Answering Clinical Questions Behind Chronic Pain Syndromes

Amanda Decimo, RN, MSN, MPH

Chronic pain is a serious public health problem that affects 100 million people in the United States today. While acute pain is protective to prevent injury, chronic pain can be debilitating. Chronic pain patients present unique challenges for the anesthesiologist. During the panel, “Visualizing Pain: From Mouse to Human,” on May 16 at the IARS 2021 Annual Meeting, researchers shared their current imaging techniques and animal models in use to address clinical questions about the biological mechanisms behind chronic pain syndromes.

Neuropathic pain can be caused by lesions in the somatosensory neurons from injury, diabetes, cancer, and chemotherapy. It can be treated with anti-inflammatories, anti-depressants, gabapentin, and opiates; but often these medications are ineffective and lead to serious side effects.

Guang Yang, PhD, Associate Professor of Anesthesiological Sciences at Columbia University Medical Center, uses neuroimaging techniques in her lab to evaluate the dysfunctional alterations in chronic pain circuits. By ligating nerves in mouse subjects, Dr. Yang models peripheral nerve injuries and monitors changes over time with neuroimaging.

She uses imaging to evaluate three components of pain circuits: the dorsal root ganglia (DRG), the primary somatosensory cortex (S1), and the anterior cingulate cortex (ACC). These regions are activated during nociception and become hyperactive with chronic pain.

Her imaging techniques help visualize maladaptive changes in the peripheral and central nervous system. Increased excitation in DRG sensory neurons with chronic pain leads to maladaptive plasticity in the cortex. Dr. Yang and her colleagues target specific subtypes of interneurons in the cortex and are able to prevent these maladaptive responses that lead to chronic neuropathic pain.

Norman Taylor, MD, PhD, Associate Professor of Anesthesiology and Michael K. Cahalan Presidential Chair, at The University of Utah School of Medicine, discusses his work on temporomandibular pain disorders (TMD). TMD occurs in 6-12% of the population yet is less studied than all other pain disorders. The contributing factors include mechanical, biochemical and psychosocial mediators and are not well understood. TMD can disrupt quality of life by causing difficulty talking, chewing, swallowing, and migraines. The OPPERA study by W. Maixner et. al. is the only previous study that identified TMD factors including genetic mutations and events such as an intubation or extended dental procedures that cause temporomandibular stress. Interestingly, sleep disruption prior to onset of TMD was also identified.

Dr. Taylor and colleagues hoped to delineate the causes and relationships between inflammation, mechanical jaw loading, and COMT deficiencies in TMD using a rat model. They employed a device called a ratgnawmeter to assess chewing function in rats. Chewing provides a concrete behavioral endpoint that correlates with TMD pain. COMT, an enzyme that inactivates catecholamines, was evaluated as patients with COMT deficiencies have a build-up of catecholamines that predispose them to TMD.

None of these factors independently produces TMD pain. However, COMT inhibition combined with mechanical jaw loading produced significant evidence of TMD, measured by chewing decreased chewing function, which suggests it’s both the predisposing factors and a stimulating event that bring about this disorder.

Finally, Hsiao-Ying Wey, PhD, from Harvard Medical School, brought the discussion full circle with her presentation on “Imaging Humans with Chronic Pain.” Her research focused on noninvasive neuroimaging techniques used in living human subjects, allowing the ability to visualize what is going on in the central nervous system and peripheral nervous system during pain.

She concentrated specifically on positive emissions tomography (PET) imaging because it is a more sensitive imaging tool, allowing imaging of different molecular targets within the brain and spinal cord. She discussed alternative radioisotopes that allow researchers to target specific pain receptors such as the mu-opioid receptor (MOR). These MORs exhibited downregulation in patients with neuropathic pain, fibromyalgia, and chronic lower back pain. This led to decreasing endogenous opioid release at the pain sites. Interestingly, after successful pain treatment, the MORs potentially reverse to normal levels.

Wey shared a recently discovered marker of neuroinflammation, translocator protein (TSPO). This intriguing discovery may lead to more effective pain control outside of traditional opioid options. In pain models, upregulation of TSPO occurs and brighter PET imaging is seen in these areas. Wey’s 2015 study (Elevated CPBR28 Binding in Chronic Low Back Pain) shows elevated TSPO in the thalamus region of patients with chronic lower back pain that was not visualized in controls. TSPO has also shown to be higher in the affected target regions, such as in the spinal cord with sciatica patients. These exciting discoveries will also allow clinicians to evaluate pain treatment efficacy by visualizing pain targets.

The contributions of pain research today provide hope for treatment modalities that attenuate chronic pain suffering in the future.