Management of mTBI Persistent

Postconcussive Symptoms:

Focus on Headache and Sleep Disturbance

Murray A. Raskind, MD

Director, VA Northwest Network Mental Illness Research, Education, 

and Clinical Center

Professor and Vice-Chair 

Dept. of Psychiatry & Behavioral Sciences

University of Washington School of Medicine

Staff Psychiatrist 

Madigan Army Medical Center

This material in part is the result of work supported by resources from the Department of Veterans 

Affairs and Department of Defense

Military Operations Medicine Research Program
2.5 million Service Members have been deployed to 

Iraq and Afghanistan

The Nature of an Emerging and Unprecedented Problem
Junior Seau had degenerative brain disease when he 

committed suicide
POLL SLIDE #1

• Do you provide clinical care for Veterans, 

service members, or civilians with mild 

traumatic brain injury?

– YES

– NO
POLL SLIDE #2

• What is your professional discipline:

– Social Worker

– RN

– ARNP

– PA

– Clinical Psychologist

– Physician

– PhD Research Scientist
Chronic Postconcussive Headache in 

OEF/OIF/OND Veterans

• Estimated 19% of OEF/OIF/OND Veterans 

have sustained deployment-related mTBI

• Majority of mTBIs are result of blast 

concussion

• Prevalence of post-traumatic headaches 

(PTHAs) is approximately 40% 
Chronic Postconcussive Headache

• International Classification of Headache Disorders 

defines PTHA:

– Secondary HA precipitated by head trauma

– In practice, new onset HAs within months of 

trauma 

• Postconcussive headaches that persist for 3 months 

or more are considered chronic
Chronic Postconcussive Headache

• Tendency for PTHAs to become chronic 

is increased by:

–Sleep deprivation

–PTSD

–Depression
Chronic Postconcussive Headache 

• In a recent cross sectional study of 978 soldiers 

with deployment-related concussion, 20% met 

criteria for chronic daily headaches (15 days or 

more/month)

– 4-5-fold higher than in general population

– 66% had headaches with migraine features

Theeler et al, Headache 52(5):732-738, 2012.
Characteristics of 

Chronic Postconcussive Headache

• Considered to be one of most disabling and difficult 

to treat headache syndromes

• Injudicious use of opioids or other analgesics can 

provoke superimposed rebound (“medication overuse”) headaches, particularly in those with frequent 

headaches at baseline

• “Medication over-use” headaches occur in 19-42% 

of patients with PTHA
Chronic Postconcussive Headache in 

Iraq/Afghanistan Veterans

• In civilian TBI population, PTHA tends to be tensiontype, migraine or mixed

• In military combat population, headaches with 

migraine features predominate

• Migraine results in significantly more functional 

impairment and more sick call days than other 

types of headaches

– 77% of migraine attacks interfered with duty 

performance on a mean of 2.4 days per month
Treatment Outcomes of Chronic Post-Traumatic Headaches 

After Mild Head Trauma in US Soldiers: An Observational Study

• Retrospective cohort study of 100 soldiers treated 

with migraine prophylaxis for chronic PTHA at 

Madigan Army Medical Center Neurology Clinic

– 77 had blast PTHA

– 23 had non-blast (impact) PTHA

– Multiple concussions significantly more common 

in those with blast PTHA (51% vs. 23%)

Erickson et al, Headache 51(6):932-944, 2011.
Treatment of Blast Concussion Migraine is 

Challenging

• Blast concussion migraine was usually responsive to acute abortive therapy with 

a triptan

– 77% reported reliable headache relief within 2 hours

– Triptans equally effective in blast and non-blast PTHA

• However, compared to impact postconcussive migraine, blast postconcussive 

migraine was poorly responsive to standard migraine prophylaxis (TCAs, 

propranolol, valproate, topiramate) 

Erickson et al, Headache 51(6):932-944, 2011.
Change at 3 Months in Headache Frequency in Response to 

Migraine Prophylaxis in Blast vs. Impact PTHA 

Headache (Days/Months) 

Baseline 

Mean (SD) 

Follow-Up 

Mean (SD) 

Change 

Mean (%) P Value Responders* 

Blast PTHA

(n=77)

17.3 (9.2) 15.8 (10.4) -1.5 (-9.1%) 0.21 22/77 (29%)

Impact PTHA 

(n=23)

16.5 (9.2) 9.8 (8.7) -6.7 (-41%) 0.003 13/23 (57%)

*Defined as  50% decline in headache frequency at follow-up compared to 

baseline. 

Erickson et al, Headache 51(6):932-944, 2011. 
Sleep Disruption by Norepinephrine 

at CNS Alpha-1 Adrenoreceptors 

•Disrupts REM sleep

•Increases light sleep

•Shortens total sleep time.
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

• In 2012, prescribed to 17% of all Veterans in VA 

health care systems with a PTSD diagnosis.
Does the PTSD Drug Prazosin Reduce Blast PTHA in 

OEF/OIF Veterans?

• OEF/OIF Veterans with blast concussion PTHA have a high prevalence of 

comorbid PTSD trauma nightmares and sleep disturbance

• Robert Ruff, MD, VA Director of Neurology, used open label prazosin to 

treat comorbid PTSD in OEF/OIF Veterans with blast mTBI manifested by 

PTHA and other postconcussive symptoms1 

• Prazosin is a CNS-active alpha-1 adrenoreceptor antagonist 

demonstrated effective for combat PTSD trauma nightmares, sleep 

disruption, and global clinical status2,3,4

1Ruff et al, J Rehabil Res Dev 46:1071-1084, 2009.

2Raskind et al, J Clin Psychiatry 63:565-568, 2002.

3Raskind et al, Biol Psychiatry 61:928-934, 2007.

4Raskind et al, Am J Psychiatry 170:1003-1010, 2013.
An Open Label Prazosin and Sleep Hygiene Trial for 

OIF/OEF Veterans with Blast mTBI 

with Comorbid PTSD (N=74)

(mean ± SD) 

Baseline Week 9 p value

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 and 

restorative” sleep

7.0% 87.8% < 0.001

Montreal Cognitive 

Assessment

24.1 ± 2.0 28.1 ± 2.2 < 0.001

Ruff et al, J Rehabil Res Dev 46:1071-1084, 2009.
• Data from our recent positive RCT of prazosin for 

PTSD combat trauma nightmares in active duty 

combat soldiers is consistent with beneficial effects 

of prazosin on PTHA and sleep

Raskind MA, Peterson K, Williams T, Hoff DJ, Hart K, Holmes H, Homas D, Hill J, Daniels C, Calohan J, 

Millard SP, Rohde K, O’Connell J, Pritzl D, Feiszli K, Petrie EC, Gross C, Mayer CL, Freed MC, Engel C, Peskind 

ER. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq 

and Afghanistan. Am J Psychiatry 170:1003-1010, 2013.
Active Duty OEF/OIF 

Prazosin RCT

• Parallel group RCT (1:1) at Joint Base Lewis 

McChord, WA

• Active duty OIF/OEF soldiers with combat 

operations PTSD (CAPS > 50) and distressing trauma 

nightmares (at least two nights/week)

• Majority of participants had comorbid mTBI

Raskind et al, Am J Psychiatry 170:1003-1010, 2013.
Design Methodology

• 6-week dose titration to maximum 20 mg qhs and 

5 mg midmorning (mean achieved dose 15 mg 

qhs and 4 mg midmorning)

• Study duration 15 weeks

• Outcome measures:

– Total Clinician Administered PTSD Scale (CAPS) 

– CAPS “recurrent distressing dreams” item

– Pittsburgh Sleep Quality Index

– Clinical Global Impression of Change

– Adverse Events (including headache)

Raskind et al, Am J Psychiatry 170:1003-1010, 2013.
GOT NIGHTMARES?

Combat Nightmare Reduction Initiative

(253) 968-4735

MAMC
Effects on PTSD Outcome Parameters in Combat Soldiers 

Randomized to Prazosin (n=32) or Placebo (n=35)

Raskind et al, Am J Psychiatry 170:1003-1010, 2013.
Emergent and Clinically Worsening 

Adverse Events

Prazosin (n=32) Placebo (n=35)

Syncope 2 0 

Dizziness 6 6 

Drowsiness 1 2 

Depressed mood 0 2 

Headache* 1 7 

Nasal congestion 5 2 

Nausea 2 5 

Palpitations 4 1 

*more frequent in placebo condition, p < 0.05

Raskind et al, Am J Psychiatry 170:1003-1010, 2013.
Participants with Chronic Headaches at 

Baseline

• Of participants who had headaches prior 

to randomization:

• 20% in placebo group had improvement 

or resolution of headache

• 50% in prazosin group had 

improvement or resolution of 

headaches

Raskind et al, Am J Psychiatry 170:1003-1010, 2013.
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

Mean Sleep time (Minutes ± SD)

500

400

300

200

100

0 

**

**

** * 

*Significant difference between prazosin and placebo group by repeated measures ANOVA

*p < 0.05, **p < 0.01

Taylor et al, Biol Psychiatry 63:629-632, 2008.
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 slightly 

increase priapism risk.

• Nasal congestion, peripheral edema, 

palpitations.
Conclusion

• Results of these studies provide 

rationale for a placebo-controlled trial 

of prazosin for blast concussion PTHA

• This study should evaluate relationship 

between sleep and PTHA