Central sensitization: when is this the right terminology?

1. Introduction The discovery of central sensitization triggered a paradigm shift in the understanding and management of acute and chronic pain, including a shift from primarily considering peripheral mechanisms to central drivers of pain which affect patient management decisions.11 It also contributed to the descriptor, nociplastic pain, introduced by the International Association for the Study of Pain (IASP) to complement nociceptive and neuropathic pain. However, the term's clinical use is debated. The formal IASP definition implies central sensitization should be used to describe physiological phenomena that can only be directly identified in animals, and not clinical features in humans possibly mediated by central sensitization. Others advocate use of the term in a wider sense such that it can be used when it seems as if elements of the central nervous system are sensitized (rather than pain occurring purely because of peripheral nociceptive input), which allows patients and clinicians to embrace a potential mechanistic approach to the understanding of pain and its management. The problem is that the term central sensitization has different meanings in different contexts. Some argue it should not be broadened from its original physiological definition for use in a clinical context, whereas others argue there are features/manifestations of pain and its responsiveness to interventions that represent central sensitization. There are potential problems if the definition is too broad or too narrow.2 This topical review aimed to: (1) present both sides of the argument of when and in what context we can or should use the term central sensitization, (2) consider the implications for clinical and research communities of a definition that is too broad or narrow, and (3) propose a rational path forward. 2. The International Association for the Study of Pain definition of central sensitization as a measurable physiological phenomenon 2.1. The International Association for the Study of Pain definition of central sensitization In 1983 Clifford Woolf16 demonstrated that repeated discharge of C-fiber nociceptor neurons triggered an increase in spinal cord excitability leading to a reduced threshold and increased response to noxious stimuli that spread to surrounding uninjured tissues, and later introduced the term central sensitization for this phenomenon.18 This underpins the IASP definition of central sensitization as “increased responsiveness of nociceptive neurons in the central nervous system (CNS) to their normal or subthreshold afferent input,” which includes a note that “sensitization” is “a neurophysiological term that can only be applied when both input and output of the neural system under study are known.” This implies that the term can only be applied to describe phenomena identified in animal models. 2.2. Issues to consider with the International Association for the Study of Pain definition Opinions differ regarding the processes included within the IASP definition. Although the wording implies that central sensitization refers to any increase in responsiveness of nociceptive neurons, some8 interpret the term to be restricted to specific dorsal horn processes where neuronal input and output have been documented, aligned to the initial observations of increased spinal excitability induced after peripheral noxious input as a mechanistic explanation for hyperalgesia/allodynia in uninjured tissue.14,18 An expanded view of central sensitization is not restricted to excitatory synaptic facilitation but includes changes in membrane excitability and loss of spinal and descending inhibition, that are not limited to the spinal cord, but include a broad state of heighted activity in central nociceptive circuits that contribute to hyperalgesia/allodynia and a spread of pain to healthy tissues, as well possibly to spontaneous pain. Furthermore, the definition restricts central sensitization to nociceptive neurons, yet similar phenomena apply to non-nociceptive neurons. The necessity, by IASP definition, to measure neuronal input and output requires consideration. From a practical standpoint, central sensitization is often not directly measured in nociceptive neurons in animal research and is inferred from behavioral measures (eg, changed thresholds and exaggerated/prolonged responses) similar to human studies. By definition, the term should not be used in this context. Is this requirement reasonable or required? Furthermore, microneurography can measure peripheral input in humans, and human fMRI studies show exaggerated CNS responses to subthreshold stimulus. Is that sufficient to meet the IASP definition? An alternative view is that although fMRI provides insights into central activity, a blanket increase in CNS responses on subthreshold stimulation may not quantify central sensitization. Some argue the IASP definition is not precise. First, the definition refers to “Increased responsiveness of nociceptive neurons.” Although the IASP defines nociceptive neurons as a “neuron of the somatosensory nervous system that is capable of encoding noxious stimuli,” it is not explicit whether this is restricted to nociceptive-specific and wide-dynamic range neurons in the spinal cord limiting the term to spinal cord processes, or whether it includes other neurons such as primary somatosensory cortex neurons that respond to nociceptive and non-nociceptive inputs, inferring application throughout the nervous system. Second, nociceptive neurons never function in isolation, which could be considered to make the narrow focus artificial and limited. 2.3. The case to retain the International Association for the Study of Pain definition Human research relies on surrogate measures (temporal summation, conditioning pain modulation, secondary hyperalgesia/allodynia)13 that are not exclusive to central sensitization.7 In a 201117 review, Woolf suggested that “because we cannot directly measure sensory inflow, and because peripheral changes can contribute to sensory amplification, as with peripheral sensitization, pain hypersensitivity by itself is not enough to make an irrefutable diagnosis of central sensitization.” Because central sensitization, as defined by the IASP, is one of many phenomena (including non-nociceptive) that might relate to a sensitized clinical state and changes in these surrogate measures, using one term to describe them may add confusion regarding underlying biological process. Restriction of the term to contexts with direct neuronal recordings would eliminate need for “inference” and exclude “exaggerated” responses that are not due central sensitization. A definition of central sensitization that is broadened to enable application in clinical contexts identified by behavioral responses has implications. First, the term may no longer convey precision regarding underlying processes. Second, if the purpose of identifying central sensitization in clinical contexts is to guide selecting the right treatment, then conflating different mechanisms under a single name could be unhelpful as it would likely fail to distinguish a patient based on pathophysiological mechanisms and its potential to guide application of a treatment targeting a specific pathophysiology.2 Third, if central sensitization is identified based on perception, then it risks circular reasoning–central sensitization amplifies pain, pain is amplified so there is central sensitization.2 3. The broad definition of central sensitization to include clinical features in humans 3.1. A broad interpretation In 1997, Gifford and Butler,4 suggested central sensitization could be applied in clinical contexts to explain observations of unfamiliar anatomical presentations of pain and remote sensitivity. From this perspective, the term is used to infer a “sensitized nervous system,” which implies “an amplification of neural signaling within the CNS that elicits pain hypersensitivity,”17 and “a general state of CNS hypersensitivity/hyperexcitability involving both spinal and supraspinal structures, explaining a variety of symptoms including pain and nonpain symptoms (eg, increased sensitivity to bright light, sounds, and odors).”10 In this context, the term is an umbrella neurophysiological concept of increased central nociceptive gain that can arise from multiple CNS processes, including reduced inhibition and/or increased facilitation within the descending pain modulatory system, as well as spinal/supraspinal amplification. This interpretation is widely used and promotes study of features associated with altered central circuit excitability in humans (eg, reduced inhibition inferred from conditioned pain modulation paradigms as a human analog of diffuse noxious inhibitory controls which measure descending inhibition in animals, and increased facilitation inferred using temporal summation as a human analog of wind-up which measures activity-dependent spinal excitability in animals). Central sensitization has been inferred from parallel changes in electrophysiological and psychophysical measures in animals and humans, respectively.12 The term is used broadly in the clinical literature, and “central sensitization pain” was used to describe a specific pain phenotype that is characterized by behavioral features related to “sensitivity.”15 Woolf17 suggested “there are some features of patients' symptoms which are more likely to indicate central rather than peripheral contribution to pain hypersensitivity,” and on this foundation, many studies have measured behavioral features such as increased sensory sensitivity in adjacent and remote body areas, among other measures (eg, allodynia). Translating preclinical research to clinical practice is crucial. This has been the intention of the inclusion of central sensitization in a broad set of phenomena that drive pain-related disease states, with the goal to identify individuals likely to respond to interventions that act on mechanisms that underpin it. Clinical correlates of central sensitization, such as the spatial spread of pain in patients over time closely mirrors observations in animal models of an initial ipsilateral dorsal horn sensitization, followed by contralateral dorsal horn, and rostral/caudal spread.5 The broader definition has been used to help understand acute and chronic pain. Research has revealed that sensitization in the CNS is not only limited to the nociceptive system but also is present in other systems originating and/or orchestrated by the CNS, such as the sympathetic nervous system, endocrine (eg, the hypothalamus–pituitary–adrenal axis), metabolic (eg, heightened postprandial glucose response to sugary drinks), and limbic (ie, emotional processing) systems. Although conflating multiple mechanisms under a single general term might prevent application of a treatment that targets a specific pathophysiology, if central sensitization is identified in a patient, this could plausibly initiate further investigation to identify the driver of central sensitization though a detailed study of their pain phenotype and relevant biomarkers such as those as proposed to distinguish between presumed top-down and bottom-up drivers of central sensitization.6 A broad definition of central sensitization can also help people in pain understand the nature and complexity of their condition. By broadening their understanding and viewpoint, we become better at engaging them in individually tailored multimodal biopsychosocial pain management. 3.2. Issues to consider with the broad interpretation The use of central sensitization as a diagnosis was considered by some as too broad, and a new term, “nociplastic” pain,9 was introduced to separate the clinical pain classification, from specific underlying mechanisms, and noting that the terms should not be conflated. Nociplastic pain is defined as “pain arising from altered nociceptive processing” and central sensitization is proposed as a contributing phenomenon. This remains controversial because altered nociceptive processing in humans may arise from other central mechanisms, including impaired descending pain modulation (reduced inhibition and/or increased facilitation) in the absence of the central sensitization as described by the IASP definition. A broader definition of central sensitization would include these processes. There is no consensus on how “altered nociceptive processing” should be assessed and some conditions that are considered to be prototypical of nociplastic pain are responsive to drugs that reduce peripheral nociceptive drive (eg, linaclotide in irritable bowel syndrome3), although this may reflect a reduction in peripheral triggers of central sensitization. Another issue relates to the Central Sensitization Inventory. This tool is not a measure of central sensitization as it conflates many clinical observations, but it has been used to infer its presence and is sometimes used to diagnose nociplastic pain. Notably, the inventory correlates with psychological constructs (eg, depression, anxiety) and has a weak correlation with experimental measures that reflect nociceptive circuit sensitivity (eg, temporal summation).1 3.3. The case to broaden the definition It might be argued that a different term could be used for the broad clinical presentation of central hyperexcitability and retain the current IASP definition. A counter argument is the need to use terminology consistently when translating research from preclinical to clinical contexts. If the term is restricted only to a narrow set of observations, it will not be translatable as there would be no human correlate. There are already terms to describe specific observations (eg, allodynia, hyperalgesia), but perhaps these are also too narrow, failing to describe the phenomenon's scope in a clinical context. There is also the risk of scientific findings getting lost with many terms used across different studies (eg, pain sensitization, central hyperexcitability) that inspire confusion surrounding the term. In has been argued that in a clinical context, the concept is important for validating a patient's problems2 and that there is unclear value of using the label “central sensitization” compared with communication tools such as active listening, nonverbal validating cues, and examples and metaphors rooted in a patients' own narratives.2 A contrary view is that the term has been broadly disseminated in clinical research, education, and practice. It is easily understood and is helpful to explain specific clinical pain states by clinicians, patients, and funders. Changing the term after its broad clinical dissemination over 28 years might be harmful, leading to confusion. It might restigmatize those clinical conditions for which the term has been helpful if it implies that there is no “evidence” of central changes. Many biological terms are imprecise. Although initially accurate, the broadening of scientific understanding reveals inaccuracies (eg, brain-derived neurotrophic factor [BDNF] is produced by peripheral tissues and not strictly “brain-derived”). Although science evolves and change is expected, it might be better to change the definition of central sensitization than to create a new term. There is a discrepancy between the global impact of the discovery of central sensitization on clinical research and health care, and a narrow biological definition of central sensitization. 4. Potential paths forward Debate surrounding the term central sensitization reflects fundamentally different priorities across mechanistic science, clinical research, and patient care. Several viable solutions exist to resolve the equipoise regarding the different perspectives on the use of the term, ranging from strict containment as a physiological mechanism, broader clinical usage based on symptom patterns, separation of mechanistic and inferential terminology, evidence-tiered attribution of central mechanisms, and condition-specific mechanistic profiling. Each offers advantages but also introduces limitations related to precision, feasibility, and interpretability (Table 1). Progress requires explicit separation of semantic and operational questions, probabilistic inference in humans, and empirical evaluation of proposed frameworks against scientific, clinical, and patient-centred criteria. Table 1 - Conceptual approaches to resolve divergent perspectives on the use of the term “central sensitization” (CS). Proposal Pros Cons Likely supporters Key risk Consensus bridge Strict mechanistic containment (“CS remains physiological”) Reserve CS for contexts with direct physiological demonstration of increased central nociceptive neuronal responsiveness; avoid using central sensitization as a clinical descriptor. Might need to consider modification of the term to “central nociceptive sensitization” in recognition of the potential for sensitization of non-nociceptive neurons Maximizes mechanistic precision; preserves original definition; avoids overclaim in humans Limited clinical utility; may widen the science–practice gap Basic scientists, methodologists The term is likely to persist in clinical use because it addresses a practical need in clinical communication Maintain a strict mechanistic definition of central sensitization while developing parallel terminology for clinical use Broadened clinical construct (“central sensitization as a clinical syndrome/heuristic”) Acknowledge the use of CS as a clinical construct describing symptom patterns (widespread pain, hyperalgesia, comorbidities, treatment responsiveness) High clinical relevance; reflects current practice Mechanistic ambiguity; risk of diagnostic reification; variable operational criteria; heterogeneous populations Clinicians; rehabilitation and pain education researchers Concerns regarding limited mechanistic specificity and testability Should be accompanied by explicit operational criteria and transparent statements regarding the absence of direct mechanistic evidence Split-term approach (“CS strict + human inference term”) Maintain a strict mechanistic definition of CS and introduce/endorse a separate term for human inference (eg, Human assumed central sensitization [HACS],16 pain sensitivity, sensory sensitivity,14 sensory hyperexcitability,2 central pain amplification,17 augmented central nociceptive processing) for patterns consistent with central contributions Preserves mechanistic integrity and supports clinical utility; scalable across settings. Clean reset; reduces semantic conflict; promotes specificity Requires adoption of new terminology despite entrenched use; risk of confusion for parallel terms; risks fragmentation into many new labels Middle-ground stakeholders; journals; trialists. Some methodologists, sceptics of CS as clinical construct If poorly defined, risks becoming another nonspecific label and increasing terminological inconsistency Standardize what counts as evidence for the inference term (minimum data set + reporting standards). Only plausible if major bodies/journals enforce it with guidance Evidence-tiered claims (“central sensitization only at high evidentiary levels”) Allow “CS contributes” only under predefined tiers of evidence*; otherwise use weaker, probability language Reviewer-proof; accommodates heterogeneity; does not require a single new term Some view tiers as arbitrary; burden of testing; may be difficult to implement in routine care Trialists, guideline groups, journals Without standard protocols, tiers will not be comparable between studies Publish a “core battery” and minimum reporting requirements Condition-specific mechanistic labelling (“no global CS label”) Avoid one umbrella term; define mechanistic hypotheses per condition (eg, fibromyalgia: Altered descending modulation; OA: peripheral + central amplification; neuropathic pain: ectopic input + central gain) High face validity; encourages targeted mechanisms and trials Harder to teach; still limited by inference; may underplay shared mechanisms Subspecialists, mechanistic trialists Overfragmentation and loss of integrative frameworks Use shared framework but report condition-specific profiles *Possible example Tiers of evidence to justify acceptability of the use of term “CS is likely contributing”—Tier 0: Symptoms-only (pain distribution, descriptors, comorbidities) → avoid reference to CS; Tier 1: Psychophysical signatures consistent with central amplification (widespread hyperalgesia, temporal summation, secondary hyperalgesia patterns, of pain modulation → clinical evidence of mediated amplification that might infer CS; Tier physiological evidence of increased central nociceptive responsiveness → CS than a requires an explicit that semantic and operational questions, (eg, central sensitization is not a human inference is and operational frameworks against criteria including feasibility, and patient A formal with and patient followed by a consensus and reporting would a transparent to 1 provides an of a rational path forward. frameworks are proposed to the use of the term central sensitization in human pain. than this a transparent which may be The are in 1. 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