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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

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.

• 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.

Marck A Schuckit. Springer, New York, 2006

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Preferred Drugs on the Street

• Short-acting

– rapid onset

• Highly lipophilic

– e.g., diazepam

• Short half-life and high potency

– lorazepam, alprazolam

• Clonazepam – high potency, long half-life

– Perceived as "safe"

– Frequently abused as a street drug

Roache & Meisch. Psychiatric Annals 1995;25(3):153-7.

BZ Use Patterns

• Recreational abuse of BZs alone is uncommon– Commonly taken as part of polysubstance -abuse

• Motivations– Euphoria

– Augment euphoriant effect of other drugs, especially opiates

• Up to 80% of opiate abusers take BZs

– To ease the "crash" from cocaine

– To ease EtOH sxs

• 29%-33% of alcohol abusers take BZs

Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. Washington, DC, APA, 1990

Nonmedical Use

• 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”

The TEDS Report (Treatment Episode Data Set) 6/2/11

http://oas.samhsa.gov/2k11/028/TEDS028BenzoAdmissions.cfm

The TEDS Report (Treatment Episode Data Set) 6/2/11

• BZ admissions ~tripled from 1998-2008

– Overall CD admissions increased 11%

• Admissions for rx of BZ abuse

– 1.3% of all CD admissions in 1998

– 3.2% in 2008

– 84.8% white, 56% ♂

• 96% also abused other substances

– In > 75% of these, BZ was the 2°drug of abuse

SAMHSA

http://oas.samhsa.gov/2k11/028/TEDS028BenzoAdmissions.cfm

Prevalence of Abuse / Dependence

• Difficult to determine

• 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.

BZs May Worsen Pain in Mice

• Mouse model

– Tail flick, hot plate tests

– Morphine (10 mg/kg) pre-medication

– Midazolam or diazepam given i.p.

– Both BZs

• decreased morphine analgesia

• decreased indomethacin analgesia

Pakulska W, Czarnecka E.Pharmazie. 2001;56(1):89-91.

BZs Worsen Sciatica?

• Acute lumbar disc prolapse with sciatica

• RCT, n = 60

• Given PT, NSAIDs x 7 days

• Plus placebo vs diazepam

• Pain reduction at day 7

– 60% vs. 50% reduction of distance of referred pain (p < 0.05)

• Hospital LOS

– PBO 8d, BZ 10 days (p = 0.008)

• Probability of ≥ 50% pain reduction

– Twice as high in placebo patients (p < 0.0015)Brötz D et al. Pain 2010;149:470–475

BZs in Low Back Pain

• Acute LBP

– Diazepam ≡ placebo Hingorani K. Ann Phys Med 1996;8:303–6.

• Review of RCTs

– Little efficacy of diazepam in acute LBP

– Either no or only minor benefit from BZs in chronic LBP

van Tulder MW et al. Eur Spine J. 2006;15 Suppl 1:S64-81

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BZs in Back Pain – Cochrane Review

• 8 trials of BZs– Duration 5-14 days

• Acute LBP– 1 high quality trial found diazepam ≡ placebo

– Another (lower quality) found diazepam > PBO (pain, overall improvement)

• Chronic low back pain– 2 high quality trials

– Tetrazepam increased odds of not experiencing pain relief or global improvement

– Lower quality, placebo controlled trial of diazepam found no benefit

Chou & Huffman, Ann Intern Med. 2007;147:505-514.

BZ Antagonism Reduces Postop Pain

• After pre-op diazepam, flumazenil (BZ antagonist) reduced postop morphine, NSAID requirement

Gear RW et al, Pain 1997

• 32 herniorraphy patients

– DB, RCT

– PRN analgesia:

• MS 2 mg vs MS 2 mg + flumazenil 0.2 mg

– Flumazenil patients

• Less morphine (14.1 vs 9.5)

• More comfortableWeinbroum AA et al. Clin J Pain. 2000;16(3):193-199.

Efficacy in Chronic Use Challenged –UK – Committee on Review of Medicines - 1980

• Noted lack of firm evidence of efficacy of … long-term BZs in insomnia and anxiety.

• US IOM, White House Office of Drug Policy, and NIDA concurred:

– “There is little evidence that sedative hypnotics, including BZs, continue to be effective when used nightly over long periods.”

• Most hypnotics lose sleep-promoting properties within 3-14 days’ continuous use.

• Little evidence that BZs help anxiety after 4 months.

Committee on Review of Medicines, BMJ 1980;2:719-720

Most Use Is Long Term

Based on several US drug surveys:

•Griffiths & Weeks calculated:

•Almost 90% of anxiolytics and > 80% of hypnotics sold in the US were consumed by people reporting daily use x ≥ 4 months

•Continuous users account for ~70% of anxiolytic and 60% of hypnotic drug sales.

Griffiths RR, Weerts EM: Psychopharmacology (1997) 134:137

Does Prolonged Use Worsen Anxiety?

• Long-term BZ users may have less anxiety after discontinuation

Ashton 1987; Cantopher et al. 1990; Rickels et al. 1990; Schweizer et al. 1990

• And less anxiety than continued usersRickels et al. 1991

• Conclusion: some chronic BZ use may be maintained by preventing rebound anxiety or withdrawal rather than reducing anxiety

Griffiths & Weerts. Psychopharmacology (Berl) 1997;134(1):1-37 .

BZ Starters – Rate of Attrition

D Isacson et al. J Clin Epidemiol 1992;45(4):429-436,

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BZ Use in Chronic Pain

• N = 114 chronic pain patients

– Academic pain management service

• 38% taking ≥ 1 BZ at assessment, of whom:

– 46% ≥ 2 years

– 58% concomitant opioids

– 86% using (all / in part) for sleep

• As many sleep problems as non-BZ group

• No signs of excessive intake

– But only 1 patient stopped benzodiazepines King SA, Strain JJ. Clin J Pain 1990;6(2):143-147.

Conclusions So Far

• BZs are heavily used in chronic pain

• Addiction (as usually understood) is uncommon

• Evidence of acute benefit is small

• Evidence of chronic benefit is absent

• Use tends to be chronic

Adverse Effects

The Down Side

Accidents

• Synergistic toxicity with other depressants

– Fatal overdoses in combination with EtOH, opiates

• Falls, hip / femur fractures

• Increased MVAsLongo LP, Johnson B. Am Fam Physician. 2000;61(7):2121-8

• N = 1213 forensic autopsies

– Active participant in MVA (driver, pedestrian)

– Ethanol – 34.7%

– BZs – 3.6%

– THC – 2.2%Mravcík V et al. Cent Eur J Public Health 2007;15(4):158-62

Rebound

• Likely after 4 mo of regular, daily dosing

– Withdrawal and rebound symptoms

– Sufficiently severe to hamper weaning

– 0-40% dependent after 6 mo of treatment

• Double-blind, controlled, prospective studies

– 4-8 months is critical time for development of therapeutic dose dependence

• Duration > dose as predictor of dependence

Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. Washington, DC,

APA, 1990

Physical Dependence

• N = 48 patients with panic disorder

• Alprazolam 4-10 mg/d x 8 mo

– χ = 5.2 mg/d

• 4 week taper

• 90+% had marked withdrawal symptoms

• Prevented discontinuation in 33%

Rickels K et al. Arch Gen Psychiatry. 1993;50(1):61-8

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Benzodiazepines – A Cause of Depression?

• Numerous case series describe onset / exacerbation of depression after BZ initiation

• Affect tended to normalize with dose reduction or elimination

• Clinical trials of anxiety disorders report depression as a side effect

• Overall, risk seems small in therapeutic use

Smith & Salzman. Hosp Community Psychiatry. 1991;42(11):1101-2.

Depression from BZs

• Cleveland Clinic Data

Chronic Pain Rehabilitation Program

–Patients on opioids or BZs had higher depression scores than those receiving neither.

–Direction of causality cannot be determined.

Dan Fishman, 2010 unpublished

“Downhill Spiral”

Does chronic opioid use lead to a downhill spiral?

•Retrospective study: n = 243 consecutive patients

•Answer – yes, but …

•Association between poor status and opioid use disappeared when controlled for BZs

•Benzodiazepine use was associated with:

– Functional impairment

– Healthcare utilization

– Depression

– Pain

•Effects were smallCiccone DS, et al. J Pain Symptom Manage. 2000;20:180–192.

Opioids + Sedatives and Status

• N = 150 chronic pain patients – Referred for psych evaluation

• Opioids and opioid + sedative groups– More pain-related surgeries, drug expense,

hospitalizations, functional impairment, daytime reclining

Turner JA et al. Pain 1982; 12:357-363

Effects on Cognition

• Literature is contradictory

• Heterogeneity of psychiatric diagnoses

• Concomitant use of alcohol, other drugs

• Variable doses

• Variable definitions of long-term use

• Variable time since last dose

• Effect of anxiety on test performance

Cognitive Effects of BZs

• Acute

– Traveler’s amnesia

– Perform normally

– Recall acutely

– Later no recallStewart SA, J Clin Psychiatry 2005;661Suppl 21:9-13

• Impair consolidation phase, without impairing sensory intake or retention

– A person who has taken a BZ will remember what he has just been told, but may be unable to recall it later.

Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. Washington, DC,

APA, 1990

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Anterograde Amnesia

• High-dose IV for presurgical anesthesia

• Therapeutic po doses of short T½, high-potency BZs

– Especially if with alcohol

• Impairment of memory after po dose

– Most common deficit is impaired acquisition of new material after a delay in time

– Not associated with degree of psychomotor impairment and sedation

– No effect on the recall of information learned prior to dosing

• The elderly are more vulnerableBenzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the

American Psychiatric Association. Washington, DC, APA, 1990

Early Findings of Cognitive Impairment

• 196 admissions to Hopkins Pain Treatment Center

– Compared users of BZs, opioids, both, neither

– EEG, WAIS, Memory Quotient, and Bender Gestalt

• Patients taking BZs alone

– Reduced cognition in 10/13

– EEG slowing or fast waves in 8/13

• 40/106 were taking both BZs + opioid at admission

Hendler N et al. Am J Psychiatry 1980;137(7):828-831

Cognitive Effects of Long-Term BZs

• Meta-analysis– 13 studies – neuropsychological tests

– Mean age – 47.6 (21–75) years

– Mean dose ≈ 17.2 mg/d diazepam

– Mean BZ use – 9.9 (1-34) yrs

• Tests categorized into 12 domains

• Long-term BZ users more impaired than controls in all categories

• Effect sizes: –1.30 to to –0.42 (χ = –0.74)

– Moderate-to-large, suggesting significantly impaired vs controls in all areas

Barker MJ et al. CNS Drugs. 2004;18(1):37-48

• 13 studies

– Use – 10 (1-29) years

– Age – 47.1 (21-75)

– Mean time between initial and post-withdrawal assessment = 3 mo

– 80% excluded hx heavy alcohol/drug use

Barker MJ et al. Arch ClinNeuropsychology 2004;19:437-454

Cognition Following Withdrawal of Long-Term Benzodiazepines

BZ + Opioid Lethality

• Medullary ventral respiratory group

– Excitation mediated by EAAs, e.g. glutamate

– Inhibition mediated via GABA, especially GABAA

– Activated by BZs, alcohol, barbiturates

• µ and δ agonists depress respiration mostly via ↓ in glutamate-induced excitation

• Many (most?) ODs are due to combined effects of opioids + other drugs

– Mostly alcohol and BZs

– Weak respiratory depressants but augment morphine

White & Irvine. Addiction 1999;94(7):961-72.

• In 2006

• About half of all U.S. opioid-related deaths involved more than one drug

• Benzodiazepines were mentioned most frequently

• Involved in 17% of the deaths

Warner M et al. NCHS Data Brief 2009;22:1–8.

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Prescription Drug Fatalities:Women in Rural Virginia

• n=330 medical examiner cases

• Most common drug classes detected

– opioids (72.4%)

– antidepressants (60.9%)

– sedative/anxiolytic/muscle relaxant (48.8%)

– all three classes in 27%

Wunsch MJ et al. J Opioid Manag. 2009; 5(4):228-36.

Utah Overdose Deaths –“Significant Other” Interviews

• n= 432 OD deaths

– 10/08-10/09.

– 278 involved at least one opioid

– 240 no illicit drugs

– 38 ≥ one illicit

– interviews on 385

• Commonly mentioned drugs:

– Oxycodone > methadone, hydrocodone and alprazolam.

• 83% of decedents had chronic pain.

Johnson E. http://health.utah.gov/prescription/advisory%20committee/UtahDrugOverdoseDecedentInterviewsReport2009.pdf

Increased Mortality in BZ Users

• Two Norwegian counties

• Cohort of 14,951

– Aged 40–42 years

– Excluded hx of CV disease, DM

– Health surveys in 1985–1989

– Mean follow-up 18 years

• Risk of death increased with frequency of BZ use

– OR for daily anxiolytics/hypnotics were 3.1♂ and 2.7♀

– After adjusting for painkiller use and smoking:hazard ratios 2.4 ♂ and 2.1 ♀

Hausken AM et al. Pharmacoepidemiol Drug Saf 2007;16(8):91318.

Use in Pain – Actual Practice

Which Pain Patients Receive BZs

“Operant Pain Patients”Use / Misuse More Drugs

• N=106

– Psychiatric pts with pain

– Hospital pts with psych consult

– Computerized interview

• Scored pain for operant vs respondent characteristics

• Operant pain patients

– More likely to use minor tranquilizers, sedatives, antidepressants and opioids

– More likely to misuse themZiesat HA et al. Addict Behav. 1979;4(3):263-6.

Predictors of Prolonged / High Dose Use

1) Current or prior sedative / hypnotic dependence

– Including alcohol and BZs

2) Chronic medical or psychiatric illnesses

3) Chronic dysphoria and/or personality disorders (borderline or dependent)

4) Chronic sleep difficulties Benzodiazepine Dependence, Toxicity, and Abuse: A Task

Force Report of the American Psychiatric Association. Washington, DC, APA, 1990

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In Practice –Patients at Highest Risk Receive the Most Drugs

• N = 4 million

• Prevalence of long-term opioid use for CNMP by drug or alcohol diagnosis and opioid diagnosis in the prior 2 years.

• Individuals with SUDs:– higher dose regimens

– more days supply

– more likely to receive Schedule II opioids

– Twice the rates of concurrent sedative-hypnotics

– More likely to receive 180+ days of sedative-hypnotics

• Similar patterns (p<0.0001) when comparing persons with opioid use disorder to those without an opioid use disorder.

Constance M et al. Pain 145 (2009) 287–293

Kaiser Northern California (solid)Group Health (dashed)

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BZ Use Predicts Opioid UseMore than Does Pain

• N = 17,074 who were opioid free in 2000–2001

• Linked to Norwegian Prescription Database during 2004–2007

• OR for moderate-high prescription frequency of opioids for previous BZ users was 7.7

• BZ use was stronger predictor of opioid use than pain

• Benzodiazepine users had more disability, CV disease and musculoskeletal pain

Skurtveit S. Pain Medicine 2010; 11: 805–814

High Opioids Predict BZ Prescription

• N = 478 veterans with CNMP

– Taking ≥ 180 mg/d MS equivalentχ = 324.9 mg/d

– 90+ consecutive days • VS

– Traditional-dose (5-179 mg/day; n=500)

– No opioid (n=500)

• High-dose patients

– more likely to have ≥ 4 pain diagnoses

– highest rates of medical, psychiatric, and substance use disorders

– 32.0% of high dose received concurrent BZ rxMorasco BJ et al. Pain 2010;151(3):625-32.ix

% using BZs

High dose

Low dose

None

Cleveland ClinicChronic Pain Rehabilitation Program

• Of 100 consecutive opioid-addicted patients

• 66 also used bzs

• 23 abused bzs

• 26 used non bz hypnotics

• 4 abused non bz hypnotics

• 7 used Soma

• 2 abused Soma

• 22/100 used none of these

Cleveland ClinicChronic Pain Rehabilitation Program

• 27 consecutive pts diagnosed with sedative/hypnotic abuse / dependence

– 2000-2009

• 23 also had opioid abuse/dependence

• Of the remaining 4

– 2 also abused alcohol

– 1 abused alcohol and barbiturates

– 1 abused non-benzodiazepine hypnoticsUnpublished data

Summary –Benzodiazepines in Chronic Pain

• BZ use disorders comprise a very small portion of addictive disorders in the US and world wide

– Despite the fact that 12% of adults and 40% of pain patients use or have used them

• Many (most?) addicts, with or without chronic pain, use BZs

– Alcoholics, opioid addicts, cocaine addicts

• BZs probably do not help pain, and they impair function

• Patients usually don’t escalate doses, no handsfulls of pills

• But they can’t stop

• Are they addicted?

– Tolerance, dependence, inability to stop, no misuse

– Consequences? They attribute to pain, others attribute to opioids, but some portion of impairment is likely bz-related.

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Summary –Benzodiazepines in Chronic Pain

• There is a group of people with chronic pain who use both opioids and bzs

– Often in high doses

• They have high levels of:

– Functional impairment

– Pain

– Addiction

– Psychiatric comorbidity

• The direction of the arrow of causality is unclear

• They improve with weaning

Non-BZ Hypnotic Abuse

• Abuse and dependence with zolpidem and zopiclone (non US drug, similar to eszopiclone)

• Mostly in patients with prior SUD, other psychiatric conditions.

• French experience:

– In 1993 <1% of abuse / dependence reports included zolpidem

– By 2002 almost 5.5%

– 6th most common rx forgery in 1998 and #1 by 2004.

– Surveys of drug abusers: Patients using zolpidem increased from <1% in 1998 to 4% in 2001.

– Nearly all patients abusing zolpidem were abusing more than one drug, 1/2 also using a benzodiazepine and 4/10 using cannabis.

Carson S et al. , McDonagh MS, Thakurta S, et al. Drug Class Review: Newer Drugs for Insomnia: Final Report Update 2 [Internet]. Portland (OR): Oregon

Health & Science University; 2008

What are we doing?What should we do?

• The worst candidates are prescribed the most sedatives

• This probably worsens functional impairment and quality of life

• Therefore –Management should include weaningReplacement with alternate therapies for anxiety, sleep

Weaning / Detoxification

• Not the focus of this presentation

• However:

– Many AEDs permit patients to comfortably and rapidly reduce / eliminate BZs, Soma, and non-BZ hypnotics

• Examples

– Pregabalin

– Valproic acid

– Gabapentin

– Carbamazepine

• Extended use may be required for subtle protracted withdrawal

Gabapentenoids Ease BZ Reduction

• Compared pregabalin to gabapentin

• Norwegian Prescription Database

• All prescriptions for the two drugs 2004-2007

• Patients – Psychiatric

– Epilepsy

– Neuropathic pain

– Non-specified

• Measured use of BZs 182 days before and after initiation of pregabalin and gabapentin

• 15%-29% of patients were able to stop using BZsafter starting pregabalin or gabapentin.

Bramness JG, et al. Basic Clin Pharmacol Toxicol. 2010

Pregabalin for Alcohol Withdrawal

• Lorazepam vs pregabalin and tiapride in alcohol withdrawal

• N=111

– 3 groups

– Treatment duration =14 d

– Maximum daily doses:pregabalin 450 mg, tiapride 800 mg, lorazepam 10 mg

• All showed reduction in CIWA-Ar score over time

• Pregabalin group

– 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

10

12

14

16

18

20

22

24

26

28

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.

14

Duloxetine in GAD(Major depression excluded)

Koponen H, et al. Anxiety Disorders Association of America 2006.

Placebo (n=175) Duloxetine 120 mg/day (n=170)Duloxetine 60 mg/day (n=168)

*** P <.001 vs placebo

* P <.05 vs placebo

Mean Change in Sheehan Disability

Scale (self-rated impairment from 0–10)

-4

-2

-6

-8

-10

******

Global

*** ***

Work

*** ***

Social

*** ***

Family/Home0

Mean Change in Total HAM-A Score

Treatment week

***

***

-8

0

-4

-12

-16

//

2

***

***

7

***

***

4

***

***

LOCF

***

***

1010

//

Antiepileptics in Anxiety Disorders

• Strongest placebo-controlled evidence

– Pregabalin• Social phobia

• GAD

• Smaller/less-robust controlled trials

– Gabapentin• Social phobia

– Lamotrigine• Post-traumatic stress disorder

– Valproic acid• Panic disorder

Van Ameringen M, et al. Drugs. 2004;64:2199–2220.

AEDs vs Benzodiazepines for Anxiety

• Evidence is present, but not conclusive:

• Function

– Benzodiazepines impair function

– AEDs improve function

• Addiction

– Benzodiazepines pose addiction risk

– AEDs lack addiction risk

• Pain

– Benzodiazepines lack analgesic effects

– AEDs diminish neuropathic pain, migraine, visceral hyperalgesia

Conclusions

• Despite being among the most used of all drugs, rates of addiction and abuse are low.

• Issue appears to be impairment > addiction

• Toxicity with opioids – especially high dose – is a serious concern

• Sedative abuse / dependence in CNMP is relatively uncommon

• Functional impact is likely to be major

– Especially in combination with multiple other psychoactive substances

– In people who are already impaired

• Evidence of benefit in chronic pain is minimal

Final Conclusions

• Benzodiazepines / sedatives are probably mildly harmful for many CNMP patients

• They are seriously harmful for a few

• Alternatives exist that Facilitate weaningImprove pain / function

• Suggestions

– Very short term use only

– Wean those taking them long term

– Use antidepressants, AEDs for anxiety, sleep