Rheumatoid arthritis

RA is a common inflammatory joint disease that greatly affects the patients’ quality of life and working productivity, and the use of health-care resources . Most RA patients consider pain their greatest problem and highest priority , and it may even cause more disability than structural joint damage . Pain is often considered a marker of inflammation, but the intensity of pain is only weakly correlated with measures of peripheral inflammation ; however, it is associated with disease activity, and it is known that radiographic changes may lead to future pain .

It is becoming increasingly possible to suppress the inflammation that causes pain, stiffness and progressive joint damage, and to ensure clinical remission , which, if rapidly achieved, improves long-term outcomes . Clinical trials have shown that early intensive treatment with DMARDs and corticosteroids leads to better pain outcomes , especially when disease activity is regularly monitored: the level of pain tends to decrease if inflammatory disease is suppressed soon after RA is diagnosed, although it often does not completely disappear and may subsequently return to its initial level. RA-related pain may occur spontaneously or be evoked when a joint is moved within its normal working range, and it may even be felt in apparently normal surrounding tissue. Further, referred pain syndromes have also been reported because the intensity of the symptom does not necessarily correlate with the severity of the underlying disease or the absence of disease exacerbations .

The pain may be worsened by damage to a joint caused by inflammatory disease or concomitant osteoarthritis (OA), and the prevalence of chronic, non-inflammatory pain syndromes such as FM is higher among patients with RA than in the general population . Patients with inflammatory arthritis and FM are more likely to have more active disease and a poorer quality of life than those without FM and, as pain also indirectly contributes to the psychological and social impact of RA, analgesia is important .

Inflammatory spondyloarthropathies

Inflammatory spondyloarthropathies (SpAs) include ankylosing spondylitis (AS), reactive arthritis and arthritis/spondylitis associated with psoriasis (PsA) or inflammatory bowel disease (IBD) .

The first is a chronic inflammatory disease of the axial skeletal system that is mainly characterised by back pain, progressive spinal stiffness, enthesopathy, arthritis and peripheral extra-articular manifestations, and it generally causes functional incapacity . It has a male/female ratio of 3–4:1, and it is more frequent and prevalent in young men . The pain can be intense, persistent and disabling , and it is the main reason for seeking rheumatological care. It may be due to active inflammation or joint damage arising from previous inflammation and tissue destruction, but it is frequently multifactorial in origin and has both central and peripheral components . Treatment with DMARDs and NSAIDs reduces the inflammatory pain symptoms , although the fact that many patients continue to experience moderate pain suggests the existence of a non-inflammatory component with a different aetiology and/or alterations in central pain regulation mechanisms .

Many researchers now believe that CWP is a disease per se, and that its location may be less relevant than genetically determined sensitivity to pain; furthermore, pain transmission may be increased by neuroplastic changes in the central nervous system (CNS) . The heightened sensitivity to pain may be associated with hyperalgesia (increased pain in response to normally painful stimuli) and/or allodynia (pain in response to normally non-painful stimuli), may be local or widespread, and may be triggered by an initial peripheral injury or inflammatory process , but the many other complex mechanisms involved include temporal summation (wind-up), long-term potentiation (LTP), heterosynaptic potentiation, dysfunctional descending pain inhibition and activation of the descending facilitatory pathway .

Rheumatoid arthritis

RA is a common inflammatory joint disease that greatly affects the patients’ quality of life and working productivity, and the use of health-care resources . Most RA patients consider pain their greatest problem and highest priority , and it may even cause more disability than structural joint damage . Pain is often considered a marker of inflammation, but the intensity of pain is only weakly correlated with measures of peripheral inflammation ; however, it is associated with disease activity, and it is known that radiographic changes may lead to future pain .

It is becoming increasingly possible to suppress the inflammation that causes pain, stiffness and progressive joint damage, and to ensure clinical remission , which, if rapidly achieved, improves long-term outcomes . Clinical trials have shown that early intensive treatment with DMARDs and corticosteroids leads to better pain outcomes , especially when disease activity is regularly monitored: the level of pain tends to decrease if inflammatory disease is suppressed soon after RA is diagnosed, although it often does not completely disappear and may subsequently return to its initial level. RA-related pain may occur spontaneously or be evoked when a joint is moved within its normal working range, and it may even be felt in apparently normal surrounding tissue. Further, referred pain syndromes have also been reported because the intensity of the symptom does not necessarily correlate with the severity of the underlying disease or the absence of disease exacerbations .

The pain may be worsened by damage to a joint caused by inflammatory disease or concomitant osteoarthritis (OA), and the prevalence of chronic, non-inflammatory pain syndromes such as FM is higher among patients with RA than in the general population . Patients with inflammatory arthritis and FM are more likely to have more active disease and a poorer quality of life than those without FM and, as pain also indirectly contributes to the psychological and social impact of RA, analgesia is important .

Inflammatory spondyloarthropathies

Inflammatory spondyloarthropathies (SpAs) include ankylosing spondylitis (AS), reactive arthritis and arthritis/spondylitis associated with psoriasis (PsA) or inflammatory bowel disease (IBD) .

The first is a chronic inflammatory disease of the axial skeletal system that is mainly characterised by back pain, progressive spinal stiffness, enthesopathy, arthritis and peripheral extra-articular manifestations, and it generally causes functional incapacity . It has a male/female ratio of 3–4:1, and it is more frequent and prevalent in young men . The pain can be intense, persistent and disabling , and it is the main reason for seeking rheumatological care. It may be due to active inflammation or joint damage arising from previous inflammation and tissue destruction, but it is frequently multifactorial in origin and has both central and peripheral components . Treatment with DMARDs and NSAIDs reduces the inflammatory pain symptoms , although the fact that many patients continue to experience moderate pain suggests the existence of a non-inflammatory component with a different aetiology and/or alterations in central pain regulation mechanisms .

Many researchers now believe that CWP is a disease per se, and that its location may be less relevant than genetically determined sensitivity to pain; furthermore, pain transmission may be increased by neuroplastic changes in the central nervous system (CNS) . The heightened sensitivity to pain may be associated with hyperalgesia (increased pain in response to normally painful stimuli) and/or allodynia (pain in response to normally non-painful stimuli), may be local or widespread, and may be triggered by an initial peripheral injury or inflammatory process , but the many other complex mechanisms involved include temporal summation (wind-up), long-term potentiation (LTP), heterosynaptic potentiation, dysfunctional descending pain inhibition and activation of the descending facilitatory pathway .

Rheumatoid arthritis

The causes of RA-related pain may be different in early and late disease stages, during and between inflammatory flares and between individuals. An inflamed synovium generates mediators such as prostaglandins and bradykinin, and pro-inflammatory cytokines such as TNF-α, interleukin-1 (IL-1), IL-6 and nerve growth factor beta (NGF-β), which sensitise peripheral nerves, thus significantly contributing to pain generation and maintenance . However, it is unlikely that the synovium is the only source of pain as sensory nerves are also located in joint capsules, ligaments, the outer regions of the menisci, subchondral bone, tendon sheaths and muscles , although articular cartilage and the inner two-thirds of the menisci are normally aneural and allow normal, pain-free weight bearing and joint movement.

Synovitis is associated with alterations in neurotransmitters such as γ-aminobutyric acid (GABA), substance P and calcitonin gene-related peptide (CGRP), and their receptors in the spinal cord , as well as the activation of the microglia and astrocytes inside the spinal cord to produce TNF-α, IL-1 and IL-6, which facilitate pain transmission . Nociceptive transmission may also be further increased as a result of greater descending activation and reduced descending inhibition . Finally, central sensitisation may be more widespread than the innervation of the inflamed joint and reduce pain thresholds in adjacent tissues .

Widespread reductions in pain pressure thresholds have been associated with moodiness and sleep disturbances , and cross-sectional surveys have found that about 8% of RA patients satisfy the FM classification criteria . However, although these criteria may identify the subgroup of patients with the most abnormal pain processing, they may conceal the larger number of patients whose symptoms are due to similar pain mechanisms.

Pain in RA may be further exacerbated by joint damage due to inflammatory disease or concomitant OA, particularly in the case of long-established disease. The structural changes associated with RA (erosions and joint space narrowing) cause greater pain, but they may explain only 2% of pain intensity after adjusting for factors such as current disease activity . Psychological factors also influence pain reporting , and depression has been associated with greater pain . The experience of pain is therefore multifaceted, and it includes both sensory and emotional components, as is shown by the fact that pain can persist despite adequate control of inflammation .

Ankylosing spondylitis

Studies have shown that widespread pain significantly increases AS disease activity , and growing evidence of an association between FM and SpA increases the need to distinguish their clinical features . The main cause of diagnostic confusion relating to the 1990 ACR criteria was the overlap between SpA-related enthesitis and FM-related tender points (TPs); the latter were therefore replaced by patient self-assessment in the 2010 ACR FM diagnostic criteria , but some confusion remains . Although pain is a cornerstone of AS, it does not necessarily reflect increased inflammatory disease activity , and sometimes it seems to be more related to a mechanism of central pain sensitisation similar to that observed in FM . However, it is difficult to assess widespread pain in AS patients because of the presence of enthesitis and tenosynovitis and, as tendon insertion sites are located throughout the body, it is not always clear whether the pain is related to disease activity or reflects an associated pain syndrome. The mechanisms leading to the development of CWP in patients with inflammatory arthritis are still unclear, but a number of studies have shown that widespread pain conditions such as FM are highly prevalent in AS patients.

Rheumatoid arthritis

The 28-joint Disease Activity Score (DAS28) is frequently used to assess joint inflammation in randomised controlled trials (RCTs) and guide treatment decisions in clinical practice. Furthermore, intensive targeted regimens require treatment escalation in patients with active disease, and some national guidelines (such as those of the UK) restrict the use of biological agents to patients with a high DAS28 score .

However, the relationship between DAS28 and inflammatory disease activity is confounded by other factors. Visual analogue scales (VAS) and tender joint counts (TJCs) increase with inflammation, and are both closely related with reported bodily pain , but they may also be increased by concomitant painful conditions such as OA, which usually affect the hand and knee joints included in the DAS28, or by changes in pain processing such as central sensitisation, which coincides with joint inflammation and may make the DAS28 more difficult to interpret . Two recent studies have found that pain significantly affects patient assessments of RA disease activity; the first involved 7028 patients entered in the Quantitative Standard Monitoring of Patients with RA (QUEST-RA) database , and it showed that pain was the single most important determinant of patient global assessments; the second involved 646 RA patients starting methotrexate (MTX) treatment at an outpatient clinic, and it found that pain explained 75.6% of the variability of the patient global assessment scores . Pain contributed less to physician global assessments (it was the fourth most important determinant), but the fact that it was one of the most significantly discordant variables between the patient and physician global assessments in both studies suggests that physicians should give it greater weight.

Spondyloarthritis

Disease activity indices are often used in patients with SpA , and there is a good correlation between self-reported indices (including the Bath Ankylosing Spondylitis Disease Activity Index, BASDAI) and the presence of CWP or FM, which suggests that the CWP frequently reported by women with inflammatory rheumatic diseases may also be frequent in women with axial SpA. This can cause diagnostic delays and may also partially explain why women’s self-reported functional limitations are worse than those of men at any given level of radiographic damage. However, women with primary FM have much higher BASDAI scores than women with AS , and the BASDAI may not be such a good means of assessing inflammatory disease activity in SpA patients. Aloush et al. studied 36 AS patients (18 males and 18 females), and they diagnosed FM in 50% of the women but none of the men. They also found that patients with concomitant diseases were more functionally impaired than those with only one disease, which led to higher BASDAI and Bath Ankylosing Spondylitis Functional Index (BASFI) scores. Another study of 71 AS patients (45.5% males and 54.5% females) found a 15% prevalence of FM, and these patients had significantly higher BASDAI, BASFI and Ankylosing Spondylitis Quality of Life (ASQoL) scores . Finally, a cross-sectional Spanish study of 462 patients with definite AS found that the prevalence of FM was 4.11% in the population as a whole, but 10.83% among women . It also found that the BASDAI, BASFI and total Bath AS Radiology Index (BASRI) were greatly influenced by the presence of FM, which was very likely in the patients with a BASDAI/BASRI ratio of ≥1.5 or a BASFI/BASRI ratio of ≥1.08. The conclusion drawn was that FM in patients with AS distorts measures of disease activity and functional damage, and that using BASDAI/BASRI and BASFI/BASRI ratios may help to avoid over-treatment .

The BASDAI is based on a subjective assessment of fatigue, stiffness and pain and, as these symptoms also characterise CWP conditions, it is difficult to establish disease activity and functional capacity in AS patients with concomitant FM . In an attempt to overcome this drawback, a study of 547 patients entered in the Scotland and Ireland Registry for Ankylosing Spondylitis (SIRAS) used four-view body manikins to obtain information concerning CWP not only on the basis of the 1990 ACR criteria for FM (ACR-CWP: i.e., chronic pain for >3 months in two contralateral body quadrants plus axial pain) but also on the basis of an alternative definition (aCWP) that required chronic pain in two contralateral body quadrants, but it excluded axial skeletal and/or buttock pain in order to avoid the potentially confounding effect of spinal disease. The results showed that the age- and gender-adjusted prevalence of aCWP among AS patients was almost three times higher than that in the general population, and it was related to both individual and clinical factors..

It is known that patients with inflammatory arthritides are more likely to develop CWP and report disability and a poor quality of life if their painful symptoms remain untreated , and it can be presumed that the same is true of patients with RA or AS.

Rheumatoid arthritis

The 3e (evidence, expertise and exchange) initiative is a 17-country collaborative project that promotes evidence-based practice in rheumatology that has recently published recommendations concerning the pharmacological management of pain in patients with inflammatory arthritis , many of which are based on a series of Cochrane database systematic reviews published in 2011–2012.

RA patients are often given NSAIDs to manage their pain, but they are not appropriate for long-term disease control . Nevertheless, although it is recognised that the early use of DMARDs is very important , pain often drives patients to take analgesics from the start, and the European League Against Rheumatism (EULAR) recommends the use of NSAIDs for symptomatic patients with early arthritis once their gastrointestinal, renal and cardiovascular status has been carefully evaluated .

However, the use of analgesics is only indirectly evidence based because it is based on the findings of RCTs involving patients with other conditions, which may actually conceal some findings of their inefficacy in arthritis. For example, paracetamol is readily available but there is little RCT-based evidence supporting its use , and trials have often used it in combination with a different class of analgesic: furthermore, paracetamol is often used in combination products and this may mask cumulative paracetamol intake, which should not exceed 4 g in healthy adults. On the other hand, typical paracetamol-containing products include opioid combinations (codeine, tramadol, oxycodone, etc.) that may provide effective analgesia at lower opioid doses than single opioids , and it has been demonstrated that the fixed-dose combination of tramadol and paracetamol leads to synergistic benefits .

However, one systematic review of 11 randomised or quasi-randomised trials comparing opioids with placebo or an active analgesic concluded that the evidence in favour of the use of weak opioids such as codeine, dextropropoxyphene, pentazocine, tilidine and tramadol is itself weak and, in comparison with placebo, there was a 2.7 greater risk of study withdrawal due to frequent constipation, dizziness, nausea and vomiting in the opioid-treated patients. Furthermore, there is a risk of opioid-induced hyperalgesia leading to greater sensitivity to pain and increased clinical pain intensity, and so it is generally recommended to minimise long-term opioid prescriptions and, when opioids are necessary, to monitor their use regularly .

One Cochrane systematic review found that the evidence supporting the use of neuromodulators to treat RA-related pain was also weak , although it only considered four small randomised, placebo-controlled trials (two of nefopam, a centrally acting analgesic used in Europe but not in the USA; one of topical capsaicin; and one of oro-mucosal cannabis), and the authors concluded that topical capsaicin could be considered as adjuvant pain treatment . Other possible adjuvant treatments recommended by the 3e initiative are gabapentin and pregabalin, although it should be remembered that these recommendations are mainly based on their efficacy in studies of pain in FM, a non-inflammatory condition of CWP .

The disease can be controlled by glucocorticosteroids and traditional DMARDs such as MTX in most patients , with biological therapies being reserved for those with very advanced or severe disease. Both glucocorticosteroids and DMARDs reduce RA-related pain and, although the analgesic effects of the former may not last longer than 3 months , the early suppression of inflammatory disease activity not only reduces pain in the short term but avoids the development of worse pain 12 months after diagnosis. Finally, DMARD combinations may be more effective than monotherapy.

However, it must be remembered that inflammation is only one factor contributing to the pain felt by many arthritic patients, and symptomatic relief is frequently incomplete even when reductions in swollen joint counts, acute-phase reactant levels and ultrasound findings of synovitis indicate inflammatory control. This and the often-slow action of DMARDs mean that alternative strategies are necessary. Appropriate analgesia can have a positive effect on disease activity scores by reducing joint tenderness and improving patient-reported general health, but it is necessary not to mistake this for the suppression of the underlying disease.

Tricyclic antidepressants (TCAs such as amitriptyline, dothiepin and imipramine) inhibit serotonin and norepinephrine reuptake and neuronal sodium channels , but their non-serotoninergic properties account for differences in their individual antinociceptive effects. Clinical trials of the use of TCAs in RA patients have led to equivocal results: a Cochrane systematic review of eight RCTs comparing antidepressant therapy with placebo or an active intervention found insufficient evidence to recommend its use to treat RA-related pain , but the 3e recommendations include TCAs as a possible adjuvant treatment for patients with inflammatory arthritis , although it was specifically noted that this only applied to a subset of patients. Nevertheless, TCAs are significantly more pain relieving than placebo and it has been proposed that, like anticonvulsants, they can be considered ‘pain-modifying drugs’.

The current stratification of analgesic treatment is based on potency or sequential trials, beginning with the least expensive low-risk treatments; individual treatment failures suggest that patients may benefit more if stratified care is based on a combined evaluation of inflammation, joint damage and central sensitisation, and that the multidimensional nature of RA and most other chronic pain indications requires a combined approach to analgesia.

Non-pharmacological treatment of RA-related pain

Because chronic pain acceptance, coping skills and self-efficacy contribute to the quality of life of RA patients, psychological interventions such as cognitive behavioural therapy (CBT) may also help . A better understanding of pain mechanisms can limit catastrophic thoughts relating to pain, and combined psychological and pharmacological treatments can facilitate pain control. Cognitive therapy alone may be effective, and it does necessarily need to be combined with behavioural strategies . RA patients with moderately active disease and restricted joint erosions may benefit from aerobic exercises and dynamic strength training. Short-term, land-based aerobic exercise alone may improve aerobic capacity immediately after the intervention, but not muscle strength or functional ability, whereas combined short- and long-term, land-based aerobic and strength training may improve both. Exercise does not seem to increase pain or disease activity and, in addition to being safe, resistance exercise can lead to statistically significant and possibly clinically relevant improvements in most RA-related pain and disability outcomes .

Joint replacement

Joint replacement surgery can give substantial relief to patients with severe, unremitting pain localised to a single joint . The underlying reasons are still unknown, but they may include the physical protection of subchondral nerves or the prevention of synovitis originating in cartilage. However, although the routine use of total joint replacement surgery in clinical practice and the more recent development of biological therapies that suppress underlying inflammatory disease have improved the quality of life of large numbers of patients, both are associated with substantial health-care expenditure . Furthermore, 15% of the patients undergoing total knee replacement surgery continue to experience persistent and disabling pain, and up to 25% of those given anti-TNF agents because of presumed active RA actually receive no meaningful benefit .

In conclusion, both short- and long-term outcomes can be optimised by combining RA treatments targeting inflammatory mechanisms (which relieve pain by suppressing synovitis and may also reduce central sensitisation by modulating neuro-immune interactions in the CNS) with pharmacological and non-pharmacological therapies aimed at relieving RA-related pain.

Spondyloarthritis

The impact of CWP on the quality of life of AS patients can raise doubts at the time of diagnosis and when assessing responses to the treatments recommended by the evidence-based Assessment of Spondyloarthritis International Society (ASAS) and the EULAR: that is, NSAIDs because of the involvement of the spine, and classic DMARDs for peripheral manifestations. In the case of a lack of response to first-line therapy, patients are usually switched to an anti-TNF-α drug , but this can raise management difficulties because, as patients with a secondary pain syndrome complain of pain even when inflammation is effectively controlled, they may undergo unnecessary treatment changes or dose escalations.

It is known that NSAIDs alone have no effect on CWP due to central sensitisation, and they are therefore unlikely to be effective in AS patients with CWP. Various studies have demonstrated that anti-TNF agents act on the symptoms and signs of AS (including acute inflammatory pain), but no study has yet investigated their effects on CWP , the treatment of which is particularly challenging because its aetiology is still not clear and patients respond poorly to conventional treatments. Controlled studies have shown that tricyclic antidepressants such as amitriptyline; selective serotonin reuptake inhibitors such as fluoxetine; and dual serotonin and norepinephrine inhibitors such as venlafaxine, milnacipran and duloxetine may be useful in treating CWP in patients with FM, but only a small proportion respond to any of these treatments alone .

Summary

The complex and multifactorial phenomenon of pain is a major component of many rheumatological conditions, and the result of physiological interactions between the central and peripheral nervous system signalling: acute pain is often primarily attributable to nociceptive inputs such as inflammation and/or peripheral structural damage, whereas chronic pain (usually defined as lasting ≥3 months) is more likely to be due to inputs from the CNS. These many different aspects can make it difficult for rheumatologists and other clinicians to diagnose the type of pain correctly and treat it appropriately.

One still open question is the origin of CWP in patients with arthritis. It may or may not be due to a genetic and/or familial predisposition, psychological factors, inflammation or cytokines; to all of these; or to just one that reflects and affect the nociceptive system. The only thing that can be done at the moment is to continue to look for joint abnormalities and central processing alterations in order to discover which come first, and then develop the most appropriate means of treating (and even preventing) arthritis-related CWP.

Practice points

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