Author’s response

TO THE EDITOR

I am grateful for the comments of Dr. John Quintner, Dr. Asaf Weisman, and Dr. Milton Cohen [1] on my recent review of the nociplastic pain concept [2].

Although detailed discussion of the mechanisms of nociplastic pain was beyond the scope of my article, I agree with most of the comments on nociception, chronic pain, sensitization, and allodynia. They provide closer definitions and are valuable contributions to the debate on the concept.

Nevertheless, I would argue that it is possible to test my suggestion that occult neuropathy can be a cause of nociplastic pain. Nociplastic pain induced in the current experimental animal models may in fact be due to pain-dependent posture alterations and consequent compressive proximal neural lesion [3]. Therefore, nociplastic pain experiments should include explorations for neural damage at the dorsal root ganglion level. The clinical means for testing my postulation in question include peripheral nerve electrodiagnostics, which are not routinely done when neuropathy symptoms are absent, e.g., in fibromyalgia patients. Preliminary electrodiagnostic evidence of occult peripheral nerve involvement in fibromyalgia has already been found [4,5]. Also, consulting experienced peripheral nerve surgeons could result in rejection of a nociplastic pain “diagnosis” in many patients. Unfortunately, these specialists are not normally included in the multidisciplinary team for persistent pain management. Of note, it is peripheral nerve surgeons who have shown that migraine can be successfully managed by decompression of extracranial sensory nerves [6]. Obviously, these clinicians may be difficult to convince that migraine headaches belong to the nociplastic pain category. There are also surgeons who advocate abandoning complex regional pain syndrome (CRPS) type I diagnosis in favor of CRPS type II, because they have very often seen cases where compressive neural lesions produced CRPS type I symptoms [7,8]. Admittedly, risks of misdiagnosis in conditions mimicking CRPS are high [8–12].

I am also reluctant to accept the criticism regarding the reality of psychologically/emotionally induced nociceptive sensitization (hypersensitivity). This phenomenon has been observed both clinically [13] and experimentally [14–16]. Remotely induced pain hypersensitivity [14–16] may currently be the only proof that nociplastic pain is pathophysiologically possible. However, in a biologically protective sense, observing others’ pain behavior or injury can be regarded as threatening damage to the observer’s body (i.e., as a signal that the observer may potentially suffer from a similar injury), which would not comply with the definition of nociplastic pain [17]. Furthermore, as the authors of the comments pointed out, nociception, sensitization, and pain are different concepts. I have also mentioned in my article that noxious (or at least sub-noxious) input is necessary for sensitization to produce physical pain. While non-noxious humoral-cellular mechanisms may be involved in nociplastic pain [18], such mechanisms should involve transient structural alterations at the receptor level to produce functional neural changes.

I remain critical of the “clinical legitimacy” of the concept. Clinical studies of nociplastic pain are proliferating and the spectrum of nociplastic pain conditions is expanding [19,20], despite the nociplastic pain mechanism still being speculative. While nocipalstic pain is not understood as a diagnosis, the process of evaluation for evidence of the presence of nociplastic pain resembles making a diagnosis [20]. Overloaded and less experienced clinicians may be tempted to overexploit this concept, which could lead to missed diagnoses. Clinical validation of the nociplastic pain construct primarily requires straightforward showing that there is a specific treatment for this type of pain. The note to the definition of nociplastic pain [17], that it can coexist with nociceptive pain, may encourage clinicians to overuse pain medication. This could drive a vicious cycle of persistent pain, because pain overtreatment can mask pain causes, such as, e.g., compressive proximal neural lesions, and thus exacerbate them [3].

In contrast to neuropathic and nociceptive pain that have specific, straightforwardly defined origins, the implied absence of physical causes of nociplastic pain [17] and its equivocal pathophysiology make this term synonymous with “pain of unknown origin.” The semantic clarity of the latter descriptor suggests that it is a clinically safer alternative to “nociplastic pain.”

Funding Statement

FUNDING No funding to declare.