

Olfson, 2014 Benefits Benzodiazepines Part II Benefits of Benzos

Appropriate for short-term (1-3 months) treatment of: • Anxiety • • Seizures • • Disorders of slow-wave (sleep walking, night terrors) WHO Guidelines, 1996

1987 Non-fatal suicide attempt on: Diazepam (during Iran-Contra Affair).

Robert McFarland, National Security Adviser to Ronald Reagan FDA Indications

• Anxiety • Anxiety with depression (alprazolam, ) • Panic disorder (alprazolam, )

• Insomnia • Alcohol withdrawal

• Muscle tension • Status epilepticus (diazepam), myoclonic epilepsy (clonazepam) • Preoperative anesthesia Ideal Use in Anxiety

• Severe, disabling anxiety that is expected to resolve quickly (1-3 mth) as stress is relieved or treatment (e.g. , therapy) takes effect. • Intermittent use (e.g. rare use for panic/phobia). • Best evidence is for use in panic disorder. • Longest panic data = 32 weeks controlled (alprazolam); 1 yr uncontrolled (clonazepam)

1994 Suicide during intoxication with: Diazepam and heroin.

Kurt Cobain, Lead Singer of Nirvana Risks Benzodiazepines Part III Long-term Use of Benzos

Practice patterns are the reverse of practice guidelines: • Most often used in the elderly, former substance abusers, and chronic anxiety disorders • 60-70% of benzo scripts are for long-term use • However, dose escalation is rare in those without a substance abuse history, and chronic (12 yr) use in anxiety disorders did not increase risk of alcohol abuse.

1996 Fatal suicide by overdose on: Clonazepam and .

Margaux Hemingway, Actress (grand-daughter of Ernest) Use in Substance Abuse Population Benzo abuse often occurs with other drug abuse: • Enhance euphoria • Reduce side effects of cocaine/amphetamines

Prescribed benzos were associated with…. • With former alcoholics: No relapse, tolerance, or new addictions when followed over 12 years (Mueller, Alcohol Clin Exp Res 2005). • Poorer outcomes in patients on methadone maintenance.

1996 Accidental overdose on: Several benzodiazepines and cocaine.

He had doctor-shopped 15,000 medications from 15 doctors, one of whom lost her license.

Don Simpson, Producer (Top Gun, Flashdance) Withdrawal Syndrome

• Occurs in 40% of users (5-75%); worse with longer use and higher doses • Peaks at 1-3 weeks • Insomnia, anxiety, irritability, depression, heightened or abnormal perception, paranoia, nightmares • Seizures, headache, tremor, tinnitus, dizziness, muscle twitching, racing heart, GI distress

2007 Accidental overdose on: Diazepam, Clonazepam, Lorazepam, .

Her physician’s medical license was revoked.

Anna Nicole Smith, Benzodiazepine Discontinuation

• 50% succeed, 30% lower their dose, 20% don’t change. • After a letter from their PCP, 22% stopped on their own. • Those who came off reported greater self-esteem and mental clarity. • Faster in the beginning, then slow down: First Week: 50% reduction Next Month: 25% reduction Next ½ Year: final 25% reduction • Or convert to diazepam and reduce by 2mg every 1-2 weeks (Ashton manual: www.benzo.org.uk) Least likely to succeed with benzo WD

Medication variables: • Higher dose, shorter half-life, chronic use, rapid taper

Patient variables: • Panic disorder (but not GAD) • Personality disorder • Active substance use disorder • Higher anxiety or depression before the taper Risks in the Elderly

Changes in drug-metabolism elevate these risks: • Dependence, falls (1.5x), memory, sedation, coordination, motor vehicle accidents • Progressively worsening syndrome resembling dementia, depression, or anxiety • Long-acting agents, and those with metabolites, more prone to accumulate Michael Jackson, Singer

2008 Accidental overdose on: Chlordiazepoxide and alcohol.

Amy Winehouse, Singer Benzos and Cognition

• Chronic use: Impairs cognition with moderate to large effect size in 12 domains, compared to anxiety w/out benzo (Crowe SF, Arch Clin Neuropsychol, 2017). • Impair formation of new memories, and spatial/temporal • MVA risk 2-4 fold higher (dose dependent) 10mg diazepam = DWI level of alcohol. Patients are unaware of the impairment; does not improve with time.

2008 Accidental overdose on: Diazepam, , Alprazolam, Opioids (Oxycodone, Hydrocodone), (). Odds Ratio

Billioti, BMJ, 2014 Heath Ledger, Actor Benzos and Cognition

• May interfere with exposure-based learning (Rothbaum, AJP, 2014) • Dementia risk: Increased 1.2-1.8 fold in elderly users of benzos (confirmed in 9/11 uncontrolled studies adjusted for confounders; worse with duration of use) Brandt J, Drugs R D 2017; Tapiainen V, Acta Psychiatr Scand 2018

2008 Accidental overdose on: Diazepam, Temazepam, Alprazolam, Opioids (Oxycodone, Hydrocodone), Antihistamine (Doxylamine). Odds Ratio

Billioti, BMJ, 2014 Heath Ledger, Actor MVA Culpability Increases with Benzo Level

None

Sub-therapeutic

Therapeutic in MVA Level Benzo

Above-therapeutic

0 10 20 30 40 50 60 70 80 90

% of MVAs where driver was culpable

Longo, 2000 Association of Drugs with Injury in MVA

Amphetamine

Opiates

Cocaine

Zopiclone

Antidepressants

Anti-asthmatics

Benzodiazepines

Penicillin Drug

Anti-histamines

Cannabis

Analgesics

0 1 2 3 4 5 6 7 Odds ratio (Meta-analysis)

Elvik, 2013 Association of Drugs with Fatal MVAs

Amphetamine

Cocaine

Zopiclone

Benzodiazepines

Drug Opiates

Cannabis

0 1 2 3 4 5 6 Odds ratio (Meta-analysis)

Elvik, 2013 Mortality Increases with Exposure

Kripke, 2012 ref: Kripke Df et al 2012BMJ open access Confounders and Hypnotic-Mortality Link

p-value adjusted for….

SOCIAL/MEDICAL: Basic plus: BASIC: SOCIAL/ SOCIAL/ Medical illness, Age, gender, MEDICAL MEDICAL All nicotine/alcohol, BMI, location +Sleep +Psych MMSE, education, confinement.

Any hypnotic 0.007 0.016 0.12 0.5 0.43

Multiple 0.003 0.013 0.13 0.44 0.47

Benzodiazepines 0.003 0.05 0.05 0.22 0.21

The positive finding by Kripke were only adjusted for: Age, gender, nicotine/alcohol, BMI, ethnicity, marital status, and prior cancer

Jaussent, 2015 ref: Kripke Df et al 2012BMJ open access Benzo Exposure Increases as Death Approaches

Neutel, 2015 ref: Kripke Df et al 2012BMJ open access Benzo Use Associated with Increased Mortality in

Benzo

Antidepressant Polypharmacy Type of Type 2

0 0.5 1 1.5 2 2.5 Hazard Ratio

Tiihonen, AGP, 2012 Baandrup JCP 2010 Benzos and Mortality in O2-dependent COPD

Ekstrom, 2014

2008 Overdose (ruled a homicide) on: Diazepam, lorazepam, and .

His physician served a two-year prison sentence for involuntary manslaughter (2011-2013)

Michael Jackson, Singer Sleep Apnea

• Low-dose benzos “relatively safe” • Z-Hypnotics improve sleep, CPAP-adherence, without impacting breathing • once thought to improve sleep apnea but larger studies negative

2009 Accidental overdose on: Two Benzodiazepines and Hydrocodone during Pneumonia.

Brittany Murphy, Actress Relative Contraindications • Elderly, Dementia, Delirium, Fall Risk • Traumatic Brain Injury (TBI) • Respiratory: Sleep apnea, myasthenia gravis, COPD • Recent trauma or post-traumatic stress • History of disinhibition on benzos • On opioids or past , alcohol, or opioid abuse • Pregnancy (class D, cleft palate)

2010 Accidental overdose on: Diazepam, hydrocodone and (Soma) during pneumonia.

He had doctor-shopped 7 physicians, obtaining 553 pills in the month before his death.

Corey Haim, Actor Benzos of Distinction

Rapid onset, brief action Diazepam, Alprazolam, Lorazepam, , Midazolam Slowest onset , , Chlordiazepoxide Most likely to Diazepam, , Chlordiazepoxide, Clorazepate, accumulate Quazepam No hepatic interactions Lorazepam, Oxazepam, Temazepam (glucuronidation) (ideal in elderly, impairment) Worst withdrawal Alprazolam Best for withdrawal Diazepam, Chlordiazepoxide Best for sleep Quazepam, Lorazepam, Temazepam, Most notorious (date-rape drug) Highest fatality index Flurazepam, Temazepam, Alprazolam, Diazepam, Clonazepam Lowest fatality index Oxazepam, Lorazepam Best overall? Oxazepam, Lorazepam Benzodiazepines by frequency of diversion in the U.S., 2011-2012 (source: DEA) 45,000

40,000

35,000

30,000

25,000

20,000

15,000

10,000

5,000

0 Alprazolam Clonazepam Diazepam Lorazepam Temazepam Accidental Deaths Benzodiazepines Part IV A New Epidemic For Americans in 2015…. • 1 in 3 were prescribed an opioid. • 1 in 12 were prescribed a benzo. • 1 in 30 were prescribed both. • 40% opioids for chronic pain also take benzos. Accidental drug overdose is currently the leading cause of injury-related death among Americans age 35-54.

2012 Accidental overdose on: Alprazolam, Marijuana, Benadryl, and Cyclobenzaprine.

Whitney Houston, Singer Deaths from Barbiturates Overdose (UK) Overdose Deaths by Intent (NC, 1999-2012) Benzos with Opioids

The combination works differently • Both suppress breathing.

• Benzos: GABAA Inhibition. Opioids: in the medulla. Benzos with Opioids

The combination works differently • Combination increases risk of fatality 2-4 fold. • Worse fatality with higher dose, but not with prn vs. daily dosing. • Synergestic euphoria: People tend to combine them, abusers and non abusers alike. • New FDA warning about combination.

2012 Accidental overdose on: Diazepam and Alcohol.

Thomas Kinkade, Painter of Light Map of Deaths by Unintentional Poisoning in NC, 2013

40 Predicted Age-Adjusted Death Rates due to Drug Poisoning:

1999-2000 2004-2005 2008-2009

Rossen et al, 2013, AJPM

41 Risk of Prescription Drug Overdose by Age

30

25 Death rates by age 45-54

35-44 20 25-34

15 55-64

10 15-24

Deaths per 100,000 per Deaths 100,000 population 5 65 & over

0 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Highest in white men age 25-55 and in mountain-regions

CDC/NCHS, National Vital Statistics System Benzos Rank 2nd in Drug-related Deaths

Most common causes of drug-related deaths in 2009 (n=8,653)

n=1,185 n=1,099 n=720 n=559 n=529 n=302 n=265

BZD: benzodiazepine. Florida Medical Examiners Report. www.fdle.state.fl.us 2009. Benzo Risks Increase with Age and Concomitant Drug/Alcohol Use What to do?

• Orient patient to sea-change. • Print treatment agreement (no early refills). • Document justification. • Involve the family. • Consider Naloxone, but not (seizures). PrescribeToPrevent.org. Naloxone 2 mg/2 ml pre-filled Luer lock–ready needleless syringes with a mucosal atomizer. Or Narcan nasal spray 4 mg.

2014 Accidental overdose on: Diazepam, Alprazolam and Heroin.

TomPhilip Petty, Seymour Musician Hoffman, Actor

Medication Alternatives

• Higher dose SSRI/SNRI • Imipramine (180 mg/day) • Mirtazapine • (225- • (300mg/night, 300mg/night) for GAD/social anxiety, but • MAOIs raises risk of opioid related • Buspirone death 1.5-fold at 300mg) • (for GAD) • (800-2,400 mg/day, for social anxiety) 2017 Accidental overdose on: Fentanyl, oxycodone, Temazepam, Alprazolam , citalopram.

PhilipTom Petty, Seymour Musician Hoffman, Actor Therapy and CAM alternatives • Cognitive behavioral • Aerobic exercise therapy (CBT) • Forest walks • Mindfulness • Caffeine reduction • Progressive muscle • Passionflower 45 drop/day relaxation • Lavender/Silexan 160mg/d • Deep breathing • Chamomile with 1.2% • Yoga 220mg/d • Sleep hygiene • Ginkgo biloba EGb 761 • Apps (Breath2Relax, 480mg/day HeadSpace, PanicRelief, Anxiety Coach)

Philip Seymour Hoffman, Actor NC Controlled Substance Reporting System

Started in 2007. Updates to legislation in 2013: • DHHS may notify MDs of suspected of doctor-shopping. • DHHS may notify NCMB of potentially improper prescribing patterns. • MDs may designate office staff to check CSRS. • Pharmacies must report within 3 days. Small dispensions (≤2 days worth) are not reported. • Register at: www.ncdhhs.gov/mhddsas/controlledsubstance