1. No category

Why the Interest?
Benzodiazepines
in Chronic Pain
Edward Covington, MD
Cleveland Clinic Foundation
• 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
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
• 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
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
Lader, M: J Subs Abuse Treatment 1991;8:53-59
1
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 BZs
8/18 studies in primates and rats did not show evidence of reinforcement
•IV
Reinforcement 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.
BZ Abuse in the Community
Conflicting information
Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force
Report of the American Psychiatric Association. Washington, DC,
APA, 1990
“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 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
• 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.
Nonmedical Use
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
The TEDS Report
(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
(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.
3
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
Diazepam Antihyperalgesic in Mice
Benzodiazepine Use in Pain
How widespread?
How useful?
• 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.
4
Benzodiazepines Do Help Pain
Benzodiazepines Do Not 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.
•
•
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
BZs May Worsen Pain in Mice
• Mouse model
• ICV midazolam
– Produced hyperalgesia on tail flick response
– Attenuated morphine analgesia
– Tail flick, hot plate tests
– 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.
BZs Worsen Sciatica?
•
•
•
•
Pakulska W, Czarnecka E.Pharmazie. 2001;56(1):89-91.
BZs in Low Back Pain
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)
• 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
Brötz D et al. Pain 2010;149:470–475
5
BZs in Back Pain – Cochrane Review
BZ Antagonism Reduces Postop Pain
• After pre-op diazepam, flumazenil (BZ
antagonist) reduced postop morphine, NSAID
requirement
• 8 trials of BZs
– Duration 5-14 days
• Acute LBP
Gear RW et al, Pain 1997
– 1 high quality trial found diazepam ≡ placebo
– Another (lower quality) found diazepam > PBO (pain,
overall improvement)
• 32 herniorraphy patients
– DB, RCT
– PRN analgesia:
• 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
• MS 2 mg vs MS 2 mg + flumazenil 0.2 mg
– Flumazenil patients
• Less morphine (14.1 vs 9.5)
• More comfortable
Chou & Huffman, Ann Intern Med. 2007;147:505-514.
Weinbroum AA et al. Clin J Pain. 2000;16(3):193-199.
Efficacy in Chronic Use Challenged –
Most Use Is Long Term
UK – Committee on Review of Medicines - 1980
• Noted lack of firm evidence of efficacy of … long-term
BZs in insomnia and anxiety.
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.
• 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 314 days’ continuous use.
Griffiths RR, Weerts EM: Psychopharmacology (1997) 134:137
• Little evidence that BZs help anxiety after 4 months.
Committee on Review of Medicines, BMJ 1980;2:719-720
Does Prolonged Use Worsen Anxiety?
BZ Starters – Rate of Attrition
• 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 users
Rickels 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
.
D Isacson et al. J Clin Epidemiol 1992;45(4):429-436,
6
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
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
King SA, Strain JJ. Clin J Pain 1990;6(2):143-147.
Accidents
• Synergistic toxicity with other depressants
– Fatal overdoses in combination with EtOH, opiates
Adverse Effects
• Falls, hip / femur fractures
• Increased MVAs
Longo LP, Johnson B. Am Fam Physician. 2000;61(7):2121-8
The Down Side
• 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
7
Benzodiazepines – A Cause of
Depression?
Depression from BZs
• Numerous case series describe onset /
exacerbation of depression after BZ initiation
• Cleveland Clinic Data
• Affect tended to normalize with dose
reduction or elimination
• Clinical trials of anxiety disorders report
depression as a side effect
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
• Overall, risk seems small in therapeutic use
Smith & Salzman. Hosp Community Psychiatry. 1991;42(11):1101-2.
“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 small
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
Ciccone DS, et al. J Pain Symptom Manage. 2000;20:180–192.
Effects on Cognition
Cognitive Effects of BZs
• Acute
•
•
•
•
•
•
•
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
–
–
–
–
Traveler’s amnesia
Perform normally
Recall acutely
Later no recall
Stewart 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
8
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 vulnerable
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
Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the
American Psychiatric Association. Washington, DC, APA, 1990
Cognitive Effects of Long-Term BZs
Cognition Following Withdrawal of
Long-Term Benzodiazepines
• 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
• 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 Clin
Neuropsychology 2004;19:437-454
Barker MJ et al. CNS Drugs. 2004;18(1):37-48
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
• 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.
White & Irvine. Addiction 1999;94(7):961-72.
9
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%
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.
Wunsch MJ et al. J Opioid Manag. 2009; 5(4):228-36.
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 ♀
Use in Pain – Actual Practice
Which Pain Patients Receive BZs
Hausken AM et al. Pharmacoepidemiol Drug Saf 2007;16(8):91318.
“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 them
Ziesat 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
10
BZ Use Predicts Opioid Use
Patients at Highest Risk Receive the Most Drugs
More than Does Pain
•
•
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
•
Prevalence (%) long-term opioid use
In Practice –
Kaiser Northern California (solid)
Group Health (dashed)
Similar patterns (p<0.0001)
when comparing persons with
opioid use disorder to those
without an opioid use disorder.
• 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
Constance M et al. Pain 145 (2009) 287–293
Cleveland Clinic
High Opioids Predict BZ Prescription
Chronic Pain Rehabilitation Program
% using BZs
• N = 478 veterans with CNMP
– Taking ≥ 180 mg/d MS equivalent
χ = 324.9 mg/d
– 90+ consecutive days
• VS
High dose
– Traditional-dose (5-179 mg/day; n=500)
Low dose
None
– 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 rx
•
•
•
•
•
•
•
•
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
Morasco BJ et al. Pain 2010;151(3):625-32.ix
Summary –
Benzodiazepines in Chronic Pain
Cleveland Clinic
Chronic 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 hypnotics
•
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
•
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?
– Alcoholics, opioid addicts, cocaine addicts
– 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.
Unpublished data
11
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?
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
• The worst candidates are prescribed the most
sedatives
• This probably worsens functional impairment
and quality of life
• Therefore –
Management should include weaning
Replacement with alternate therapies for
anxiety, sleep
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
Pregabalin for Alcohol Withdrawal
•
•
•
•
• Measured use of BZs 182 days before and after
initiation of pregabalin and gabapentin
• 15%-29% of patients were able to stop using BZs
after starting pregabalin or gabapentin.
Bramness JG, et al. Basic Clin Pharmacol Toxicol. 2010
•
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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Parsimonious Polypharmacy
Analgesic
Anxiolytic
Alternatives
β-blockers
AEDs
Neuroleptics?
Benzodiazepines
NSAIDs
Local anesthetics
Topicals
Antiarrhythmics
Opioids
TCAs
SNRIs
If not benzodiazepines,
carisoprodol, hypnotics
Then what?
SSRIs
Bupropion
Antidepressant
TCAs for Anxiety
Antidepressants for GAD
• Strongly anxiolytic
• Review of RCTs
– Doxepin is as anxiolytic as diazepam
– Imipramine
– Venlafaxine
– Paroxetine
– All superior to placebo
d'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
Kapczinski F, et al. Cochrane Database Syst Rev. 2003;(2):CD003592.
Pregabalin & Venlafaxine in GAD
Generalized Anxiety Disorder
28
Moderate to Marked Improvement
Mean HAM-A Score
80
Percent
70
60
50
40
30
24
Placebo (n=100)
18
16
14
12
10
Base
Trazodone Imipramine
Placebo
Rickels K et al. Arch Gen Psychiatry. 1993;50:884-895.
VENLA-75 mg/day (n=110)†
20
10
Diazepam
PGB-600 mg/day (n=104)*
22
20
0
PGB-400 mg/day (n=94)*
HAM-A Total
Score
26
Wk 1
Wk 2
Wk 3
Wk 4
Week
Wk 6 LOCFEnd
*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.
13
Duloxetine in GAD
Antiepileptics in Anxiety Disorders
(Major depression excluded)
Mean Change in Sheehan Disability
Scale (self-rated impairment from 0–10)
Mean Change in Total HAM-A Score
Treatment week
0
1
2
4
7
10
LOCF
0
0
Global
Work
Social Family/Home
-2
-4
*** ***
-8
*** ***
*** ***
-4
***
//
***
-12
***
***
***
-16
***
***
//
***
-8
-10
Placebo (n=175)
• Smaller/less-robust controlled trials
– Gabapentin
– Lamotrigine
***
***
***
• Social phobia
• GAD
• Social phobia
-6
***
• Strongest placebo-controlled evidence
– Pregabalin
Duloxetine 60 mg/day (n=168)
• Post-traumatic stress disorder
*** P <.001 vs placebo
* P <.05 vs placebo
– Valproic acid
• Panic disorder
Duloxetine 120 mg/day (n=170)
Van Ameringen M, et al. Drugs. 2004;64:2199–2220.
Koponen H, et al. Anxiety Disorders Association of America 2006.
AEDs vs Benzodiazepines for Anxiety
Conclusions
• Evidence is present, but not conclusive:
• Function
• 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
– 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
– 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 weaning
Improve pain / function
• Suggestions
– Very short term use only
– Wean those taking them long term
– Use antidepressants, AEDs for anxiety, sleep
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