Prazosin (and Other Medications) for PTSD and mtbi. Murray A. Raskind, MD. Prazosin. Questions

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Prazosin (and Other Medications)

for PTSD and mTBI

Murray A. Raskind, MD

Director, VISN-20 Mental Illness Research, Education, and Clinical Center

Professor and Vice-Chair Dept. of Psychiatry & Behavioral Sciences University of Washington School of Medicine

Prazosin

A generic lipid-soluble alpha-1 adrenoreceptor (AR) antagonist introduced in 1973 as “Minipress” for treatment of hypertension

Short duration of action (6-10 hours)

Costs pennies per day

Questions

What is the evidence for bedtime prazosin efficacy for nighttime PTSD symptoms and global clinical status?

What are the effects of bedtime prazosin on sleep physiology in PTSD?

Does daytime prazosin reduce alcohol consumption in alcohol dependence?

Does prazosin reduce behavioral and somatic symptoms of mTBI?

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Neurobiologic Model of PTSD

Brain “adrenaline rush” that saves lives in combat becomes persistent and maladaptive.

Long-lasting upregulation of brain postsynaptic adrenoreceptor (AR) response to norepinephrine at the alpha1AR (in prefrontal cortex,

amygdala?) contributes to reexperiencing and hyperarousal symptoms.

CNS Effects of Alpha-1

Adrenoreceptor Stimulation Potentially

Contribute to PTSD Symptoms

Increase “anxiogenic” corticotrophin releasing factor (CRF) release.

Favor “fight/flight” cognition at prefrontal cortex1.

Disrupts REM sleep, increases light sleep.

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Prazosin Treatment of PTSD Grew

from Clinical Observations

The first veteran treated for severe treatment-resistant Vietnam combat PTSD nightmares (1996) was given the beta-blocker propranolol (case report suggesting benefit--Kolb, 1984).

After two weeks the veteran said “Doc, we are going the wrong direction; my nightmares are even worse.”

Intensifying dreams is an established adverse effect of beta-adrenergic blockade.

What to do Next?

Brain alpha-1 adrenergic effects are often opposed to brain beta-adrenergic effects.

Would blocking brain alpha-1 adrenergic receptors with prazosin suppress nightmares?

Prazosin Appeared Helpful

Prazosin was begun at 1 mg q.h.s. to avoid “first-dose effect” of orthostatic hypotension.

After two weeks of gradual prazosin dose increase to 6 mg q.h.s., nightmares disappeared!

This veteran continues nightmare-free (and alcohol-free) for past 12 years (no tolerance to prazosin effect in PTSD).

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First Efficacy Demonstration:

Prazosin/Placebo Crossover Study

10 Vietnam combat veterans (age = 53 ± 3 years) randomized to:

» placebo followed by prazosin (n = 5) » prazosin followed by placebo (n = 5)

Titration schedule:

» 1 mg q.h.s. x 3 nights, 2 mg x 4 nights, 4 mg x 7 nights, 6 mg x 7 nights, 10 mg for 6 weeks

Two Prazosin RCTs in Vietnam Veterans with PTSD: CAPS Recurrent Distressing Dreams (“Nightmares”)

Two Prazosin RCTs in Vietnam Veterans with PTSD: Clinical Global Impression of Change (CGIC)

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Individual PTSD Symptoms Responsive

to Prazosin in Crossover Study

CAPS Item

Recurrent distressing dreams Difficulty falling/staying asleep Physiological reactivity to

trauma reminders Irritability or anger outbursts Intrusive trauma recollections Diminished interest/participation in activities Restricted affect…numbing Hypervigilance pvalue < 0.001 < 0.01 <0.01 < 0.05 < 0.05 < 0.05 < 0.05 < 0.1

Inferential Effectiveness

Steadily increasing use of prazosin across the Northwest (and more gradually across the U.S.) supports effectiveness for PTSD.

There have been intermittent prazosin shortages in 2006 and 2007.

“Penetrance” of Prazosin Among Veterans with

PTSD Across Northwest VISN 20

60 50 40 30 20 10 0 2000 2001 2002 2003 2004 2005 Walla Walla Puget Sound White City Boise Spokane Anchorage Portland Roseburg

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Sleep Physiology of Trauma

Nightmares and PTSD

Trauma nightmares arise from disrupted REM sleep and light sleep (stages 1 and 2).

In animals, alpha-1 stimulation with methoxamine disrupts REM sleep and lengthens light sleep. These effects are reversed by prazosin.

Taylor FB, et al., Biol Psychiatry63:629-32, 2008.

Prazosin and Sleep Physiology: A

Placebo-Controlled Crossover Study

We evaluated the effects of bedtime prazosin vs. placebo on sleep physiology and PTSD symptoms in 13 civilian trauma PTSD subjects with persistent trauma nightmares and sleep disturbance.

Prazosin and Sleep Physiology:

A Placebo-Controlled Crossover Study

REMview® device recorded sleep vs. wake and REM vs. non-REM.

10 of 13 participants provided a full three nights of REMview data in both

maintenance prazosin condition (3.1 ± 1.3 mg hs) and placebo condition.

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Effects of Prazosin vs. Placebo on Sleep Measures in PTSD Subjects with Nocturnal Symptoms

Placebo Prazosin Total Sleep Time REM Sleep Time Sleep Latency REM Latency Mean REM Period Duration M ean Sleep tim e (M inut es ± S D) 500 400 300 200 100 0 ** ** ** *

*Significant difference between prazosin and placebo group by repeated measures ANOVA *p < 0.05, **p < 0.01

Clinical Outcome Measures:

Prazosin Superior to Placebo in

Civilian Trauma PTSD

aAnalysis of variance, significance of group by time interaction

Outcome Measure P valuea Effect Size

(Cohen's d) CAPS”Recurrent Distressing Dreams” (item #2) 0.027 0.96 Non-nightmare distressed awakenings 0.048 1.2 CGI-I scores 0.002 1.5

PTSD Dream Rating Scale 0.006 1.4

PCL-C 0.025 0.79

Prazosin and Alcohol

Veterans with PTSD who “self-medicate” with alcohol often stop drinking with prazosin Rx.

Does prazosin reduce alcohol consumption in non-PTSD alcohol dependent persons seeking abstinence?

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Placebo-Controlled Trial of Prazosin in Alcohol

Dependent Persons Seeking Abstinence:

Subjects and Methods

17 alcohol dependent men without PTSD (46 ± 7 years).

Two week titration to target dose of prazosin (or placebo) 4 mg BID, 8 mg HS.

Maintained at target dose for 4 weeks.

Simpson, TL et al., Alcohol Clin Exp Res31:60A, 2007.

Controlling for drinking days per week at baseline and week number, the prazosin group reported fewer drinking days per week than the placebo group during the final 3 weeks of the study (β = -1.84; 95% CI = -2.74, -.93; p < 0.001).

Mean Drinking Days Per Week by Condition

(Male Completers Only)

Relationships Between mTBI and PTSD:

Epidemiology

C.W. Hoge, et al., NEJM, 1/31/08

» After adjustment for PTSD and depression, mTBI was no longer associated with postconcussive and general somatic symptoms - except for headache.

A.I. Schneiderman, et al., Am J Epidemiology

4/17/08

» The strongest factor associated with postconcussive symptoms was PTSD, even after overlapping symptoms were removed from the PTSD score.

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mTBI in U.S. Soldiers Returning From Iraq:

C.W. Hoge, et al., 1/31/08

Surveyed 2525 infantry soldiers 3-4 months after return from Iraq.

Of the 5% with loss of consciousness following injury, 44% met PTSD criteria.

mTBI “loss of consciousness” group compared to no mTBI “other injury” group had greater physical symptoms (sleep disturbance, headache, chest pain, heart pounding) and “other postconcussive symptoms” (memory, balance, ears ringing, concentration, irritability).

C.W. Hoge, et al., (continued)

Multivariate logistic regression assessed whether PTSD and depression mediated relationships between mTBI with loss of consciousness and physical health outcomes.

Only headache remained significant after adjustment for PTSD (and depression).

In contrast, PTSD was strongly associated with all physical health outcomes.

C.W. Hoge, et al.: Caveats

Only assessed subjective symptoms.

No neurologic or neuropsychologic objective parameters assessed.

Sleep disturbance was not separated into sleep initiation disturbance vs. disruptive awakenings.

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E-mail Received 9/2008

“Dear Dr. Raskind,

You probably do not know me, but I was so impressed with a presentation that you gave about the utility of prazosin for nightmares with PTSD that I started using it for vets with mTBI/PTSD complex with great success. I have also been lobbying for more extensive use in VA….

I am writing to let you know that prazosin will be included in the VA/DoD treatment guidelines for mTBI

Rob Ruff

Neurology Director for VA”

An Open Label Prazosin and Sleep

Hygiene Trial for OIF/OEF Blast mTBI

• Robert C. Ruff, MD, Director of VA Neurology

• Subjects: 80 OIF/OEF returnees with blast mTBI plus neuropsych and/or neurologic deficits (particularly olfactory deficits).

» 74/80 had headaches and met criteria for PTSD

• Methods: All treated with prazosin to 7 mg qhs plus sleep hygiene for 9 weeks.

• Results: Significant improvement in headaches, sleep disturbance, marital discord, and cognitive function by MOCA cognitive screen instrument.

Prazosin for Somatic Symptoms Following

mTBI in Operation Iraqi Freedom Veterans*

74 OIF veterans with blast trauma mTBI

Mean blast experiences with loss of consciousness = 4.1

Prazosin started at 1 mg qhs and increased weekly by 1 mg to maintenance dose of 7 mg qhs

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Change in mTBI Symptoms Following Prazosin

(mean ± SD)

Baseline Week 9 pvalue Headaches per month 12.4 ± 8.1 4.8 ± 2.9 < 0.001 Headache intensity 7.1 ± 1.4 4.1 ± 1.6 < 0.001 Daytime sleepiness

(Epworth)

16.1 ± 2.4 7.3 ± 2.9 < 0.001 % subjects with restful

sleep

7.0% 87.8% < 0.001

Montreal Cognitive Assessment

34.1 ± 2.0 28.1 ± 2.2 < 0.001

Prazosin is Not a Cure

Nightmares usually return soon after prazosin is discontinued (1-2 days).

Prazosin must be taken every night.

Although modest dose increases sometimes necessary over years of treatment, loss of efficacy rarely observed.

Adding a 10 am dose (1mg-5 mg) is helpful for persistent daytime reexperiencing and hyperarousal symptoms.

Prazosin: Adverse Effects

Generally, very well tolerated.

“First dose” hypotension avoided with low dose initiation - but some vets need titration to 20 mg or more.

Orthostatic dizziness more common in young women and persons already on a beta-blocker or ED drug.

Concurrent use with trazodone may increase priapism risk.

Nasal congestion, peripheral edema, headache possible.

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Prazosin - Helpful “Side Effects”

Gentle BP reduction.

Enhances urine flow in older men with prostate hypertrophy.

Can enhance erectile function.

No pharma reps will call.

Large Prazosin RCTs for Combat Trauma

PTSD (with trauma nightmares) Underway

VA Cooperative Study #563 at 13 VA sites.

DoD study in Active Duty OIF/OEF Returnees at Madigan AMC and Walter Reed AMC.

Other Medications for PTSD: Trazodone

Sedating antidepressant with some “prazosin-like” alpha-1 blocker activity

Can initiate sleep with variable effect on nightmares

Daytime “hangover” is common

Used widely but no placebo-controlled trials (generic)

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Other Medications for PTSD:

Atypical Antipsychotics

One placebo-controlled trial of risperidone » showed modest efficacy--particularly irritability/anger

One small placebo-controlled trial of olanzapine

» improved sleep but not global status » 12 lb. weight gain over 10 weeks

Quetiapine widely used, probably for alpha-1 blocker and sedating antihistamine effects.

Using atypical antipsychotics chronically risks metabolic syndrome and cardiac mortality.

Other Medications for PTSD (continued)

Benzodiazepines and zolpidem are widely used in VA but no evidence of efficacy for core PTSD symptoms.

» can help sleep initiation to augment prazosin sleep normalization

Anticonvulsives not effective in controlled trials.

Beta-adrenergic blocker propranolol: no placebo-controlled trials for treatment, being evaluated for post-trauma prophylaxis.

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