One of the most difficult aspects of finding effective and safe therapies for chronic pain is the lack of knowledge about the etiology of this pervasive problem. “In other words, symptoms that profoundly affect billions of people across the globe have remained unexplained,” say the authors of a narrative review recently published in Autoimmunity Reviews.¹
Passive Transfer as a Pain Pathway
Andreas Goebel, PhD, director of the Pain Research Institute at the University of Liverpool, an expert in complex regional pain syndrome (CRPS), and lead author of the paper, had previously suggested that autoantibodies can cause chronic pain by attaching to peripheral tissues and causing sensory nerves to misfire.¹⁻³ Along similar lines, a variety of experiments have been done using passive immunoglobin transfer, a technique in which human serum immunoglobulins thought to be pathogenic are isolated from patients and transferred to rodents, to test whether they show signs of the disease.
These studies have been largely successful in demonstrating the concept. For example, as long ago as 1975, a study demonstrated that rodents developed muscle weakness associated with myasthenia gravis after being injected with IgG donated by patients with the illness.⁴
Chronic Primary Pain Models
Based on experiments such as these, subsequent researchers have hypothesized that a similar immunoglobulin transfer might identify a role for autoantibodies in chronic primary pain. In the past decade, a variety of passive-transfer experiments using different CPP (chronic primary pain) models have proved remarkably successful, according to this analysis. The methods used in the reviewed studies varied depending on the conditions being examined, which included CRPS, post-traumatic chronic limb pain, rheumatoid arthritis, fibromyalgia syndrome, and neuropathic pain conditions.
However, the material from the patients with CPP were consistently shown to contain pathogenic pro-nociceptive antibodies, while people who did not have chronic pain always tested negative for such antibodies. Once injected into rodents, the antibodies produced pain phenotypes similar that of the patient donors, strongly suggesting an autoimmune mechanism in the development of chronic pain. This body of research represents, the authors of the review paper write, “a paradigm shift for our understanding of chronic pain aetiologies.”¹ In addition, they believe these findings on the etiology of pain should make it be possible to develop new effective treatments for CRPS and chronic pain.¹
The researchers also pointed out that “these findings corroborate the validity of 2-hit autoimmunity models – both antibodies and trauma are required – for regional antibody-mediated disorders.”¹ Although it remains to be discovered which target cells and molecular structures are involved, they argue that CRPS should no longer be considered “unexplained.”¹
Rethinking Assumptions about the Roots of Pain
The research is intriguing, and the paper examines the science behind some poorly understood pain complexes, Kevin Byram, MD, assistant professor of rheumatology and immunology at Vanderbilt University Medical Center, told PPM. However, he pointed out that there is still a lot of work to be done. “The idea that there might be disease features on the fringes that are nonspecific but still related to antibodies is possible; it’s just very hard to prove.”
In addition, said Dr. Byram, many things can cause pain, and there are many different pain pathways. While these studies on immunoglobulin transfer are interesting, ultimately pain may have multiple sources in a single patient. This makes for complex challenges, clinically and in the lab. “What we call fibromyalgia today might actually be five or six or even 10 different diseases, all with different mechanisms,” he said.
Dr. Goebel’s team agrees that more research is needed to identify specific molecular targets, although some cellular binding targets, such as dorsal root ganglion satellite glia cells and neurons have already been established. Nonetheless, they say that this body of research identifies a potentially transformative approach to understanding and seeking treatments for one of the most challenging issues clinicians and patients face: unexplained chronic pain.
Even short of new therapies, these results offer an opportunity to rethink some of the assumptions researchers and clinicians alike have sometimes made about chronic pain.
“The reviewed studies into non-destructive immune processes,” Dr. Goebel’s team wrote, “call for scrutiny about any assumed correlations between the degree of tissue destruction caused by a certain pathophysiological mechanism and the relevance of this factor for patients’ quality of life.” The experiments reviewed in the article show that solely “functional, non-destructive biological processes can cause exquisite hypersensitivities which severely affect daily living.”¹
