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 benzodiazepines 2. Short and long-term risks with benzodiazepines 3. The role of benzodiazepines in unintended overdose History Benzodiazepines Part I Sedatives Before Benzos 1903 Barbiturates seen as a safer replacement for opioids, bromides, and chloral hydrate 1940-60 Barbiturate use peaks, 24 pills per U.S. citizen; overdoses rise Deaths from barbiturate overdose Judy Garland Marilyn Monroe Jimi Hendrix Bruce Lee Benzos 1960-1980 1960 Chlordiazepoxide (Librium) released, followed by diazepam (Valium) in 1963 1963 Benzodiazepine withdrawal identified 1970-4 Usage peaks: 10-20% of US adults take benzos 1975-9 Abuse recognized, moved to schedule-IV 1981 Alprazolam (Xanax) released 1977 Accidental overdose on: Diazepam, Opioids (Codeine, Morphine, Meperidine), Barbiturates (Amobarbital, Pentobarbital), Other Sedatives (Methaqualone, Ethchlorvynol, Ethinamate, Carbromal), Amitriptyline His physician’s medical license was suspended for 3 months and later revoked in 1995 for overprescribing to Jerry Lee Lewis and others. Elvis Presley, 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 Admitted to a 35-year addiction to: 1983 Diazepam and alcohol. 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 • Insomnia • Seizures • Muscle relaxant • Disorders of slow-wave sleep (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, lorazepam) • Panic disorder (alprazolam, clonazepam) • 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. antidepressant, 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 Phenobarbital. Margaux Hemingway, Actress (grand-daughter of Ernest) Use in Substance Abuse Population Benzo abuse often occurs with other drug abuse: • Enhance opioid 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, Chloral hydrate. Her physician’s medical license was revoked. Anna Nicole Smith, Model 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, Temazepam, Alprazolam, Opioids (Oxycodone, Hydrocodone), Antihistamine (Doxylamine). 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 Benzo Level 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 Hypnotic 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 hypnotics 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 Schizophrenia Benzo Antidepressant Polypharmacy Type of Type 2 Antipsychotics 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, midazolam and propofol. 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 • Mirtazapine 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 sedative, alcohol, or opioid abuse • Pregnancy (class D, cleft palate) 2010 Accidental overdose on: Diazepam, hydrocodone and carisoprodol (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, Triazolam, Midazolam Slowest onset Oxazepam, Clorazepate, Chlordiazepoxide Most likely to Diazepam, Flurazepam, Chlordiazepoxide, Clorazepate, accumulate Quazepam No hepatic interactions Lorazepam, Oxazepam, Temazepam