Why the Interest? • 33 years in chronic pain rehabilitation Benzodiazepines • Many patients are dysfunctional, depressed, in Chronic Pain regressed, and cognitively impaired while taking opioids plus benzodiazepines. • Engendered a negative attitude Edward Covington, MD • Stimulated curiosity about what we Cleveland Clinic Foundation do and do not know about these drugs in pain patients, especially in combination with opioids Disclaimer History Much of the data that I could find is quite old • For centuries, humans have sought anxiolysis, euphoria • Alcohol was followed by sedatives and anxiolytics • 19th century – Bromides (“take a powder”), choral hydrate (Mickey Finn), paraldehyde • Barbiturates synthesized in 1903 • Meprobamate in 1950 Benzodiazepine Introduction Benzodiazepine Use in America • Chlordiazepoxide introduced in 1960 • BZs are the most prescribed CNS depressants • Addictiveness and lethality of barbiturates (and similar drugs) led to their replacement by BZs • Estimated past year prevalence of BZ use in • Use of BZs increased dramatically the USA = 12.9% – US sales peaked in 1975 – Anxiolytics / hypnotics accounted for 10% of all • 14.2% of these have taken the drug ≥ 12 mo prescriptions Barker MJ et al. Arch Clin Neuropsychology 2004;19:437-454 • WHO recommended scheduling BZs in the early • About 100 million prescriptions in 1999 1980s DEA Lader, M: J Subs Abuse Treatment 1991;8:53-59 1 Mechanism of Tranquilization How Reinforcing are BZs? - • GABA binding permits Cl influx Humans • Hyperpolarizes cell, •Normal (light drinkers without anxiety or insomnia) rendering it less excitable – BZ (diazepam, lorazepam, flurazepam) not preferred to placebo •Moderate social drinkers, no hx alcohol problems • BZ binds to GABA A receptor • Potentiates GABA effect – Benzodiazepines (po) are reinforcers – Three studies confirm – Increases opening frequency Animals • Cell becomes more refractory •Oral BZs • Subtypes of BZ receptors 8/18 studies in primates and rats did not show evidence of reinforcement – α1 – sedative •IV – α2 – anxiolytic Reinforcement demonstrated with alprazolam, chlordiazepoxide, clorazepate, clonazepam, diazepam, flurazepam, lorazepam, – α1, α2, and α5 – anticonvulsant bromazepam, medazepam, midazolam, and triazolam – All BZs bind, to variable extents, with all subtypes Griffiths & Weerts Psychopharmacology (Berl). 1997;134(1):1-37. Conventional Wisdom • Most chronic benzodiazepine users do not escalate their original dose, even after many years. BZ Abuse in the Community • The reinforcing effects are considerably weaker than other sedative hypnotics, Conflicting information stimulants, and opiates, but stronger than drugs with little abuse potential, e.g., chlorpromazine. Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. Washington, DC, APA, 1990 “Pharmacies Besieged by Addicted Thieves” Street Prices 2006 The New York Times • Diazepam and clonazepam ≈ $2.00-$4.00/pill February 6, 2011 • Many who seek these drugs for a "high" quickly move on to other agents • More than 1,800 US pharmacy robberies in • High risk for continued misuse of BZs: the last three years – Heroin dependent / methadone maintenance • 75%+ admitted taking BZs to enhance • The most common targets are oxycodone, intoxication or treat withdrawal hydrocodone, and Xanax . – Alcoholic • Perhaps for anxiety, insomnia, withdrawal sxs Drug and alcohol abuse: a clinical guide to diagnosis and treatment. Marck A Schuckit. Springer, New York, 2006 2 Preferred Drugs on the Street BZ Use Patterns • Short-acting • Recreational abuse of BZs alone is uncommon – rapid onset – Commonly taken as part of polysubstance -abuse • Highly lipophilic • Motivations – e.g., diazepam – Euphoria • Short half-life and high potency – Augment euphoriant effect of other drugs, especially opiates – lorazepam, alprazolam • Up to 80% of opiate abusers take BZs • Clonazepam – high potency, long half-life – To ease the "crash" from cocaine – To ease EtOH sxs – Perceived as "safe" • 29%-33% of alcohol abusers take BZs – Frequently abused as a street drug Roache & Meisch. Psychiatric Annals 1995;25(3):153-7. Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. Washington, DC, APA, 1990 The TEDS Report Nonmedical Use (Treatment Episode Data Set) 6/2/11 • Most nonmedical use is occasional use of therapeutic doses for sx relief – Not associated with escalation or high-dose abuse Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. Washington, DC, APA, 1990 That is ... Most nonmedical use is not “recreational use” http://oas.samhsa.gov/2k11/028/TEDS028BenzoAdmissions.cfm The TEDS Report Prevalence of Abuse / Dependence (Treatment Episode Data Set) 6/2/11 • BZ admissions ~tripled from 1998-2008 • Difficult to determine – Overall CD admissions increased 11% • 2002 survey: ≈ 200,000 Americans treated for sedative / hypnotic use • Admissions for rx of BZ abuse – often in the context of other SUD – 1.3% of all CD admissions in 1998 • During the same period – 3.2% in 2008 – 2.2 million received rx for EtOH-related disorders – 84.8% white, 56% ♂ – 100 times more – Rate of treatment for alcoholism was ≈1% of the population, • 96% also abused other substances treatment for CNS depressants was 0.07% – In > 75% of these, BZ was the 2°drug of Wesson. D. R.. Smith. D. E.. Ling. W.. & Seymour. R. B. Sedative-hypnotics. In J. H. abuse Lowinson. P. Ruiz, R. B. Millman, & J. G. Langrod (Eds.). Substance Abuse: A Comprehensive Textbook (4th cd.). Baltimore. MD: Lippincott. Williams & Wilkins. SAMHSA 2004. pp. 302-312. http://oas.samhsa.gov/2k11/028/TEDS028BenzoAdmissions.cfm 3 Prevalence of Substance Use Disorder National Comorbidity Survey • N = 8098 • Substance use disorder develops in 5-10% – representative sample of adults • Up to 10% of general medical/surgical patients and 30% • 17.0% had been prescribed sedatives, denied of patients with serious psychiatric histories have felt misuse psychologically dependent on antianxiety or hypnotic • 7.1% reported non-prescribed use drugs • Lifetime prevalence of self-perceived sedative dependence was 0.5% • Sedative use and misuse associated with Wesson DR et al. in JH Lowinson, P Ruiz, RB Millman, JG Langrod (Eds.). Substance Abuse: A Comprehensive Textbook (4th ed.). – psychopathology Baltimore. MD: Lippincott. Williams & Wilkins. 2004. pp. 302-312. – suicide risk – parental abuse of Rx medications Goodwin RD et al. Addiction. 2002;97(5):555-62. Anxiolytic SUD Is Uncommon • N= 34,653 face-to-face surveys – National Epidemiologic Survey on Alcohol and Related Conditions • 11.8% of respondents had received rx for anxiolytic, of whom: – 16.0% reported lifetime nonmedical use – 4.6% reported abuse / dependence Fenton MC et al. Am J Psychiatry 2010;167(10):1247-53 Annual Numbers of New Nonmedical Users of Prescription Type Drugs, by Drug Category: 1965–2000 Diazepam Antihyperalgesic in Mice • Loss of DH inhibition is a major factor in chronic pain • Spinal BZs are profoundly antihyperalgesic in Benzodiazepine Use in Pain animals and humans • Knockout mice with BZ-insensitive GABA A receptor a1 subunit are resistant to motor/sedative action of diazepam How widespread? • Formalin test: How useful? – Systemic diazepam was antinociceptive without sedation • Suggests that systemic BZs reduce pain at cord level Knabl J et al. Pain 141 (2009) 233–238. 4 Benzodiazepines Do Help Pain Benzodiazepines Do Not Help Pain • Hydroxyzine, prochlorperazine, chlordiazepoxide vs PBO • 100 chronic pain patients – Adjunctive to analgesics in cancer and arthritic pain – Alprazolam 1.5 mg/d • 9 pts, each exposed to 3 phases with drugs and 1 with PBO – No other interventions – Double-blind, counter-balanced design – Each phase lasted 2 weeks • 83 evaluated at 12 weeks • Assessed – Pre- and post-phase anxiety, depression, hostility – 61 (73.5%) showed improvement – Daily pain, mood, and medication intake – 5 discontinued because of side effects • No antianxiety drug was better than PBO – Mean pain score (0-5 scale) decreased from – For pain, analgesic use or hostility • Chlordiazepoxide 3.6 to 2.2. – Reduced anxiety and depression Westbrook L et al., Clin J Pain. 1990; 6(1):32-6. – Produced most side effects (e.g., drowsiness) Yosselson-Superstine S et al. Isr J Med Sci. 1985; 21(2): 113-7. Midazolam Reduces Morphine Analgesia BZs May Worsen Pain in Mice • ICV midazolam • Mouse model – Produced hyperalgesia on tail flick response – Tail flick, hot plate tests – Attenuated morphine analgesia – Morphine (10 mg/kg) pre-medication – Midazolam or diazepam given i.p. • Both effects antagonized by ICV flumazenil – Both BZs • decreased morphine analgesia • decreased indomethacin analgesia Ito K et al. Eur J Pharmacol. 2008;586(1-3):139-44. Pakulska W, Czarnecka E.Pharmazie. 2001;56(1):89-91. BZs Worsen Sciatica? BZs in Low Back Pain • Acute lumbar disc prolapse with sciatica • Acute LBP • RCT, n = 60 – Diazepam ≡ placebo • Given PT, NSAIDs x 7 days Hingorani K. Ann Phys Med 1996;8:303–6. • Plus placebo vs diazepam • Pain reduction at day 7 • Review of RCTs – 60% vs. 50% reduction of distance of referred pain (p < 0.05) – Little efficacy of diazepam in acute LBP • Hospital LOS – Either no or only minor benefit from BZs in – PBO 8d, BZ 10 days (p = 0.008) chronic LBP • Probability of ≥ 50% pain reduction van Tulder MW et al. Eur Spine J. 2006;15 Suppl 1:S64-81 – Twice as high in placebo patients (p < 0.0015) Brötz