Substance Use Guidelines - Benzodiazepines

GUIDE

Substance Use Guidelines: Benzodiazepines September 2023

Introduction • •

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Benzodiazepines cause central nervous system depression and are utilized for their anxiolytic (anxiety-relieving) and sedative effects.

Benzodiazepines can be short-acting (ex: lorazepam, alprazolam) or long-acting (ex: diazepam, clonazepam, chlordiazepoxide). The use of benzodiazepines with a shorter half-life, at higher doses, and for long durations is associated with the development of benzodiazepine dependence. i The non-prescribed benzodiazepine supply includes pharmaceutical-grade prescriptions and novel, lab-manufactured counterfeit “pressed” pills. Benzodiazepines can be ingested, crushed, and insufflated (snorted), or dissolved and injected. Deaths from synthetic opioids used in combination with benzodiazepines rose tenfold in the general population from 1999 to 2021. ii Data from emergency departments and post-mortem studies showing increases in overdoses have involved these non-medically manufactured benzodiazepines. iii Little is known about the prevalence of benzodiazepine use in people experiencing homelessness.

However, benzodiazepine and opioid-involved overdose deaths are the second most common polysubstance-involved deaths in this patient population, with rates far exceeding that of the general population. iv This document provides guidance for healthcare providers to understand the prevalence and effects of benzodiazepine use in adults experiencing homelessness. It provides practical guidance to reduce the harms associated with benzodiazepines. It also provides evidence-based treatment guidance for benzodiazepine use disorder.

Key Terms and Definitions • •

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Common terms used for benzodiazepines: Xanax, “Xannies,” “Bars,” “Bricks” (alprazolam), “Pin,” “K” (clonazepam), and “V” (Valium) Sedative hypnotics: A class of substances that depress the function of the central nervous system.

Includes benzodiazepines, nonbenzodiazepine sleep inducers (z-drugs), barbiturates, muscle relaxants, and anti-epileptics, among others. This guide is focused on benzodiazepines; however, literature will often discuss the use of benzodiazepines under the broader term of sedative-hypnotic use and use disorders.

Pressed pill: Substances sold in a pill or bar form created by an individual with a pill press. It is often hard to distinguish between pharmaceutical (medical grade) and pressed pills. Pressed pills may contain dangerous adulterants like fentanyl, or “designer” benzodiazepines such as etizolam, clonazolam, diclazepam, and flualprazolam that are either not prescribed in the US or not approved for medical use anywhere in the world.

Trauma-informed care: A patient-centered approach to care that recognizes the impacts of trauma and actively works to prevent re-traumatization and promote recovery. The principles of TIC are

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grounded in establishing a trusting relationship and a safe physical and psychological space in which to address needs.

Harm reduction: A philosophical approach to care that establishes individual agency and selfdetermination as central to all efforts toward well-being. Harm reduction approaches call for the non-judgmental, non-coercive provision of services and resources to people who use substances to assist them in reducing harms related to their substance use or other health behaviors. Harm reduction-based care is collaborative, provides education on available interventions, and centers the goals of the individual in care planning.

Clinical Considerations Physical and Behavioral Health Impacts •

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Low (therapeutic) doses of benzodiazepines can impair motor activity and immediate memory recall. Mild to moderate toxicity includes slurred speech, ataxia, and incoordination. Severe intoxication can include stupor and coma. v Benzodiazepines are a major cause of overdose when ingested in combination with other drugs because of their synergistic effects. Nearly 30% of fatal opioid overdoses in the US involve benzodiazepines.

Common withdrawal symptoms often include anxiety, insomnia, dizziness, headache, anorexia, phonophobia, and irritability. Signs of moderate withdrawal syndrome include tremors, sweating, palpitations, fasciculations (muscle twitching), body aches, gastrointestinal upset, elevated heart rate and blood pressure, and depression. Severe signs include hypothermia, vital sign instability, seizures, delirium, and psychosis. Severe withdrawal from benzodiazepines can be life-threatening and should be managed in a hospital setting.

The length of time until someone experiences withdrawal symptoms varies by the half-life of the benzodiazepine used. Withdrawal can develop within 2-3 days in shorter-acting agents and within 510 days in longer-acting agents.

The intensity of the withdrawal syndrome varies based on potency and duration of action of the benzodiazepines used. Rapid-acting and high-potency benzodiazepines create a higher tolerance and can cause a more severe withdrawal syndrome. Benzodiazepine withdrawal symptoms can last up to 28 days, with seizure risk decreasing after 12 days. vi Post-acute withdrawal syndrome (PAWS) can develop after the acute phase (after 28 days), lasting 12 months after the last use. It often has a waxing and waning course with symptoms of insomnia, perceptual disturbances, tremors, photosensitivity, tinnitus, and anxiety. Patients should be reassured that these symptoms are self-limited and will resolve, and should also be offered symptomatic treatment (i.e., propranolol for tremors, gabapentin for anxiety, etc.)

Use of Benzodiazepines and Experiences of Homelessness •

There is a lack of qualitative or self-reported literature to describe the benefits benzodiazepines provide to individuals who experience homelessness. Individuals use drugs for a wide array of reasons. If someone desires treatment for a substance use disorder, it is important to understand the reasons they are using drugs to provide an individually tailored treatment approach.

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Non-prescribed benzodiazepines can be used for a number of pragmatic reasons. Self-medication for anxiety or insomnia is common. Other reasons could include enhancement of high when used in combination with other depressants like alcohol or opioids. Benzodiazepines can be used to potentiate the effects of poor-quality heroin and for self-management of opioid withdrawal symptoms. Benzodiazepines may also be sought out to augment the unwanted effects of stimulants, for example anxiety and paranoia. vii

Models of Care Delivery •

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The entire spectrum of harm reduction and treatment for substance use disorders should not be contingent on one’s willingness to stop using. It is imperative to create low-threshold models of care that employ a harm reduction approach to care for the entire spectrum of benzodiazepine use in people experiencing homelessness.

In a traditional setting, low-threshold services might look like having space to see patients on a walkin and immediate basis. Treatment for benzodiazepine use disorder (see below) is reliant on frequent encounters for medication management, often through taper protocols. Walk-in availability and outreach efforts should be prioritized to make this accessible to patients experiencing homelessness.

Clinical space should be arranged in a way that is mindful of patients who come to the clinic intoxicated. Ideally, clinics and programs should create monitored spaces where patients who are intoxicated can safely sober from the effects of sedatives.

Street outreach or mobile programs can be very effective in engaging and offering naloxone in case of co-use of opioids or opioid use around them, harm reduction supplies like safer use kits, and drug-checking materials. It is important to note that naloxone will not reverse benzodiazepine overdose but is vital in responding to opioid overdoses.

Leveraging an interdisciplinary model is important for supporting people who use benzodiazepines.

Clients may need coordination of primary care, wound care, substance use treatment, psychiatric care, and hospital care, in addition to housing and other social supports. Peers, community health workers, and case management services are key to providing patient-driven care.

Harm Reduction Strategies: General Principles •

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Inconsistent and unsafe supply impacts potency and carries the potential for dangerous adulterants, such as fentanyl and novel benzodiazepines whose properties are less understood. “Start low and go slow” is a helpful safety reminder. Use the drug in small, consecutive doses to achieve the desired effect. This reduces overdose risk despite supply variability.

“Never use alone.” Individuals who use drugs should use with at least one other person who would be able to respond in the event of an overdose.

Providing new supplies is essential to reduce blood-borne pathogens irrespective of the route of administration. The provision of injection equipment through syringe service programs (SSP) reduces HIV and HCV transmission. viii, ix Shared snorting is an under-recognized source of possible transmission. Individuals with non-injection drug use have higher rates of HCV infection than the general population, thought to be from the sharing of equipment and transmission through breaks in the skin and mucosal surfaces or through high-risk sexual practices. x Naloxone, though designed to reverse opioids and not benzodiazepines, should be provided with education on proper administration. Individuals who use drugs are best equipped to intervene and

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reverse an overdose of someone they are using with. In the era of illicitly manufactured fentanyl that is adulterating the street drug supply, naloxone should be provided to everyone who uses drugs, not just those who use opioids.

Counsel patients to not quit abruptly due to the risk of complicated withdrawal. It is advised to taper off benzodiazepines, ideally in a medically supervised setting.

Harm Reduction Strategies: Route of Administration The risks associated with consumption of benzodiazepines vary based on the method of consumption.

There are ways to reduce harm within each method of consumption as well as changing the method of consumption to decrease risk.

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Ingestion, “Swallowing”: One of the most common routes of administration with the least associated harm.

Insufflation, “Snorting”: Use a clean straw instead of a dollar bill. If there is no access to straws, you can use the edge of rolled paper, post-its notes, etc. Whatever is used for insufflation should not be shared to prevent the transmission of infectious diseases.

Injection, “Shooting”: Injection use of benzodiazepines is high risk, and counseling on other routes of administration should be prioritized. Safer injection practices include using an aseptic technique, using equipment and sterile water with each use, and injecting in low-risk areas of the body, among others. See safer drug injection use in the Resources section below for more details.

Rectal Administration, “Boofing,” or “booty bumping”: Rectal administration can be a safer alternative to injection. The distal 1/3 of the rectum bypasses first-pass metabolism by the liver, which can result in a more intense high and would need smaller doses to achieve the same desired effect. Rectal administration can cause trauma and microtears/cuts in the rectum from drug-related debris.

Drug Checking •

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Counterfeit or “pressed pills” are common in the nonprescribed drug supply and can be very difficult to distinguish from pharmaceutical-grade benzodiazepines. Drug checking, especially when coming from a new batch or new supplier, can reduce incidental ingestion of toxic substances.

Fentanyl test strips can be helpful in identifying illicitly manufactured fentanyl and its analogs by dipping the strip in a small amount of the dissolved drug. Fentanyl test strips are originally manufactured as urine tests; they may not detect certain fentanyl analogs in lethal concentrations. xi A negative test should be interpreted cautiously, and other principles of safer drug use should still be adhered to (i.e., test shot, never using alone, etc.).

Treatment and Supportive Services • • •

There is minimal literature on the treatment of benzodiazepine use disorder (BUD). There are some behavioral health therapies that have evidence for the treatment of benzodiazepine use disorder.

There are no FDA-approved pharmacotherapies for BUD. The majority of literature on pharmacotherapy involves tapering benzodiazepines to achieve complete abstinence.

Offering inpatient treatment for benzodiazepine use can be preferable as it is rapid and effective.

Longer-acting medications, such as phenobarbital, are safe and effective in the inpatient setting, and may be desirable. xii

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Behavioral therapy •

Cognitive behavioral therapy (CBT), motivational interviewing, and a brief intervention of mailing letters advising discontinuation have a low quality of evidence for efficacy. xiii It is uncertain what effect behavioral therapies have on the discontinuation of high-dose benzodiazepine use.

Withdrawal management •

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Individuals at high risk of complications from Benzodiazepine Taper Protocol Example: (Miller, withdrawal should be admitted for medical 2018) monitoring, at least in the initial days of withdrawal. Consideration of inpatient treatment • Start by estimating the daily benzodiazepine would also include withdrawal from other dose. This estimate may be inaccurate when substances, especially alcohol. considering pressed pills.

With the protracted nature of benzodiazepine • Convert daily dose into long-acting withdrawal, treatment can last for weeks to benzodiazepine equivalents using clonazepam, months, requiring transitions of care from chlordiazepoxide or diazepam. Oxazepam or inpatient to outpatient and frequent follow-up lorazepam may be used in patients with liver with longitudinal providers. disease.

Outpatient medically supervised withdrawal may • The calculated daily dose is converted to a be reasonable if able to start at high enough dose split dosing schedule and maintained for week equivalents of benzodiazepines and with the 1 to stabilize. capacity for frequent interval visits every few days • The dose is then reduced weekly or every to weekly. other week by 5mg diazepam equivalents or Benzodiazepine taper is the most common 10% of the prior dose. method for supervised withdrawal.

• It is recommended to slow the final 1/3 tail of In one randomized control trial (RCT) of a the taper. The tail is often less tolerated than benzodiazepine taper protocol, only 30% the initial portion. Can use adjunctive remained abstinent on 15 months of follow-up. xiv medications in this phase as needed.

CBT plus a taper is more likely to result in the successful discontinuation of benzodiazepines than taper alone.xiii Other management protocols using phenobarbital and anti-epileptics have been described and typically require an inpatient level of care.v There is very low-quality evidence for the use of adjunctive medications to help reduce symptoms of benzodiazepine withdrawal in benzodiazepine tapers. In particular, SSRIs, tricyclic antidepressants, pregabalin, valproate, and carbamazepine may be helpful. xv

Non-abstinence based pharmacotherapy •

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Literature on the treatment of benzodiazepine use disorder uses almost entirely abstinence-based outcomes and focuses on tapering off benzodiazepines entirely. This is in conflict with the harm reduction approach that centers treatment priority on the patient’s goals, recognizing that abstinence is not the only pathway to recovery.

Tapering from a high, non-prescribed dose to a maintenance dose using long-acting benzodiazepines could be considered in some patients. xvi

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Additional Resources • • • •

Waterloo Region Integrated Drug Strategy: Harm Reduction for Benzos North Carolina Harm Reduction Coalition: Safer injection drug use resource Pharmacopedia: Benzodiazepine Dose Conversion Calculator The Curbsiders Internal Medicine Podcast: Addiction Medicine Series. Episode #6 Get Hip to Sedative-Hypnotic Use Disorders

References de las Cuevas, C., Sanz, E., & de la Fuente, J. (2003). Benzodiazepines: more “behavioural” addiction than dependence. Psychopharmacology, 167(3), 297–303. https://doi.org/10.1007/s00213-002-1376-8 ii National Institute on Drug Abuse (NIDA). (2023). Drug Overdose Death Rates. Retrieved February 26, 2023, from https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates iii Abeed Sarker, Mohammed Ali Al-Garadi, Yao Ge, Nisha Nataraj, Londell McGlone, Christopher M Jones, Steven A Sumner, Evidence of the emergence of illicit benzodiazepines from online drug forums, European Journal of Public Health, Volume 32, Issue 6, December 2022, Pages 939–941, https://doi.org/10.1093/eurpub/ckac161 iv Fine, D. R., Dickins, K. A., Adams, L. D., De Las Nueces, D., Weinstock, K., Wright, J., … Baggett, T. P. (2022). Drug Overdose Mortality Among People Experiencing Homelessness, 2003 to 2018. JAMA Network Open, 5(1), e2142676. https://doi.org/10.1001/jamanetworkopen.2021.42676 v Miller, S. (2018). The ASAM Principles of Addiction Medicine (6th ed.). Wolters Kluwer Health. vi Brett, J., & Murnion, B. (2015). Management of benzodiazepine misuse and dependence. Australian Prescriber, 38(5), 152–155. https://doi.org/10.18773/austprescr.2015.055 vii May, T., Holloway, K., Buhociu, M., & Hills, R. (2020). Not what the doctor ordered: Motivations for nonmedical prescription drug use among people who use illegal drugs. International Journal of Drug Policy, 82, 102823. https://doi.org/10.1016/J.DRUGPO.2020.102823 viii Aspinall, E. J., Nambiar, D., Goldberg, D. J., Hickman, M., Weir, A., Van Velzen, E., … Hutchinson, S. J. (2014). Are needle and syringe programmes associated with a reduction in HIV transmission among people who inject drugs: a systematic review and meta-analysis. International Journal of Epidemiology, 43(1), 235–248. https://doi.org/10.1093/ije/dyt243 ix Platt, L., Minozzi, S., Reed, J., Vickerman, P., Hagan, H., French, C., … Hickman, M. (2017). Needle syringe programmes and opioid substitution therapy for preventing hepatitis C transmission in people who inject drugs.

Cochrane Database of Systematic Reviews, 2017(9). https://doi.org/10.1002/14651858.CD012021.pub2 x McMahon, J. M., & Tortu, S. (2003). A potential hidden source of hepatitis C infection among noninjecting drug users. Journal of Psychoactive Drugs, 35(4), 455–460. https://doi.org/10.1080/02791072.2003.10400492 xi Bergh, M. S.-S., Øiestad, Å. M. L., Baumann, M. H., & Bogen, I. L. (2021). Selectivity and sensitivity of urine fentanyl test strips to detect fentanyl analogues in illicit drugs. International Journal of Drug Policy, 90, 103065. https://doi.org/10.1016/J.DRUGPO.2020.103065 xii Kawasaki, S. S., Jacapraro, J. S., & Rastegar, D. A. (2012). Safety and effectiveness of a fixed-dose phenobarbital protocol for inpatient benzodiazepine detoxification. Journal of Substance Abuse Treatment, 43(3), 331-334. xiii Darker, C. D., Sweeney, B. P., Barry, J. M., Farrell, M. F., & Donnelly-Swift, E. (2015). Psychosocial interventions for benzodiazepine harmful use, abuse or dependence. Cochrane Database of Systematic Reviews, (5). https://doi.org/10.1002/14651858.CD009652.pub2 xiv Voshaar, R. C. O., Gorgels, W. J., Mol, A. J., van Balkom, A. J., Mulder, J., van de Lisdonk, E. H., … Zitman, F. G. (2006). Predictors of Long-Term Benzodiazepine Abstinence in Participants of a Randomized Controlled Benzodiazepine Withdrawal Program. The Canadian Journal of Psychiatry, 51(7), 445–452. https://doi.org/10.1177/070674370605100706 xv Baandrup, L., Ebdrup, B. H., Rasmussen, J. Ø., Lindschou, J., Gluud, C., & Glenthøj, B. Y. (2018). Pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users. Cochrane Database of Systematic Reviews, 2018(3). https://doi.org/10.1002/14651858.CD011481.pub2 i

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Liebrenz, M., Schneider, M., Buadze, A., Gehring, M.-T., Dube, A., & Caflisch, C. (2016). Attitudes towards a maintenance (-agonist) treatment approach in high-dose benzodiazepine-dependent patients: a qualitative study.

Harm Reduction Journal, 13(1), 1. https://doi.org/10.1186/s12954-015-0090-x

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