Whats the Harm? Prescribing Buprenorphine and Benzodiazepines - - PowerPoint PPT Presentation

What’s the Harm?

Prescribing Buprenorphine and Benzodiazepines

Sherry Nykiel, M.D. Act ing Medical Direct or Chief of Addict ion Psychiat ry

Obj ectives



By the end of the presentation, participants will:

 Understand the hazards associated with the prescribing of benzodiazepines in

general

 Know the risks of combining benzodiazepines and buprenorphine  Recognize the dangers of denying treatment with buprenorphine to taking

prescribed or illicit benzodiazepines

 Identify appropriate treatment plans for patients on buprenorphine and

benzodiazepines

Benzodiazepines –A Brief History



1955 – Leo S ternbach synthesizes chlordiazepoxide while working on tranquilizer development at Hoffman-LaRoche

 He initially found the results disappointing and abandoned the results



1957 - co-worker, Earl Reeder, was spring cleaning the lab and rediscovered the compound and submitted it for animal testing

 Rather than being negative as expected, it showed strong sedative, anticonvulsant

and muscle relaxant properties 

1960 – Librium is introduced to the world



1963 – Diazepam (Valium) is marketed by the same company



1970’s – these two medications largely replace barbiturates due to their improved safety profile

Benzodiazepines –A Brief History

 1965 – oxazepam released  1975 – clonazepam released  1977 – lorazepam released  1981 – temazepam released  1982 – triazolam released  1985 – midazolam released  Today: 35 benzodiazepine derivatives exist

 21 of these are approved internationally

Benzodiazepines –A Brief History

 1965 – oxazepam released  1975 – clonazepam released  1977 – lorazepam released  1981 – temazepam released  1982 – triazolam released  1985 – midazolam released  Today: 35 benzodiazepine derivatives exist

 21 of these are approved internationally

1980’s – risk of dependence becomes evident

• Benzodiazepines were the subj ect of the

largest class action suit (at that time) against drug manufacturers in Great Britain

• 14,000 patients using 1800 law firms

alleged that the pharmaceutical company was aware of the dependence potential but withheld this information from physicians

• Lack of funding and concerns re: expert

witnesses (psychiatrists) had a conflict of interest

Why prescribe?



All BZD have anxiolytic, hypnotic, muscle relaxant, anticonvulsant and amnesic effects



Most common indications for new BZD prescriptions are insomnia and anxiety

 BZDs are prescribed at greater rates than antidepressants for the treatment of

depression and anxiety, despite evidence that supports antidepressants as first line medications

 The maj ority of these prescriptions are written by general practitioners

 Between 1996 and 2013:

 The number of people prescribed a benzodiazepine increased 67%

and continues to rise

 The total quantity more than tripled



Generally considered safe when prescribed for short term use (2-4 weeks)

S

• yka, 2019

ht t ps:/ / vaww.portal2.va.gov/ sit es/ ad

Why prescribe?

Why prescribe?

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Why prescribe?



25-76%

• f those newly prescribed a BZD will remain on it long-term

 Long term is considered more than 4-8 weeks, which is when one will begin to have

some physiologic dependence 

The maj ority of those taking BZD for more than 8 weeks will have some withdrawal

 Most of those who are on long-term will have difficulty tapering off  Many long term patients will never successfully taper off

 The goal for these patients is tapering to the lowest possible dose

Long-term BZD use

ht t ps:/ / vaww.portal2.va.gov/ sit es/ ad

Long-term BZD use



Most patients prescribed BZDs long-term remain within recommended dosage levels



A small percentage will develop “ high dose dependence”

 Long-term prescription abuse (more than 2 times the prescribed dose) following

treatment of an underlying condition

 A consequence of BZD use for recreational purposes



High dose dependent users:

 S

uffer more frequently from co-occurring mental disorders

 Are less likely to tolerate current discontinuation and withdrawal strategies  Have a higher risk of inj ury or impairment as a result of use

BZD withdrawal syndrome



Has been documented to occur following attempts to withdrawal from even low dose BZD



S ymptoms generally occur between 2-3 days (for shorter acting BZDs) and 5-10 days (for longer acting BZDs) and may include:

 Anxiety  Panic attacks  S

leep disorders

 Cognitive impairment  Muscle spasms  Depersonalization  Hallucinations/ psychosis  S

eizures

BZD withdrawal syndrome



Not unlike opioids, fear of BZD withdrawal symptoms often deters patients from attempts to discontinue their use

Re-evaluating the Use of Benzodiazepines



The overdose death rate involving benzodiazepine from 2001– 2014 increased five fold

ht t ps:/ / vaww.portal2.va.gov/ sit es/ ad

Re-evaluating the Use of Benzodiazepines

ht t ps:/ / vaww.portal2.va.gov/ sit es/ ad

Re-evaluating the Use of Benzodiazepines

Re-evaluating the Use of Benzodiazepines



The overdose death rate involving benzodiazepine from 2001– 2014 increased five fold, with opioids involved in 75% of these deaths

 After opioids, benzodiazepines are the drug class most commonly involved in

intentional and unintentional pharmaceutical OD deaths (29.4% )

 Rate of co-prescribing benzodiazepines and opioids has nearly doubled between

2001-2013

ht t ps:/ / vaww.portal2.va.gov/ sit es/ ad

S ubstances Abused with Benzodiazepines

The Opioid Epidemic

The Opioid Epidemic

The Opioid Epidemic

ht t ps:/ / www.legit script .com/ blog/ 2018/ 09/ nsduh-report -opioid-abuse/

The Opioid Epidemic

The Opioid Epidemic



Family medicine (32% ), internal medicine (23% ), and orthopedics (11% ) were the most common high- volume prescribing specialties



Across specialties, hydrocodone and

• xycodone were the most-

frequently prescribed opioid types

Nataraj N, et.al., 2019

The Opioid Epidemic

In 2010, enough prescription

• pioids were prescribed to

medicate every American adult around the clock for a month



Family medicine (32% ), internal medicine (23% ), and orthopedics (11% ) were the most common high- volume prescribing specialties



Across specialties, hydrocodone and

• xycodone were the most-

frequently prescribed opioid types

The Opioid Epidemic

In 2010, enough prescription

• pioids were prescribed to

medicate every American adult around the clock for a month



Family medicine (32% ), internal medicine (23% ), and orthopedics (11% ) were the most common high- volume prescribing specialties



Across specialties, hydrocodone and

• xycodone were the most-

frequently prescribed opioid types

https:/ / www.cdc.gov/ drugoverdose/ pdf/ pubs/ 2018-cdc-drug-surveillance-report.pdf

In 2015, enough prescription

• pioids were prescribed to

medicate every American adult around the clock for three weeks

The Opioid Epidemic

The Opioid Epidemic

The Opioid Epidemic

The Opioid Epidemic

The Opioid Epidemic

https:/ / www.drugabuse.gov/ drugs-abuse/ opioids/ benzodiazepines-opioids

Treatment

Withdrawal management vs. “ maintenance”

Goals of Withdrawal Management



Reduce discomfort



S how empathy



Link with aftercare (on-going) services

Goals of Withdrawal Management



Reduce discomfort



S how empathy



Link with aftercare (on-going) services



It is unrealistic to think that successful withdrawal management will lead to continuous abstinence

Buprenorphine Treatment



Formally known as “ maintenance”

Buprenorphine Treatment



Benefits of treatment include:



Reduced illicit use



Improved social functioning



Increased retention in treatment



Decreased morbidity and mortality



Reduced risk of infectious disease transmission



Reduced engagement in criminal activity

ht t ps:/ / www.drugabuse.gov/ publicat ions/ research-reports/ medicat ions-to-treat -opioid-addict ion/ efficacy-medicat ions-opioid-use-disorder

Buprenorphine Treatment

ht t ps:/ / www.researchgat e.net / figure/ mu-Recept or-Pharmacology_fig1_258857065

Buprenorphine Treatment

Buprenorphine and Benzodiazepines



U.S . Treatment outcomes Prospective S tudy (TOPS )

 74%

• f heroin users entering treatment reported BZD within the past year

 25%

were found to be using daily 

Lavie et. al., 2009 showed that among buprenorphine treated patients in France:

 67%

reported lifetime prevalence of BZD use

 54%

reported use within the last month 

Methadone patients have similar prevalence rates of benzo use



Estimates of problematic BZD use in these groups ranges from 18-50%

 Not all opioid users will experience harm or develop BZD use disorder (Lintzeris

et.al., 2009)

Buprenorphine and Benzodiazepines



S tudies have consistently shown that BZD-using buprenorphine patients have:

 Higher levels of psychopathology (including depression and anxiety)  Higher levels of polydrug use  Poorer psychosocial functioning (including unemployment and criminal activity)  Greater overdose history  Greater risk of behaviors leading to infectious disease

Lintzeris et.al.,2009

Buprenorphine and Benzodiazepines

Buprenorphine and Benzodiazepines

Buprenorphine and Benzodiazepines

Buprenorphine and Benzodiazepines

Ceiling effect is lost and buprenorphine now act ing like a full agonist

Buprenorphine and Benzodiazepines



Bupe + BZD = lethal overdose

Buprenorphine and Benzodiazepines



Bupe + BZD = lethal overdose?



Not necessarily – when does the risk increase?

Buprenorphine and Benzodiazepines



Bupe + BZD = lethal overdose?



Not necessarily – when does the risk increase?

 Therapeutic buprenorphine + supra-therapeutic BZD  Therapeutic buprenorphine (IV) + therapeutic BZD (IV)

Buprenorphine and Benzodiazepines



Bupe + BZD = lethal overdose?



Not necessarily – when does the risk increase?

 Therapeutic buprenorphine + supra-therapeutic BZD  Therapeutic buprenorphine (IV) + therapeutic BZD (IV)



Lethal overdose would be unexpected to occur with controlled, oral co- administration of therapeutic dosages of buprenorphine and BZD

Schumann-Olivier et.al., 2014

Buprenorphine and Benzodiazepines



S chumann-Olivier et.al. compared patients in buprenorphine treatment with and without a BZD prescription and found no significant difference in primary clinical outcomes including:

 Treatment retention  Illicit opioid or cocaine use

Buprenorphine and Benzodiazepines



S chumann-Olivier et.al. compared patients in buprenorphine treatment with and without a BZD prescription and found no significant difference in primary clinical outcomes including:

 Treatment retention  Illicit opioid or cocaine use



However… They did find a significant increase in accidental inj uries resulting in emergency room visits

Buprenorphine and Benzodiazepines



In S eptember 2017, the FDA releases a Drug S afety Communication addressing “ opioid addiction medications” and BZDs

 “ Based on our additional review, the US

Food and Drug Administration is advising that the opioids medications buprenorphine and methadone should not be withheld from patients taking benzodiazepines or other drugs that depress the central nervous system.

 The combined use of these drugs increases the risk of serious side effects;

however, the harm caused by untreated opioid addition can outweigh these risks.”

https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-urges-caution-about-withholding-opioid-addiction-medications

Buprenorphine and Benzodiazepines

Only 1 in 10 people with an SUD get any treatment

Buprenorphine and Benzodiazepines

Buprenorphine and Benzodiazepines



We need to stop insisting that patients achieve total abstinence as a condition

• f treatment



Patients will ALWA YS do better in treatment than not



Harm reduction is a worthy goal!

Buprenorphine and Benzodiazepines



Both managing a buprenorphine patient who continues taking a BZD and attempting to taper are difficult!



Educate patients about the serious risks of combined use, including overdose and death, that can occur with BZD when used either as prescribed or illicitly



Develop strategies to manage the use of prescribed or illicit BZD when starting buprenorphine



Verifying the diagnosis if a patient is receiving prescribed BZD for anxiety or insomnia and considering other treatment options for these conditions



Recognize that patients may require buprenorphine indefinitely and that it should continue for as long as patients are benefiting and reaching treatment goals



Coordinate care to ensure that other prescribers are aware of the patient’s buprenorphine treatment



Monitor for illicit drug use, including urine or blood screening



Taper the BZD to discontinuation if possible

https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-urges-caution-about-withholding-opioid-addiction-medications

Buprenorphine and Benzodiazepines



If attempting to taper, the general rule is GO S LOW

 Tapering to the lowest dose the patient is able to tolerate is a success



For those patients unable or unwilling to taper, consistent monitoring is key

 Consider more frequent prescriptions to avoid misuse  Document all treatment decisions, particularly given the lack of evidence

supporting long-term BZD use

S ummary



Prescribers should avoid starting new prescriptions of BZDs and if prescribing,

• nly short term (2 weeks or less) or only as (rarely) needed



Combining BZDs and opioids is potentially lethal



While still possible, lethal overdose with co-use of buprenorphine and BZDs at therapeutic doses is likely safe (unless used intravenously)



Patients taking prescribed or illicit BZDs should not be denied agonist-based medications for opioid use disorder

Questions

 S

herry Nykiel, MD: sherry.nykiel@ delaware.gov