Treatment of nightmares with prazosin

(1)

Treatment of nightmares with prazosin

Simon Kung, M.D.

Assistant Professor of Psychiatry

Philippine-Minnesotan Medical Association Annual Meeting

(2)

Disclosures

•

None

(3)

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

(4)

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.”

(5)

Trauma Nightmares

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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%

(6)

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

(7)

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

(8)

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

(9)

(10)

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

Post-traumatic stress disorder OR sleep disorder* OR sleep disrupt* OR sleep distress)]

(11)

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)

(12)

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) Full-text articles assessed (n=30) Full-text articles excluded (n=9): 3 abstract, 2 proposal/algorithm, 2 no outcome on nightmares, 1 narrative review, 1 irrelevant Studies included in qualitative synthesis (n=22): 5 RCT, 4 open label, 4 chart reviews, 9 case reports Records excluded (n=142)

(13)

Outcome measures: Clinician-Administered

PTSD Scale (CAPS) B-2 Nightmares

National Center for PTSD, VA, 2000

Maximum score = 8

(14)

Outcome measures: CAPS D-1 Insomnia

Maximum score = 8

(15)

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

(16)

Results: 22 studies

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4 Open label case series

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4 Retrospective chart reviews

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9 Case reports

(17)

Results: 4 Open label case series

Reference Duration Demo-graphics 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 5 (1 M) civilians Ages 35-58 1.8 CAPS-B2: mean Δ from 6.8 to 1.8 CGI-C: 3 markedly improved, 2 moderately

PTSD diagnosis and initial CAPS-B2 ≥ 4. One patient reported return of nightmares when prazosin dose missed. Longest follow-up 13 months, prazosin still beneficial.

Peskind 2003; J Geriatric Psychiatry & Neurology 8 wks 9 M (8 veterans, 1 civilian) Mean age 76 + 2 yrs 2.3 + 0.7 CAPS-B2: mean Δ from 6.6 to 0.9 CGI-C: 3 markedly improved, 5 moderately, 1 minimally

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. Pre-treatment mean BP 144/74 vs post 134/72. Calohan 2010; J Traumatic Stress Duration unspecified 13 (11 M) active combat Mean age 26.7 + 3.2 yrs 4.1 + 2.2 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

PTSD or acute stress disorder.

9 of 13 patients experienced at least 50% improvement in nightmares, with 5

(18)

Results: 4 Retrospective chart reviews

Reference Duration Demo-graphics 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 from 7.0 to 3.5 Δ 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

(19)

Results: 9 Case reports

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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

(20)

Results: 5 RCT (

3 older

+ 2 newer)

Reference Duration Demo-graphics 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

post-prazosin 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 CGI-C: 2.4 vs PBO 3.7, p=0.02

PTSD diagnosis and initial CAPS-B2 ≥ 5. 15 patients (9 prazosin, 6 PBO) with transient dizziness.

4 patients dropped out due to side effects.

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

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 “non-nightmare distressed awakenings.”

(21)

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.

(22)

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

(23)

Results: Nightmares, Sleep Quality

P<0.001

(24)

Outcome measures: Clinician-Administered

PTSD Scale (CAPS) B-2 Nightmares

Maximum score = 8

(25)

Results: CGI, CAPS Total Score

P<0.001

(26)

Cochrane Risk of Bias Tool ratings for randomized placebo-controlled trials

Ref Adequate sequence generation? Allocation conceal-ment? Blind-ing? Incomplete outcome data addressed? Free of selective report-ing? Free of other bias? Raskind 2003 Raskind 2007 Taylor 2008 Germain 2012 Raskind 2013 ? ? ? ? ? ? + + + + + + + + + + + + + + + - - _- + + + + + +

(27)

(28)

Synthesis

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13 studies of 326 patients + 9 case reports

•

5 RCT of good quality but n=163

•

Older 3 RCT positive results

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Two newer RCT: one positive, one negative

•

4 open label: 84% (n=31) response rate for

decrease in nightmares

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3 of 4 chart reviews: 57% (n=97) with CGI of at

(29)

Prazosin dosing

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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,

(30)

Prazosin effects

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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

(31)

Prazosin used in…

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No evidence for non-PTSD related nightmares

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Evidence for PTSD, subsyndromal PTSD, acute

stress disorder

•

Needs more research for non-PTSD nightmares

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Given low side effect profile, clinically try it for

(32)

Diffusion of knowledge

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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

(33)

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

(34)

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

(35)

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.

(36)

http://www.medscape.com/viewarticle/760070;