Abstract
BACKGROUND:
Nociplastic pain has been recently introduced as a third mechanistic descriptor of pain arising primarily from alterations of neural processing, in contrast to pain due to tissue damage leading to nociceptor activation (nociceptive) or due to lesion or disease of the somatosensory nervous system (neuropathic). It is characterized by hyperalgesia and allodynia, inconsistency and reversibility, as well as dynamic cross-system interactions with biological and psychobehavioral factors. Along with this renewed understanding, functional pain disorders, also classified as chronic primary pain, are being reframed as biopsychosocial conditions that benefit from multimodal treatment.
OBJECTIVE:
To summarize the current understanding of nociplastic pain and functional pain disorders, with a focus on conditions that are common in neurology practice.
METHODS:
This was a narrative literature review.
RESULTS:
Chronic back pain, fibromyalgia syndrome and complex regional pain syndrome are best understood within a biopsychosocial framework of pain perception that considers structural factors (predispositions and sequelae) and psychobehavioral mechanisms. Although pain is often the primary complaint, it should not be the only focus of treatment, as accompanying symptoms such as sleep or mood problems can significantly impact quality of life and offer useful leverage points for multimodal treatment. Analgesic pharmacotherapy is rarely helpful on its own, and should always be imbedded in a multidisciplinary setting.
Background
Among all possible symptoms, pain of various locations is the most common and the most bothering one (Beutel et al., 2020). Pain is also reported to be the most common chronic health problem in the community (Mills, Nicolson, & Smith, 2019). Chronic pain is usually associated with other conditions, but can persist independent of somatic or mental comorbidity, and is strongly associated with low functioning and quality of life, and high health care utilization and cost (Breivik, Collett, Ventafridda, Cohen, & Gallacher, 2006; Burke, Mathias, & Denson, 2015). In the past decade, clinical experience with the rising number of chronic pain patients, including the tragic opioid crisis in the U.S., as well as new etiological insights have fundamentally changed our understanding of pain. A neuroscientific framework that links cellular and cognitive processes and allows for individualized, multimodal and mechanism-based management, requires the attention of neurologists and rehabilitation medicine specialists among other specialties involved in the interdisciplinary treatment of pain.
Mechanisms and functions of pain
Pain is an evolutionarily old perceptual construct with potent warning and communicative functions that serve to increase the likelihood of survival. Pain perception guides behavior, such as slowing down, finding a cause or seeking help or shelter to avoid further harm (Craig, 2003; Tabor, Van Ryckeghem, & Hasenbring, 2020). In social organisms, communication and observation of pain triggers empathy and prosocial action (Riecansky & Lamm, 2019).
Modern theories of pain chronification integrate concepts from neurophysiology and cognitive neuroscience, such as somatosensory amplification, sensitization, learning processes, and expecation-based perception (Kube, Rozenkrantz, Rief, & Barsky, 2020; Wiech, 2016). They acknowledge that pain processing comprises various structures (from nociceptors over spinal wide dynamic range neurons to a mesolimbic network), various functions (from extinction, inhibition and habituation to conditioning, amplification and sensitization), and various directions (bottom-up and top-down within the nervous system, cross-system with immune and endocrine systems, and between organisms and their external environments). This allows for high individuality and adaptability, but also bears the risk of error on different levels, through structural damage, pharmacological manipulation, plasticity and memory, and cognitive biases.
Most sensations are anticipated as non-threatening, and thus trigger little to no arousal, attentional focus, negative appraisal or stress response. Salient stimuli that contradict their prediction, however, provoke immediate alert and action to restore homeostasis (or to reduce prediction error in computational terms): this usually occurs through some kind of action that allows for a correction of expectations (“this foot position is painful; I’ll change it – now it should feel better”). However, if predictions and appraisals are very potent, for example due to intense fear or adverse experiences, perception can be distorted to meet expectations (“this foot injury looks very painful, it certainly hurts a lot”) (Henningsen et al., 2018; Tabor et al., 2020; Wiech, 2016). Thus, the multidimensional experience of pain can be regarded as a “homeostatic emotion” that is established by active integration of sensory, cognitive, and affective input (Craig, 2003). In some situations, this allows for pain reduction. Under extreme distress (e.g. in life-threatening situations), self-perception can completely shut off nociceptive inputs and lead to dissociative analgesia, a useful biopsychological mechanism that increases the likelihood of survival (Kozlowska, Walker, McLean, & Carrive, 2015). Pain can be reduced temporarily through distraction, as lifting of attention will generally decrease the computational “weight” of prior pain expectation. Alternatively, pain expectation can be modulated by suggestion, as in placebo analgesia (Colloca & Barsky, 2020).
In clinical practice, the inverse dynamic is more common: pain is disproportionately intense and can persist even without adequate stimuli. Amplification and chronification of pain can involve changes on various levels, from receptor function (e.g. peripheral sensitization, sympatho-afferent coupling or opioid-induced hyperalgesia) to higher-level cortical processes (e.g. phantom pain or empathic pain). Pain can be perceived upon suggestion, imagination, attention focusing and expectation, which can be subsumed under “nocebo pain” (Colloca & Barsky, 2020). Pain perception can be maintained and intensified by cognitive distortions such as catastrophization, an external locus of control and lack of acceptance or readiness to change (Flink et al., 2020). Pain perception and pain behavior in self and others depend on social contexts including internal and external gain (Craig, 2003; Flink et al., 2020; Tabor et al., 2020). In the medical context, for example, verbal and nonverbal pain expression steers physician behavior (e.g. with respect to prescriptions); then again, negative nonverbal physician behavior and a cold communication style lower the pain threshold and diminish placebo effects (Colloca & Barsky, 2020).
Terminology and classification
In medicine, pain is usually regarded as a symptom and thus as an indicator for underlying conditions. However, since the 2000 s it has been postulated that – due to its considerable impact on quality of life and functioning as well as its need for medical treatment and care – chronic pain can become an illness “in its own right” (Niv & Devor, 2004). Since then, there has been a lot of re-framing and re-naming of “functional pain disorders", with considerable vagueness and overlap.
Various polysymptomatic syndromes with chronic pain as a cardinal feature have been defined across disciplines, such as irritable bowel syndrome (IBS), fibromyalgia syndrome (FMS) or complex regional pain syndrome (CRPS). As an overarching concept for these and other such conditions, ICD-11 will introduce “chronic primary pain”, with visceral, musculoskeletal, headache/orofacial and widespread subtypes. It will also include CRPS type I (without neural damage), with type II (with neural damage) listed additionally as a focal or segmental autonomic disorder (Nicholas et al., 2019).
When there are concomitant psychobehavioral symptoms such as excessive attention towards it, persistent and distressing pain can be classified as “persistent somatoform pain disorder” in the ICD-10, as “bodily distress disorder” in the upcoming ICD-11, or as “somatic symptom disorder” in the DSM 5. These conceptualizations emanate from a general tendency to perceive and communicate symptoms (formerly called “somatization”) and thus allow any type, number and location of symptoms.
These different conceptualizations show significant overlap with each other, with non-pain-dominated functional syndromes, with other pain-dominated disorders such as migraine, and with psychiatric disorders such as depression and anxiety (Khan, Michelini, & Battaglia, 2020; Taylor et al., 2015; Wessely, Nimnuan, & Sharpe, 1999).
The confusing discrimination of “localized” versus “generalized”, “pain” versus “non-pain”, “somatic” versus “mental” symptom disorders has often been criticized, mainly because discrepant names and criteria have contradictory allocative functions in health care: Classification as “organic” illnesses within certain medical subspecialties may allow more organ-specific treatments (e.g. IBS within gastroenterology or back pain within orthopedics) – but may risk neglecting other physical and psychosocial aspects (e.g. fatigue, catastrophizing). Classification as mental disorders may sharpen the view for psychobehavioral symptoms and treatments – but is felt to be stigmatizing and can be difficult to integrate in established care pathways. Plus, clearly visible bodily signs, such as edema or scarring, are often perceived as contradictory to a psychiatric classification, although this kind of mind-body dualism is being increasingly abolished.
The new concept of “chronic primary pain” is neutrally located in the ICD-11 section “general symptoms” and highlights the common features of its subtypes – but de-emphasizes other symptoms besides pain, such as fatigue or cognitive impairments. Another etiologically neutral and antidualistic approach has recently been introduced: “Functional somatic disorders” (multisystem/single system/single symptom; gastrointestinal/musculoskeletal/nervous system/cardiorespiratory/genito-urinary/fatigue-related subtypes) acknowledge distressing somatic symptom conditions as disorders and at the same time overcome classificatory dualism, unidirectionalism, and monocausalism (Burton, Fink, Henningsen, Lowe, & Rief, 2020). Their core pathology is assumed maladaptive central/cognitive functioning in tandem with bodily/behavioral changes.
To account for different clinical pain phenomena in relation to the underlying neural mechanism, three types of pain have been defined. Pain that arises from peripheral nociceptors in the presence of tissue damage such as a sports injury, a dental procedure, or arthritis, but with normal function of the somatosensory nervous system is called nociceptive. In contrast, neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory nervous system, for example due to injury or an underlying disease like diabetes. Recently, a third descriptor, nociplastic pain, has been suggested for pain that results from dysfunction of the somatosensory nervous system despite mostly intact neural and non-neural structures (Kosek et al., 2016). Of course, several pain types can occur at the same time, so pain management should follow an individualized, multimodal regimen.
Bringing terminologies together, both chronic primary pain and functional pain disorders are dominated by nociplastic pain. The term “functional” leaves room for multifactorial etiologies and emphasizes the potential for reversibility, whereas “primary” suggests unknown or absent contributors and can imply fewer prevention and treatment options. Thus, in order to highlight the relatedness with other functional disorders (somatic, neurological, etc.) as well as the potential for recovery, we prefer to use the term functional pain disorders here for chronic nociplastic pain conditions. It should not, however, be equated with “psychogenic", as it usually emerges in the interplay between psychological and physical factors (e.g. injury and catastrophizing, anxiety and genetic predisposition). “Functional” can lay to rest polarizing debates regarding the direction of causality, and instead focus on individual factors and the therapeutic leverage they offer. Nociplastic pain is the primary, but not the exclusive underlying mechanism: neuropathic and nociceptive pain can contribute significantly to the clinical picture. Lastly, this classification should be reappraised continually, as the underlying pathophysiology is being elucidated further.
Overview of treatment strategies
Treatment of chronic pain has followed many, in parts contradictory paradigms. For example, strict bed rest was the cornerstone of back pain treatment for decades, often accompanied by pharmaceutical sedation. In the 1990 s and 2000 s, invasive procedures became popular to “fight” pain, e.g. by a marked increase of lumbar fusions and the invention of spinal cord stimulation. The 2000 s and the first half of the 2010 s were characterized by an avalanche of opioid prescriptions. It was postulated that patients with pain had been left alone by medicine, that they needed more attention and more intervention. Pain treatment was called “a fundamental human right” (Brennan, Carr, & Cousins, 2007). The outcomes of passive and invasive approaches were not convincing, however, and they were not associated with a decrease in the prevalence of chronic pain. In fact, the number of patients with chronic pain kept going up, along with the number of pain specialists and pain pharmaceuticals. There was even a subtype defined for chronic back pain after surgery, the “failed back (surgery) syndrome”. Reasons for this were an increase in population number and age, the righteous acceptance of subjective pain even in the absence of tissue pathology, and the subsequent proclamation of pain disorders. Lastly, market forces might have at times exerted an undue influence, tipping the scale towards surgery and prescriptions, at the expense of active exercise or psychological approaches.
Today, as our understanding of the biopsychosocial dynamics of pain perception becomes clearer, a trend towards multidimensional, more individual, more psychosocial, and much more active pain treatment can be observed. Tailored, activity-based approaches that view patients as subjects rather than objects are regarded as superior to the unidimensional, passive and invasive hunt for “freedom from pain” with procedures that are often no better than sham interventions (Jonas et al., 2019). Psychosocial factors including embodied expectations and behavioral patterns are regarded the best modifiable factors, with communication, information, motivation and active participation being the key issues in pain treatment and prevention (Castelnuovo et al., 2016; Flink et al., 2020; Henry & Matthias, 2018; Tabor et al., 2020). Put simply, patients cannot change their genes or biological sex, they cannot unmake childhood abuse or accidents – but they can stop smoking, lose weight, improve sleep hygiene and treatment adherence, and change their attitudes and beliefs about pain. In the following, selected pain syndromes with special relevance for neurology and neurorehabilitation are discussed in detail.
Selected pain syndromes in neurology and neurorehabilitation
Chronic back pain
Clinical picture
Back pain continues to be the most common “background symptom” in the population (Beutel et al., 2020). About 80% of adults have non-specific low back pain at some point in their lifes, and, increasing with age, about one in three to four adults will have had low back pain during the past three months. Acute back pain tends to improve on its own, but shows persistent symptoms or frequent recurrences in about 50– 70% (da C. Menezes Costa et al., 2012; Itz, Geurts, van Kleef, & Nelemans, 2013). This may be due to unknown or untreated underlying disease, so clinical management should always consider a broad differential diagnosis, aiming to exclude specific reasons for acute pain or exacerbation of preexisting pain. Non-specific chronic back pain cannot be explained by another disease and is independent of structural damage; it is important to exclude red flags for malignancy, fracture, infection, radiculo-/neuropathy or cauda equina syndrome in history and examination (Chenot et al., 2017; Verhagen, Downie, Popal, Maher, & Koes, 2016). It is associated with disproportionally high mental distress and morbidity, and poses the most frequent reason for filing a workers’ compensation claim (Chenot et al., 2017). There are two main types of chronic back pain that share clinical as well as prognostic features: chronic neck pain and chronic (low) back pain. In the context of rehabilitation medicine, it should be noted that back pain is among the leading causes for new pensions, and that non-specific back pain makes the largest contribution (38% of cases) (Raspe, 2012).
Pathophysiology
The pathophysiology of chronic back pain is heterogeneous and multifactorial. It results from an individual interplay between local changes (irreversible, e.g. structural degeneration, as well as reversible/functional, e.g. irritation or strain), and system-wide functional adaptation, such as sensitization and avoidance, often shaped by earlier experiences and beliefs ("I’m breaking my back at work") and current life stressors (professional, personal or health-related). There are also systemic and interactional, often medicocultural and iatrogenic contributors (e.g. legal concerns, compensation pay, lucrative passive procedures, miscommunication, repeated sick certificates).
Since the most important moment in the pathophysiology of chronic back pain is its transition from acute to chronic pain, thorough history taking, physical examination and medical decision-making are indispensable at this point. In the absence of red flags, imaging does not add useful information and is therefore discouraged (Chenot et al., 2017; Chou, Fu, Carrino, & Deyo, 2009). As an “intervention”, imaging has even been associated with worse outcomes, increased pain, a lower overall health status and more health care utilization including pharmacotherapy and surgery, even when it is randomly assigned (Kendrick et al., 2001; Powell et al., 2019). The specificity of imaging signs of structural pathology, such as effusion and edema suggesting facet joint arthropathy, can be increased significantly when combined with positive clinical signs, such as manual segmental pain provocation tests (Mainka et al., 2013).
Treatment
There are many national and international, mostly multidisciplinary evidence-based guidelines for the clinical management of back pain (Bernstein, Malik, Carville, & Ward, 2017; Chenot et al., 2017; Qaseem, Wilt, McLean, & Forciea, 2017). In summary, they express a broad consensus for a balanced biopsychosocial approach and for preferring conservative over invasive, and active over passive interventions. Pain reduction is considered not the only and not the most important outcome; treatment should rather focus on functionality and participation. Physical activity should be advised as early as possible to prevent (further) chronification. Recommendations include several types of exercise as well as simple educational and psychological interventions targeted at dysfunctional motivation, beliefs and behavior, which can – and should – be carried out by the treating neurologist, orthopedist or occupational/physical therapist. To enable active movement, short-term oral analgesia can be considered, but needs to be reevaluated periodically regarding benefit and adverse effects; other medication is not recommended. Invasive procedures require strict indications and need to be embedded in more holistic treatment plans. Two interesting metanalyses compared a wide variety of active and inactive treatments and found a very similar course after all of them, with initial improvement at 6 weeks followed by smaller improvement at long-term follow-up – suggestive of both significant placebo effects and frequent spontaneous remission (Artus et al., 2010; Artus et al., 2014).
Fibromyalgia syndrome
Clinical picture
Chronic widespread pain, defined as diffuse pain in at least three body quadrants plus axial regions for at least three months, affects up to 10% of the general population. When chronic widespread pain presents in combination with cognitive dysfunction, unrefreshing sleep and/or depressed mood, the symptom complex is referred to as fibromyalgia syndrome and affects about 2% of the general population (Wolfe, Brahler, Hinz, & Hauser, 2013). In neurology practice fibromyalgia is common: it accounts for 15% of all multiple sclerosis misdiagnoses, for example, and can be diagnosed in a third of all chronic migraine patients (Peres, Young, Kaup, Zukerman, & Silberstein, 2001; Solomon et al., 2016).
Besides its wide distribution, the pain is characterized by variability in location and severity, and is often associated with hyperalgesia and allodynia. The cognitive dysfunction ("fibro fog") is generally characterized by distractibility, forgetfulness and disorganized thought, attributable to a reduced attentional reserve (Teodoro, Edwards, & Isaacs, 2018). Sleep problems are thought to affect non-REM sleep and present as tiredness and fatigue (Eich et al., 2017). The diagnosis is made by identifying all characteristic symptoms, and is not a diagnosis of exclusion, although care should be taken not to overlook relevant comorbidities or differential diagnoses (Rahman, Underwood, & Carnes, 2014). As with any functional disorder, it can develop “on top” of another disease, as a consequence of injury or sickness, or in the absence of a triggering event. Other functional pain disorders such as chronic headache, irritable bowel syndrome or temporomandibular disorder are common comorbidities, as are functional neurological symptoms or mood disorders (Sumpton & Moulin, 2014).
Pathophysiology
Fibromyalgia syndrome is best understood as a biopsychosocial condition, where biological, experiential, cognitive and social factors are all important, and a universal, monocausal pathophysiology is unlikely. In the absence of underlying diseases causing nociceptive or neuropathic pain (e.g. polymyalgia rheumatica or multiple sclerosis), the condition is assumed to be determined by maladaptive alterations of central pain pathways, in accordance with the new definition for nociplastic pain (Sommer et al., 2008). These processes can be accompanied by psychosocial factors such as catastrophizing and fear-avoidance (Häuser et al., 2015). Recently, peripheral morphological changes such as a reduction in dermal unmyelinated nerve fibre bundles and reduced corneal fiber density have been reported (Grayston et al., 2019; Uceyler et al., 2013), which may indicate a neuropathic pain component in some patients. The extent of small fiber pathology is related to severity of pain, anxiety and disability, highlighting multi-level interactions of pathophysiology (Evdokimov et al., 2019). Whether the above mentioned morphological changes are potentially reversible in patients with successful treatment, is still unclear. A genetic endophenotype is assumed, as siblings of affected individuals have a 14 times higher incidence than the general population (Lesley M. Arnold et al., 2013). First degree relatives are 8.5 times more likely to also have fibromyalgia than relatives of patients with rheumatoid arthritis (L. M. Arnold et al., 2004). Various cross-system interactions can potentially link pathophysiological aspects, such as allodynia with disuse and peripheral nerve rarification, or catastrophizing with sleep loss and associated lowering of pain thresholds (Häuser et al., 2015). Such entanglements can result in vicious circles of pathology, whereby it becomes difficult to determine a clear direction of pathogenesis. One should not be overly confident in attributing the disorder to any single biological or psychological cause, and identifying contributing factors at various levels can offer more promising treatment options than monocausal therapy (e.g. analgesic pharmacotherapy only).
Treatment
Treatment has to begin with a clearly communicated clinical diagnosis that emphasizes potential contributing factors and secondary pathology, but does not imply unidirectional causation (e.g. “it’s mostly genetic” or “it’s just your anxiety”). Patient education should highlight the idea of a vicious cycle of biological and behavioral factors that cannot be stopped by operating a single lever (e.g. medication), but only by acting on multiple sites. This can help distinguish functional pain from other painful conditions such as cancer or rheumatic disease, and can motivate patients to engage with treatments that are not intuitively associated with pain (e.g. sleep hygiene). Basic treatment strategies include an increase in physical and social activities (e.g. walks, gardening) and aerobic exercises (at least 20/min per day, 2-3 times per week) (Rahman et al., 2014). Passive physical therapies, such as massage and electrotherapy are less likely to help (Fitzcharles et al., 2013). Psychological approaches such as cognitive-behavioral therapy can be helpful, especially if marked avoidance, catastrophizing, anxiety or depression contribute to the illness. However, psychotherapy on its own is unlikely to reduce pain intensity (Rahman et al., 2014). The utility of pain medication is limited in scope and time, and it should be used primarily to allow for physical activity or therapy to take place. For example, the average ‘number needed to treat’ for achieving a 50% reduction in pain in one patient is 4 for amitriptylin, 8 for duloxetine and 14 for pregabalin (Lunn, Hughes, & Wiffen, 2014; Moore, Derry, Aldington, Cole, & Wiffen, 2015; Wiffen et al., 2013). Other antidepressants or antiepileptics used for pain control are unlikely to be more helpful. Tramadol has been tested with very limited success; more potent opioids should not be used (Fitzcharles et al., 2013). The effectiveness of non-steroidal antiinflammatory drugs or paracetamol has not been established.
Complex regional pain syndrome
Clinical picture
Complex regional pain syndrome (CRPS) is a rare complication of peripheral trauma characterized by persistent pain with hyperalgesia and allodynia as well as autonomic and trophic changes (Birklein, Ajit, Goebel, Perez, & Sommer, 2018). The diagnosis of CRPS should be made according to the Budapest-Criteria (Harden et al., 2010). These require chronic pain, disproportionate to the preceding noxious event, as well as three reported symptoms and two observed signs from the following categories: (1) hyperesthesia, allodynia; (2) asymmetry of skin temperature or color; (3) edema or sweating changes; (4) motor dysfunction or trophic changes (hair, nail, skin). By definition, the symptoms cannot be explained by the tissue damage of the initial injury and there is no other diagnosis that better explains the signs and symptoms. Further, in 3– 11% of cases an initial physical trauma cannot be determined (de Rooij et al., 2010). All symptoms affect predominantly the distal extremity, appear generalized and are not restricted to the innervation territory of any single nerve, dermatome or central nervous structure. It can be argued that some of the sensorimotor deficits resemble the characteristics and distribution of symptoms seen in functional neurological disorder (previously known as psychogenic or conversion disorder), which is considered an important differential diagnosis, but might have partially overlapping pathophysiology (Hausteiner-Wiehle & Henningsen, 2018; Popkirov, Hoeritzauer, Colvin, Carson, & Stone, 2019). Nowadays, CRPS is often incorrectly “overdiagnosed". In a Canadian study from 2014, in 72% who were referred to a tertiary clinic with a suspected CRPS, the diagnosis was not confirmed. While an alternative disease was clearly diagnosed in 86% of them, the remaining patients showed symptoms and signs indicative of a dissociative or faticious disorder (Mailis-Gagnon, Lakha, Allen, Deshpande, & Harden, 2014). Other differential diagnoses include rheumatic, infectious or postthrombotic disease, as well as neurological disorders such as nerve and plexus compression, compartment syndrome, Lyme and post-herpetic neuropathies or polyradiculitis (Borchers & Gershwin, 2017). Technical investigations such as triple-phase bone scintigraphy (TPBS) within the first 5– 9 months after disease onset, skin-temperature measurements or other imaging techniques like MRI or computer tomography can be used to increase the specificity of the diagnosis, and might be beneficial especially if there are doubts concerning any possible differential diagnoses (Krumova et al., 2008; Schurmann et al., 2007). The occurrence of “post-stroke” CRPS in hemiplegia is highly relevant for neurorehabilitation practice, though its incidence varies significantly between studies (2– 50%) (Chae, 2010). A recent study considering the results of a TPBS in addition to clinical diagnostic criteria reported a prevalence of 6% in a selected study population of patients with post-stroke shoulder and wrist pain (Kim et al., 2016). Central post-stroke pain, pain due to spasticity and pain after shoulder subluxation are relevant differential diagnoses to be considered in patients with chronic pain after stroke (O’Donnell et al., 2013).
Pathophysiology
Current theories on CRPS pathophysiology assume a close interaction between biological predisposition regarding sustained local inflammation and autonomic activation following peripheral injury, and maladaptive cognitive schemas and behaviors that contribute to chronification (Borchers & Gershwin, 2017). Acute tissue inflammation promotes hyperalgesia via cytokine-induced sensitization of peripheral nociceptors, which in turn release calcitonin gene– related peptide and substance P, thus leading to neurogenic inflammation (Birklein, Ajit, et al., 2018). Maladaptive central neuronal plasticity is another important mechanism which seems to develop in parallel to the peripheral inflammation (Dimova et al., 2020). The controversial debate whether chronic pain in CRPS is purely nociplastic is currently unresolved. A nociceptive component might play a role at least during the acute inflammation, as well as in the chronic phase due to morphological changes like contractures. In type II CRPS, nerve damage can cause neuropathic pain. Pain that is experienced as threatening (in scope or context) can establish or reactivate cognitive-perceptive schemas that sustain hyperalgesia and allodynia far beyond local nociceptive effects. These schemas entail protective behaviors and disuse, attentional focusing, withdrawal and even dissociative phenomena (Hausteiner-Wiehle & Henningsen, 2018). If sustained for longer periods, such natural responses to injury and pain lead to autonomic and trophic changes which in turn promote hyperalgesia (e.g. hypertrichosis following cast application or disuse osteoporosis) (Terkelsen, Bach, & Jensen, 2008). Pain-related fear and avoidance (Vlaeyen & Linton, 2012), contribute to disturbances of body schema (Schulte-Goecking et al., 2020) and voluntary movement (Hodges & Tucker, 2011) including slowness and weakness (Popkirov et al., 2019). On a neurophysiological level, pain-related maladaptive cortical reorganization can be visualized experimentally, and normalizes with successful pain treatment, suggesting nociplastic mechanisms (Maihofner, Handwerker, Neundorfer, & Birklein, 2004; Pleger et al., 2005; Stude et al., 2014).
Treatment
The mainstay of CRPS treatment is step-wise, active mobilization through occupational therapy and physiotherapy in tandem with educational and psychotherapeutic approaches that normalize pain expectation (Birklein, Humm, et al., 2018). Medication is helpful initially to increase mobility, but cannot be expected to alleviate pain permanently or reverse the disease on its own. Exposure-based treatments, informed by principles of cognitive-behavioral psychotherapy and guided by physiotherapists can reduce pain-related fears, catastrophizing, avoidance, and, ultimately, pain and disability (den Hollander et al., 2016).
Pain in functional neurological disorders
Pain is a common complaint in functional neurological disorders. Up to two thirds of patients with functional movement disorders report concomitant pain (Driver-Dunckley, Stonnington, Locke, & Noe, 2011; Gelauff, Rosmalen, Gardien, Stone, & Tijssen, 2020; Vechetova et al., 2018). In a large study of functional weakness, a third of patients reported pain in the affected limb, and two thirds had pain in other body regions (Stone, Warlow, & Sharpe, 2010). In patients with psychogenic nonepileptic seizures, 47– 67% have a (primary) chronic pain condition (Driver-Dunckley et al., 2011; Gazzola et al., 2012). About a third of patients with functional motor symptoms or psychogenic nonepileptic seizures take opioids regularly (Hantke, Doherty, & Haltiner, 2007; O’Connell, Nicholson, Blackman, Tavener, & David, 2019).
Unfortunately, neither pain nor its potential (nociplastic) mechanisms and interactions have been sufficiently studied in patients with functional neurological disorders. The high rate of comorbidity and a significant overlap of risk factors, however, suggest that shared mechanisms might exist, and that clinicians and therapists involved with treatment of functional disorders might be well equipped to help with accompanying chronic pain (Popkirov et al., 2019).
Conclusions
Pain perception shows high inter- and intra-individual as well as inter-situational variability and is not necessarily proportionate to the evoking stimuli. The mechanisms of pain chronification are not entirely known, but are most likely multifactorial and best understood within a biopsychosocial framework. Regardless of its localization and distribution, chronic pain is associated with disruptions in attentional control, emotion regulation, sleep, mobility, and social functioning, which can lower pain thresholds, promote maladaptive sensitization and, thus, further increase pain.
Instead of “fighting” pain perception alone (at the level of nociception), diagnosis and treatment of chronic pain should incorporate a wider range of neurophysiological and psychobehavioral factors, and offer multidimensional approaches to recovery. Interventions should preferably be active, both physical and psychological, and include education and motivation that enable participatory, self-initiated and self-efficacious activity. Therefore, endorsement of daily activities, stress management, sleep hygiene and the pursuit of personal goals can be promising therapeutic starting-points. Importantly, much is achieved by avoiding typical mistakes: Pain treatment should not blind to other symptoms and comorbidities, and should not risk (iatrogenic) passivation and endangerment. Non-deceptive placebo effects should be utilized, nocebo effects should be avoided. In the management of chronic pain, less is more, and that does not imply to leave the patient in the lurch.
Who “owns” chronic pain – physiatry, anesthesiology, psychosomatic medicine, or neurology? It remains open how the relationship between nosological classification, the corresponding allocation to subspecialties and their specific treatment strategies will evolve in the future. Ideally, classification, prevention, diagnosis, treatment and, last but not least, research must be multidisciplinary and always judged with regard to the patients’ preferences, functioning, and quality of life. Furthermore, pain medicine will remain an interprofessional endeavor, requiring close collaboration between nurses, psychologists, physicians and therapists.
Conflict of interest
SP reports no conflict of interest; E. E.-K. holds an endowed professorship funded by the German Social Accident Insurance (DGUV), and has received a travel grant from Mundipharma GmbH and Bayer Vital GmbH, speaker fees from Grünenthal GmbH and Pfizer GmbH as well as consultant fees from painCert GmbH and Casquar GmbH; TM reports no conflict of interest; MH reports no conflict of interest; CHW reports no conflict of interest.
Funding
This work was created in part through an interdisciplinary workshop on functional neurological disorders supported by the Institute for Advanced Study Berlin and the Fritz Thyssen Stiftung.