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Benzodiazepines in Chronic Pain:
Benefits, Risks, Abuse
Edward Covington, MD
Cleveland Clinic Foundation
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Edward Covington, Disclosures
• None related
The contents of this activity may include discussion of off label or investigative drug uses. The faculty is
aware that is their responsibility to disclose this information.
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Planning Committee, Disclosures
AAAP aims to provide educational information that is balanced, independent, objective and free of bias
and based on evidence. In order to resolve any identified Conflicts of Interest, disclosure information
from all planners, faculty and anyone in the position to control content is provided during the planning
process to ensure resolution of any identified conflicts. This disclosure information is listed below:
The following developers and planning committee members have reported that they have no
commercial relationships relevant to the content of this webinar to disclose: AAAP CME/CPD
Committee Members Dean Krahn, MD, Kevin Sevarino, MD, PhD, Tim Fong, MD, Tom Kosten,
MD, Joji Suzuki, MD; and AAAP Staff Kathryn Cates-Wessel, Miriam Giles, Sharon Joubert
Frezza, and Justina Andonian.
All faculty have been advised that any recommendations involving clinical medicine must be based on evidence that is
accepted within the profession of medicine as adequate justification for their indications and contraindications in the care
of patients. All scientific research referred to, reported, or used in the presentation must conform to the generally
accepted standards of experimental design, data collection, and analysis. The content of this CME activity has been
reviewed and the committee determined the presentation is balanced, independent, and free of any commercial bias.
Speakers must inform the learners if their presentation will include discussion of unlabeled/investigational use of
commercial products.
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Target Audience
• The overarching goal of PCSS-O is to offer evidence-based
trainings on the safe and effective prescribing of opioid medications
in the treatment of pain and/or opioid addiction.
• Our focus is to reach providers and/or providers-in-training from
diverse healthcare professions including physicians, nurses,
dentists, physician assistants, pharmacists, and program
administrators.
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Educational Objectives
• At the conclusion of this activity participants should
be able to:
Describe the role of benzodiazepines in patients
with chronic non-cancer pain
Describe the rationale and consequences of
long-term benzodiazepine treatment
Select agents that facilitate weaning of
benzodiazepines
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Background
• Benzodiazepines have been in use for 55 years
• Perceived safe led to wide use - up to 13% of US
adults in a year
• They act by binding to the GABA* receptor,
increasing GABA-ergic inhibition throughout the
CNS‡
* Gamma amino-butyric acid ‡ Central nervous system
Marks IM, et al. Br J Psychiatry. 1993;162:776-87.
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Background
• Acute efficacy is clear
• Chronic efficacy has been disputed by the UK, US
IOM*, ONDCP‡, NIDA†
• Benzodiazepines may even interfere with the
benefit provided by other anxiolytic treatments
* Institute of Medicine ‡ White House Office of National Drug Control Policy
† National Institute on Drug Abuse
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Alprazolam in Panic
• RCT, chronic panic disorder + agoraphobia
• N = 154, alprazolam 5 mg/d x 8 wks
• alprazolam + exposure or
• alprazolam + relaxation or
• placebo + exposure or
• placebo + relaxation
• Drug taper weeks 8 – 16
• Follow-up to week 43
• Exposure had twice the benefit of alprazolam
• Alprazolam gains were lost during taper and f/u
• Gains after exposure were maintained
• Combining alprazolam with exposure impaired improvement at f/u.
• Relapse was usual after alprazolam was stopped
• Gains persisted to after exposure ceased Marks IM, et al. Br J Psychiatry. 1993;162:776-87.
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Benzodiazepine Use in Chronic Pain
• Animal studies of the effects of benzodiazepines
on pain are inconsistent
Some show more pain, others show less
• In human sciatica and low back pain, the evidence
is that they are not helpful
• Postoperative pain is actually reduced by
antagonists of benzodiazepines in patients who
received bzs pre-op
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Adverse Effects
• MVAs
• Depression
• Physical dependence / rebound
• Acute and persisting cognitive decline, even
months after weaning
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Benzodiazepines and Dementia
• Literature review / meta-analysis
• Six studies eligible for inclusion
45,391 participants,11,891 with dementia
• Compared with never users, risk ratios for dementia:
ever users – 1.49
recent users – 1.55
past users – 1.55
• The risk of dementia increased by 22% for every additional 20 defined daily doses per year
Zhong G et al. PLoS One. 2015;10(5)
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Benzodiazepine Use vs Dementia
Systematic review
• Observational studies of BZ use vs dementia
• 9/10 studies showed increased risk of dementia in BZ users
• Increased risk factors
Cumulative dose
Treatment duration
Long-acting molecules
• Causal nature of association unproven, but suggested
Billioti de Gage S et al. Expert Opin Drug Saf. 2015;14(5):733-47
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BZ Use vs Risk of Alzheimer's
• Any history of benzodiazepine use
Increased risk of Alzheimer's disease
Adjusted OR = 1.51
Adjustment for anxiety, depression, and insomnia did not markedly alter the result
• The strength of association (ORs) increased with
Exposure density 1.32 for 91-180 daily doses 1.84 for >180 daily doses
Drug half life 1.43 for short acting 1.70 for long acting
Billioti de Gage S et al. BMJ 2014;349:g5205
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Patients Prescribed Any Hypnotic
Hazards of Dying
Doses/yr Hazard ratio
0.4-18 3.60
18-132 4.43
132+ 5.32
• N = 10,529 patients prescribed hypnotics 23,676 matched controls
• Followed = 2.5 years Data adjusted for age, gender, smoking, BMI, ethnicity, marital
status, alcohol use, prior cancer
• Hazard Ratios elevated
zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates, sedative antihistamines
Kripke DF et al. BMJ Open 2012;2: e000850
Park TW et al. BMJ. 2015;350:h2698.
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Benzodiazepine, Opioid Deaths
• 1,049,903 individuals prescribed controlled medications in West Virginia
PMP data
600 deaths related to controlled medication
State forensic drug database
• Rx for opioid / benzodiazepine in 6 mo prior to death
• Drug-related deaths:
Benzodiazepine only: OR = 7.2
Opioid only: OR = 3.4
≥ 1 rx for opioid + BZ: OR = 14.9
Peirce GL, Smith MJ, Abate MA, Halverson J. Doctor and pharmacy shopping for controlled
substances. Med Care 2012;50:494–500.
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Opioid OD and BZs
• National VA sample
Excluded methadone
maintenance,
palliative care
N - 2400 fatal ODs
while receiving opioids
422,786 random controls
• ODs quadrupled with BZs
Park TW et al. BMJ 2015;350:h2698.
Opioid Use (mg/d) OD
death
s p
er
10,0
00 p
ers
on
yrs
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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 alcohol-related symptoms
− 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
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The TEDS Report (Treatment Episode Data Set) 6/2/11
http://oas.samhsa.gov/2k11/028/TEDS028BenzoAdmissions.cfm
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Most Common Co-drugs
http://oas.samhsa.gov/2k11/028/TEDS028BenzoAdmissions.cfm
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6-Fold Rise in Combined Admissions
• SAMHSA Treatment Episode Data Set for 2010
• Admissions for combined addiction to benzodiazepines and opioids rose 569.7% from 2000 to 2010
Overall substance abuse admissions rose 4%
• 91.4% non-Hispanic whites
vs 55.8% of other admissions.
http://archive.samhsa.gov/data/2k12/TEDS-064/TEDS-Short-Report-064-Benzodiazepines-
2012.pdf
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Alternatives to Bzs
• Tricyclics
• SSRIs
• SNRIs
• Antiepileptic drugs
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Case Discussion: Karen
• Single woman in her 40s with 20 years of benzodiazepine use for anxiety/panic/insomnia
• History borderline personality, childhood rape, maternal neglect
• Multifocal pains, mostly fibromyalgia, chronic pelvic pain, and headaches
• History of prior hallucinations/delirium with benzodiazepine withdrawal
• Treated in a pain rehabilitation program
• Initiated wean from clonazepam 4 hs and alprazolam 1 bid
• Gabapentin titrated to 3600 mg/d, alprazolam stopped
• Clonazepam 1 mg q4h prn
• Valproic acid titrated to 1500 mg/d
• Clonazepam reduced to qid, then reduced 0.5-1 mg every 3 days depending on
Pulse
Tremor
DTRs
Sleep
• Currently 3 years post wean, remains benzodiazepine free Continues in psychotherapy
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Question 1
Is it better to use short-acting benzo's or long-acting
ones like Klonopin with addictive personalities and
chronic pain?
Response:
• Long-acting appears worse for dementia
• Short-acting is probably more reinforcing
• Avoiding benzodiazepines is best
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Question 2
What is your strategy for tapering zolpidem in the
elderly?
Response:
• Gabapentin / pregabalin for withdrawal
• Trazodone, melatonin, mirtazapine, or
quetiapine for sleep
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Question 3
Any benzodiazepines for patients attending Methadone
Maintenance program?
Response: No.
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Question 4
Why did you not review Dr. Isaac Marks early work
showing alprazolam use inhibits psychologic
treatment results, phobic anxiety?
Response: I did not know about it. See slide 8
included in overview presentation.
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Question 5
Please expand upon the cognitive effects, especially the
persistent effects after cessation of treatment.
Response:
• See slide 13 on Alzheimer’s in benzodiazepine users.
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Question 6
When new chronic pain patients are already on benzodiazepines, they are often resistant to discontinue bzs. Any suggestions for motivating them?
Response:
1. There is no evidence that bzs have long-term benefit, although they create an illusion of benefit to patients.
2. There are other meds that do have long-term benefit, though they don't produce the immediate effect that bzs do.
3. Agencies in US and Europe confirm that long-term bzs do more harm than good.
4. If persuasion doesn't work, I use coercion. "I will not prescribe opioids to patients taking bzs because the literature shows that it's unsafe to do so."
5. If you told me that nothing but cyanide was really helpful for you, I still wouldn't prescribe it. ;-)
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Question 7
What are the statistics regarding the risk of accidental
OD/death in people co-prescribed benzodiazepines
and opiates vs opiates?
Response:
In 2010:
• 22,000 deaths from pharmaceutical OD
• 16,650 involved opioids
• 30.1% of these involved benzodiazepines Jones CM et al. JAMA 2013;309(7):657-659
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Question 7 (response cont.)
Response:
• National VA sample
Excluded methadone maintenance, palliative care
N - 2400 fatal ODs while receiving opioids
422,786 random controls
• ODs quadrupled with BZs Park TW et al. BMJ 2015;350:h2698
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Question 8
How do benzodiazepines decrease pain relief from opiates?
Response:
Microinjections of GABAA antagonists in the periaqueductal gray or rostral ventromedial medulla reduce nociception. Benzodiazepines activate GABAA receptors and subsequently decrease morphine analgesia.
It may be that bzs are analgesic at the spinal level and anti-analgesic at higher levels.
For references, see:
• Gear RW et al. Benzodiazepine mediated antagonism of opioid analgesia. Pain. 1997;71(1):25-9.
• Weinbroum AA et al. Flumazenil Potentiation of Postoperative Morphine Analgesia. Clin J Pain. 2000;16(3):193-199.
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Pain Patients Using
Benzodiazepines Fare Worse
• Cross sectional study
• N = 229 patients entering pain rehabilitation
• BZ use was associated with worse mood, pain,
and function
• Authors speculated that BZ effect was due to
impaired mood, coping, cognition, and ability to
tolerate pain.
Gauntlett-Gilbert J, Gavriloff D, Brook P Clinical Journal of Pain, e Pub ahead of print
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Question 9
Can you address:
1. cognition following withdrawal, and
2. mechanism and evidence for worsening pain?
Response: See next 3 slides.
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Cognition Following Withdrawal of
Long-Term Benzodiazepines
13 studies
• Use – 10 (1-29) years
• Age – 47.1 (21-75)
• 3 mo – mean time between
initial and post-withdrawal
assessment
• 80% excluded hx heavy
alcohol/drug use
Barker MJ et al. Arch Clin Neuropsychology 2004;19:437-454
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Benzodiazepines and Dementia
• Literature review / meta-analysis – 6 studies
Risk ratios for dementia:
ever users – 1.49
recent users – 1.55
past users – 1.55
Dementia risk increased 22% for every additional 20 defined
daily doses per year
• 10 observational studies
9/10 showed increased risk of dementia in bz users
Increased risk with dose, duration, LA drugs
Zhong G et al. PLoS One. 2015;10(5)
Billioti de Gage S et al. Expert Opin Drug Saf. 2015;14(5):733-47
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BZ Use vs Risk of Alzheimer's Disease
• Benzodiazepine ever use
increased risk of Alzheimer's disease
Adjusted OR = 1.51
Adjustment for anxiety, depression, and insomnia did not markedly alter the result
• The strength of association (ORs) increased with
Exposure density 1.32 for 91-180 daily doses 1.84 for >180 daily doses
Drug half life 1.43 for short acting 1.70 for long acting
Billioti de Gage S et al. BMJ 2014;349:g5205
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Comment
Many of the drugs you recommend as options also
have significant adverse effects, i.e. Depakote
Response: Agreed. All drugs are toxic at some dose.
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References
• American Psychiatric Association: Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the
American Psychiatric Association. Washington, DC, APA, 1990
• Barker MJ, Greenwood KM, Jackson M, Crowe SF: Persistence of cognitive effects after withdrawal from long-term
benzodiazepine use: a meta-analysis. Arch Clin Neuropsychology 19 (2004) 437-454
• Barker MJ, Greenwood KM, Jackson M, Crowe SF: Cognitive effects of long-term benzodiazepine use: a meta-analysis.
CNS Drugs. 2004;18(1):37- 48
• Bianchi GN, Phillips J: A comparative trial of doxepin and diazepam in anxiety states. Psychopharmacologia.
1972;25(1):86-95
• Billioti de Gage S, Moride Y, Ducruet T, Kurth T, Verdoux H, Tournier M, Pariente A, Bégaud B:Benzodiazepine use and
risk of Alzheimer's disease: case-control study. BMJ. 2014;349:g5205
• Billioti de Gage S, Pariente A, Bégaud B: Is there really a link between benzodiazepine use and the risk of dementia?
Expert Opin Drug Saf. 2015;14(5):733-47
• BMJ. 2015;350:h2698.
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References
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• Ciccone DS, Just N, Bandilla EB, Reimer E, Ilbeigi MS, Wu W: Psychological correlates of opioid use in patients with
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• Committee on Review of Medicines (UK). (1980). Systematic review of the benzodiazepines. British Medical Journal, 2,
719-720
• d'Elia G, Von Knorring L, Marcusson J, Mattsson B, Perris C, Persson G: A double blind comparison between doxepin
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• Fredheim, Olav Magnus S; Borchgrevink, PC; Mahic, Milada; Skurtveit, S:A pharmacoepidemiological cohort study of
subjects starting strong opioids for nonmalignant pain: A study from the Norwegian Prescription Database.
Pain 2013;154(11):2487-2493
• Gauntlett-Gilbert J, Gavriloff D, Brook P. Benzodiazepines May be Worse than Opioids: Negative Medication Effects in
Severe Chronic Pain. Clin J Pain. 2015 May 8. [Epub ahead of print]
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References
• Gear RW, Miaskowski C, Heller PH, Paul SM, Gordon NC, Levine JD: Benzodiazepine mediated antagonism of opioid analgesia. Pain. 1997;71(1):25-9
• Griffiths RR, Weerts EM. Benzodiazepine self-administration in humans and laboratory animals--implications for problems of long-term use and abuse. Psychopharmacology (Berl). 1997;134(1):1-37
• Hausken AM, Skurtveit S, Tverdal A. Use of anxiolytic or hypnotic drugs and total mortality in a general middle aged population. Pharmacoepidemiol Drug Saf 2007;16(8):91318
• Hollister L, Muller- Oerlinghausen B, Rickels K, Shader R. Clinical uses of benzodiazepines. J Clin Psychopharmacol 1993;13(suppl 1):1-169
• Ito K, Yoshikawa M, Maeda M, Jin XL, Takahashi S, Matsuda M, Tamaki R, Kobayashi H, Suzuki T, Hashimoto A. Midazolam attenuates the antinociception induced by d-serine or morphine at the supraspinal level in rats. Eur J Pharmacol. 2008;586(1-3):139-44
• Jones JD, Mogali S, Comer SD: Polydrug abuse: A review of opioid and benzodiazepine combination use. Drug Alcohol Depend. 2012; 125(1-2): 8–18
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• Kripke DF, Langer RD, Kline LE: Hypnotics' association with mortality or cancer: a matched cohort study. BMJ Open. 2012 Feb 27;2(1):e000850
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• Longo LP, Johnson B:Addiction: Part I. Benzodiazepines--side effects, abuse risk and alternatives. Am Fam Physician. 2000;61(7):2121-8
• Marks IM, Swinson RP, Başoğlu M, Kuch K, Noshirvani H, O'Sullivan G, Lelliott PT, Kirby M, McNamee G, Sengun S, et al. Alprazolam and exposure alone and combined in panic disorder with agoraphobia. A controlled study in London and Toronto.Br J Psychiatry. 1993;162:776-87.
• Montgomery SA, Tobias K, Zornberg GL, Kasper S, Pande AC: Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder: a 6-week, multicenter, randomized, double-blind, placebo-controlled comparison of pregabalin and venlafaxine. J Clin Psychiatry. 2006;67(5):771-82
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References
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• Peirce GL, Smith MJ, Abate MA, Halverson J: Doctor and pharmacy shopping for controlled substances. Med Care 2012;50:494–500
• Rickels K, Downing R, Schweizer E, Hassman H: Antidepressants for the treatment of generalized anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam. Arch Gen Psychiatry. 1993;50(11):884-95
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PCSS-O Colleague Support Program
and Listserv
• PCSS-O Colleague Support Program is designed to offer general information to health
professionals seeking guidance in their clinical practice in prescribing opioid
medications.
• PCSS-O Mentors comprise a national network of trained providers with expertise in
addiction medicine/psychiatry and pain management.
• Our mentoring approach allows every mentor/mentee relationship to be unique and
catered to the specific needs of both parties.
• The mentoring program is available at no cost to providers.
• Listserv: A resource that provides an “Expert of the Month” who will answer questions
about educational content that has been presented through PCSS-O project. To join
email: pcss-o@aaap.org.
For more information on requesting or becoming a mentor visit:
www.pcss-o.org/colleague-support
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PCSS-O is a collaborative effort led by American Academy of Addiction Psychiatry (AAAP) in partnership
with: Addiction Technology Transfer Center (ATTC), American Academy of Neurology (AAN), American
Academy of Pain Medicine (AAPM), American Academy of Pediatrics (AAP), American College of
Physicians (ACP), American Dental Association (ADA), American Medical Association (AMA), American
Osteopathic Academy of Addiction Medicine (AOAAM), American Psychiatric Association (APA), American
Society for Pain Management Nursing (ASPMN), International Nurses Society on Addictions (IntNSA), and
Southeast Consortium for Substance Abuse Training (SECSAT).
For more information visit: www.pcss-o.org
For questions email: pcss-o@aaap.org
Twitter: @PCSSProjects
Funding for this initiative was made possible (in part) by Providers’ Clinical Support System for Opioid Therapies (grant no. 5H79TI025595) from SAMHSA. The
views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department
of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government.