Study Finds Pain-Related Brain Anomalies in ‘Gulf War Illness’

by U.S. Medicine

June 21, 2013

WASHINGTON — Veterans suffering from “Gulf War Illness” appear to have anomalies in the bundles of nerve fibers that connect brain areas involved in the processing and perception of pain and fatigue — changes not seen in unaffected individuals.

Researchers at Georgetown University in Washington found the axonal damage after scans of 31 veterans with the illness, compared with 20 control subjects, according to the study, published recently in PLOS ONE.1

The DoD-funded study used diffusion tensor imaging to find that damage to the right inferior fronto-occipital fasciculus was significantly correlated with the severity of pain, fatigue and tenderness.

Lead author Rakib Rayhan, MS, noted, “This tract of axons links cortical gray matter regions involved in fatigue, pain, emotional and reward processing.”

“Pain and fatigue are perceptions, just like other sensory input, and Gulf War Illness could be due to extensive damage to the structures that facilitate them,” Rayhan added. “Some of the veterans we studied feel pain when doing something as simple as putting on a shirt. Now we have something to tell them about why their lives have been so greatly affected.”

He also noted that the study findings offer “validation” for veterans who have had difficulty convincing the medical establishment their symptoms are real.

“This provides a completely new perspective on Gulf War Illness,” the study’s senior investigator. James Baraniuk, MD,  added. “While we can’t exactly tell how this tract is affected at the molecular level — the scans tell us these axons are not working in a normal fashion.”

The authors said the axonal changes are distinct from multiple sclerosis, major depression, Alzheimer’s disease and other neurodegenerative diseases.

Background in the article noted that more than one-fourth of the 697,000 veterans deployed to the 1990-1991 Persian Gulf War report mysterious medical symptoms, and brain alterations could help provide an answer. Symptoms of Gulf War Illness range from mild to debilitating and can include widespread pain, fatigue and headache, as well as cognitive and gastrointestinal dysfunctions.


  1. Rakib U. Rayhan, Benson W. Stevens, Christian R. Timbol, Oluwatoyin Adewuyi, Brian Walitt, John W. VanMeter, James N. Baraniuk. Increased Brain White Matter Axial Diffusivity Associated with Fatigue, Pain and Hyperalgesia in Gulf War Illness. PLoS ONE, 2013; 8 (3): e58493 DOI: 10.1371/journal.pone.0058493

Pain Improved Faster Than Other Issues for Wounded Warriors

FORT LAUDERDALE, FL — While pain showed the most improvement three to six months after hospitalization for major limb injuries, other mental-health symptoms took much longer to resolve in combat veterans, according to research presented this spring at the 29th Annual Meeting of the American Academy of Pain Medicine.

The investigative team, led by Rollin M. Gallagher, MD, MPH, noted that, as long as two years post-injury, patients reported little improvement in symptoms of depression, anxiety, post-traumatic stress disorder (PTSD) and other mental-health problems. Pain improved the most within three to six months and tended to level off after a year, according to the poster session.1

“Our research confirms that chronic daily pain, including neuropathic pain, continues to be a burden for limb-injured servicemen, [but] that post-traumatic stress is a far more prominent feature of recovery than in other chronic pain populations, and that returning to meaningful role functioning in their lives is challenging for many,” said Gallagher, who is VA’s deputy national program director for pain management and clinical professor of psychiatry and anesthesiology at the University of Pennsylvania and the Philadelphia VAMC.

Few studies have examined short- and long-term pain-related and behavioral-health outcomes in returning military personnel with major limb trauma, according to the researchers.

“The difficulty lies in developing an effective methodology that not only enables investigators to classify, in detail, the nature and severity of injuries and to characterize psycho-social and initial treatment variables, but that also enables investigators to evaluate the longitudinal outcomes of wounded warriors as they seek to recover in geographically dispersed localities, Gallagher said.

For the study, researchers conducted phone interviews with 277 combat-injured servicemembers — all of whom had major injuries to extremities — every three months for two years, beginning after their initial acute treatment at military hospitals. About half of the study subjects, who averaged 28 years old, were married, and more than 40% had some college education.

Of the study participants, 83.2% had suffered lower extremity (LE) injury, and 48.7% had upper extremity (UE) injury. About one- third, 33.5%, had undergone lower extremity amputation, 8.9% had bilateral LE amputation, and 8.9% had UE amputation.

The questionnaire was designed to measure multiple outcomes related to pain and behavioral health and employed measurement tools such as the Brief Pain Inventory (BPI), Neuropathic Pain Scale (NPS), Treatment Outcomes in Pain Survey (TOPS) and VA Behavioral Health Laboratory.

Researchers found that the BPI average and worst pain and the NPS items and subscales were significantly lower post-treatment compared with baseline, with no significant statistical differences noted at timepoints beyond six months.

Across various timepoints, 13.5% of survey respondents reported depression, 5% suicidal ideation, and 13.9% generalized anxiety disorder. Nearly half of the participants, 45.9%, reported a low level of PTSD and an additional 11.7% reported a high level.

Gallagher suggested, based on the results, severely injured veterans will need ongoing bio-behavioral pain and psychological care to help them cope with their injuries in the longer term.

  1. Gallagher RM, et.al. Poster 144 – A Longitudinal Investigation of Major Combat Limb Injuries: The Regional Analgesia Military Battlefield Pain Outcomes Study (RAMBPOS). Presented at the 29th Annual Meeting of the American Academy of Pain Medicine. April 11-13, 2013. Fort Lauderdale, FL

Low-Dose Ketamine Reduces Morphine for Surgical Patients

FORT LAUDERDALE, FL — Low-dose ketamine could significantly reduce the amount of post-operative morphine needed for patients on large-dose opioids who are undergoing surgery.

That’s according to a presentation, led by Air Force Maj. Jonathan A. Day, MD, at the 29th Annual Meeting of the American Academy of Pain Medicine.1

“After anecdotal reports of improvement in fibromyalgia symptoms in fibromyalgia patients receiving ketamine, we conducted a retrospective study to provide a more systematic initial assessment of the potential impact of ketamine on fibromyalgia pain,” according to the report abstract, based on research at the Mayo Clinic in Jacksonville, FL.

Researchers conducted a retrospective chart review of 25 consecutive patients with fibromyalgia, 10 having total hip replacement and 15 having knee arthroplasty. All were given the same regional anesthetic blockade, except that 10 patients — five hip and five knee — also received low dose ketamine infusion.

The study was conducted from November 2009 to July 2011, with the mostly female patients ranging in age from 28 to 82.

The authors noted that their focus “was on 48-hour post-operative oral morphine equivalent use.”

Researchers noted that the morphine equivalent use in patients without ketamine was 250 mg, while the median with ketamine was 135 mg.

“Despite the small sample size, this was marginally statistically significant with p=0.054, and consistent with the anecdotal reports,” they added.

Researchers said they chose to study fibromyalgia because it is a “complicated disease process which, despite modern treatment often, leaves these patients in significant pain. The subsequent high use of narcotics further complicates their care. Low-dose ketamine, with its proven narcotic sparing effects, may provide a novel avenue of treatment for patients with fibromyalgia and more in depth prospective studies are warranted to investigate this further.”

1.  Day JA, et.al. Poster 113 – Perioperative Ketamine Reduces Post-Operative Opioid Consumption After Major Orthopedic Surgery in Patients with Fibromyalgia: A Retrospective Chart Review of 26 Cases. Presented at the 29th Annual Meeting of the American Academy of Pain Medicine. April 11-13, 2013. Fort Lauderdale, FL.

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