Chronic Postconcussive Headache: A Placebo-Controlled Treatment Trial of Prazosin

Headaches following combat-related post-concussive injury are common, and in some patients
can increase in frequency and severity to become very debilitating. Posttraumatic headaches
(PTHAs), particularly those following blast-related head injury, can be resistant to standard
headache therapies. The objective of this study is to evaluate the effectiveness of the
medication prazosin as a prophylactic (preventive) agent in treating combat-related PTHAs.
Prazosin is a generic drug originally marketed over 30 years ago as a treatment for high
blood pressure. It has subsequently been found to be safe and effective for treating other
problems, including most recently posttraumatic stress disorder (PTSD) and disrupted sleep in
active duty Iraq/Afghanistan Service Members and Veterans. In preliminary studies, prazosin
has also been found to substantially reduce the intensity and frequency of PTHAs in this
population. This finding is the motivation behind this study.

The investigators' hypotheses are (1) that prazosin will be more effective than placebo in
easing the effects of chronic PTHAs, including headache frequency, duration, severity, use of
abortive/analgesic medications, and disability caused, and (2) that improvement in headache
parameters will be associated with improvement in sleep quality, PTSD symptom severity, mood,
cognition, health-related quality of life, and global clinical status, and with moderation of
alcohol consumption.

The total trial length is 22 - 24 weeks. Following an initial clinic visit to determine
preliminary study eligibility, there will be a 4-week pre-treatment preliminary screening
period, during which participants will keep a daily headache diary. The purpose of this is to
confirm eligibility for randomization per inclusion/exclusion criteria and to collect
baseline data for headache-related outcome measures. Participants confirmed to be eligible to
continue in the study will then have a one-week sleep evaluation including actigraphy and
keeping a daily sleep diary. This will be followed by a baseline study visit, during which
baseline data for secondary outcome measures will be collected using validated structured
self-reports and clinician interviews. Participants will be randomized 2:1 to prazosin or
placebo, and the study drug dose will be gradually titrated over a 5 to 7-week period to 5 mg
in the morning and 20 mg in the evening or the maximum tolerated dose. The dose titration
will be followed by 12 weeks at steady-dose. For the last week of the steady-dose phase,
participants will repeat the sleep evaluation. Participants will keep a headache log through
the duration of the study. Results will be analyzed using standard statistical techniques.

Inclusion Criteria:

- Veterans or active duty service members aged 18 or older of either gender

- Good general health

- History of blast and/or impact head/neck trauma meeting DVBIC criteria for mild TBI,
i.e., injury as manifested by at least one of the following:

- 1) any period of loss of consciousness

- 2) any loss of memory for events immediately before or after the accident

- 3) any alteration in mental status at the time of the accident (e.g., feeling
dazed, disoriented, or confused)

- 4) focal neurological deficit(s) that may or may not be transient, with severity
of injury not exceeding loss of consciousness 30 minutes, Glasgow Coma Scale
<13-15 after 30 minutes, or posttraumatic amnesia >24 hrs,

- Headaches that started within 3 months of a head/neck injury or pre-existing headaches
that markedly worsened (by a two-fold or greater increase in frequency and/or
severity) within 3 months of a head/neck injury. Headaches must either 1) last 4 or
more hours a day and reach a moderate to severe intensity at any point during the
headache or 2) may be of any severity or duration if the participant uses a medication
or other agent in an effort to stop the headache. Headaches meeting these criteria
must have been present on average at least 8 days per 4-week period over the 3 months
preceding study enrollment.

- Comorbid PTSD or other anxiety disorder is not exclusionary.

- Fluency in English is required.

- Persons of all races and ethnicities are eligible.

- Female participants must agree to abstain from sexual relations that could result in
pregnancy or use a reliable form of birth control during the study.

- Continued use of prophylactic migraine medication other than the study drug is
permissible if the participant has been on a stable dose for at least 4 weeks prior to
the preliminary screening period and intends to continue the medication for the
duration of the trial.

Exclusion Criteria:

- History of TBI more severe than that classified as mild by DVBIC criteria

- History of penetrating head injury

- Acute or unstable chronic medical illness (e.g., unstable angina, myocardial
infarction within 6 months, congestive heart failure, symptomatic or concerning
cardiac arrhythmias; pre-existing hypotension (systolic BP<110) or orthostatic
hypotension (systolic drop >20 mm mercury (Hg) after 2 min standing accompanied by
lightheadedness). Also exclusionary are chronic renal or hepatic failure, Meniere's
disease, insulin-dependent diabetes, diagnosed but untreated sleep apnea, history of
epilepsy, stroke, dementia, active psychosis or psychotic disorder, severe depression,
severe psychiatric instability or severe situational life crises, including evidence
of being actively suicidal or homicidal, dementia, delirium within the prior 3 months.
Other conditions will be evaluated on a case-by-case basis.

- Current substance use disorder per DSM-V criteria except caffeine- or tobacco-related
disorders.

- Structural brain abnormalities on any prior imaging with associated clinically evident
manifestations.

- Current participation in transcranial magnetic stimulation studies.

- Unable to reliably keep the headache log on a minimum of 80% of recordable days

- Women of childbearing potential must not be pregnant, planning to become pregnant
during the study period, or nursing.

- Participation in a headache support group or other activity such as meditation or yoga
intended to mitigate headache or other chronic pain must be stable for at least 4
weeks prior to beginning the preliminary screening period and should be intended to be
continued for the duration of the trial. Participants will be encouraged to defer
enrolling in such activities until they have completed the treatment trial.

Medication Exclusions:

- Current use of prazosin at a dose of >2 mg or other alpha-1 antagonist for any purpose

- Use of prazosin at a dose of 2 mg or less is not excluded, however there will be a
2-week wash-out period prior to beginning the baseline headache log-keeping period.

- Allergy or previous adverse reaction to prazosin or other alpha-1 antagonist

- Subjects must be on a stable dose of the following medications/treatments for at least
4 weeks prior to the preliminary screening period, and must intend to continue the
medication for the duration of the trial: psychoactive drugs, for example
anticonvulsants, benzodiazepines, antidepressants, sedative/hypnotics;
antihypertensive medications, including beta blockers, calcium channel blockers,
angiotensin converting enzyme inhibitors, and angiotensin receptor blockers; magnesium
prescribed specifically for headache.

- Potential participants who have been taking trazodone will undergo a 2-week washout
period before beginning the preliminary screening period. Because combining prazosin
and trazodone may increase risk of priapism, trazodone is not allowed during the
study.

- Sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra)
will not be permitted during the dose titration period, because of increased risk of
hypotension in combination with alpha-1 blockers, but will be allowed at half the
usual starting dose following the study drug dose titration period, per VA prescribing
guidelines.

- Use of butalbital within 4 weeks of beginning the preliminary screening period through
the end of study involvement.

- Use of supplements containing nitrates and supplements containing stimulants (such as
ephedra) within 2 weeks of beginning the preliminary screening period through the end
of study involvement.

- Use of prescribed stimulants (such as amphetamine or dextroamphetamine containing
medications) within 2 weeks of beginning the preliminary screening period through the
end of study involvement.