Study: Chronic Pain May Really Be ‘All in Your Head’

“Increasingly recognized as a source of immune cells in health and disease,” the skull bone marrow also may promote and/or maintain chronic pain from elsewhere in the body, researchers said.

Advanced imaging in 125 people with chronic knee or back pain and 22 healthy controls showed elevations in 18-kDa translocator protein (TSPO) — produced in skull bone marrow and thought to help drive neuroinflammation — were strongly linked with pain intensity and its interference with normal activities, according to Marco L. Loggia, PhD, of Massachusetts General Hospital in Boston, and colleagues.

“[T]hese findings indicate that increased immune activity in the SBM [skull bone marrow] is linked to chronic pain and its associated symptoms,” the group wrote in Science Translational Medicine. “This work highlights the emerging importance of SBM immunity in the development of chronic pain and possibly other conditions involving brain inflammation.”

TSPO is already in research use as a marker of brain inflammation, via PET/MRI scans with a radiolabeled binding molecule. But it’s also found outside the nervous system, “highly expressed in peripheral immune cells,” Loggia and colleagues explained. The same group had previously found this to be true in migraine patients, which in turn suggested “an increased density of myeloid cells in the SBM” that may contribute to the condition.

Studies by other groups yielded similar findings in a variety of neuropsychiatric disorders, pointing to the possibility that “skull marrow activation might not be unique to migraine,” Loggia’s team wrote, but may “represent a more fundamental neuroimmune response” — which might include chronic pain in orthopedic conditions. The latter had not been investigated before now.

The researchers therefore recruited 88 patients with chronic lower back pain and 37 with pain from knee osteoarthritis (OA), along with 22 people without chronic pain. PET/MRI scans were performed to quantify TSPO within the skull bone marrow. Findings were checked against molecular analyses of postmortem skull bone marrow samples taken from a donor who suffered from chronic pain and from another person without pain.

Patients with chronic back pain were substantially younger on average than either those with knee OA or the healthy controls (47, 67, and 56 years old, respectively). Half the control group were women, versus 59% of those with back pain and 43% of the knee OA patients. The patients’ average pain was not very great, rated at a little over 4 in both groups on the standard 0-10 scale. Fatigue, depression, anxiety, and sleep problems were more common in patients than controls, while social functioning was significantly lower.

As the researchers hypothesized, TSPO levels were substantially higher in the patients with chronic pain versus controls, a difference that was greater in the knee OA group than in the back pain patients. Standardized uptake values averaged about 0.3 in controls, 0.42 with back pain, and 0.5 with knee OA.

Similarly, TSPO levels also correlated with pain intensity, and more strongly with knee OA (r=0.59) than in back pain (r=0.34). The same was seen for pain interference, albeit to a lesser degree (r=0.54 vs r=0.49). Several of the comorbid conditions analyzed in the study, including sleep disturbance, anxiety, and depression, also showed correlations with TSPO levels in the skull bone marrow.

Loggia and colleagues also noted that TSPO elevations weren’t distributed evenly across the skull bone marrow. These elevations, compared with controls, were concentrated in the frontal and parietal regions, in both hemispheres.

These findings were generally confirmed in detailed histochemical analyses of skull bone marrow samples, taken from two 62-year-old men, one with a history of diabetic neuropathic pain and headaches, the other with no record of chronic pain. TSPO was present in 82% of cells from the pain patient versus 55% of those from the control donor; total cell numbers were higher in the pain donor as well.

The point of such research, of course, is to better understand the origins of chronic pain in order to design more targeted and effective therapies, which are frequently wanting for both lower back pain and OA pain. Connecting these dots, however, will require a lot more research. Referring to the skull bone marrow, Loggia and colleagues called for “further investigating this previously overlooked structure, which remains largely underexplored in the context of pain.”

They also suggested that “SBM-targeted pharmacological or stimulation techniques” such as photostimulation and low-power ultrasound could be examined in future studies for their analgesic potential.