Treatment of nightmares with prazosin Simon Kung, M.D. Assistant Professor of Psychiatry Philippine-Minnesotan Medical Association Annual Meeting August 9, 2014 2011 MFMER slide-1
Disclosures None Off-label use of prazosin will be discussed 2011 MFMER slide-2
The data to support prazosin for nightmares is: 1. Strong 2. Moderate 3. Weak 4. Wasn t aware that prazosin could be used for nightmares 2011 MFMER slide-3
Nightmares DSM-IV-TR: Repeated awakenings from the major sleep period or naps with detailed recall of extended and extremely frightening dreams, usually involving threats to survival, security, or self-esteem. General population prevalence: 3-5% APA 2000; http://www.ptsd.va.gov/public/pages/nightmares.asp 2011 MFMER slide-4
Trauma Nightmares Occur after traumatic events, frequently related to PTSD (Post-traumatic Stress Disorder) Realistic, re-enacts trauma Associated physical symptoms: increased pulse, breathing, sweating Prevalence of PTSD: 7% PTSD-related nightmares prevalence: 52-96% http://www.medscape.com/viewarticle/760070; Kessler RC. Arch Gen Psychiatry 2005;62:593-602; http://www.ptsd.va.gov/public/pages/nightmares.asp 2011 MFMER slide-5
Role of norepinephrine (NE) Involved with PTSD nightmares, arousal, attention, vigilance Higher NE cerebrospinal fluid (CSF) levels in PTSD patients, correlated with severity Enhanced postsynaptic adrenergic receptor responsiveness Consistently elevated central nervous system (CNS) noradrenergic activity might disrupt normal REM (rapid eye movement) sleep, thus contributing to nightmares Geracioti TD. Am J Psychiatry 2001; 158:1227-1230. Boehnlein JK. J Psychiatric Practice 2007;13:72-78. 2011 MFMER slide-6
Prazosin α-1 adrenergic receptor antagonist Introduced in the 1970 s Crosses blood-brain barrier Reduces CNS sympathetic outflow FDA approved for hypertension but not commonly used for hypertension Used off-label for benign prostatic hypertrophy Dose up to 20 mg/day 2011 MFMER slide-7
Prazosin and PTSD nightmares American Academy of Sleep Medicine, August 2010: Level A recommendation (Randomized controlled trials or high quality cohort studies) Veterans Administration (VA)/Department of Defense (DoD), 2010: Level B recommendation, based on at least fair evidence that the intervention improves health outcomes and that benefits outweigh harm Aurora RN. J Clinical Sleep Medicine 2010;6:389-401; VA/DoD Clinical Practice Guideline for Management of Post-traumatic Stress 2010 at http://www.healthquality.va.gov/post_traumatic_stress_disorder_ptsd.asp 2011 MFMER slide-8
What s the evidence? 2011 MFMER slide-9
Systematic Review Goals: evidence for prazosin in nightmares, not limited to PTSD-related EMBASE, MEDLINE, Pubmed, Cochrane, Scopus, Web of Science through March 9, 2012 Keywords were [(prazosin) AND (dream* OR nightmare* OR night terror* OR dyssomnia* OR insomnia* OR parasomnia* OR PTSD OR Posttraumatic stress disorder OR Posttraumatic stress disorder OR sleep disorder* OR sleep disrupt* OR sleep distress)] 2011 MFMER slide-10
Systematic Review Inclusion Criteria Any clinical trial, retrospective review, or case report Had to use outcome measurement for nightmares (except for case reports) Abstracts reviewed independently by 2 authors Zelde Espinel, M.D., M.P.H. Maria I. Lapid, M.D. (senior author) Disagreements resolved by consensus 2011 MFMER slide-11
PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram Records identified by database searches (n=150) Additional records identified through other sources (n=23) Records after duplicates removed (n=172) Records screened (n=172) Records excluded (n=142) Full-text articles assessed (n=30) Studies included in qualitative synthesis (n=22): 5 RCT, 4 open label, 4 chart reviews, 9 case reports Full-text articles excluded (n=9): 3 abstract, 2 proposal/algorithm, 2 no outcome on nightmares, 1 narrative review, 1 irrelevant 2011 MFMER slide-12
Outcome measures: Clinician-Administered PTSD Scale (CAPS) B-2 Nightmares Maximum score = 8 (Frequency 4 + Intensity 4) National Center for PTSD, VA, 2000 2011 MFMER slide-13
Outcome measures: CAPS D-1 Insomnia Maximum score = 8 (Frequency 4 + Intensity 4) National Center for PTSD, VA, 2000 2011 MFMER slide-14
Outcome measures: Global Clinical Impression of Change (CGI-C) Overall improvement in clinical status Score Meaning 1 Markedly improved 2 Moderately improved 3 Minimally improved 4 Unchanged 5 Minimally worse 6 Moderately worse 7 Markedly worse 2011 MFMER slide-15
Results: 22 studies 4 Open label case series 4 Retrospective chart reviews 9 Case reports 5 Randomized controlled trials 2011 MFMER slide-16
Results: 4 Open label case series Reference Duration Demographics Mean dose (mg/d) Results Comments Raskind 2000; J Clinical Psychiatry 8 wks 4 M African- American veterans Ages 50-75 4.75 CAPS-B2: mean Δ from 7.5 to 1.75 CGI-C: 2 patients markedly improved, 2 moderately PTSD diagnosis and initial CAPS-B2 6. Two patients with transient lethargy and one with transient dizziness. Post-trial, 1 patient stopped prazosin and nightmares returned, resolved after restart. Taylor 2002; J Clinical Psychopharm 6 wks Peskind 2003; J Geriatric Psychiatry & Neurology 8 wks Calohan 2010; J Traumatic Stress Duration unspecified 5 (1 M) civilians Ages 35-58 9 M (8 veterans, 1 civilian) Mean age 76 + 2 yrs 13 (11 M) active combat Mean age 26.7 + 3.2 yrs 1.8 CAPS-B2: mean Δ from 6.8 to 1.8 2.3 + 0.7 4.1 + 2.2 CGI-C: 3 markedly improved, 2 moderately CAPS-B2: mean Δ from 6.6 to 0.9 CGI-C: 3 markedly improved, 5 moderately, 1 minimally CAPS-B2: mean Δ from 7.0 to 2.9 CAPS-D1: mean Δ from 6.7 to 3.7 CGI-C: 6 markedly improved, 3 moderately, 3 minimally, 1 none PTSD diagnosis and initial CAPS-B2 4. One patient reported return of nightmares when prazosin dose missed. Longest followup 13 months, prazosin still beneficial. PTSD diagnosis and initial CAPS-B2 5. 8 of 9 pts had at least 50% improvement in nightmares, with 6 remissions. 7 pts on anti-hypertensives already. Pretreatment mean BP 144/74 vs post 134/72. PTSD or acute stress disorder. 9 of 13 patients experienced at least 50% improvement in nightmares, with 5 experiencing complete remission. 2011 MFMER slide-17
Results: 4 Retrospective chart reviews Reference Duration Demographics Mean dose (mg/d) Results Comments Raskind 2002; J Clinical Psychiatry 8 wks 59 M veterans Mean age 51 + 1.2 yrs 9.6 + 0.9 CAPS-B2: mean Δ from 7.0 to 3.5 CGI-C: 2 markedly improved, 14 moderately, 24 minimal, 11 none PTSD diagnosis and initial CAPS-B2 5. 15 pts (29%) had side effects including dizziness (3), headaches (3), nausea (2). CGI-C exclusive of nightmares, and at least moderately improved in 16 (31%) of 51 pts. Daly 2005; Military Medicine 2 wks-3 mo 28 (27 M) veterans Ages 20-41 1-5 CGI-C: 20 markedly improved, 2 moderately improved, 1 unchanged PTSD diagnosis not formally established. One patient reported return of nightmares when stopping prazosin and cessation when resuming. CGI-C at least moderately improved in 22 (96%) of 23 patients. Thompson 2008; J Traumatic Stress 1 wk after stable dose 22 M veterans Ages unspecified 9.6 + 6 CAPS-B2: Δ of 1.4 CAPS-D1: Δ of 3.1 NNDA: Δ of 3.1 CGI-C: Δ of 2.7 PTSD diagnosis. Boynton 2009; J Psychiatric Practice 8 wks 23 (8 M) refugees Mean age 49.8 +15.3 yrs 2.3 + 1.4 CAPS-B2: Δ of 6.9 CGI-C: 6 markedly improved, 11 moderately, 6 minimally PTSD diagnosis. Most common side effect was dizziness. CGI-C exclusive of nightmares, and at least moderately improved in 17 (74%) of 23 patients. 2011 MFMER slide-18
Results: 9 Case reports 5 adults 3 successful 50 y.o. F sexual trauma, 9 mg, initially helpful 42 y.o. M firefighter responder, 6 mg 38 y.o. M emergency relief worker, 1 mg 2 unsuccessful, both male veterans ages 25 and 42, stopped at 1 mg due to side effects 4 child/adolescents, all successful 7 y.o. M sexual trauma, 1 mg 15 y.o. F childhood abuse, 4 mg 16 y.o. F robbery victim, 2 mg 16 y.o. M witnessed friend s violent death, 1.5 mg 2011 MFMER slide-19
Results: 5 RCT (3 older + 2 newer) Reference Duration Demographics Mean dose (mg/d) Results Comments Raskind 2003; Am J Psychiatry 20 wks, 10 wk cross-over 10 M Vietnam vets Mean age 53 + 3 yrs 9.5 CAPS-B2: Δ of 3.3 vs PBO 0.4, p<0.001 CAPS-D1: Δ of 3.4 vs PBO 0.2, p<0.01 CGI-C: 2.0 + 0.5 vs PBO 4.5 + 1.8, p<0.01 PTSD diagnosis and initial CAPS-B2 6. Two patients with BP decreases and dizziness which resolved during titration. Five patients experienced rapid return of distressing nightmares during postprazosin washout, with four discontinuing the study for open-label prazosin. Raskind 2007; Biol Psychiatry 8 wks 40 (38 M) veterans Mean age 56 + 9 yrs 13 + 3 CAPS-B2: Δ of 3.3 vs PBO 0.9, p=0.02 PSQI: Δ of 3.8 vs PBO 0.8, p=0.008 PTSD diagnosis and initial CAPS-B2 5. 15 patients (9 prazosin, 6 PBO) with transient dizziness. 4 patients dropped out due to side effects. CGI-C: 2.4 vs PBO 3.7, p=0.02 Taylor 2008; Biological Psychiatry 7 wks, washout and crossover at 3 wks 13 (2 M) civilians Mean age 49 + 10 yrs 3.1 + 3 CAPS-B2: Δ of 1.5 vs PBO 0, p=0.04 CAPS-D1: NS NNDA: Δ of 2.8 vs PBO 0.1, p=0.05 CGI-C: 2.6 vs PBO 4.1, p=0.002 PTSD diagnosis and initial CAPS-B2 4 and CAPS-D1 4. Dizziness occurred 3 times in both prazosin and PBO. NNDA is a modification of CAPS-B2 replacing distressing dreams with nonnightmare distressed awakenings. 2011 MFMER slide-20
Results: Newer RCT 2012 8 wks duration, 50 (45 M) veterans, mean age 40.9 ± 13.2 yrs Patients with PTSD (n=29) and subsyndromal PTSD (n=21) Randomization: 18 to prazosin, 15 to placebo, 17 to behavioral sleep intervention Final mean dose 8.9 ± 5.7 mg/day Sporadic mild orthostatic symptoms in both prazosin and placebo No reduction in nightmare frequency across all three groups Sleep improvements in 61.9% of those who completed active treatment versus 25% assigned to placebo. Germain A. J Psychosomatic Res 2012;72:89-96 2011 MFMER slide-21
Results: Newer RCT Sep 2013 Raskin MA, American Journal of Psychiatry 15 wks duration, 67 (57 M) active duty soldiers (and 2 veterans), mean age 30.4 yrs Patients with PTSD, exclude substance abuse within 3 months Randomization: 32 to prazosin, 35 to placebo Final mean dose men 4.0 mg qam + 15.6 mg qhs women 1.7 mg qam + 7 mg qhs Most common side effect in both groups was light-headedness (about 20-25%); one incidence of syncope with prazosin Second most common side effect was nasal congestion, more in prazosin group No significant blood pressure differences Raskind MA. Am J Psychiatry 2013;170:1003-1010 2011 MFMER slide-22
Results: Nightmares, Sleep Quality P<0.001 P<0.01 Raskind MA. Am J Psychiatry 2013;170:1003-1010 2011 MFMER slide-23
Outcome measures: Clinician-Administered PTSD Scale (CAPS) B-2 Nightmares Maximum score = 8 (Frequency 4 + Intensity 4) National Center for PTSD, VA, 2000 2011 MFMER slide-24
Results: CGI, CAPS Total Score P<0.001 P<0.05 Raskind MA. Am J Psychiatry 2013;170:1003-1010 2011 MFMER slide-25
Cochrane Risk of Bias Tool ratings for randomized placebo-controlled trials Ref Adequate sequence generation? Allocation concealment? Blinding? Incomplete outcome data addressed? Free of selective reporting? Free of other bias? Raskind 2003 Raskind 2007 Taylor 2008 Germain 2012 Raskind 2013?? + + + + +? + - + +?? + + + + +? + - - + + + + + + + + Low risk of bias - High risk of bias? Unclear 2011 MFMER slide-26
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Synthesis 13 studies of 326 patients + 9 case reports 5 RCT of good quality but n=163 Older 3 RCT positive results Two newer RCT: one positive, one negative 4 open label: 84% (n=31) response rate for decrease in nightmares 3 of 4 chart reviews: 57% (n=97) with CGI of at least moderately improved 2011 MFMER slide-28
Prazosin dosing 1 mg before bedtime, be aware of first dose hypotension Increase by 1 mg every 2-3 days, then by 2-5 mg every 7 days, to maximum of 15 mg at the end of 4 weeks Patients at both extremes (ages 7 to 83) successfully treated with lower dosages 4 mg Civilian patients, who were mostly female, needed lower dosages less than 3.1±3 mg 2011 MFMER slide-29
Prazosin effects Symptom improvement seen within a few days to weeks, duration continued for months Regularly, nightmares returned rapidly when prazosin was discontinued, and resolved when prazosin was restarted Common side effects of transient dizziness and orthostatic hypotension 2011 MFMER slide-30
Prazosin used in No evidence for non-ptsd related nightmares Evidence for PTSD, subsyndromal PTSD, acute stress disorder Needs more research for non-ptsd nightmares Given low side effect profile, clinically try it for non-ptsd nightmares? 2011 MFMER slide-31
Diffusion of knowledge Originated at Puget Sound VA in WA 12 of 13 studies from same group The one study not from group was negative Fast local geographic diffusion 2004-2006: prazosin prescriptions for VA PTSD patients Diffusion across specialties, countries? Harpaz-Rotem I. Arch Gen Psychiatry 2009;66(4):417-421 2011 MFMER slide-32
Other treatments for nightmares American Academy of Sleep Medicine Level A prazosin (PTSD nightmares) Image rehearsal therapy Level B Systematic desensitization and progressive deep muscle relaxation (idiopathic nightmares) Level C clonidine Aurora RN. J Clinical Sleep Medicine 2010;6:389-401 2011 MFMER slide-33
The data to support prazosin for nightmares is: 1. Strong 2. Moderate 3. Weak 4. Wasn t aware that prazosin could be used for nightmares 2011 MFMER slide-34
Summary Prazosin can reduce PTSD nightmare severity and frequency. The evidence base is small to medium but positive. No evidence for prazosin for non-ptsd nightmares. Prazosin well tolerated up to 20 mg daily. Most studies were from a common VA research group. 2011 MFMER slide-35
Thank you! Questions? 2011 MFMER slide-36