1 Benzodiazepines in Chronic Pain Edward Covington, MD Cleveland Clinic Foundation Why the Interest? • 33 years in chronic pain rehabilitation • Many patients are dysfunctional, depressed, regressed, and cognitively impaired while taking opioids plus benzodiazepines. • Engendered a negative attitude • Stimulated curiosity about what we do and do not know about these drugs in pain patients, especially in combination with opioids Disclaimer Much of the data that I could find is quite old History • 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 • Chlordiazepoxide introduced in 1960 • Addictiveness and lethality of barbiturates (and similar drugs) led to their replacement by BZs • Use of BZs increased dramatically – US sales peaked in 1975 – Anxiolytics / hypnotics accounted for 10% of all prescriptions • WHO recommended scheduling BZs in the early 1980s Lader, M: J Subs Abuse Treatment 1991;8:53-59 Benzodiazepine Use in America • BZs are the most prescribed CNS depressants • Estimated past year prevalence of BZ use in the USA = 12.9% • 14.2% of these have taken the drug ≥ 12 mo Barker MJ et al. Arch Clin Neuropsychology 2004;19:437-454 • About 100 million prescriptions in 1999 DEA
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Why the Interest? Benzodiazepines in Chronic Pain · 2018-11-19 · misuse • 7.1% reported non-prescribed use • Lifetime prevalence of self-perceived sedative dependence was 0.5%
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Benzodiazepines in Chronic Pain
Edward Covington, MD
Cleveland Clinic Foundation
Why the Interest?
• 33 years in chronic pain rehabilitation
• Many patients are dysfunctional, depressed, regressed, and cognitively impaired while taking opioids plus benzodiazepines.
• Engendered a negative attitude
• Stimulated curiosity about what wedo and do not know about thesedrugs in pain patients, especiallyin combination with opioids
Disclaimer
Much of the data that I could find is quite old
History
• 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
• Chlordiazepoxide introduced in 1960
• Addictiveness and lethality of barbiturates (and similar drugs) led to their replacement by BZs
• Use of BZs increased dramatically
– US sales peaked in 1975
– Anxiolytics / hypnotics accounted for 10% of all prescriptions
• WHO recommended scheduling BZs in the early 1980s
Lader, M: J Subs Abuse Treatment 1991;8:53-59
Benzodiazepine Use in America
• BZs are the most prescribed CNS depressants
• Estimated past year prevalence of BZ use in the USA = 12.9%
• 14.2% of these have taken the drug ≥ 12 moBarker MJ et al. Arch Clin Neuropsychology 2004;19:437-454
• About 100 million prescriptions in 1999DEA
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Mechanism of Tranquilization
• GABA binding permits Cl- influx
• Hyperpolarizes cell, rendering it less excitable
• BZ binds to GABAA receptor
• Potentiates GABA effect– Increases opening frequency
• Cell becomes more refractory
• Subtypes of BZ receptors– α1 – sedative
– α2 – anxiolytic
– α1, α2, and α5 – anticonvulsant
– All BZs bind, to variable extents, with all subtypes
How Reinforcing are BZs?
Humans
•Normal (light drinkers without anxiety or insomnia)
– BZ (diazepam, lorazepam, flurazepam) not preferred to placebo
•Moderate social drinkers, no hx alcohol problems
– Benzodiazepines (po) are reinforcers
– Three studies confirm
Animals
•Oral BZs8/18 studies in primates and rats did not show evidence of reinforcement
•IVReinforcement demonstrated with alprazolam, chlordiazepoxide, clorazepate, clonazepam, diazepam, flurazepam, lorazepam, bromazepam, medazepam, midazolam, and triazolam
• Most chronic benzodiazepine users do not escalate their original dose, even after many years.
• The reinforcing effects are considerably weaker than other sedative hypnotics, 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
BZ Abuse in the Community
Conflicting information
“Pharmacies Besieged by Addicted Thieves”
The New York Times
February 6, 2011
• More than 1,800 US pharmacy robberies in the last three years
• The most common targets are oxycodone, hydrocodone, and Xanax.
Street Prices 2006
• Diazepam and clonazepam ≈ $2.00-$4.00/pill
• Many who seek these drugs for a "high" quickly move on to other agents
• High risk for continued misuse of BZs:
– Heroin dependent / methadone maintenance
• 75%+ admitted taking BZs to enhance intoxication or treat withdrawal
– Alcoholic
• Perhaps for anxiety, insomnia, withdrawal sxsDrug and alcohol abuse: a clinical guide to diagnosis and treatment.
• 2002 survey: ≈ 200,000 Americans treated for sedative / hypnotic use
– often in the context of other SUD
• During the same period
– 2.2 million received rx for EtOH-related disorders
– 100 times more
– Rate of treatment for alcoholism was ≈1% of the population, treatment for CNS depressants was 0.07%
Wesson. D. R.. Smith. D. E.. Ling. W.. & Seymour. R. B. Sedative-hypnotics. In J. H. Lowinson. P. Ruiz, R. B. Millman, & J. G. Langrod (Eds.). Substance Abuse: A
Comprehensive Textbook (4th cd.). Baltimore. MD: Lippincott. Williams & Wilkins. 2004. pp. 302-312.
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Prevalence of Substance Use Disorder
• Substance use disorder develops in 5-10%
• Up to 10% of general medical/surgical patients and 30% of patients with serious psychiatric histories have felt psychologically dependent on antianxiety or hypnotic drugs
Wesson DR et al. in JH Lowinson, P Ruiz, RB Millman, JG Langrod(Eds.). Substance Abuse: A Comprehensive Textbook (4th ed.).
Baltimore. MD: Lippincott. Williams & Wilkins. 2004. pp. 302-312.
National Comorbidity Survey
• N = 8098– representative sample of adults
• 17.0% had been prescribed sedatives, denied misuse
• 7.1% reported non-prescribed use
• Lifetime prevalence of self-perceived sedative dependence was 0.5%
• Sedative use and misuse associated with
– psychopathology
– 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
Benzodiazepine Use in Pain
How widespread?How useful?
Diazepam Antihyperalgesic in Mice
• Loss of DH inhibition is a major factor in chronic pain
• Spinal BZs are profoundly antihyperalgesic in animals and humans
• Knockout mice with BZ-insensitive GABAA receptor a1 subunit are resistant to motor/sedative action of diazepam
• Formalin test:
– Systemic diazepam was antinociceptive without sedation
• Suggests that systemic BZs reduce pain at cord level
Knabl J et al. Pain 141 (2009) 233–238.
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Benzodiazepines Do Help Pain
• 100 chronic pain patients
– Alprazolam 1.5 mg/d
– No other interventions
• 83 evaluated at 12 weeks
– 61 (73.5%) showed improvement
– 5 discontinued because of side effects
– Mean pain score (0-5 scale) decreased from 3.6 to 2.2.
Westbrook L et al., Clin J Pain. 1990; 6(1):32-6.
Benzodiazepines Do Not Help Pain
• Hydroxyzine, prochlorperazine, chlordiazepoxide vs PBO
– Adjunctive to analgesics in cancer and arthritic pain
• 9 pts, each exposed to 3 phases with drugs and 1 with PBO
– Double-blind, counter-balanced design
– Each phase lasted 2 weeks
• Assessed
– Pre- and post-phase anxiety, depression, hostility
– Daily pain, mood, and medication intake
• No antianxiety drug was better than PBO
– For pain, analgesic use or hostility
• Chlordiazepoxide
– Reduced anxiety and depression
– 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
• ICV midazolam
– Produced hyperalgesia on tail flick response
– Attenuated morphine analgesia
• Both effects antagonized by ICV flumazenil
Ito K et al. Eur J Pharmacol. 2008;586(1-3):139-44.
– Higher reduction on headache and orientation (P < 0.01)
– Larger number remaining alcohol free (P < 0.05).
• Efficacy of pregabalin was superior to tiapride, used largely in research trials and, for some measures, to that of the 'gold standard', lorazepam.
Martinotti G et al. Addiction. 2010;105(2):288-99
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Alternatives
If not benzodiazepines, carisoprodol, hypnotics
Then what?
Antidepressant
TCAs SNRIs
NSAIDsLocal anesthetics
TopicalsAntiarrhythmics
Opioids
SSRIs
Benzodiazepines
Anxiolytic Analgesic
Bupropion
β-blockersAEDs
Neuroleptics?
Parsimonious Polypharmacy
TCAs for Anxiety
• Strongly anxiolytic
– Doxepin is as anxiolytic as diazepamd'Elia G, et al. Acta Psychiatr Scand Suppl. 1974;255:35–46.
Bianchi GN, Phillips J. Psychopharmacologia 1972;25:86–95
• Additional benefits
– Promote sleep
– Reduce neuropathic pain, fibromyalgia and migraine
– Improve mood
Antidepressants for GAD
• Review of RCTs
– Imipramine
– Venlafaxine
– Paroxetine
– All superior to placebo
Kapczinski F, et al. Cochrane Database Syst Rev. 2003;(2):CD003592.
Generalized Anxiety Disorder
Rickels K et al. Arch Gen Psychiatry. 1993;50:884-895.
Perc
en
t
0
10
20
30
40
50
60
70
80
Diazepam Trazodone Imipramine Placebo
Moderate to Marked Improvement
Pregabalin & Venlafaxine in GAD
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12
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Base Wk 1 Wk 2 Wk 3 Wk 4 Wk 6 LOCF-
End
Mean
HA
M-A
Sco
re
PGB-400 mg/day (n=94)*
PGB-600 mg/day (n=104)*
VENLA-75 mg/day (n=110)
Placebo (n=100)
Week
†
HAM-A Total Score
*PGB (400 mg and 600 mg) significant vs placebo Weeks 1 through 6.†VENLA significant vs placebo Weeks 2 through 6.PGB = pregabalin; VENLA = venlafaxine
Montgomery SA, et al. J Clin Psychiatry 2006;67:771–82.
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Duloxetine in GAD(Major depression excluded)
Koponen H, et al. Anxiety Disorders Association of America 2006.