Amir Minerbi1 & Mary-Ann Fitzcharles2,3 1 Institute for Pain Medicine, Rambam Health Campus, Haifa, Israel 2 Division of Rheumatology, McGill University Health Centre, Montréal, Québec, Canada 3 Alan Edwards Pain Management Unit, McGill University Health Center, Montréal, Québec, Canada Rheumatic diseases include inflammatory arthritis (IA). of which rheumatoid arthritis (RA) is the most common, as well as degenerative arthritis including peripheral and spinal osteoarthritis (OA) and the spectrum of soft tissue rheumatic complaints of tendonitis and bursitis [1]. Pain associated with rheumatic diseases typically arises from non‐infectious inflammation of joints and/or soft tissues, from degenerative pathologies of joints and from sensitization of nociceptive pathways leading to nociplastic pain. Fibromyalgia (FM), previously considered to be a rheumatic disease involving soft tissues, is now considered a nociplastic disorder, as evidence points to dysregulation of pain‐processing mechanisms as its main pathophysiologic mechanism [2–4]. The most common presenting symptom of each of these conditions is pain. Rheumatic conditions are threefold more common today than 40 years ago, with a further future expected increase due to the prevalence of OA as populations age [5]. Some form of arthritis currently affects at least 50% of individuals over the age of 65 years, with doctor‐diagnosed arthritis present in more than 21% of adults at any one time. Rheumatic pain, among the most prevalent pain syndromes worldwide, is the leading cause of disability in the USA, and will be experienced by almost all persons at some time during their lifetime [6]. While rheumatic diseases are a prevalent cause of chronic pain, pain is the most common symptom in rheumatic diseases [7–10], and its alleviation is considered by patients as a primary treatment priority (11). The Pain Management Task Force of the American College of Rheumatology has acknowledged pain management as a critical aspect of the medical management of patients with rheumatic diseases [9]. As there is no imminent cure for either IA or OA, the pain associated with these conditions will continue to require attention. As with other painful conditions, rheumatic pain has important negative consequences to overall health with impaired quality of life and poor functional outcome. Therefore, healthcare professionals should be sensitive to the complaint of pain in patients with arthritis and soft tissue rheumatism and should assess and treat pain in parallel with management of the underlying disease. Rheumatic pain has previously been categorized as predominantly nociceptive, arising from activation of nociceptors at peripheral sites of tissue damage or inflammation. A primary inflammatory process initiates the pain message, which is conducted via first order sensory neurons through relays in the dorsal horn to the somatosensory cortex. However, in recent years there is growing appreciation of the pertinence of other pain mechanisms, which have been implicated in the pathophysiology of pain in rheumatic diseases. In the context of a purely nociceptive pathogenesis, treatments were previously focused on use of anti‐inflammatory drugs and simple analgesics. Now, as the involvement of more pain mechanisms in rheumatic pain is recognized, a wider choice of treatment modalities is available and can be tailored to the needs of the individual patient. With the exception of healthy cartilage, all joint structures are richly innervated with sensory neurons, which can mediate the pain response [17]. Under normal circumstances, the structures of the joint are not sensitive to strong pressure or even vigorous movement. In contrast, diseased joints that have been primed by inflammatory molecules, develop sensitivity to seemingly benign movements and have a low threshold of activation to noxious stimuli. Pathogenic mechanisms in IA and OA show considerable similarities with both demonstrating variable degrees of inflammation and structural tissue damage. IA has a more pronounced inflammatory phase than OA, with synovial infiltration of immune cells, leading to invasion of ligaments, cartilage and bone. Structural changes occur in both with time, with radiographic erosions present in IA and subchondral sclerosis and osteophyte formation in OA. Changes in juxta‐articular bone, bone marrow edema and bone marrow vascular stasis all play a part in pain generation [18]. Ongoing inflammatory as well as degenerative articular processes sensitize the peripheral and central nervous systems, leading to decreased pain thresholds, increased nociceptor receptive fields and altered pain‐modulation activity [19]. Extra‐articular soft tissues such as muscles, fascia and ligaments are prone to chronic pain in inflammatory and degenerative rheumatic diseases. Soft‐tissue pain is not only common but also an important contributor to the symptomatic burden in rheumatic diseases [16]. The major stimulus initiating pain in an active inflammatory process is the outpouring of inflammatory molecules at the local tissue site [19, 20]. This occurs to a lesser degree in OA. This neuroactive and inflammatory milieu lowers the firing threshold of high threshold nociceptors to mechanical, thermal or chemical stimuli and a cycle of pain is set in motion. The success of the numerous NSAIDs can be attributed to the importance of inflammatory mechanisms in rheumatic pain. In contrast, chronic pain resulting from tissue destruction and mechanical changes to cartilage, bone and soft tissues is mostly sustained by activation of neurogenic mechanisms. Peripheral and central sensitization contribute to the chronicity of pain [21]. Afferent neuronal pathways are in turn influenced by descending neuron projections, synapsing in the laminae of the dorsal horns, with messages mediated by molecules such as serotonin, norepinephrine, endogenous opioids and cannabinoids. For these reasons, the management of chronic pain is more challenging and often less successful than that of acute pain. Furthermore, chronic pain differs from acute pain not only in the underlying pathophysiologic processes, but also in the psycho‐social burden that it imposes on the lives of affected individuals [8, 22]. A specific diagnosis is the first step to effective management, as early disease‐modifying treatment may have important prognostic value in certain inflammatory diseases [23, 24]. IA encompasses a wide spectrum of connective tissue diseases occurring mainly in the middle years of life. Although RA is the most readily recognized IA, other conditions of equal importance are seronegative arthritis, with a negative rheumatoid factor, including psoriatic arthritis, inflammatory spondyloarthritis and reactive arthritis. There is also an array of immunological diseases that have an arthritis component, such as systemic lupus erythematosus, scleroderma, Sjogren’s syndrome and others. Crystal‐induced inflammation due to gout or pseudogout, a cause of acute joint inflammation, is seen in the older population and presents with acute pain and swelling localized to one or a few joint or tendon sites (Table 31.1). Table 31.1 Classification of rheumatic painful conditions. Next, the mechanisms underlying the patient’s pain should be identified. Active inflammation can be inferred based on the history, physical examination, laboratory tests and imaging [24]. Similarly, degenerative, nociplastic, neuropathic and myofascial components should be identified. The level of disability is gauged, as well as potential psycho‐social factors that may play a role in the burden of symptoms. In the setting of continued pain there is often an associated sleep disturbance, fatigue and mood disorder, all well described components of FM [3], which must be addressed. The first goal of treatment for IA must be to control the disease process, reduce the inflammatory activity and prevent chronic joint damage. This is usually achieved to a moderate degree with the use of disease‐modifying agents (DMARDs) which may be synthetic such as methotrexate, hydroxychloroquine and others or a biologic such as the tumor necrosis factor targeted molecules and others [24]. Failure to address the global disease will result in continued symptoms, even with the best attention to pain. In contrast, there is no DMARD available for treatment of OA, which is therefore treated symptomatically (25). Musculoskeletal pain is described as dull and aching, interfering with daily function and sleep, but seldom extreme, except for severe inflammation of infection or crystal arthritis. Inflammatory pain generally improves with gentle exercise and is aggravated by immobility. Morning stiffness lasting for over an hour is common. OA pain can be associated with stiffness, but usually lasting minutes rather than hours. Rheumatic pain can vary considerably from day to day and can also be influenced by various environmental factors. One example is the effect of weather on rheumatic pain, which is a matter of ongoing controversy. Weather‐related changes are more prevalent in women than in men, are not well understood and apply to temperature, barometric pressure and precipitation changes [26, 27]. Intrinsic factors, such as mood, sleep and physical activity also have an important role in pain variability. Pain management must be tailored to the individual patient, taking into account age, comorbidity, specific rheumatic process, involved pain mechanisms and personal beliefs of the patient. Pain control for one individual may be facilitated by reduction of anxiety, whereas for another it may be simply the advice to use an assistive device such as a cane or supportive pillow. Not every pain requires treatment with a pill and patients should be informed that most pain‐relieving drug treatments offer only a modest effect for some patients, with adverse effects often outweighing the beneficial effects [28]. Any pain management strategy must begin with non‐pharmacologic management. Patients should be encouraged to develop an internal locus of control and become active participants in their healthcare. There should be emphasis on the importance of good lifestyle practices that include sufficient health‐related physical activity, good eating habits and weight control and attention to sufficient sleep. Mood disorders should be addressed as persistent poor mood will be a barrier to effective care. Realistic treatment goals should be identified with the objective to reduce the pain as well as to improve function. Treatment modalities include lifestyle and self‐help interventions, physical measures, pharmaceutical measures and psycho‐social interventions. An effective treatment plan typically includes more than one modality [28]. Accompanying symptoms of sleep disturbance, mood disorder and fatigue need also to be addressed. The efficacy of any treatment should be carefully balanced with treatment‐related side effects and the need for continued treatment must be carefully evaluated. Treatment of pain should also occur in parallel with the best management of the underlying rheumatologic process. Exercise is considered one of the most effective, low‐cost and safe interventions for both IA and OA. Physical activity has been shown to improve pain, function and quality of life of affected individuals [29]. In addition, the direct anti‐inflammatory effect of physical exercise, putatively mediated by the secretion of anti‐inflammatory myokines from skeletal muscles, is thought to attenuate the elevated cardiovascular risk associated with IA [30]. Benefits of physical activity include stimulation of reparative processes in cartilage, maintenance of muscle tone and activation of the natural descending inhibitory pain pathway, via release of endogenous opioids and activation of (supra)spinal nociceptive inhibitory mechanisms orchestrated by the brain [31]. Recent research has, however, shown dysfunction of this endogenous analgesic response to exercise in some patients with chronic pain (i.e.with FM) with a report that exercise induces more pain. Therefore, exercise therapy should be tailored to the specific patient needs, with care to avoiding flares of pain. Exercise should be part of a normal healthy lifestyle routine, appropriate for the patient’s age and physical condition and enjoyable to encourage adherence. Both traditional exercise modalities, such as strengthening, aerobics and flexibility and non‐traditional modalities including Tai‐Chi, yoga and aquatic training, have been shown to be effective, whether supervised, semi‐supervised or unsupervised [32]. Tai chi or a water exercise program are acceptable forms of exercise for many patients. Some people may prefer the slightly more active program of yoga or a low impact exercise program. Exercise combined with weight reduction improves symptoms of arthritic pain in the lower limbs, with one unit of body weight translated into a 4‐unit load through the knee joints with every step taken. A frequent question by patients with rheumatic pain is whether dietary manipulation could have impact on their pain. This has been the subject of debate for decades [33]. In recent years, there is growing appreciation of the role of the gut microbiome in the development and severity of certain rheumatic diseases including RA [34], spondyloarthropathies [35] and OA [36]. The composition and function of the gut microbiome is readily affected by dietary intake, rendering dietary interventions biologically plausible [37]. Mediterranean diet and fish‐oil‐rich diets have been shown to improve symptomatic burden in patients with RA, although the level of evidence remains limited [38
Chapter 31
Clinical pain management in the rheumatic diseases
Introduction
Basic mechanisms in rheumatic pain
Anatomic considerations
The active inflammatory setting
The chronic rheumatic process
Clinical practice
Inflammatory arthritis
Rheumatoid arthritis
Seronegative arthritis: psoriatic arthritis, inflammatory spondyloarthritis, reactive arthritis, other connective tissue diseases
Crystal‐related arthritis: gout, pseudogout
Infectious arthritis
Osteoarthritis
Peripheral osteoarthritis: small joints hands, large joints (mostly weight‐bearing)
Spinal osteoarthritis
Soft tissue rheumatism
Tendonitis, bursitis
Treatment
1. Lifestyle and self‐help measures
Exercise
Diet
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