This four-part series on central sensitization is intended for clinicians, researchers, students, patients, laypeople, and any health care professional who values empirical evidence over blind conjecture when discussing mechanisms of chronic pain.
This is a pain mechanisms-heavy piece but don’t let that intimidate you. In 2004, I knew none of these things. So my goal is to shrink wrap 15 years of knowledge and experience into a neat summary that helps you to navigate the pain literature, conference lectures, and social media conversations with more confidence. Yes, there is some technical language that some may find challenging. I read stuff I don’t understand all the time, so don’t sweat it! The technical parts are followed by summary statements that will reinforce what is worth remembering.
Let’s Start from A Beginning
To treat chronic pain, we ideally need to understand what initiates and maintains it. The biopsychosocial model is a cornerstone for organizing such efforts because pain is a conscious experience that reflects sensory input, our cognitive-emotional models of the world, sense of self in space, and self in relation to others. This particular piece will focus on one of many biological processes that impacts the strength and persistence of nociceptive signals that can contribute to pain perception: central sensitization.
The misinterpretations of central sensitization have reached epidemic proportions. As a clinical psychologist with training in chronic pain physiology, quantitative sensory testing, and neuroimaging, I find this continuing trend of misinformation to be a dangerous hurdle for translating basic science to patient care. If you have tried to read the literature on central sensitization and feel more confused than ever, I GET IT. Basic scientists in the pain field have done a poor job in communicating their findings in a way that is accessible to the clinical audiences who need the information most. Moreover, many clinical researchers and clinicians have not held one another accountable for misinterpretations of the concept. The problem is that many people have not invested their energy into carefully studying the concept prior to propagating these distorted ideas.
Instead, misinterpretations of central sensitization have been disseminated like a disastrous game of “telephone.” Who suffers the consequences? The health care professionals whose clinical care is informed by these reverberating half-truths, and the patients who are assessed and treated according to flawed logic.
A Brief Aside
Why should you listen to me? Why do I think I have all the answers? I base my confidence on seven (looooong) years of graduate training at McGill University, which is renowned for the pain research program founded by the pain pioneer Ron Melzack. It is a rich multidisciplinary environment where basic scientists attend clinical rounds, where clinicians combine adventurous creativity with pain-mechanism based approaches, and where I developed mouse models of chronic pain based on my patient observations in the clinic. And as a clinical psychology trainee in a multidisciplinary chronic pain clinic, I have been exposed to a wide spectrum of pain populations and bizarre symptom presentations that no longer phase me.
Painless complex regional pain syndrome, anyone? I’ve seen it.
I have embraced many opportunities to listen to people smarter than myself discuss pain mechanisms: graduate courses on acute and chronic pain physiology, lectures by major figures in pain research, drunken conversations at rowdy IASP parties. And as a postdoc, I trained with a brilliant pain neuroimager whose science is 5+ years ahead of the field. So I know some things about pain.
I approach the topic of central sensitization from a basic science perspective that adheres closely to the original phenomenon first described by Clifford Woolf (1983). I see this as an appropriately conservative perspective that prioritizes empirically-derived knowledge of pain mechanisms over speculation, even clever speculation. Regarding central sensitization in clinical contexts, I do think that this can be deduced from certain symptom patterns but I am swayed only by reasonable evidence that a patient’s symptoms are consistent with features of the original phenomenon. In the absence of such evidence, I find it irrational and dangerous to claim that we are certain about what central sensitization can and cannot “do” in a clinical setting. Premature conclusions about pain mechanisms do not enrich clinical assessment or treatment. Rather, these speculations seem to restrict the clinical hypotheses that are considered and limit treatment.
With that said, I believe that peripheral, spinal, and brain mechanisms distinctly contribute to clinical pain, that their respective contributions could be deduced with proper evidence, and that such an approach will point to individualized multidisciplinary treatments that actually relieve pain.
Nociception vs Pain
We can all agree that nociception and pain are not the same thing. However, studies in multiple species show a close correspondence between the magnitude of pain perception (or pain behavior in non-humans) and sensory neuron firing properties. For example, this classic microneurography study reveals that neural firing patterns of nociceptors closely track with perceived pain. This is the rationale underlying the idea that subjective pain perception (or “pain” behavior in animals) can be used to deduce general properties of neuronal function.
If you are interested in a general overview of nociception check this out by Ardem Patapoutian, the guy who discovered piezo receptors. For physical therapists, you may want to check out a more specialized reference on muscle and nociception by the classic muscle physiologist Siegfried Mense.
The Game Plan
This discussion will approach central sensitization from many angles. Specifically, I will:
- Critically assess how the word “sensitization” is used and abused.
- Introduce the beginning of the cascade leading to central sensitization: peripheral nociceptor sensitization.
- Provide an in-depth walk-through of Woolf’s original 1983 paper.
- Highlight the essential features of spinally-mediated (“classical”) central sensitization.
- Critique and discuss common misinterpretations of spinally-mediated central sensitization.
- Contrast the beautifully specific mechanisms identified by Woolf with the misguided and hypothetical phenomena referred to as “central sensitivity syndromes,” “centralized pain,” “central hypersensitivity,” and similar variants of these terms.
- Offer advice on how to critically navigate existing and future literature on these topics.
Use and Abuse of “Sensitization”
In biology, the term sensitization describes a progressive enhancement of a response with repeated exposure to a stimulus. Sensitization is like the mounting frustration you feel when someone leans toward you, their finger wagging an inch away from your face, saying, “I’m not touching you! I’m not touching you! I’m not touching you!” of my favorite musings on sensitization
It is an adaptive process rather than a mechanism per se.
Adaptations are achieved in different ways in the periphery, spinal cord, and brain. This means sensitization is not a generic process that can be generalized across nervous systems (check out a great paper on this perspective). For this reason, it’s important to preface the term “sensitization” with a location (e.g., peripheral sensitization, central sensitization), which reflects the location of the primary physiological mechanism(s) of sensitization. Stating that a patient is simply “sensitized” is mechanistically and clinically meaningless because such a statement contains no information about where (or whether!) sensitization is actually occurring. You will soon see why this distinction is needed when trying to attribute pain symptoms to the periphery versus spinal cord versus brain.
The Hyperactive Nociceptor
The most basic form of sensitization occurs in nociceptors in response to repeated or intense noxious stimulation. Inflammation is the most common “cause” of peripheral sensitization, which doesn’t say much because many things cause inflammation (noxious heat, repeated skin scratching, ultraviolet radiation, invading pathogens) and inflammation is a non-specific response. In the pain literature, the discussion of inflammation is often limited to the notorious “inflammatory soup” that bathes the end of the nociceptor in a pool of molecules that change how responsive the nociceptor is to noxious input.
Instead of stopping at this level of detail, I want to take you a little further . Stating that a nociceptor is affected by inflammation doesn’t tell you how it is affected. The how is important for understanding the difference between peripheral and central sensitization. Keep in mind that acute and chronic inflammation likely operate by different rules, as well.
When a nociceptor is sensitized, its firing rules change. One new rule is that less noxious input is needed to for the nociceptor to generate an action potential (this may underlie reduced pain thresholds, or allodynia). Another new rule is that the magnitude of the neuron’s response may be amplified (leading to increased pain perception, or hyperalgesia). Yet another rule is that the nociceptor may fire randomly, even when there’s no noxious input detected at the nerve ending (which may further enhance allodynia or hyperalgesia, or contribute to “spontaneous” pain). I strongly recommend Gary Bennett’s superb piece on potential mechanisms of spontaneous pain.
These changes are triggered and maintained by neurochemical changes throughout the nociceptor, not only at the nerve ending. Therefore the increased nociceptor excitability (or hyperexcitability) that defines nociceptor sensitization may reflect multiple underlying processes near the site of injury.
Note that peripheral sensitization does not explain altered detection thresholds for heat, tactile, vibration, or any other sensory stimulus. Detection thresholds are determined by receptors at the end of sensory neurons (aka, the peripheral terminal). Finis.
Mechanisms of Peripheral Sensitization
To date, five changes in nociceptor function have been linked with peripheral sensitization. These changes don’t necessarily occur at the same time and various combinations of these changes may be responsible for amped up nociceptor excitability depending on the type and/or severity of insult.
(a) Nociceptors have reduced activation thresholds due to changes in their membrane potentials (described here).
(b) The magnitude of nociceptor signaling is enhanced.
(c) A nociceptor spontaneously emits signals with no stimulus (i.e., ectopic discharges).
Xiao & Bennett used a common rat model of inflammatory pain (Complete Freund’s Adjuvant) to show that over 20% of A-delta and C-fibers fire spontaneously (the effect normalized within a couple of weeks).
(d) The magnitude of nociceptor signaling is enhanced with repeated stimulation (wind-up).
(e) “Silent” nociceptors become active contributors to sensitization.
Silent nociceptors normally don’t respond to noxious mechanical stimulation (mechanically insensitive afferents). But during inflammation or with exposure to certain inflammatory mediators, they are “unsilenced” and begin firing in response to noxious mechanical input. Subsets of C-fibers nociceptors and A-delta nociceptors are unsilenced during peripheral sensitization.
Is Peripheral Sensitization Purely Peripheral?
Peripheral sensitization begins to ramp up activity in spinal cord neurons, which technically means that it also impacts part of the central nervous system. However, the initiating mechanisms underlying peripheral sensitization are rooted in the peripheral nervous system, and therefore any downstream effects are still considered peripheral in origin. This is why temporal summation (“wind-up”)—which reflects short-term increases in the excitability of spinal interneurons following the repeated stimulation of C-fiber nociceptors—is still considered a peripheral phenomenon. Researchers were able to dissociate the peripheral and spinal contributions to wind-up by delivering identical series of noxious pinprick or heat stimulation to the skin surface at a particular frequency to amp up C-fiber activity. Because the intensity of peripheral input was kept constant, they could dissociate pain perception related to the peripheral input (baseline) from the additional spinal amplification of the signal (following “wind-up”). However, wind-up requires stimulation of C-fiber nociceptors to persist. if you remove C-fiber input, the spinal interneurons will quickly return to their baseline states.
Wind-up happens in everyone. But in a subset of people with inflammatory, neuropathic, and/or other types of chronic pain, wind-up may occur more quickly than in healthy people and they report more intense peak pain. If a patient exhibits symptoms of enhanced wind-up, this is strong evidence of ongoing C-fiber nociception at/near the tissue that is being prodded…because without C-fiber stimulation, this phenomenon extinguishes. Importantly, absence of increased wind-up just means chronic pain is mediated by factors other than amped up C-fiber nociception.
Wait…Temporal Summation is Peripheral?
At this point, some readers may be reeling from the idea that wind-up is actually a peripheral phenomenon… For those who wonder why any sane person would “reel” from that idea, consider that wind-up is often cited as a proxy measure for central sensitization in the clinical literature.
There’s a logical reason why people think this, and a logical reason for why this belief is mistaken. It is true that enhanced wind-up is ONE of the MULTIPLE physiological changes observed with central sensitization. However, in the absence of the other hallmark features of central sensitization, wind-up is just wind-up . Alone, it is not a valid proxy for central sensitization. In contrast, if wind-up is enhanced AND there is clinical evidence of pinprick hyperalgesia or dynamic mechanical allodynia, I would consider it moderately strong evidence of current central sensitization. This means that the authors of all of those quantitative sensory testing studies that claim wind-up evidence is sufficient proof of central sensitization are lying to you and to themselves.
In the end, enhanced wind-up can only tell us that spinal nociception is abnormal, nothing more. It is one clue that the degree of peripheral input has begun to affect the excitability of spinal cord interneurons, which is the first of many steps toward central sensitization. The only thing that will return the nociceptor to its baseline state is a lack of noxious input, disabling the capacity of the nociceptor to fire (via lidocaine, bupivaine, etc), or disrupting the molecular changes that enhance nociceptor excitability. Even then, it takes some time for the nociceptor’s excitability to return to its normal level.
Uses of the Term “Central Sensitization”
Part of the confusion surrounding central sensitization is that people use the term in different ways, and only one of these uses is supported by empirical evidence. Three definitions of central sensitization are currently used in clinical and scientific settings.
1. Spinally-Mediated Central Sensitization
Clifford Woolf’s original term central sensitization describes quantifiable changes in the excitability of spinal cord neurons. This definition is rooted in experimental evidence that has been replicated by many international laboratories over dozens of years. It is fantastically precise in the pain symptoms it can explain.
2. IASP’s Definition
I don’t agree with IASP definition of central sensitization and I’ll tell you why.
IASP’s revised term expands Woolf’s observations to all nociceptive neurons in the CNS, despite:
(i) There is minimal evidence of nociceptive-specific neurons in the CNS. In over 50 years of pain science, less than 300 nociceptive-specific neurons have been identified across different animal studies. You slough off more dead skin cells washing your hands. Note that if a study does not also evaluate a neuron’s response to non-nociceptive stimuli, it cannot be considered specific to nociception. That’s how science works.
Most recently, Iannetti’s group showed that the “pain matrix”—a mythical group of brain regions that was thought to be necessary and sufficient to create the conscious perception of pain—is not specific to pain when the appropriate control tasks are included to account for stimulus intensity and variability.
(ii) No data in the neuroscience literature indicates that spinal and cortical neurons adapt to information in the same ways. Ted Price covers this issue beautifully and I refer the gentle reader to his work.
(iii) The spine and the brain are not so physiologically similar that they can be haphazardly grouped together just because they are both part of the central nervous system. This is the logical equivalent of saying that the visual cortex and the cerebellum are functionally equivalent because they are both made of neurons. The field of neuroscience is based on understanding specialization within the nervous system and appreciating why different structures follow different rules of engagement. We can’t mix and match parts of the central nervous system.
My impression is that this false equivalence is symptomatic of the biased pain researchers who developed the IASP definition of central sensitization (the IASP Task Force on Taxonomy). From what I can tell, there were no Task Force members who had the expertise to make such an assertion.
Instead, this perspective also betrays a gross disinterest in how the brain uniquely mediates pain perception.
(iv) The IASP taxonomy comes with an important caveat: “It is important to emphasize…that the terms have been developed for use in clinical practice rather than for experimental work, physiology, or anatomical purposes.”
And now comes the most popular use of the term…
3. A Hypothetical Umbrella Term
A term used to describe any type of change within the CNS that could lead to enhanced pain perception. This use of the term reflects a very limited understanding of Woolf’s original concept and limited understanding of chronic pain physiology, yet it is the most popular use of the term as the putative mechanism underlying the dubious “central sensitivity syndrome.” I strongly believe that this is the most harmful misuse of the term and I’ll be going into some detail about how this came to pass.
How Did We Get Here?
To understand how the ideas of central sensitization have evolved and mutated, our next step is to revisit the original phenomenon. In Part 2, I will describe the findings Woolf’s original paper so you can understand the basic phenomenon for yourself.
In Part 3, the most common clinical misinterpretations of central sensitization will be critically examined.
In Part 4, awful logic underlying the conception of “Central Sensitivity Syndrome” will be ruthlessly interrogated.