Benzodiazepines, Other Anxiolytic Medications, and Meditations: Selected Topics in Anxiety Management

1. Benzodiazepines, Other Anxiolytic Medications, and Meditations: Selected Topics in Anxiety Management 16thAnnual ETSU Nurse Practitioner/Physician Assistant Primary Care Conference March 27, 2011 , Johnson City, TN Jay M Griffith MD MHC Asst. Chief, QuillenVAMC Clinical Associate Professor, ETSU Dept of Psychiatry and Behavioral Sciences Diplomate, ABPN Psychiatry and Pain Medicine

2. ANXIETY DISORDERS BIOLOGY- Limbic System – Prefrontal Cortex AMYGDALA Drives autonomic and emotional responses HIPPOCAMPUS Evaluates threat contexts PREFRONTAL CORTEX Regulates limbic responses of amygdala and hippocampus PFC HC AMYG Diagram from Bisson 2007 BMJ Content created by Karleyton Evans, MD. Adapted from Rauch, et al. CNS Spectrums. 1998;3(suppl 2):30-34.

5. PFC DANGER - HC - AMYG

6. ANXIETY DISORDERS - LIFETIME PREVALENCE - Social Phobia 13.3% - Post Traumatic Stress Disorder (PTSD) 7.8% - Generalized Anxiety Disorder (GAD) 5.1% - Panic Disorder 3.5%

7. ANXIETY DISORDERS - EPIDEMIOLOGY - 25% Lifetime prevalence for all anxiety disorders - High Comorbidity (depression, other anxiety disorders, substance use disorders) - Generally occur in Females > Males - 1/3 of Americans will experience a panic attack

8. ANXIETY DISORDERS BIOLOGY-NEUROTRANSMITTER SYSTEMS - Serotonin (SE) is most frequently implicated - Norepinephrine (NE) and Dopamine (DA) have roles - Calcium, glutamate, oxytocin, and other neurotransmitter/neuropeptide systems are relevant (eg. Oxytocin Nasal decreases fear responses of social phobics to anxiety provoking social stimuli)

9. Differential Diagnosis of Anxiety Disorders DSM-IV-TR 1. Anxiety, fear, avoidance, or increased arousal 2. R/O physiological/medication causes 3. R/O substance induced (caffeine) and obtain UDS 4. Unexpected Panic Attacks: Panic Disorder 5. Fear of humiliation: Social Phobia 6. 6 mos of excessive worry and anxiety: GAD 7. Traumatic event + reexperiencing: PTSD

10. Panic Disorder, Social Phobia, GAD, and PTSD Which of these anxiety disorders can have associated panic attacks? Panic Disorder – basis of the diagnosis Social Phobia – in public situations GAD – during peaks of anxiety PTSD – during heightened arousal

11. Panic Attack A Panic Attack is a discrete period in which there is the sudden onset of intense apprehension, fearfulness, or terror, often associated with feelings of impending doom. During these attacks, symptoms such as shortness of breath, palpitations, chest pain or discomfort, choking or smothering sensations, and fear of "going crazy" or losing control are present. DSMVI-TR

12. Diagnostic criteria for Adjustment Disorder With Anxiety orWith Mixed Anxiety and Depressed Mood The development of emotional or behavioral symptoms in response to an identifiable stressor(s) occurring within 3 months of the onset of the stressor(s). These symptoms or behaviors are clinically significant as evidenced by either of the following: • marked distress that is in excess of what would be expected from exposure to the stressor • significant impairment in social or occupational (academic) functioning Specify if: Acute: if the disturbance lasts less than 6 months Chronic: if the disturbance lasts for 6 months or longer With Anxiety With Mixed Anxiety and Depressed Mood DSIVM-TR

13. For all anxiety disorders in DSMIV –TR, there must be: Significant impairment in social or occupational (academic) functioning

14. Anxiety Disorder Treatments Panic Disorder – SSRI/SNRI – (use BZP early or late); Cognitive Behavior Therapy (CBT) Social Phobia – SSRI/SNRI, (BZP), CBT; for performance anxiety (B-blocker, Toastmasters International) GAD – SSRI/SNRI , buspirone, (BZP), pregabalin in Europe, CBT PTSD – SSRI/SNRI(SNRIs not for hyperarousal), for nightmares and possibly hyperarousalconsider prazosin off label, no BZPs, Exposure-Based CBT It may take 8-12 weeks to see a response CONSIDER OFF-LABEL MIRTAZAPINE FOR ALL DIAGNOSES START LOW AND GO SLOW WITH ALL MEDICATIONS AT ½ THE STANDARD STARTING DOSE FOR SSRIs/SNRIs

15. Buspirone in GAD • 5 HT1A partial agonist • NE metabolite • Begin 7.5mg bid then increase by 5mg q 2-3 days • BID or TID • Faster increases may produce jitteriness • 2-3 weeks before onset • A study demonstrated less efficacy for buspirone in those previously treated with a benzodiazepine

16. Buspirone Advantages - No adverse cognitive effects - No physiological dependence - Not cross-tolerant with alcohol - Few side-effects (jitteriness, headache)

17. Case Middle-aged male with a history of “panic attacks” 3-4 times a month and two phobias. + sexual side effects on SSRIs/SNRIs Consumes 2-3 oz of liquor equivalents nightly and 3-4 oz on some occasions Further history demonstrates he experiences GAD and when panic attacks occur during elevations of GAD intensity 1 month later 10mg tid of buspirone decreases anxiety by 70%

18. Case continued… 3 months later the patient calls to report increases of all anxiety symptoms He is missing midday doses of medication Change to BID and he’s had sustained benefit

19. Prazosin in PTSD - α -1 adrenergic antagonist - Most lipophilic drug in its class (crosses the blood brain barrier) - Previous indications for hypertension (also used off label for benign prostatic hypertrophy) (triple play) - Murray Raskind et al. reported a series of studies into its impact on the re-experiencing of PTSD symptoms, particularly nightmares

20. Prazosin - Begin at 1mg hs and increase by 1mg/week to 10mg to 12 mg hs in males; 3mg hs in females - Side Effects: First dose syncope and possible priapism; lowers LDL - Efficacious in war-related and civilian PTSD - May also be uptitrated in the AM at < than the HS dose • Addressing hyperarousal/hyperadrenergic c/o First line PTSD treatment in the 2011 Harvard Algorithm (psychopharm.mobi)

21. BENZODIAZEPINES

22. Anxiety Stories: Year 1 “I’ve been feeling more stressed because ________ happened last week. Can give me something for this?” “I need a nerve pill.” “Yeah, my anxiety is better on the medication (citalopram) but I sure wish you’d give me something for my nerves.” (Longing for the halcyon days).

23. Anxiety Stories: Year 2 • “If you aren’t giving me Valium then I don’t want any of your other medications” (walks out of the office) • “I want to make a complaint about one of your doctors who’s committing malpractice” • “Cancel my appointment with that doctor…he’s useless”

24. Benzodiazepines, Other Anxiolytic Medications, and Meditations: Selected Topics in Anxiety Management

25. Benzodiazepine Literature • Dispersed across 50 years • Many questions are still unanswered including: appropriate indications for and durations of therapy and short and long-term adverse effects • There are vast differences of opinion both within the US and between the US and other countries regarding these issues

27. Benzodiazepines, Other Anxiolytic Medications, and Meditations: Selected Topics in Anxiety Management WHAT DO WE KNOW ABOUT BENZODIAZEPINES?

28. Benzodiazepine Prescribing Patterns From 1969 to 1982 diazepam was the most prescribed medication in America with 2.3 billion tablets sold in 1978Lader 2011

30. World Health Organization Programme on Substance Abuse: Rational Use of Benzodiazepines 1996 “In all studies concerning prescription patterns of benzodiazepines, it is noted that scarce information is given on diagnosis and/or indications for benzodiazepine prescriptions on patient charts, in contrast to prescriptions of various other (non-psychotropic) drugs (Buchsbaum et al. 1986).” “… it was found that initial benzodiazepine prescriptions were given in 35 and 38.5 per cent of cases respectively for other reasons than the recognized indications (van der Waals et al., 1993) (Zisselman et al., 1994).” Writing controlled substances for non-FDA approved reasons

31. Benzodiazepines “One user in four uses the benzodiazepine for a year or longer.” Balter 1991 “Rates of use increase with age. Persons older than 65 years account for 27% of all benzodiazepine prescriptions and 38% of all benzodiazepine hypnotics.” IMS America 1991 APA Textbook of Psychopharmacology Benzodiazepine studies were 2 months in duration

32. Benzodiazepine Effects • Hypnotic-sedative • Anxiolytic • Muscle relaxant • Anterograde amnesia • Antiseizure

33. Benzodiazepine Pharmacology • Enhance GABA effects at the GABA-A receptor producing increased Cl- flux and inhibitory neurotransmission • Decrease SE and NE turnover (can generate depression) • Dependence involves dopaminergic systems • Endozapines are purported endogenous benzodiazepines

34. Benzodiazepine Pharmacodynamics www.benzo.org. ukAshton

36. Benzodiazepine Prescribing Patterns Ranked 11th among all prescriptions in the USA, alprazolam is the #1 psychiatric drug With 46.3 million in 2010, aprazolam prescriptions increased by 3 million/yr since 2006 IMS Health, National Prescription Audit, Dec 2010

37. TN Top 10 Most Prescribed Controlled Substances 2010 TN Top 10 Most Prescribed Controlled Substances 2010 1 Hydrocodone (Lortab, Vicodin) (TN is #2 in the US) 2 Alprazolam (Xanax) – steady for 3 years 3 Oxycodone (OxyContin, Roxicodone, generic) 4 Codeine 5 Clonazepam (Klonopin) – first year in the top ten 6 Zolpidem (Ambien) 7 Lorazepam (Ativan) 8 Diazepam (Valium) 9 Propoxyphene (Darvon, Darvocet) 10 Pregabalin (Lyrica) TN Drug Diversion Task Force

38. Alprazolam: The Most Difficult Benzodiazepine to Manage? • Because of its short half-life, alprazolam is associated with behavioral reinforcement and interdose anxiety (“clock watching” ) • These phenomena produce elevated anxiety and dose escalations The Alprazolam to Clonazepam Switch Herman et al. 1987

39. Problematic Prescription • ALPRAZOLAM 1MG TID PRN ANXIETY • Develop physiological tolerance while attempting to get control over anxiety • Later try taking as a prn • Withdrawal and anxiety which will be defined as anxiety or as “panic attacks” • Conditioned to rely upon Xanax (anecdote: crying spells with the mention of a minute dose reduction)

40. Benzodiazepines revisited—will we ever learn? Lader 12/2011 Addiction With long term use there is: Impaired performance on simple repetitive tasks for up to one year and for several years on tests of attention Even after months or years the effects on episodic memory persist Verbal memory is particularly affected May take more than 6 months for the memory effects to completely resolve after stopping

41. Benzodiazepines revisited—will we ever learn? Lader 2011 Addiction Accidents Increased risk of falls in the elderly Increased risk of MVAs Behavior problems- may cause paradoxical excitement in vulnerable groups including: Borderline personality disorder Impulse control diosrder Ongoing alcohol disorders

42. Benzodiazepine Respiratory Effects Sleep apnea: Inhibit respiratory response to CO2 and relax upper airway muscles Can worsen sleep apnea or convert snoring into sleep apnea Many authorities, including the FDA, consider benzodiazepines contraindicated in sleep apnea

43. Benzodiazepines revisited—will we ever learn? Lader 2011 Addiction “The niggling question of possible long term anatomical and biochemical changes in the brains of long-term users needs urgent attention to allay mounting concerns in view of the continuing extensive use of BZDs.”

44. Maine Benzodiazepine Study Group GUIDELINES FOR THE USE OF BENZODIAZEPINES IN OFFICE PRACTICE IN THE STATE OF MAINE “There is no evidence supporting the long term use of BZDs for any mental health indication” http://www.benzos.une.edu/resources.htm

45. Emergency Department Visits Related to Non-Medical Use of Agents DAWN 2009 1,079,683 medications Benzodiazepines 312,931 Alprazolam 112,552 Clonazepam 57,633 Diazepam 25,150 Lorazepam 36,582

46. MMWR July 8, 2011 CDC • During 2003--2009, death rates increased for all substances except cocaine and heroin. The death rate for prescription drugs increased 84.2%, from 7.3 to 13.4 per 100,000 population. The greatest increase was observed in the death rate from oxycodone (264.6%), followed by alprazolam (233.8%) and methadone (79.2%). By 2009, the number of deaths involving prescription drugs was four times the number involving illicit drugs.

47. What are the leading sources for prescription drug abuse? Family and Friends

48. Tennessee Drug Diversion Task Force • Diverted Rx Drugs of Greatest Concern & Sources • “Hydrocodone(Lortab, Lorcet, Vicodin and generic equivalents), oxycodone(OxyContin, Roxicodone, and generic equivalents), and alprazolam (Xanax) are the top three most prescribed drugs and primarily are among the most commonly diverted and abused pharmaceuticals in the State of Tennessee. These three drugs prescribed and taken together form what is known to law enforcement as “the cocktail.”

49. Tennessee Prescription Safety Act of 2012 TN Drug overdose deaths in Tennessee rose from 422 in 2001 to 1,059 in 2010 This bill, if approved, would require all prescribers and dispensers of schedule II, III, IV or V controlled substances to register in the PMP and check the database regularly All new starts require a database review Reviews could be conducted by licensed healthcare personnell and by one non-licensed person per practiceJ. Dreyzehner MD TN Commissioner of Health Prescription Substance Abuse Conference, ETSU, 2012

50. Addiction and Diversion: Purposes • Addicted • Use with other illicit drugs to intensify the intoxicating effects, eg., benzodiazepine + methadone • Profit • To manage withdrawal symptoms associated with addictions to other drug classes