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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.

3

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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• 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

• Knabl J, Zeilhofer UB, Crestani F, Rudolph U, Zeilhofer HU: Genuine antihyperalgesia by systemic diazepam revealed by experiments in GABAA receptor point-mutated mice. Pain 141 (2009) 233–238

• 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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Analgesia. Clinical Journal of Pain. 2000;16(3):193-199

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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

46

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.