For decades, pain researchers have set their sights on understanding pain mechanisms—the cellular and molecular machinery underlying chronic pain. In doing so, they became increasingly aware that the terms they used to describe the neurobiological workings of pain did not always match what they had learned.
But now, official adoption by the International Association for the Study of Pain (IASP) of an IASP terminology task force recommendation for a so-called “third mechanistic descriptor” of chronic pain could move the field forward in its efforts to more fully characterize the known pathophysiological mechanisms of pain. The new term, christened “nociplastic pain,” joins “nociceptive pain” and “neuropathic pain” as terms officially adopted by the association to describe the underlying neurobiological basis of chronic pain.
Pain researchers have long recognized the need for an additional mechanistic descriptor and are applauding the endeavor to create one, even if some don’t agree with the specific term chosen by the task force.
“It’s a big step forward,” says Daniel Clauw, University of Michigan, Ann Arbor, US. “I’m looking at the glass three-quarters full. I hate the term ‘nociplastic’—the average practicing clinician won’t at all understand it, and patients won’t know what it is—but I like everything else” about the attempt to develop a new term that reflects an underlying mechanism of chronic pain.
But others have reacted more favorably to the appellation, and some investigators, such as David Bennett, University of Oxford, UK, say the new descriptor could help to validate the experience of patients with pain, and also benefit researchers as they strive to learn more about pain.
“For the management of pain, it’s quite helpful for the patient to get some feeling that there’s a neurobiological understanding of what they’re experiencing,” Bennett said. “I also think this effort will have an effect on people’s thinking research-wise—how we need to get better techniques to measure sensitization within the sensory nervous system. That’s also a good thing,” said Bennett, a pain researcher and neurologist who studies pain mechanisms.
A topical review by the task force discussing the need for a third mechanistic descriptor appeared in July 2016 in PAIN, with several letters to the editor from Clauw and others subsequently published in the journal. The task force was led by Eva Kosek, Karolinska Institute and Stockholm Spine Center, Stockholm, Sweden, and the descriptor was officially adopted by IASP in October of last year.
The road to “nociplastic pain”
IASP defines “nociceptive pain” as “Pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors.” Meanwhile, in 2011, the association revised its earlier definition of “neuropathic pain” from “Pain due to lesion or dysfunction of the nervous system” to “Pain caused by a lesion or disease of the somatosensory nervous system.” The decision to remove the word “dysfunction” from the 2011 definition of “neuropathic pain” stemmed from a recognition that many heterogeneous groups of patients could fit into the original definition, creating a crude and unsatisfactory lumping together of patients whose chronic pain could emanate from very different underlying mechanisms.
For Kosek, while she agreed with the update of the definition of “neuropathic pain,” it was her clinical experience with patients whose pain was not adequately characterized as either “nociceptive pain” or by the revised definition of “neuropathic pain” that spurred her interest in terminology and the need for a new mechanistic descriptor.
“I’m a clinician in addition to being a pain researcher, and so throughout my career I have met a lot of patients whose pain was misunderstood,” Kosek told PRF. “They have been very unhappy in the healthcare system because doctors could not find a peripheral explanation for their pain, so, for example, there was not enough pathology on an x-ray to explain it. And we had known for a long time that the correlation between peripheral pathology and the amount of pain and symptoms that patients have is poor. On the other hand, it is very clear that altered pain modulation within the nervous system plays a major role.”
Since the shortcomings that Kosek saw in sufficiently characterizing pain were widely recognized by pain clinicians and scientists alike throughout the world, many used their own terms to describe what they were seeing and learning. “Pathological pain,” “centralized pain,” “dysfunctional pain,” and others were all employed, but none were suitable, she says.
“These terms lacked effective definitions, and so there was large confusion in the community because people used different terms with slightly different meanings, and this, of course, is extremely confusing,” Kosek explained.
The terminology task force considered many different terms, and after much discussion opted for three candidates they deemed most acceptable, including “nociplastic pain,” “algopathic pain,” and “nocipathic pain.” Members of the IASP community, including chairs of IASP Special Interest Groups (SIGs), IASP chapter presidents, and the IASP council then voted for their choice among the three possibilities. “Nociplastic pain” emerged as the winner, a descriptor that Kosek says also turned out to be the one that most, though not all, task force members liked the best.
What is it?
So what is “nociplastic pain”? The new mechanistic descriptor is defined as “Pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain.”
The new designation could help to describe the pain that underlies many different chronic pain states, including fibromyalgia, complex regional pain syndrome, other types of musculoskeletal pain such as chronic low back pain, as well as visceral pain disorders such as irritable bowel syndrome and bladder pain syndrome. “Nociplastic pain” is not a diagnosis, the task force emphasizes, but rather a way to understand the neurobiological workings of the nervous system that lead to pain when they go astray.
The evidence that nociplastic pain underlies many different forms of chronic pain is very strong, Kosek says, and comes from studies based on subjective methods such as quantitative sensory testing, as well as those based on more objective techniques such as sensory-evoked potentials and functional magnetic resonance imaging; these investigations all point to altered processing of nociceptive stimuli in these patient groups.
“And even more interesting is that often the degree of altered nociception is related to pain intensity in these patients. The scientific evidence for altered nociception in these individuals who are designated as having ‘nociplastic pain’ is extremely strong,” Kosek said.
No single term is perfect
One of the criticisms of the new mechanistic descriptor that Clauw and some others have is that it is new and unknown, and so it would have been better to use a term that was more widely recognized.
“I think there were a lot of terms that could have been chosen that would have been more understandable to clinicians,” Clauw told PRF, who said he would have preferred a term with “central” in it, such as “centralized pain,” “central sensitization,” or “central hypersensitivity.” “It just does not seem necessary to invent new jargon when almost any descriptor that includes the word ‘central’ will be much more likely to be understood by non-pain specialists,” he wrote with five of his University of Michigan colleagues in response to the task force’s topical review. It is a sentiment that he still stands by, Clauw told PRF. Further, because “nociplastic pain” will have no meaning to patients, Clauw said, he doesn’t think it will have much of an impact on them.
Clauw is not alone in his distaste for the new descriptor. For example, in another letter to the editor published in response to the review article, Lars-Petter Granan, Oslo University Hospital, Norway, and University College of Southeast Norway, Drammen, Norway, wrote that “the new terminology is so imprecise and vague that it can aid neither clinical thinking nor research.”
Kosek is sympathetic toward criticism of the new mechanistic descriptor. “The problem is that there was no single term that was more widely recognized, understood, or used more than any other term,” she said. “It’s natural for people to like their own term and think that term should be the one that is used—I have full understanding that people think that—but as a task force we had to be more stringent and think more broadly.”
Kosek also told PRF that she has heard much positive feedback from the community about the new term. “It is my experience that the term has been very warmly welcomed by most clinicians, patients, and patient organizations.” She also pointed to adoption of “nociplastic pain” by the Swedish Medical Products Agency, which is using the term in its new recommendations for the treatment of chronic pain, as another example of this favorable reception.
What will the impact be?
Despite his criticisms of the specific term that was chosen, Clauw nonetheless believes that putting a focus squarely on mechanisms underlying chronic pain can only help matters, here expressing that sentiment using his and his colleagues’ preferred term, “centralized pain,” rather than “nociplastic pain.”
“One of the reasons this third mechanism is important is that it can occur and in fact often does occur in combination with the other two mechanisms,” he said. “It’s really important that clinicians see that someone with neuropathic pain with superimposed centralized pain, or nociceptive pain with superimposed centralized pain, needs to be treated differently because some of that pain is coming more so from the central nervous system, and peripherally directed treatments are not going to work for that.”
Meanwhile, Bennett says that a focus on mechanisms will help validate the experience of patients, who still are often told that their pain is not real. The new descriptor “probably represents some kind of sensitization within the sensory nervous system. This can be helpful to explain mechanistically what’s happening to patients. The big advance is that patients aren’t told it’s ‘all in their head.’”
Kosek, too, believes the new descriptor could help patients in this way, if it is disseminated widely and effectively. Further, by drawing attention to altered nociception as an important mechanism behind chronic pain—one that should be screened for in the clinic, she says—diagnosis and treatment could be improved, once there are new diagnostic criteria to achieve this aim. Kosek also thinks the third mechanistic descriptor will facilitate doctor-patient communication, pain research efforts, the establishment of treatment guidelines, and therapeutic strategies to relieve pain.
Interestingly, Kosek suggested that “nociplastic pain” could have a beneficial impact on the drug development process. Here, maybe new medications could be advanced with mechanistic indications in mind. That is, rather than advance a drug based on a diagnosis—of fibromyalgia, for instance, or low back pain—the drug could instead be developed for nociceptive pain, or nociplastic pain, or neuropathic pain. And, perhaps, increasing awareness of nociplastic pain could help mitigate the opioid epidemic, according to Kosek. While acknowledging that abuse issues are very important in this regard, she said, “The opioid epidemic is partially due to the fact that patients with nociceptive pain who initially may respond to opioids may in time actually develop nociplastic pain, and opioids are not indicated for nociplastic pain conditions—they might even make things worse.”
Finally, Kosek hopes the new mechanistic descriptor spurs a more widespread recognition that pain is a disease in its own right, a concept that is familiar to pain researchers at the forefront of knowledge but has still not spread sufficiently beyond that group. “Pain research and pain clinics are underdeveloped in relation to the clinical need, and that is because pain is regarded as secondary; it’s regarded as a symptom. But nociplastic pain is not necessarily a symptom of anything, but a disease or condition in its own right,” Kosek told PRF. Ultimately, she says, “Rightly used, ‘nociplastic pain’ could have a huge impact on healthcare, treatment, research funding,” and other areas.
In terms of future research, one important gap is the current inability to fully gauge nervous system sensitization underlying nociplastic pain. “We need better physiological measures of sensitization that we can apply clinically,” says Bennett. “The difficulty we have as a field is that we don’t yet have the tools in clinical practice to absolutely demonstrate that there is an altered stimulus-response function in the patient. How such hypersensitivity should be determined” is unclear at the moment.
Kosek agrees that one of the important next steps is to develop clinical criteria that can accurately identify patients with nociplastic pain. As the chair of the task force, she is now assembling a new group to develop those criteria, with an initial focus on musculoskeletal nociplastic pain, and then another group within the task force will be convened to develop separate criteria for visceral nociplastic pain.
“We now have a new task that is perhaps even more challenging, so this is not a process that has ended in any way,” Kosek told PRF.
Kosek also emphasized that creating terminology is an evolving activity that should reflect current understanding, so terms may change as researchers learn more about chronic pain. While Kosek believes “nociplastic pain” won’t be an ephemeral term, it is important, she said, to remember that terminology must always be revisited so that it mirrors the latest knowledge.
Finally, since pain is not solely a physical phenomenon, but one that involves psychosocial and other factors as well, a focus on neurobiological mechanisms must fit into a framework that incorporates those elements.
“[C]lassification of pain by descriptive terms is only one part of a broader framework for understanding the lived experience of pain, including psychosocial, lifestyle, genetics, and environmental factors that may contribute to sensitisation processes,” wrote Niamh Moloney, Macquarie University, Sydney, Australia, and THRIVE Physiotherapy, St. Martin, Guernsey, along with colleagues, in a letter responding to the task force review article.
Indeed, Moloney, a clinician and researcher in the area of musculoskeletal physiotherapy and pain management, told PRF, “When you are evaluating somebody with pain, assessing the dominant pain mechanism is just one part of an overall assessment profile. We shouldn’t be so linear in our thinking that just because we’ve classified the pain mechanism then that means we’ve assessed the whole person,” she said. It is a sentiment with which Kosek fully agrees.
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Neil Andrews is a science journalist and executive editor of PRF.
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