1. Tae Woo PARK, MD, MSC Boston university School of medicine
Are benzodiazepines an appropriate treatment for anxiety disorders in patients with substance use disorders? YES
Tae Woo PARK, MD, MSC
Boston university School of medicine

2. Disclosures
I have no actual or potential conflict of interest in relation to this presentation

3. FIRST DIRECTOR OF NIDA ME

4. Arguments Should anxiety be treated?
YES
Are benzodiazepines effective treatments for anxiety?
YES, with some unknowns
Are the risks of benzodiazepines overstated?
YES, with some exceptions
Should all addiction patients receive benzodiazepines?
NO, but some can and there are ways to treat that can minimize risks

5. Anxiety should be treated
Benzodiazepines are efficacious
The risks of benzodiazepines are overstated
When should benzodiazepines be prescribed?

6. Anxiety disorders are harmful
Lower quality of life and psychosocial functioning
Treatment significantly increases quality of life
Associated with increased mortality
Untreated anxiety is costly
$65 billion in 1994
Mendlowicz et al., 2000
Chesney et al., 2014
Dupont et al., 1996

7. Anxiety is common in SUD
General population
19% with alcohol use disorder had anxiety disorder
28% with drug use disorder had anxiety disorder
Addiction treatment population
33% with alcohol use disorder had an anxiety disorder
43% with drug use disorder had an anxiety disorder
ECA, Regier et al., 1990
NESARC, Grant et al., 2004

8. Anxiety and relapse
Anxiety associated with relapse and poorer treatment outcomes in SUDs
Five times increased risk of re-admission for alcohol treatment
Associated with worse SUD treatment outcomes
Driessen et al., 2001
Tomasson & Vaughn, 1998
Compton et al., 2003

9. Anxiety should be treated
Benzodiazepines are efficacious
The risks of benzodiazepines are overstated
When should benzodiazepines be prescribed?

10. Efficacy of benzodiazepines in non-SUD patients
Meta-analysis for GAD, panic, and SAD
Bandelow et al, 2015

11. Head-to-head in non-SUD patients: Benzodiazepines vs. Antidepressants
Against tricyclic antidepressants
Benzodiazepines more effective for panic disorder
Benzodiazepines more tolerable
Against SSRI/SNRIs
Benzodiazepines comparable or better effectiveness
Offidani et al, 2013

12. Benzodiazepines in co-occurring anxiety and SUD
No RCTs
One recent suggests feasibility
Open-label trial (lorazepam + disulfiram)
Reduced anxiety
No evidence for loss of control of benzodiazepine use
Bogenschutz et al., 2016

13. Other treatments for co-occurring anxiety and SUD
Pharmacotherapy
Buspirone: 3 positive, 2 null
SSRIs: 1 positive, 1 null
Psychotherapy
CBT for anxiety and alcohol: 1 positive, 3 null
Exposure-based therapy: effective for PTSD symptoms

14. Advantages of benzodiazepines
Good tolerability
Fast onset of action
Can use for as-needed treatment

15. Problems with other treatments
Non-benzodiazepine anxiolytics (e.g. SSRIs, buspirone)
Tolerability
Anxiety
Insomnia
Nausea
Sexual dysfunction
Slow onset of action
Withdrawal syndrome
Psychotherapies
Significant barriers to dissemination
Intervention length

16. Anxiety should be treated
Benzodiazepines are efficacious
The risks of benzodiazepines are overstated
When should benzodiazepines be prescribed?

17. Risk of benzodiazepine addiction

18. Treatment admissions for benzodiazepines
TEDS, 2016

19. Drug self-administration studies
Without SUDs:
Placebo is preferred over benzodiazepines
With SUDs:
Benzodiazepines are preferred over placebo
Barbiturates, stimulants, and opioids are preferred over benzodiazepines
Majority of studies only include people with sedative use disorders

20. Benzodiazepine use disorder can be difficult to diagnose
Rarely observed in patients prescribed benzodiazepines
Tolerance
Dose escalation
Much time spent using drug
Activities given up to use drug
Nagy et al., 1989
Pollock et al., 1993
Soumerai et al., 2003
Romach et al., 1995

21. Do patients with SUD history lose control of benzodiazepine use?
Harvard Anxiety Research Program (HARP)
343 participants followed for 1 year
29% with past or current alcohol use disorder
No escalation of use
No loss of control
Mueller et al., 1996

22. Benzodiazepines and opioids

23. Why do opioid users use benzodiazepines?
Most common reasons
To manage anxiety
To manage sleep
To get high
Opioid detoxification:
The majority used them for therapeutic reasons
The minority use them to get high (24%)
Stein et al., 2016

24. Risk of overdose
Benzodiazepines can cause respiratory depression, particularly in presence of other CNS depressants
Benzodiazepines are commonly involved in opioid overdose cases
Benzodiazepines are associated with increased risk of overdose death in patients using opioids

25. Benzodiazepines and risk of opioid overdose
Hazard ratio
95% CI
Benzodiazepine exposure
None
1.00 (ref) -
Currently prescribed
3.72
Benzodiazepine dose
>0-10
>10-20
1.59
>20-30
2.27
>30-40
2.47
>40
2.93
Park, 2015

26. Benzodiazepine use is common in opioid overdose
Benzodiazepines are the most common prescription drug involved in opioid analgesic overdose death (30%)
Anxiety is common in opioid users
Benzodiazepines are common treatments for anxiety
Therefore, the proportion of benzodiazepine use in opioid overdose cases should be high

27. Antidepressant use is also common in opioid overdose
Specific Drug Involvement in Opioid Analgesic Overdose Deaths, 2010
Drug or Drug Class
Overdose Deaths (%)
Benzodiazepines
30.1
Antidepressants
13.4
Antiepileptic and antiparkinsonism drugs
6.8
Antipsychotic and neuroleptic drugs
4.7
Jones et al., 2013

28. Antidepressants are also associated with overdose
Prescription drugs associated with opioid toxicity or overdose
Zedler et al., 2014

29. Do benzodiazepines cause overdose death in opioid users?
All benzodiazepine and overdose studies are observational
Benzodiazepines may be a marker for severe anxiety
Anxiety is associated with increased risk of overdose death

30. Anxiety should be treated
Benzodiazepines are efficacious
The risks of benzodiazepines are overstated
When should benzodiazepines be prescribed?

31. Distinguishing appropriate from inappropriate benzodiazepine use
Intent: Why is the patient using benzodiazepines?
Effect: What is the effect of using benzodiazepines on the patient’s life?
Control: Is the benzodiazepine use controlled by both the patient and the prescriber?
Legality: Is the benzodiazepine use legal?
Pattern: What is the pattern of benzodiazepine use?
Dupont, 2005

32. Assess potential benefits
Assess current function What can patient expect to do with medication that s/he cannot do now? Think of medication prescription as a TEST

33. Not Enough Benefit?
Consider escalating dose as a “test” No effect = no benefit; hence, benefit cannot outweigh risks – so STOP medication

34. Assess potential risks
Sedation, overdose, etc.
Addiction or diversion
Use consistent approach, but set level of monitoring to match risk

35. Monitoring and universal precautions
Contracts/agreement form Drug screening Prescribe small quantities Frequent visits Single pharmacy Pill counts Prescription monitoring programs

36. Case
A 42 year old female seeking buprenorphine maintenance treatment for daily heroin use. After stabilization with buprenorphine, she reports that she has started to have severe panic attacks, several times a week. The panic attacks cause chest pain and SOB and are caused by crowded spaces. This has lead her to avoid taking the bus, making it difficult to run errands and attend appointments.
The patient reports that she has tried several SSRI’s that were discontinued because “they didn’t do anything”. She agreed to try a different SSRI but after 6 weeks, did not report any benefit.
Clonazepam was initiated and the patient was stabilized on 1 mg twice a day. Over the course of the following year, the patient has been adherent to her appointments, has not used any illicit substances, not asked for higher clonazepam doses, not appeared oversedated, and has been able to work and repair damaged family relationships.