Prazosin for Post-Concussive Headaches

Background and Rationale: Headaches following mild traumatic brain injury (mTBI) are common,
can be refractory to standard therapies, and may persist and worsen to become a debilitating
chronic pain syndrome. The purpose of this study is to evaluate the centrally acting alpha-1
adrenoreceptor (AR) antagonist drug prazosin as a prophylactic treatment for chronic
posttraumatic headaches (PTHAs). The impetus for this study comes from a large open-label
case series in Iraq and Afghanistan Veterans with mTBI and PTHAs and data from a
placebo-controlled trial evaluating use of prazosin for posttraumatic stress disorder (PTSD)
in active-duty Servicemembers (SMs). Findings from these studies showed that in addition to
decreasing PTSD-related symptoms and improving sleep quality, prazosin decreased the
frequency and severity of headaches, which were common in the study populations.

Study Objectives, Specific Aims, and Hypotheses: The objective of this study is to evaluate
the efficacy of prazosin as a prophylactic treatment for persistent PTHAs, which will be
accomplished by conducting a randomized placebo-controlled double blind trial of prazosin vs.
placebo in active-duty SMs and Veterans who were in military service at any time from October
7, 2001 to the present with persistent PTHAs.

- Specific Aim 1: To determine the effect of prazosin compared to placebo on headache
frequency, headache severity and duration, use of abortive/analgesic medications, and
headache-related disability.

- Specific Aim 2: To determine the effect of prazosin on sleep disturbance, PTSD symptoms,
depressive symptoms, alcohol consumption, global cognitive function, health-related
quality of life, and global clinical status.

Inclusion Criteria:

- Male and female Active-duty Servicemembers or Veterans aged 18 or older who are in
good general health.

- History of blast and/or impact head trauma mTBI meeting Defense and Veterans Brain
Injury Center (DVBIC) mTBI criteria.

o Mild TBI is defined as an injury to the head causing at least one of the following:
alteration in consciousness (for up to 24 hours after the injury), loss of
consciousness (0-30 minutes), and/or post-traumatic amnesia (up to 1 day post-injury).
If available, the Glasgow Coma Scale score must be 13-15, and head imaging findings
(if imaging was performed) must be negative.

- Frequent headaches (HAs) that started within 3 months after a head injury or marked
worsening (a two-fold or greater increase in frequency and/or severity) of
pre-existing headaches within 3 months of head injury.

- HAs either 1) must 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 takes a medication or other agent in an effort to
stop or treat a headache.

- HAs meeting these criteria must have been present on average at least 8 days per
4-week period, starting within 3 months after head injury and occurring by
self-report for at least 3 months prior to the Initial Screening Visit. The
4-week HA frequency/severity criteria must be confirmed during the Preliminary
Screening Period.

- Women of childbearing potential must agree to abstain from sexual relations that could
result in pregnancy or use an effective method of birth control acceptable to both
participant and the clinician prescriber during the study. Men are not required to use
contraception during the study.

- Participants must have English fluency sufficient to complete study measures.

Exclusion Criteria:

- Participation in other interventional research.

- History of penetrating head injury

- History of TBI more severe than mild by DVBIC criteria

- A primary non migraine and/or tension-type HA disorder (for example hemicrania
continua; cluster) that accounts for the majority of current symptoms.

- HAs of any kind of moderate or severe intensity on an average of more than 4 days per
month preceding the concussive trauma

- Acute or serious medical illness or unstable chronic medical illness (e.g., unstable
angina, myocardial infarction within 6 months, congestive heart failure, clinically
significant or concerning cardiac arrhythmias; preexisting hypotension [systolic blood
pressure<110] or orthostatic hypotension [systolic drop >20 mm Hg after 2 min standing
accompanied by lightheadedness], chronic renal or hepatic failure, acute pancreatitis,
Meniere's disease, or diagnosed but untreated sleep apnea). The eligibility of
potential participants having acute serious and/or chronic medical illnesses other
than those listed will be evaluated on a case-by-case basis by a study physician,
PA-C, or ARNP.

- Use of prazosin or other alpha-1 antagonist (including but not limited to alfuzosin,
doxazosin, silodosin, tamsulosin, terazosin) for any purpose in the 2 weeks prior to
initial screen (P1) visit and prohibited throughout the study

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

- Active psychosis or psychotic disorder, severe depression (as determined per clinician
prescriber judgment), severe psychiatric instability or severe situational life crisis
(including evidence of being actively suicidal or homicidal).

- Meets Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)
criteria for any Substance Use Disorder except caffeine-related disorders, or
tobacco-related disorders.

- History of delirium within the prior 3 months, epilepsy, stroke, dementia, psychotic
disorder, or bipolar disorder

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

- Current participation in transcranial magnetic stimulation studies

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

- Participation in a HA support group or other activity such as meditation or yoga
intended to mitigate HA or other chronic pain must be stable at least 4 weeks prior to
beginning the initial screen (P1) visit and may not be started during the study

- Failure to record HA data for at least 80% of days during the Screening Period

- Not suitable for study per clinician judgement.

Medication-and other Treatment-Related Considerations:

- The use of HA rescue or symptom-relieving medications will be allowed during the
study. This includes triptans, ergotamines, opioids, simple analgesics (e.g.
acetaminophen, aspirin, or non-steroidal anti-inflammatories [NSAIDS], and combination
analgesics. Their use will be recorded on the concurrent medication CRF during the
Preliminary Screening Period (P1) and throughout the remainder of the study.
Randomization of participants will be stratified based on whether their use of HA
medications meets ICHD-3 beta criteria for overuse of these medications, as described
in section 5.5 below.

- Opioid Medications: Use of opioids for treatment of HA or non-HA-related pain or for
any other purpose is allowed during the study. Any opioid use would ideally be
excluded due to potential confounding effects on interpretation of response to
treatment. However, in this population, particularly in Veterans with chronic pain or
undergoing minor orthopedic or dental procedures, opioid use is common. Use of
opioids, including frequency and dose, will be recorded on the concurrent medication
CRF.

- Cannabis: The use of cannabis in any form is not excluded unless its use meets
criteria for Cannabis Use Disorder. All use of cannabis will be documented.

- Other Medications: Participants who are taking other medications on a routine basis
must be on a stable dose for at least 4 weeks prior to the Preliminary Screening
Period (P1), and must intend to continue the medication at the same regimen for the
duration of the trial unless lack of efficacy, safety, or tolerability dictates
otherwise. The following medications are not excluded:

- Psychoactive drugs (for example, anticonvulsants, benzodiazepines,
antidepressants, sedative/hypnotics),

- Antihypertensive medications (including beta-blockers, calcium channel blockers,
angiotensin converting enzyme [ACE] inhibitors, and angiotensin receptor
blockers),

- The use of magnesium in any dose that is prescribed for the purpose of HA
prevention or treatment must be stable for at least 4 weeks. The incidental use
of magnesium in multi-vitamins, laxatives, etc. is permissible but must be
documented.

- Hormones (for example, testosterone, estrogen, or progesterone) in any form.

- The "as-needed" (prn) use of psychoactive and other drugs such as antibiotics is
not excluded; however, such use must be discussed with a clinician prescriber and
documented.

- The use of butalbital in any form within 4 weeks of beginning the Preliminary
Screening Period (P1) through the end of the participant's study involvement is
exclusionary.

- Participants who have been taking trazodone will undergo a 2-week washout period
before the Preliminary Screening Period (P1 visit). Combining prazosin and trazodone
may increase the risk of priapism. We have decided to begin the washout period before
the Preliminary Screening Period in order to remove any confounding variables while on
the headache log and actigraphy.

- Sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra)
will not be permitted during the study drug 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 supplements containing nitrates and supplements containing stimulants (such as
ephedra) are exclusionary in the two weeks prior to initial screen (P1) visit and
prohibited throughout the study. Participants who take these supplements will be asked
to discontinue them for a minimum of two weeks before the Preliminary Screening Period
(P1 visit).

- Use of prescribed stimulants (such as amphetamine or dextroamphetamine containing
medications) is exclusionary in the 2 weeks prior to the initial screen (P1) visit and
prohibited throughout the study. Participants who take these medications will be asked
to discontinue them for a minimum of 2 weeks before the Preliminary Screening Period.

- Participants with sleep apnea must be stable on CPAP settings for at least 2 weeks
prior to the initial screen (P1) visit..