Treatment of nightmares with prazosin

Full text

(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

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

4 Open label case series

4 Retrospective chart reviews

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

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

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

(29)

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,

(30)

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

(31)

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

(32)

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

(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)

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