Nutrition for Post-Traumatic Headache

Migraine-like PTH is an ideal patient population to test the effects of the H3-L6
intervention for several reasons. First, although PTH is considered a secondary headache
syndrome, the fact that migraine-like PTH has a phenotype indistinguishable from primary
migraine disorders and shares common pain-related comorbidities (e.g. anxiety, depression)
suggests that shared biochemical mechanisms may underlie both conditions. Second, many PTH
patients experience poor or incomplete therapeutic responses to available treatments, often
while suffering from drug-related adverse effects. The prospect of improved headache outcomes
with concurrent reduction in medication use (as seen in the Chronic Daily Headache Trial) may
be particularly beneficial in PTH, since certain headache medications (e.g. opiates, muscle
relaxants, sleep aids) have cognitive side effects, which may worsen residual cognitive
impairment from Traumatic Brain Injury (TBI).

While PTH is an important cause of disability after TBI, problems with memory, executive
function, depression, anxiety, irritability, fatigue, post-traumatic stress, and other
neurobehavioral disorders are also common after TBI and contribute to disability. The H3-L6
(High Omega-3 Low Omega-6) intervention increased circulating concentrations of several key
bioactive mediators which could hypothetically also have favorable effects on these
TBI-associated non-headache impairments associated with TBI combat injuries. Omega-3 fatty
acids have been widely studied in pre-clinical models and human TBI and demonstrate promising
evidence of both neuroprotective and neurorestorative efficacy.

Potential mechanisms include antioxidant, anti-inflammatory, and pro-neurogenic effects. In
our pilot study, the H3-L6 intervention significantly increased circulating levels of
docosahexaenoic acid-eicosapentaenoic acid (DHA-EPA) , a potent stimulator of neurite growth
and synaptogenesis in hippocampus and other central nervous system (CNS) tissues.
Corresponding increases in the synaptamide biosynthesis in central nervous system tissues
could hypothetically assist cognitive and functional neurorecovery associated with traumatic
brain injury. Further, the reduction of proinflammatory metabolites of omega-6 fatty acids
may provide additional benefits beyond what can be achieved through omega-3 supplementation
alone.

Study Type: Interventional, Phase 2, double blind Study Design: Allocation: Randomized,
parallel group Masking: Double Blind (Participant, Investigator, Outcomes Assessor) Primary
Purpose: Treatment

Primary Outcome Measures:

Hypothesis and Objective: The investigators will obtain support for the following hypotheses
through three specific aims:

Specific Aim 1: To compare the efficacy of the H3-L6 Diet to the Control Diet, in reducing
headache pain and improving headache-related quality of life.

Hypothesis 1: Compared to the Control Diet, the H3-L6 Diet will produce significant
improvement in:

(1a) the Headache Impact Test—a headache-specific quality of life measure-Primary Clinical
Outcome);

(1b) mean total Headache Hours per day; and

(1c) mean Severe Headache Hours per day.

Secondary Outcomes Measures:

Specific Aim 2: To evaluate whether the H3-L6 Diet can increase circulating anti-nociceptive
omega-3 metabolites, and reduce pro-nociceptive omega-6 metabolites, in patients with
Posttraumatic Headaches.

Hypothesis 2: Compared to the Control Diet, the H3-L6 Diet will produce significant increases
in anti-nociceptive omega-3 metabolites including 17-hydroxy DHA (Primary Biochemical Aim),
and reductions in pro-nociceptive omega-6 metabolites.

Other Outcomes Measures Specific Aim 3: To explore the potential of the H3-L6 intervention
for improving non-headache TBI outcomes.

Hypothesis 3: Compared to the Control Diet, the H3-L6 Diet will produce significant
improvement in:

(3a) non-headache pain; (3b) depression/anxiety; (3c) symptoms of post-traumatic stress
disorder; (3d) cognitive function; (3e) sleep quality; and (3f) will significantly reduce the
use of acute pain medications. Enrollment: Up to 300 total participants enrolled among the 3
military sites for 120 12-week diet completers

Inclusion Criteria:

- In order to be included in the study, you must be a person of either gender who is at
least 18 years of age, meets criteria of having had a traumatic brain injury, a
physiological disruption of brain function, 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 of mental state at the time of the accident (e.g., feeling
dazed, disoriented, and confused)

4. . Focal neurologic deficits that may or may not be permanent.

- Traumatically induced includes the head being struck, the head striking an
object, or the brain undergoing an acceleration/deceleration movement (i.e.
whiplash) without direct external trauma to the head.

- Meets Internation Classification of Headache Disorders-version III (ICHD-III) criteria
for persistent post-traumatic headache which is defined as a headache of at least 3
months duration caused by a traumatic injury to the head.

- Meets ICHD-III criteria for episodic/chronic migraine, with or without aura (excepting
exclusion for organic disease):

1. . Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated)

2. . Headache has at least 2 of the following characteristics:

1. unilateral location

2. pulsating quality

3. moderate or severe pain intensity

4. aggravation by or causing avoidance of routine physical activity (eg,
walking or climbing stairs)

3. . During headache at least 1 of the following:

1. nausea and/or vomiting

2. photophobia and phonophobia

- A potential candidate for this study must be under the care of a physician for
headaches and have an incomplete response to standard headache treatments.

- Must have headache frequency of more than 8 days per month.

- Must have a headache history of more than 6 months

- Must be able to attend or remotely participate (by video conference or telephone) in
seven dietitian counseling sessions, and adhere to diet supplied to study
participants.

- Must be a Department of Defense (DoD) healthcare beneficiary and eligible to receive
care at Walter Reed National Military Medical Center (WRNMMC), Fort Belvoir Community
Hospital (FBCH) or Womack Army Medical Center (WAMC).

Exclusion Criteria:

- A person cannot be in this study if they have a history of specific food allergies,
especially to fish, dairy or gluten.

Also exclusionary are:

- Pregnancy or anticipated pregnancy

- Aversion to eating fish

- History of organic brain disorder other than TBI (vasculitis, encephalitis,
meningitis, brain tumor)

- Major medical illness such as malignancy, diabetes, autoimmune or immune deficiency
disorders, history of stroke or myocardial infarction

- Anticipated deployment or move to alternate location in the next 16 weeks

- Inability to read and communicate in English

- Regular use of fatty acid containing supplements

- Active or recent (2 years) history of treatment for substance abuse

- Cognitive impairment that prevents understanding of the protocol and completion of
study procedures including compliance with the diet, blood draws and maintaining a
daily headache diary.