How to Distinguish Non-Inflammatory from Inflammatory Pain in RA?

Abstract

Purpose of the Review
Managing non-inflammatory pain in rheumatoid arthritis (RA) can be a huge burden for the rheumatologist. Pain that persists despite optimal RA treatment is extremely challenging for patient and physician alike. Here, we outline the latest research relevant to distinguishing non-inflammatory from inflammatory RA pain and review the current understanding of its neurobiology and management.

Recent Findings
Nociplastic pain is a recently introduced term by the international pain community. Its definition encompasses the non-inflammatory pain of RA and describes pain that is not driven by inflamed joints or compromised nerves, but that is instead driven by a functional reorganisation of the central nervous system (CNS).

Summary
Insights from all areas of nociplastic pain research, including fibromyalgia, support a personalised pain management approach for non-inflammatory pain of RA, with evidence-based guidelines favouring use of non-pharmacological interventions. Future developments include novel CNS targeting pharmacotherapeutic approaches to treat nociplastic pain.

Full text

Vol.:(0123456789)
Curr Rheumatol Rep (2024) 26:403–413
https://doi.org/10.1007/s11926-024-01159-4
REVIEW
How toDistinguish Non‑Inflammatory fromInflammatory Pain inRA?
SharmilaKhot1· GeorgeTackley2· ErnestChoy3
Accepted: 17 July 2024 / Published online: 9 August 2024
© The Author(s) 2024
Abstract
Purpose of the Review Managing non-inflammatory pain in rheumatoid arthritis (RA) can be a huge burden for the rheuma-
tologist. Pain that persists despite optimal RA treatment is extremely challenging for patient and physician alike. Here, we
outline the latest research relevant to distinguishing non-inflammatory from inflammatory RA pain and review the current
understanding of its neurobiology and management.
Recent Findings Nociplastic pain is a recently introduced term by the international pain community. Its definition encom-
passes the non-inflammatory pain of RA and describes pain that is not driven by inflamed joints or compromised nerves,
but that is instead driven by a functional reorganisation of the central nervous system (CNS).
Summary Insights from all areas of nociplastic pain research, including fibromyalgia, support a personalised pain manage-
ment approach for non-inflammatory pain of RA, with evidence-based guidelines favouring use of non-pharmacological
interventions. Future developments include novel CNS targeting pharmacotherapeutic approaches to treat nociplastic pain.
Keywords Rheumatoid arthritis· Nociplastic· Inflammatory· Chronic pain
Introduction
Rheumatoid arthritis is a chronic, inflammatory, autoim-
mune disease that mainly affects joints but is known to have
extra articular effects on pulmonary, nervous and cardiovas-
cular systems [1]. Pain remains a widely prevalent symp-
tom in RA despite substantially improved disease modify-
ing antirheumatic drugs (DMARDs). Indeed, pain is often
disproportionate to disease activity measures and frequently
persists even where clinical, biochemical and imaging evi-
dence of inflammation has resolved [2, 3].
The focus of rheumatological management tends to be dis-
ease control and the biomedical model has historically viewed
pain as a symptom secondary to disease, with the in-built
assumption that treatment of the disease should eliminate pain.
Therefore, the patient who has ongoing pain complaints may
suspect their symptoms are being dismissed as less important
than disease control or even feel ‘not believed’ [4].
Helpfully, there is a growing recognition that inflamma-
tory and non-inflammatory pain phenotypes can co-exist in
RA [5–9]. Herein we use 'inflammatory pain' to describe pain
that is proportionate to the level of RA activity, as meas-
ured by inflammatory markers and joint imaging, and 'non-
inflammatory pain' to describe pain disproportionate to RA
presentation. We explore the mechanisms of inflammatory
and non-inflammatory pain in RA, recommend some clinical
techniques to help differentiate them, and suggest a manage-
ment approach that can be adapted to tackle multiple underly-
ing pain aetiologies.
What isPain?
Pain has been defined as “an unpleasant sensory and emo-
tional experience associated with, or resembling that associ-
ated with, actual or potential tissue damage” (International
* Sharmila Khot
khots@cardiff.ac.uk
1 Department ofAnaesthesia, Intensive Care andPain
Medicine, Cardiff andVale University Health Board, Cardiff
CF14 4XW andCardiff University Brain Research Imaging
Centre (CUBRIC), Cardiff University, Maindy Road,
Cardiff, WalesCF244HQ, UK
2 Cardiff University Brain Research Imaging Centre
(CUBRIC), Cardiff University, Maindy Road, Cardiff,
WalesCF244HQ, UK
3 Head ofRheumatology andTranslational Research
attheDivision ofInfection andImmunity andDirector
oftheCardiff Regional Experimental Arthritis Treatment
andEvaluation (CREATE) Centre atCardiff University
School ofMedicine, Cardiff, Wales,UKCF144YS
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404 Curr Rheumatol Rep (2024) 26:403–413
Association for the Study of Pain (IASP) [10, 11]. Pain is
always a personal, multidimensional experience, learnt con-
ceptually through life experiences and influenced to varying
degrees by neurobiological, psychological, and social factors
[11], features that hold true for RA pain [7]. Nociception is
the neurobiological process by which a painful stimulus is
conveyed by the nervous system to the brain. Pain (the aver-
sive experience) and nociception (the transmission of noxious
information) are therefore distinct phenomena: pain cannot
be inferred solely from activity in nociceptive neurons.
Nociception
Nociceptors are sensory receptors that detect molecules or
signals from tissues often due to damage and/or inflamma-
tion. Nociceptors are at the nerve endings of thinly myeli-
nated (Aδ) and unmyelinated (c) fibres which are the main
neuronal fibres implicated in the detection of mechanical,
chemical (including inflammatory mediators), and thermal
noxious stimuli. These fibres synapse with neurons in the
superficial laminae of the spinal cord dorsal horn, a site that
is subject to local and distant modulatory inputs (including
direct top-down inputs from the brainstem), before ascend-
ing predominantly via the spinothalamic tract [12].
The spinothalamic pathway terminates in discrete sub-
divisions of thalamic nuclei known as the ventral posterior
lateral nucleus and the ventromedial nucleus. From these
nuclei, nociceptive information is relayed to various corti-
cal and subcortical regions, including the amygdala, hypo-
thalamus, periaqueductal grey (PAG), basal ganglia, and
regions of cerebral cortex such as the somatosensory cor-
tices I and II (SI–II), the prefrontal cortex (PFC), the ante-
rior cingulate cortex (ACC) and the insular cortex (IC).
Most notably, the insula and anterior cingulate cortex are con-
sistently activated when nociceptors are stimulated by noxious
stimuli, and activation in these brain regions is associated with
the subjective experience of pain [13]. In turn, these integrated
thalamocortical and corticolimbic structures, collectively have
been termed by some the pain “neuromatrix,” [14].
Top-down modulation of pain is driven from many brain-
stem sites, including the PAG, rostroventromedial medulla
(RVM) and locus coeruleus (LC), and is largely subserved by
noradrenergic and serotonergic neurons. Top-down modula-
tion can both inhibit and facilitate nociceptive transmission
at the level of the spinal cord superficial dorsal horn (SDH).
The balance between excitatory and inhibitory signals to the
secondary sensory neurons helps filter the sensory informa-
tion reaching the brain [15]. (See Fig.1)
Pain inRA
Pain is important for health and survival. It has evolved as a
powerful alarm signal that motivates protective behaviours,
e.g., nursing a damaged limb, or withdrawing from a damaging
stimulus. Pain becomes a problem when it is present but no
longer serves this protective role whilst retaining its strongly
salient and aversive nature. This pathological pain may be clas-
sified as nociceptive, neuropathic or nociplastic [7, 9].
Nociceptive pain is pain caused by actual or threatened
damage to tissues and due to the activation of nociceptors
[10, 11]. Active synovitis of RA would be an example of
nociceptive pain caused directly by inflammation. Neuro-
pathic pain is caused by a lesion or disease of the soma-
tosensory system [10]. This type of pain is often described
as burning, shooting, tingling, stabbing and in RA can be
caused by nerve entrapment or secondary peripheral neu-
ropathy, e.g. carpal tunnel syndrome, or neuropathic pain
secondary to co-existing diabetes.
Nociplastic pain is a new mechanistic descriptor that seeks
to capture pain that is neither nociceptive nor neuropathic.
This is defined by IASP as "pain that arises from altered noci-
ception 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" [10, 11, 16]. Patients may have a combina-
tion of nociceptive and nociplastic pain (10). Nociplastic pain
can involve various organ systems e.g. IBS and occur either as
a primary pain pathology e.g. fibromyalgia or in tandem with
pre-existing nociceptive e.g. in RA or neuropathic pain con-
ditions e.g. in Multiple Sclerosis. Fibromyalgia is considered
the archetypal nociplastic pain condition, wherein pain exists
without evidence of nociceptive or neuropathic mechanisms.
Nociplastic symptoms are common in RA, sometimes fulfill-
ing the fibromyalgia diagnostic criteria (then termed second-
ary fibromyalgia), and by definition presenting as pain that is
out of proportion to underlying RA disease activity [17, 18].
In reality, these three pain pathologies often co-exist. It is
perhaps equally helpful then to consider the various mecha-
nisms by which pain might become pathological.
Mixed Pain
Mixed pain is a complex overlap of the different known pain
types (nociceptive, neuropathic, nociplastic) in any combi-
nation, acting simultaneously and/or concurrently to cause
pain in the same body area. Either mechanism may be more
clinically predominant at any point of time. Mixed pain can be
acute or chronic [19]. However, some mixed pain may also be
a manifestation of an entirely independent pathophysiological
mechanism, and this is an area that needs further research [20].
Inflammatory Pain inRA
The treatment of inflammatory pain is a staple of rheuma-
tological practice. It is largely understood as a nociceptive
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405Curr Rheumatol Rep (2024) 26:403–413
form of pain, originating from synovial and periosteal noci-
ceptors signalling inflammatory changes [21].
Mechanisms ofInflammatory Pain inRA
Pain is a cardinal feature of inflammation. Inflammatory
joint pain in RA is a type of nociceptive pain initiated by
pro-inflammatory mediators such as prostaglandins, brad-
ykinins and neurotrophic growth factors released during
synovial inflammation [22]. These proinflammatory media-
tors induce an inflammatory cascade and the synoviocytes
interact with cells of the adaptive and innate immune system
further causing a hyperplastic synovium, bone erosions and
cartilage destruction [21]. Nociceptors innervating the syn-
ovium and subchondral bone are responsible for arthritic
pain; these include joint nociceptors specialised in the detec-
tion of chemical stimuli, including the above inflammatory
mediators, as well as mechanical or thermal noxious stimuli
[23]. In RA chronic inflammation is also thought to cause
structural and functional alterations in the peripheral inner-
vation of joints leading to pain [24].
Cytokines and chemokines such as CXCL1 act on periph-
eral terminals of nociceptor neurons activating them and
causing pain [23, 25]. Inflammation sensitises nociceptors
to noxious and innocuous stimulation reducing firing thresh-
olds. Noxious inflammatory mediators such as cytokines and
prostaglandin E2 released by innate immune cells have been
shown to stimulate pain and pain sensitisation in the carra-
geenan mouse model of inflammatory pain [26, 27] and the
Complete Freund’s Adjuvant (CFA) arthritis model [23].
Clinical Clues andManifestations ofInflammatory
Pain
Inflammatory pain tends to be worse after inactivity so
typically early morning. It is also associated with stiff-
ness. Joint swelling and tenderness are the signs and
symptoms of synovial membrane inflammation following
immune activation and can be elicited via clinical exami-
nation and imaging (e.g. joint ultrasound). Elevations of
the erythrocyte sedimentation rate (ESR) and C-reactive
protein (CRP) level are consistent with the presence of an
inflammatory state and can reflect the degree and extent
of (local) synovitis and systemic inflammation in RA.
Joint swelling and raised inflammatory markers are there-
fore commonly combined to assess disease activity, such
as in the 28-joint Disease Activity Score (DAS28) [28].
Unsurprisingly, raised CRP levels are also associated with
greater pain in RA [29]. Interestingly, systemic inflamma-
tion and autoimmunity are detectable several years prior
to the onset of detectable joint inflammation [30] and
autoantibody positivity and pain is highly predictive for
development of RA [31], suggesting pain symptoms may
precede diagnosis of RA, and highlighting the nuanced
dichotomy of inflammatory and non-inflammatory pain
mentioned above.
Non‑Inflammatory Pain ofRA
Several diseases with inflammatory and immune mediated
pathogenesis such as inflammatory bowel disease [32], multiple
sclerosis [33] and RA [3] include reports of pain severity being
disproportionate to disease activity. Indeed, a third of patients
diagnosed with RA report significant and severe widespread
pain out of proportion to measures of systemic inflammation [3].
This out-of-proportion pain is often labelled 'non-inflammatory'.
Other causes of non-inflammatory pain in RA not cov-
ered in this article, include mechanical damage to articular
surfaces causing nociceptive pain [34] and compressive neu-
ropathies leading to neuropathic symptoms [35, 36].
Non-inflammatory pain in RA may sometimes manifest
before evidence of inflammation and commonly persists
despite adequate control of inflammation. The former suggests
that mechanisms other than inflammation can contribute to
nociplastic pain [37], findings that are corroborated in animal
models [38, 39].
Non-inflammatory pain in RA rarely presents in isolation
but instead is usually found alongside inflammatory pain
aetiologies in something of a continuum. There is evidence
that non-inflammatory and inflammatory pain share com-
mon aetiologies during the earlier stages of the disease, with
pro-inflammatory pathways causing hyper-nociception in
early RA and providing an environment for the potential
development of nociplastic pain [23, 40].
Mechanisms ofNon‑Inflammatory Pain ofRA
See Fig.1 for an overview of non-inflammatory pain mecha-
nisms. Non-inflammatory pain in rheumatoid arthritis (RA)
is maintained via altered pain processing in the central nerv-
ous system (CNS). This manifests as pain out of proportion
to underlying RA disease activity, including pain amplifica-
tion from joint inflammation and from typically innocuous
stimuli (e.g. pressure delivered to non-joint regions, such as
the medial border of the scapula).
Pain is amplified in the brain and superficial dorsal horn
of the spinal cord (SDH). The SDH is the site of integration
of ascending pain signals (primary sensory neurons), spinal
interneurons, and descending modulatory inputs. The SDH is
thus subject to top-down (descending modulatory) influences
that facilitate pain transmission and is vulnerable to neuroplas-
tic changes that may arise as a consequence of persistent pain
(or inflammatory) states. Local inflammatory milieu, including
activated microglia, cytokines (such as IL6) and chemokines,
can also have direct effects facilitating pain transmission.
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406 Curr Rheumatol Rep (2024) 26:403–413
Brainstem nuclei (such as the rostro-ventromedial
medulla, the locus coeruleus, peri-aqueductal grey, amongst
many others) receive bottom-up pain input from the SDH,
and top-down input from several brain regions, including
those related to attention and executive function (e.g. dlPFC
& ACC), mood and fear (e.g. amygdala), context and memo-
ries (e.g. hippocampus). The top down and bottom-up inputs
integrate in the brainstem contributing to the descending
modulatory influences that act directly on the SDH (primar-
ily via serotonergic and noradrenergic neurons). These corti-
cal areas involved in pain processing are also vulnerable to
neuroplastic change and the inflammatory milieu and have a
complex relationship with the individual's psychological state
and their social environment (See [9, 12, 13, 15] for review).
Central Sensitisation
Central sensitisation (CS) is defined as an amplification of neu-
ral signalling within the CNS that elicits pain hypersensitiv-
ity [16] either in the form of allodynia (perceiving innocuous
stimuli as painful) or hyperalgesia (perceiving exaggerated
pain in response to painful stimuli) [41]. Allodynia and hyper-
algesia are typical features of neuropathic and nociplastic pain
conditions. CS is sometimes referred to as ‘pain augmentation’.
CS cannot be directly determined in humans but certain
tools are available, although primarily used in research,
that can provide some clues to its presence in RA. Lowered
pressure pain thresholds in non-joint regions, high scores
on neuropathic pain symptoms scales (such as Pain Detect
Questionnaire, PDQ) and central sensitisation measures
(Central Sensitisation Inventory, CSI), high tender joint
count (TJC) and patient global assessment of disease activity
(PtGA) have all been shown to associate with dysregulated
central pain processing in RA [42–53].
Temporal Summation andWind‑up
Repeated painful stimuli ordinarily lead to increased pain
perception of the same stimulus. This phenomenon is termed
temporal summation. Temporal summation is a feature of
all healthy pain systems, however enhanced temporal sum-
mation, which may arise secondary to uncontrolled joint
inflammation in RA, is considered a marker of 'pathologi-
cal' CNS change [54]. Repetitive and high-intensity stimula-
tion due to peripheral joint inflammation causes increased
responsiveness of primary and secondary sensory neurons
by up-regulating excitatory receptors in the spinal cord dor-
sal horn [55]. If left uninterrupted this has the potential for
reorganisation of synaptic connections in the nervous system
resulting in neuroplasticity and chronic nociplastic pain in
RA patients [56].
Altered Descending Modulatory Control
Descending modulation is the mechanism by which brain
processes have influences on pain processing at the level of
the spinal cord. These top-down mechanisms can facilitate
or inhibit pain transmission [15].
Fig. 1 Mechanisms of non-
inflammatory pain in RA
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407Curr Rheumatol Rep (2024) 26:403–413
The periaqueductal grey (PAG), rostroventromedial
medulla (RVM), nucleus raphe magnus (NRM) and locus
coeruleus are some of the key brainstem regions recognised
to be involved in descending modulatory processes, exerting
their influences via descending noradrenergic and seroton-
ergic efferents synapsing in the SDH [57–61].
Dysregulation of these pathways can either lead to disinhi-
bition or facilitation, both causing pain amplification [18, 44].
Serotoninergic noradrenergic reuptake inhibitors (SNRIs) may
exert some of their analgesic actions here [62, 63].
Conditioned pain modulation (CPM) uses a “pain inhibits
pain” principle that is theorised to reveal the strength of
descending inhibition [64]. It uses a painful conditioning
stimulus to influence (in health: to inhibit) a painful test
stimulus [65, 66]. Within RA, in-line with the non-inflam-
matory pain hypothesis, inefficient CPM is predictive of a
reduced response to DMARD’s [44]. In these patients then,
a different approach to pain management would be needed.
Role ofCytokines withSpecial Focus onIL6
Major cytokines involved in RA that have been shown to have
direct effect on sensory neurones in experimental systems
include TNF, IL-6, IL-1, IL-17. IL-6 is a proinflammatory
cytokine that contributes to pathogenesis of RA and circulat-
ing IL6 levels are higher in RA patients than healthy controls.
Preclinical research supports the hypothesis that IL-6 contrib-
utes to RA-associated symptoms and co-morbidities through
its effects on the HPA axis [67]. IL-6 has a key role in noci-
plastic pain, supposedly through activation of the Jak/STAT3
pathway, chemokine overexpression and glial-cell activation
[68–71]. Modulation of the IL-6 pathway may therefore atten-
uate pain-like behaviour in nociplastic pain in RA [67, 68, 72].
Role ofMicroglia
Microglia are macrophage-like immune cells found in the
CNS. Chronic activation of microglia causes secretion of pro-
nociceptive mediators including proinflammatory cytokines
such as TNF and IL-1β, chemokines, reactive oxygen species
(ROS), and proteases which have all been implicated in the
development of central sensitisation [73–75]. Macrophages
play a crucial role in RA cytokine-induced inflammation [76].
Microglia's influence on synaptic plasticity and contribu-
tion to brain inflammation [77] are considered so critical to
chronic pain that some researchers describe chronic pain as a
gliopathy [75, 78]. Peripheral inflammation in RA is thought to
be essential for activation of microglia and activated M1 micro-
glia directly induce pain via proinflammatory mediators such
as IL-1β, TNF, IL-6 causing synaptic plasticity and hypernoci-
ception in animal models of RA [40, 76]. Thus, microglia are
considered prime future targets for developing CNS-modulating
analgesic treatments for nociplastic RA pain [79].
Role ofToll likeReceptors (TLRs) andChemokines
Toll-like receptors (TLRs) are a family of receptors that are
involved in the recognition of conserved pathogen-associ-
ated molecular patterns, highly expressed in synovial tissues
of RA patients [80]. Functional, genetic or pharmacological
blockade of TLRs reverses arthritis in different experimental
models [81]. Of relevance to nociplastic pain, MyD88, an
adaptive protein recruited by TLRs, is thought to play an
important signalling role in arthritic pain by stimulating pro-
inflammatory cytokine release, in turn promoting production
of prostaglandins and sympathetic amines. Murine studies
have shown that TLR/MyD88 signalling is required in the
hypernociceptive response seen after chemically induced
joint inflammation [82, 83]. Early preclinical studies report a
role for TLR4 antagonists in reversal of inflammation in RA
and improvement in allodynia and hyperalgesia in nerve pain
models and therefore of potential benefit for both inflamma-
tory and nociplastic pain in RA [84].
Autoantibodies against citrullinated protein (ACPA) are
found in ~50% of RA patients [85]. In mice injected with
human and murinised ACPA, long lasting prolonged pain
like behaviour, in the absence of inflammation, has been
demonstrated. This pronociceptive effect was coupled with
release of nociceptive chemokine CXCL1 which is an ana-
logue of human IL-8 [86] and a candidate cytokine impli-
cated in maintaining pain states [87]. IL-8 inhibitors have
been shown to inhibit neuropathic pain [88] and may poten-
tially benefit RA pain [46, 87].
Clinical Clues andManifestations
Nociplastic pain mechanisms are often obscure, however
risk factors for nociplastic pain are well described: family
history, past pain experience, and psycho-social factors
including psychological, emotional and physical trauma,
are all recognised to increase the risk of developing noci-
plastic pain. An 'initiating' risk-factor may be considered a
'trigger', and include stressors that might be psychosocial,
or as is often the case for secondary FM in RA, underlying
inflammatory disease [89]. Pain severity disproportion-
ate to RA disease activity, disabling fatigue, sleep distur-
bances or unrefreshed sleep, mood disturbances/disorders,
neuropathic symptoms, brain fog, worsening physical and
mental health, are all clues indicative of nociplastic pain
[18, 90].
Fibromyalgia is the archetypal nociplastic pain and is
common in RA patients with a 13-40% prevalence [48,
91–95]. Fibromyalgia has clear diagnostic guidelines,
and historically labelled ‘secondary’ fibromyalgia in RA
patients can be considered a form of nociplastic pain [17,
89]. A tender joint count (TJC) score 7 or more than the
corresponding swollen joint count (SJC) (i.e. TJC minus
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408 Curr Rheumatol Rep (2024) 26:403–413
SJC ≥7) or SJC/TJC ratio of <0.5 is proposed to be highly
predictive of concomitant fibromyalgia [48, 94] and there-
fore of nociplastic pain in RA [18].
Composite disease activity indices commonly used in
routine clinical practice to guide ‘treat-to-target’ include
Tender Joint Count (TJC) and patient global assessment
(PtGA) [96, 97]. Both TJC and PtGA are influenced by the
presence of nociplastic pain, leading to higher reported
disease activity scores driven by pain unresponsive to
escalating RA treatments [49, 53, 98, 99].
Higher reported pain scores are seen in patients with
RA reporting disturbed sleep [100], anxiety and depres-
sion [101–103] which further contributes to enhanced pain
sensitivity, indirectly impacting PtGA and disease activity
scores and patient satisfaction with RA treatment.
Pain predicts functioning, health and QOL in RA and
is thought to be a more important cause of disability than
joint damage [104–106].
Therefore, use of multidimensional questionnaires
assessing pain, mood, functioning and sleep may be a
useful addition in clinic to assist with mechanistic classi-
fication of pain and support appropriate pain management
leading to improved patient reported global satisfaction
scores [7, 107, 108].
Management
Maintaining a high index of suspicion for presence of
non-inflammatory pain in early RA is key to instituting
an early biopsychosocial approach to patient assessment
and promoting appropriately combined pharmacological
and non-pharmacological therapeutic modalities early in
the course of their disease [89, 108]. The NICE Chronic
Pain Guidelines visual summary is helpful here (https://
www. nice. or g. uk/ guida nce/ ng193/ r esou rces/ visual- summa
ry- pdf- 90734 73517) [109].
Developing aBiopsychosocial Perspective
We have emphasised above that pain is not simply a linear
track from noxious stimulus to perception but that frequently
for RA, pain severity and extent are disproportionate to
underlying evidence of active rheumatological disease [110].
Despite maximal treatment of the 'biological' component,
with DMARDS, NSAIDs and corticosteroids, pain persists.
Having optimised biological management of RA, and in
the presence of clues pointing to a non-inflammatory (noci-
plastic) aetiology, a careful combination of pharmaceuti-
cal and psychosocial targeted therapies should be sought,
often with emphasis on the latter. Simple evaluation of psy-
chosocial risk factors in clinic, where appropriate tools are
available, can facilitate the institution of early and appropri-
ate treatments, and consideration of referral to chronic pain
management services or condition specific self-management
programs is recommended [53].
NICE guidelines [109] provide a broad general frame-
work to assess and manage chronic primary nociplastic
pain (e.g. fibromyalgia) and chronic secondary pain (e.g.
non-inflammatory pain of RA) with an emphasis on shared
decision making and a non-pharmacological psychosocial
driven approach.
NICE explicitly recommend against the use of standard
analgesia for 'chronic primary pain' or pain out-of-proportion
with underlying disease (i.e. nociplastic pain, such as fibromy-
algia). Instead, NICE recommends using antidepressants with
established analgesic profiles for which there is mounting evi-
dence of efficacy within non-nociceptive pain [62, 109, 111].
First-line antidepressants are amitriptyline and duloxetine,
favoured for their dual actions on noradrenergic and seroton-
ergic systems [63, 109, 112]. Amitriptyline is particularly
beneficial in people with severe sleep disturbances. Trama-
dol and pregabalin are also options that are recommended for
severe pain in fibromyalgia (nociplastic pain) in the European
League Against Rheumatism (EULAR) guidelines which pre-
date the NICE 2021 guidance for pharmacological manage-
ment of chronic primary pain (fibromyalgia) [63, 109].
International EULAR guidelines align with NICE [113]
in recommending individualised tailored therapy and
emphasising the first-line role of non-pharmacological
interventions [63, 89, 114]. Physical activity, exercise inter-
ventions, psychological interventions, educational interven-
tions, orthotics, weight management, and multidisciplinary
treatment overall have positive effects on pain and are ubiq-
uitously recommended for nociplastic pain [63, 109, 114].
Exercise has a strong evidence base in inflammatory
and non-inflammatory pain [115, 116]. Patient preferences
should be considered with low impact exercise sometimes
proving more sustainable for painful RA [117].
Management should be aimed at improving health-related
quality of life and not just pain severity reduction [63, 114].
Psychological therapies are recommended for mood disorder,
or in those with unhelpful coping strategies, with CBT deemed
effective at producing modest, long-term reductions in pain,
disability and improving mood [114].
Cognitive behavioural therapy (CBT) was found to have
positive impacts on relieving anxiety, depression, and fatigue
in RA. However, effect sizes for relief of pain in RA were
small for CBT, with a recent Cochrane review suggesting
small reductions in pain and distress [118, 119].
Mindfulness is the awareness that emerges from paying
attention to things as they are, on purpose, in the present
moment and non-judgementally [120]. Mindfulness practice
can reduce pain intensity and unpleasantness [121, 122] and
help with depressive symptoms in RA [123–125].
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409Curr Rheumatol Rep (2024) 26:403–413
CBT and mindfulness-based therapies for chronic pain
have the additional benefit of improving physical function-
ing. Therefore, mindfulness-based therapies could be offered
additionally to CBT for improving pain severity and reducing
pain interference and psychological distress in in patients with
RA [124, 126].
Multimodal rehabilitation programmes are recommended
for those with severe disability.
Other therapies such as TENS machine or massage may
provide pain reduction via stimulation of large sensory nerves
(conveying innocuous sensations from the skin) suppressing
transmission in small pain fibres. However, evidence for such
therapies in RA is lacking.
Whilst some therapies such as physiotherapy, exercise and
mindfulness would benefit both inflammatory and non-inflam-
matory pain, we would recommend that analgesic therapy is
best guided via identification of pain type.
DMARD’s andBiologics inRA Pain Management
Some contemporary biologics have recently shown promis-
ing analgesic effects on residual or disproportionate pain in
RA [127, 128]. IL-6 inhibitors, e.g. tocilizumab and sari-
lumab, and anti-TNF adalimumab, are known to have anal-
gesic efficacy with emerging evidence that they confer a dual
benefit in RA patients, treating both inflammatory disease
and non-inflammatory (nociplastic) pain [128, 129]. Simi-
larly, Jakstat-inhibitor Tofacitinib demonstrated analgesic
benefit beyond that associated with reduction of inflamma-
tion implying an additional reduction of RA non-inflamma-
tory (nociplastic) pain [127].
Conclusion
Pain in RA is complex and multifactorial but should not be
confined to the remit of pain specialists. Pain reduction is
an important outcome for patients and non-inflammatory
(nociplastic) RA pain benefits from early rheumatological
management. Empowered with the latest pain neuroscience
knowledge, rheumatologists can support early patient edu-
cation and navigate a logical approach to pharmacological
and non-pharmacological pain management. The apparent
disconnect between treat-to-target guidance and patient
expectations can then be partially bridged using a biopsy-
chosocial approach to clinical assessment early on in disease
presentation. It is known that psychosocial approaches based
on the individual presentation and preference often improve
quality of life and perceived pain [114, 130, 131]. However,
distinguishing pain as a symptom or a disease in its own
right can often be difficult and an interdisciplinary approach
for difficult to treat RA pain is encouraged and is likely to
demonstrate improved clinical outcomes [132].
Author Contribution S.K drafted the work. G.T, E.C and S.K revised
it critically for important intellectual content.
G.T prepared Fig.1. S.K and E.C contributed and approved pub-
lished version.
All authors reviewed and revised the manuscript and approved the
version to be published.
Funding Information Dr Sharmila Khot has received speaker fee from
Galapagos.
Dr George Tackley has no funding to declare.
Professor Ernest Choy has received research grants from Bio-Can-
cer, Biogen, Novartis, Pfizer, Roche, Sanofi and UCB, consultancy
from Abbvie, Amgen, Biogen, Biocon, Chugai Pharma, Eli Lilly, Fre-
senius Kabi, Gilead, Janssen, Merck Serono, Novartis, Pfizer, Regen-
eron, Roche, RPharm, Sanofi and Viatris, speakers fee from Abbvie,
Amgen, Bristol Myer Squibbs, Chugai Pharma, Eli Lilly, Fresenius
Kai, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, RPharm,
Roche, Sanofi, UCB and Viatris.
Data Availability No datasets were generated or analysed during the
current study.
Declarations
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any
of the authors.
Conflicts of Interest The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article's Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article's Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.
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