Prazosin for Post-Concussive Headaches
Prazosin for Post-Concussive Headaches
Mild traumatic brain injury (mTBI) caused by blast effects of explosive devices has been
 called the "signature injury" of soldiers who served in the Iraq and Afghanistan conflicts.
 mTBI can also occur from impact or hitting the head on an object or the ground. Although
 termed "mild" in comparison to major brain injuries, people with mTBI can have problems with
 their memory and concentration. People with mTBI can also find they are more irritable, have
 more anxiety, and have trouble with their mood and sleep.

 The purpose of this study is to see if a medication called prazosin can help treat chronic
 headaches in people with mTBI. The Food and Drug Administration (FDA) has approved prazosin
 for treating people with high blood pressure. At this time, the FDA has not approved prazosin
 in the treatment of mTBI or headaches. Some people who have posttraumatic stress disorder
 (PTSD) and have been taking prazosin for their medical conditions or who have taken it in
 research studies have said they have fewer 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 SMs 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 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, or acute
 pancreatitis. 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 any non-exclusionary medications is allowed;
 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.