Research Examining Gulf War Illness in Our Nations Service Members

At least 1 in 4 of the 700,000 U.S. Veterans who served in the 1990-1991 Gulf War suffer from
Gulf War Illness (GWI). Despite considerable research, effective treatments remain elusive.
GWI refers to a complex of symptoms that typically include widespread chronic pain,
persistent headache, memory and concentration problems, gastrointestinal difficulties, sleep
disturbances and unexplained fatigue. This symptom profile is similar to that of fibromyalgia
syndrome (FMS), a multi-symptom condition similar to GWI. Whereas, effective treatments for
GWI have yet to be found, progress has been made in identifying medications to treat FMS. For
example, the FDA has approved a number of medications including Duloxetine and Pregabalin for
the treatment of FMS. Compared to placebo (PBO) Duloxetine (a serotonin norepinephrine
reuptake inhibitor) and Pregabalin (an alpha-2-alpha-subunit calcium-channel ligand)
significantly improved pain responses and fatigue. The capacity of Duloxetine to increase
central levels of serotonin and norepinephrine as well as the more complex alterations of
neurotransmitters and central nervous system (CNS) mediators of pain attributed to pregabalin
are thought to be responsible for the medication's effects on pain, mood and sleep. Clinical
practice and one open-label trial support the use of these medications in combination to
achieve optimal symptom improvement amongst GWI sufferers; however, such combinations have
not been formally tested in randomized controlled trials. The lack of progress in finding
effective treatments for GWI, and the similarities between GWI and FMS, provides a rationale
for determining if these FDA approved medications can provide significant symptomatic relief
to Veterans who suffer from GWI. Central Texas is home to one of the highest number of Gulf
War Veterans in the nation, thus the investigators' research team is ideally situated to
conduct the proposed study. In a randomized, double-blind, controlled trial, 180 Veterans who
meet defining criteria for GWI and whose symptom profile includes chronic widespread pain and
sleep disturbances will be treated with one of the following medications; 1) AM Duloxetine+
PM placebo (PBO); 2) PM Pregabalin + AM PBO or 3) AM PBO + PM PBO. All active treatments will
titrate from a lower dose in 2-week increments to the full therapeutic doses (FDA-approved
for FMS). The outcome of the PBO double-dummy period will be compared statistically with 18
weeks of active therapy (weeks 5-22).

Inclusion Criteria:

- Living in Central Texas near Killeen, Austin, Temple or Waco

- Served on active military duty and deployed to the Persian Gulf region for some period
between August 1990 & July 1991

- English speaking and able to understand the consent form and study questionnaires

- Willing to be randomized to treatment and participate in 1-month follow up

- men & women between the ages of 43 to 70

- meet Kansas GWI case definition for the diagnosis of GWI

- report a baseline score > 4 on a 10-point Pain Visual Analog Scale (VAS)

- female participants of childbearing potential must test negative for pregnancy at the
time of enrollment based on a urine pregnancy test and agree to use a reliable method
of birth control (for example, oral contraceptives or Norplant; a reliable barrier
method of birth control [diaphragms with contraceptive jelly; cervical caps with
contraceptive jelly; condoms with contraceptive foam); intrauterine devices; partner
with vasectomy; or abstinence) during the study and for 2 months following the last
dose of the study drug. [Note that this inclusion criterion applies only to females of
childbearing potential. Females of childbearing potential are defined as women not
surgically sterilized and between menarche and 2 years post-menopause.]

Exclusion Criteria:

- Unstable or poorly controlled chronic medical illness such as Diabetes type-II,
Hypertension (HTN), heart disease, endocrine disorders, narrow angle glaucoma

- Significant Central Nervous System disease including transient ischemic attacks (TIAs)
or stroke, Dementia, syncopal episodes, severe head trauma, multiple sclerosis

- Serious or advanced heart disease or clinically relevant abnormal electrocardiogram
(ECG), postural hypotension

- Untreated sleep apnea or body mass index placing patients at risk for undiagnosed
sleep apnea (BMI> 35 kg/m2)

- Diabetes type-I and patients with Diabetes type-II associated with peripheral
neuropathy, hepatitis, liver failure/cirrhosis

- End stage renal disease

- History of hypersensitivity reaction to pregabalin, duloxetine, venlafaxine; active
treatment with duloxetine or pregabalin; History of failure of duloxetine or
pregabalin at therapeutic doses; history of angioedema reaction to pregabalin

- Active systemic infectious disease such as tuberculosis and HIV, shingles

- Autoimmune mediated illnesses such as systemic lupus erythematosis, rheumatoid
arthritis, scleroderma

- History of mental illness requiring hospitalization (depression, bipolar illness, post
traumatic stress disorder, history of suicide attempts, psychosis, schizophrenia
spectrum); Current major depression of dysthymia; patients lacking capacity to make
medical decisions

- Use of monoamine oxidase inhibitors (MAOIs) within 2 weeks of evaluation; Active
ongoing use of the following agents: desvenlafaxine, fenfluramine, linezolid,
milnacipran, phentermine, tryptophan, tramadol, opiates

- Current (meets criterion within the last 6 months) for drug or alcohol dependence
(except for nicotine and caffeine)

- Cancer other than non-melanoma skin cancers

- Women who are pregnant or desire to become pregnant, breastfeeding, who use unreliable
contraception methods

- Those with occupations requiring use and/or operation of hazardous heavy equipment or
professional drivers

- Patients for whom the potential risk outweighs the potential benefit in the opinion of
the treating psychiatrist