|Ahead of print publication
Management of pain in rheumatic diseases
Neha Goyal1, Mohit Goyal2, Vinod Ravindran3
1 Department of Anaesthesiology, Pain Clinic, American International Institute of Medical Sciences; CARE Pain and Arthritis Centre, Goyal Hospital, Udaipur, Rajasthan, India
2 CARE Pain and Arthritis Centre, Goyal Hospital; Department of Rheumatology, GBH American Hospital, Udaipur, Rajasthan, India
3 Centre for Rheumatology, Kozhikode, Kerala, India
CARE Pain and Arthritis Centre, Goyal Hospital, 328-A, Sector-5, Hiran Magri, Udaipur - 313 002, Rajasthan
Source of Support: None, Conflict of Interest: None
Pain is often the presenting symptom of many rheumatic diseases, the predominant disabling symptom, the reason for frequent visits to the physician and a major cause of medical absenteeism, loss of work hours, and financial burden on the society. Pain in rheumatic diseases is now understood to be a result of interplay of inflammation, tissue damage, and neurogenic responses. Besides control of inflammation, the structural changes, central sensitization, and the associated issues of disturbances of sleep, mood, and cognition also need to be addressed. Apart from the useful addition of neuromodulators to our traditional repertoire of pain medications consisting of analgesics, nonsteroidal anti-inflammatory drugs, steroids, and opioids, there is a place for interventions in situations where pain persists even after reasonable control of widespread inflammation. These interventions are mostly percutaneous and have found applications in inflammatory, structural, as well as neurogenic pain. Interventional spine procedures, platelet-rich plasma therapy, ozone therapy, and radiofrequency ablation of neural structures have added new dimensions to the management of pain.
Keywords: Interventional pain procedures, ozone therapy, platelet-rich plasma therapy, radiofrequency ablation, rheumatic pain, treatment
| Introduction|| |
Defined as a highly unpleasant sensation caused by an illness or an injury, pain has been recognized and designated by the Joint Commission on Accreditation of Healthcare Organizations as the fifth vital sign, which recommends that it be monitored with the same vigilance as blood pressure, pulse, temperature, and respiratory rate. Pain accompanying rheumatic and musculoskeletal conditions has come to be recognized as an illness entity on its own, thus it warrants management on a parallel with that of the underlying disease. Musculoskeletal pain associated with rheumatic diseases causes limitation of activity, fatigue, and disability leading to loss of work hours and increased medical absenteeism. Chronic pain can further lead to sleep and mood disturbances, depression, and anxiety. Pain is one of the most commonly reported complaints in patients with rheumatic diseases and is a major determinant of the patient global assessment. Studies have shown how most patients with arthritis perceive pain as the major predicament in their disease and alleviation of the same is the top priority for them, more so than any functional limitation. Chronic pain may persist in even those who have achieved adequate control of their underlying disease, and this may result in artificially inflated disease activity scores.
| Mechanism of Pain in Rheumatologic Conditions|| |
Pain in inflammatory arthritis
Pain in inflammatory arthritis has long been considered to be nociceptive, resulting from peripheral inflammation and mechanical damage (articular and peri-articular). With advancement in understanding of the disease mechanisms, role of neurogenic mechanisms and changes in the processing of signals by the central nervous system have come to be recognized. Mechanisms driving central sensitization might include inflammation, both local within the joint, and through systemic circulation of cytokines and other neuromodulatory factors. Apart from the commonly recognized inflammatory molecules targeted by steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs), norepinephrine, serotonin, endogenous opioids, and cannabinoids have roles in a complex interplay resulting in pain. In arthritides, inflammatory molecules initiate the first-order somatosensory neurons, thus triggering the pain cascade. Earlier thought to be just a continuous signal being relayed to the somatosensory cortex, pain in inflammatory arthritis (IA) is more complex with modulations in the thalamus and other higher centers., Seemingly benign movements to which joint structures are not sensitive under normal circumstances, cause pain in chronically diseased joints. There is a perceivable low pain threshold mediated by neurogenic inflammation. Opioids which can modulate presynaptic and postsynaptic nerve endings and receptor blockers at noradrenergic and muscarinic sites affect the excitability of neurons in chronic pain, thus making it a greater management challenge than acute pain.
Understanding the characteristics of pain, and its underlying mechanisms, is essential in deciding the most appropriate treatment. Escalation of disease-modifying antirheumatic drugs (DMARDs) for pain in patients in whom pain is predominantly structural is likely to be ineffective and exposes them to unwarranted adverse events from treatment. Animal models have shown that pain in rheumatoid arthritis (RA) substantially improves following intraarticular ozone (O3). O3 administration can effectively suppress the pain cascade by reducing the oxidative stress that is a part of the degenerative process. Significant relief in pain motivates patient for physical activity and muscle strengthening exercises, thereby improving the quality of life.
Despite good disease control with conventional synthetic DMARDs and biological DMARDs (bDMARDs), many patients with IA continue to experience musculoskeletal pain. Evidence from randomized controlled trials suggests that complete alleviation of pain is the most uncommonly achieved outcome after treatment with bDMARDs even in cases where adequate control of disease activity has been achieved.
Pain in connective tissue disorders
Apart from the synovitis, pain occurs as a result of ischemia in Raynaud's phenomenon and digital ulcers in systemic sclerosis and other connective tissue disorders. Where pain persists after therapy with iloprost, phosphodiesterase inhibitors, calcium channel blockers, and endothelin receptor antagonists, injection of botulinum toxin and digital sympathectomy may be undertaken. These procedures may help delay amputations. Ulcers and other gastrointestinal symptoms also contribute to pain in systemic sclerosis.
Low back pain
Low back pain (LBP) is an extremely common problem that most people experience at some point in their lives and has a lifetime prevalence of over 70% in most industrialized countries. It has been cited as the third most frequent reason for a surgical procedure. The socioeconomic impact of chronic LBP (cLBP) is huge. The prevalence is high, but ironically, a minority of patients with cLBP and the consequent disability account for the majority of the economic burden. Degenerative conditions of spine, like lumbar disc degeneration, disc herniation, and facet joint osteoarthritis (OA) are major causes of mechanical back pain. Spondyloarthritis (SpA) an often under-recognized cause of LBP among nonrheumatologists is an important cause of inflammatory LBP. Interventional procedures can be put to use in mechanical LBP as well as where there are structural changes in rheumatic disease. Other rheumatic conditions associated with back pain are fibromyalgia and DISH syndrome.
Pain in osteoarthritis
OA is the most common of the musculoskeletal diseases and knee is the most commonly involved anatomical site. Along with nociceptive pain due to joint damage, there is peripheral and central sensitization in OA. The structurally damaged and inflamed articular and peri-articular structures relay a continuous and intense nociceptive sensation leading to profound neurochemical and metabolic changes and a neurologic reorganization within the segments of the spinal cord. The resultant excitability of the neurons of the dorsal horns heightens the pain sensitivity in a segmental distribution. The combination of these central and peripheral mechanisms of sensitization leads to hyperresponsive neural structures which then start responding to weaker stimuli that would not be enough to generate a response under normal circumstances. This results in hyperalgesia and allodynia in patients with OA. Once this complex interplay of mechanisms starts, the treatment approach should be to also target central nervous system structures by neuromodulators rather than unjust use of anti-inflammatory agents alone.
Pain in fibromyalgia
Possible mechanisms involved in the etiology and pathogenesis of fibromyalgia are dysfunction of the autonomic and central nervous systems and also abnormalities in genetic and environmental factors. Central pain phenotype includes female sex, strong family history of chronic pain, history of mood disturbances, sleep disturbances, history of adverse psychosocial events, and a low threshold for pain. There is upregulation of N-methyl D-aspartate (NMDA) receptors at the dorsal horn synapses resulting in enhanced signaling of pain. Nonpharmacological therapies that reduce stress like cognitive behavior therapy and exercises have a very important role in management of fibromyalgia. Pharmacotherapy includes antiepileptic and antidepressant group of drugs. Drugs such as pregabalin and gabapentin are effective in its management as they reduce the magnitude of the enhanced proprioception process. Serotonin-norepinephrine reuptake inhibitors like duloxetine are also effective.
| Clinical Assessment of Pain|| |
A thorough clinical assessment for pain should be able to answer the pain's location, severity, radiation, quality or nature, response to NSAIDs, aggravating and relieving factors, absence or presence of stiffness, and impact of pain on patient's quality of life. We should remember that pain is a subjective symptom and its assessment should be individualized for every patient as pain perception is influenced by genetic background, psychosocial factors, and previous experiences of pain in life. The various scales to assess severity of pain are given in [Table 1].,,
Ideal treatment of pain associated with rheumatic diseases should be through a multimodal approach, involving pharmacologic and nonpharmacological therapies while taking psychosocial factors into account.
| Management of Pain|| |
Nonpharmacological therapy for pain
Patients with chronic pain present with psychological disorders such as depressed mood and cognitive impairment. Psychological interventions such as cognitive behavioral approaches which include relaxation techniques such as deep breathing, homework assignment, positive affirmation, and biofeedback help patient to cope up with pain. Reassurance, simple explanation, alleviating fear, and encouraging the use of self-help improve the patient's quality of life.
There is disruption of occupational performance in chronic pain patients due to psychosocial factors and loss of independent lifestyle. With the help of occupational therapy, patients learn to manage their routine activities and lead an active and productive life. Developing a lifestyle which includes adequate rest, exercise, healthy nutrition, and positive attitude is always helpful.
Physical activity in any form is vital for global health in all patients with musculoskeletal pain. Exercise not only helps maintain muscle tone and improve function but also induces the production of endogenous opioids, endorphins, and other natural painkillers. Muscle strengthening exercises improve support of musculature around the joint which leads to decreased stiffness. Physical therapies with heat or cold can reinforce therapeutic effects.
Transcutaneous electrical nerve stimulation may be done by a very low voltage electric current delivered through a small battery operated device. With electrodes placed on the skin near the source of pain, the electric current stimulates the nerves and disrupts the pain perception. It has been found to have good efficacy in pain of arthritis, herniated disc, spinal stenosis, back injuries, and fibromyalgia.
An integrated approach to pain management requires the participation of a variety of allied health professionals who work as a team with the physician to facilitate behavioral and cognitive approaches. The various members that need to form a cohesive team with the treating physician may include a physical therapist, an occupational therapist, a psychologist and/or psychiatrist, a nutritionist/dietician, and a social worker.
Pharmacologic options in the management of pain
A stratified or step-by-step approach is to be adopted when caring for a patient with pain. A three-step analgesic ladder was proposed by the WHO in 1990, which was later expanded to a four-step ladder to include interventions as shown in [Figure 1]. The ladder has been used to guide the management of musculoskeletal pain and may be employed in structural component of the pain in rheumatic diseases.
All structural pain may not respond to NSAIDs. Medication should be tailored specifically for each patient depending on the severity of pain. The various groups of medications used to treat pain in clinical practice are given in [Table 2].
Interventional approaches for management of pain
The various interventional modalities, which usually are percutaneous techniques have a place right in the middle of conservative care with pain-relieving medications, exercise, and physical therapy on one side and major surgeries on the other. When carried out by skilled physicians with due precautions, they are safe and carry very low risk for the patient. Some common interventional procedures of use in rheumatic conditions are listed in [Table 3].
|Table 3: Interventional procedures and novel measures for pain in rheumatic diseases|
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O3 has had various applications in medicine due to its anti-inflammatory and antioxidant properties. Medical O3 is a mixture of oxygen (O2) and O3 in appropriate proportion. It is used for O3 nucleolysis in herniated lumbar disc causing LBP with or without radiculopathy. O3 nucleolysis causes desiccation of nucleus pulposus, thereby reducing the disc volume and relieving the pressure on nerve roots. It also relieves pressure on nerves by reducing venous stasis and improving microcirculation of neurons and also by reducing the level of inflammatory cytokines.
For the same antioxidant and anti-inflammatory properties, O3 has also been used to relieve pain in OA of knees. Nonhuman studies have also shown the downregulating effects of intraarticular O3 injection on tumor necrosis factor-α.
A safe and sterile mixture of O3 and O2 is prepared in a medical O3 generator by passing the O2 through a crystal glass electrode. O3 concentration can be controlled by regulating the power of the piezoelectric cell in the generator or by adjusting the O2 flow rate. O3 concentration up to 40 mcg/ml of O2 is safe. Recommended dose in knee OA is 25–30 mcg/ml. Although of benefit in all stages of OA, O3 therapy is particulary useful in patients with Grade 2 and 3 OA (Kellgren and Lawrence classification). It can also be done as a palliative or pain relieving procedure in patients with grade 4 OA who are unfit or unwilling to undergo joint replacement or wish to defer it for some time. O3 can be safely injected by blind technique (although use of fluoroscopy or ultrasound guidance improve accuracy, especially in patients with severe loss of joint space or deformed joints). Standard aseptic precautions are taken and the procedure is preferably performed in a surgical theater or a dedicated procedure room considering the slightly longer time duration of procedure compared to intraarticular steroid or hyaluronate injections. Intraarticular O3 injection is a safe procedure lasting 20–30 minutes and does not routinely require the patient to be admitted. Muscle strengthening exercises are advised after a relative rest of 2–3 days.
Platelet-rich plasma therapy
Platelet-rich plasma (PRP) therapy is an autologous therapy. This fraction of plasma on account of a high platelet count is rich in cytokines and growth factors such as platelet-derived growth factor, insulin-like growth factor, vascular endothelial growth factor, platelet-derived angiogenic factor, and transforming growth factor beta which aid in the regeneration of damaged cartilage, tendons, and ligaments and promote soft-tissue healing. PRP is prepared by centrifuging the patient's blood twice. The first centrifugation results in separation of the red blood cells from the plasma. The second centrifugation or commonly called “concentration” separates the plasma into platelet poor and platelet-rich fractions. This PRP is injected at the desired site.
PRP therapy is useful in knee OA where some cartilage is still preserved, that is, up to Grade 3 disease. It is less effective when cartilage is extensively damaged. The procedure is usually repeated three times with each sitting roughly a week apart. PRP is also useful in tears of the rotator cuff, supraspinatus and lateral and medial epicondylitis, Achilles tendinopathy, and plantar fasciitis. PRP therapy is useful in tendon and ligament damage sustained in sports injuries or other accidents. It promotes regeneration and healing and is particularly effective in noncomplete tears of tendons and ligaments where some substrate is still left for the growth factors to work upon. A list of applications of PRP in management of pain is given in [Table 4]. Ultrasonography guidance improves accuracy, especially when injecting at smaller sites as in rotator cuff tears, Tennis elbow, or Golfer's elbow. Fluoroscopic or ultrasound guidance may be used when injecting into the knee so as to deposit maximum PRP at the site of maximum damage. Standard aseptic precautions are taken while performing PRP therapy. NSAIDs are to be avoided for a week after the therapy so as to not affect therapeutic function of platelets. As PRP promotes natural process of healing and is autologous so does not have any adverse effects. It is performed as a day-care procedure.
Radiofrequency ablation of genicular nerve
Genicular nerve RF is a minimally invasive procedure for patients with chronic knee pain due to OA, especially those with Grade 3 and Grade 4 OA. Knee joint is innervated by branches from femoral, saphenous, tibial, obturator, and common peroneal and sciatic nerves. Superior medial, superior lateral, and inferomedial branches are targeted while inferolateral is left to avoid injury to the common peroneal nerve.
Standard aseptic measures are taken and under fluoroscopic guidance, 10-cm 22G RF needles (with 10 mm active tip) are positioned at superomedial, superolateral, and inferomedial periosteal areas connecting the femur and tibia shaft to their respective epicondyles. Sensory stimulation of 0.15 v is given at 50 Hz to further confirm the RF needle position. After confirming the absence of motor stimulation, a 2 Hz radiofrequency is given at 60° C for 90–120 s. Genicular nerve RF ablation is helpful for patients with advanced knee OA who are not able to undergo knee replacement due to some comorbidities or other reasons. A diagnostic genicular nerve block may be performed with 1 ml of local anesthetic injected at each branch before radiofrequency ablation.
Fluoroscopy-guided spine procedures
Spine involvement is frequently seen in rheumatic conditions. It is important to identify the pain generating structure before deciding on the specific intervention. The so-called “pain generators” in the spine are given in [Table 5].
The various fluoroscopy-guided interventions are discussed below. In each of these procedures, standard aseptic measures are observed and skin and soft tissues are infiltrated with local anesthetic after the patient is in the desired position.
Facet joint injection
Facet joints or zygapophyseal joints can be the source of pain like any other synovial joint. Arthritis of facet joints is characterized by joint effusion, synovitis, erosions, and bone marrow edema. These findings can be detected on magnetic resonance imaging and are best seen in axial scans. Facetogenic back pain is paramedian in location and a tenderness can be elicited on palpation. This pain may radiate to hips and thighs but does not travel beyond as can happen in lumbar radiculopathy. Extension of back (e.g., getting up or standing from sitting position) aggravates facetogenic pain. Intraarticular facet joint injection with corticosteroid can be helpful. It is administered with fluoroscopic guidance under local anesthesia and standard aseptic precautions are observed. Position of the spinal needle is confirmed by injecting a small amount of radiopaque dye such as iohexol, and then the corticosteroid is injected. Sometimes, it may be possible to aspirate some of the excessive fluid collected in the facet joints.
Medial branch radiofrequency ablation
Nerve supply of facet joints is from the medial branch of the posterior primary ramus. Medial branch neurotomy is done to relieve recurrent back pain secondary to facet joint involvement. With patient in prone position and image intensifier positioned to obtain an anteroposterior view, target point is the junction of the transverse process with the base of superior articular process at desired level of vertebra. Nerve supply of facet joints is from the medial branch of dorsal rami of the corresponding level and one vertebral level above. For example, if L4-L5 facet joint is involved, then RF ablation is done at L4 and L3. RF needle is positioned under fluoroscopic guidance and a tunnel view is obtained. Sensory stimulation is done at 50 Hz to further confirm the needle position. Motor stimulation at 2 Hz is done to avoid injury to nerve fibers of ventral rami. Two cycles of RF are performed at 70°–90° C for 60 s. Before going for medial branch RF ablation, diagnostic medial branch block with 0.5 ml of 0.5% bupivacaine or 0.5 ml of 1%–2% lignocaine is performed to confirm the pain generating structure. If patient experiences more than 50% relief in pain, the source of pain is confirmed and efficacy of medial branch RF can be positively predicted.
Cervical epidural steroid injection
Cervical spine involvement is seen in rheumatoid arthritis and SpA. Facet joint involvement is a common cause of neck pain. Inflammation at the facet joints may result in erosions and with disease progression there may be new bone formation and ankylosis. Interventional therapies includes selective facet joint injection, medial branch RF, and cervical epidural steroid injection under fluoroscopic guidance. Epidural injection is particularly effective when radicular pain accompanies.
Transforaminal epidural steroid injection
Radicular pain is a common finding in degenerative conditions of the spine such as disc herniation causing compression over nerve root leading to radiation of pain in the involved dermatomal segment. Radicular pain is also a contributing factor in neck and back pain in rheumatoid arthritis and spondyloarthropathies. Osteophytes and bone fragments can lead to foraminal narrowing and nerve root compression in both the cervical and lumbar spine. Where pharmacotherapy fails or is unable to provide adequate relief, spinal interventions have an important role. LBP with radicular hip, thigh, and leg pain can be treated by transforaminal epidural steroid injection under fluoroscopic guidance.
With patient in prone position, image intensifier is positioned in anteroposterior view to identify the involved vertebral level. In oblique position of fluoroscope, Scottie dog view of the vertebra is obtained and a 22G 10-cm spinal needle with a bent tip is inserted. Position of needle is confirmed by injecting small amount of radiopaque dye and observing the dye spread along the foramen. Local anesthetic and steroid are injected through the spinal needle. This targeted approach delivers steroid in adequate concentration near the compressed nerve root and reduces inflammation leading to decompression of root.
Stellate ganglion block
It is indicated in sympathetically mediated pain of complex regional pain syndrome (CRPS) type 1 of the upper limb. Stellate ganglion block can be done under ultrasound guidance, computed tomography guidance as well as under fluoroscopic guidance. Patient is given supine position and fluoroscope is positioned in anteroposterior view. A 22G 10-cm spinal needle is targeted at the junction of transverse process of C7 vertebra and vertebral body. Position of needle is further confirmed by injecting 0.5 ml of contrast dye and visualizing the spread. Once the needle position is confirmed, 5–10 ml of 0.25% of bupivacaine is injected through the spinal needle. Effect of block is confirmed by increase in limb temperature and onset of Horner's syndrome. During the procedure, electrocardiogram and O2 saturation are monitored.
Lumbar sympathetic block
It is indicated in sympathetically mediated pain in CRPS of lower limbs. Patient is placed in prone position and image intensifier positioned to identify spinous process of L3 vertebra. A 15-cm 22G spinal needle is inserted 7–10 cm lateral to spinous process and directed to anterolateral edge of the vertebra. Position of needle is visualized both in anteroposterior as well as in lateral fluoroscopic view. Dye and lignocaine are then injected as in stellate ganglion block. If patient experiences <50% relief, sympathetic origin of pain is confirmed. In the next sitting, the final procedure of chemical neurolysis is done with alcohol (50%) or phenol (6%–8%). Increase in temperature of the limb on the involved side indicates success of the intervention. Apart from alcohol or phenol, neurolysis can also be done with radiofrequency technique. Vitals should be monitored as in any spinal procedure.
Sacroiliac joint injection
The sacroiliac joint may be injected when it is the focus of pain and disease is not very active at other sites. Corticosteroid injection reduces inflammation of the joint in SpA and fluoroscopy guidance improves accuracy. Radiofrequency ablation may be undertaken when the pain load is due to structural changes.
In fibromyalgia resistant to nonpharmacological measures and oral medications where severe pain is persisting, ketamine infusion can be administered in subanaesthetic doses. Ketamine is a phencyclidine derivative and it produces strong analgesia by blocking NMDA receptors, therefore, affecting central sensitization. Infusion is started at a low dose of 0.5 mg/kg/day and completed over 4–5 h. It may be repeated for 4–14 days until good analgesia is achieved. Antiemetics and low-dose benzodiazepines may be coadministered to prevent side effects. Starting with low dose of infusion on the 1st day and slow escalation increase chances of tolerability. If benefits of ketamine outweigh side effects, it can be administered in a specific subgroup of patients with fibromyalgia with disabling pain, resistant to other measures.
Trigger point injections
Trigger points are palpable taut bands of the skeletal muscle fibers found in myofascial pain syndrome. Noninvasive treatment of trigger points is done by local analgesic spray, massage, stretching, and transcutaneous electrical stimulation. For symptomatic relief in pain, trigger points can be modulated by dry needling and injection of local anesthetic or corticosteroid or botulinum toxin-A.
| Conclusion|| |
Pain is an important feature and a major determinant of morbidity in various rheumatic diseases. Apart from nociceptive pain arising from inflammation and structural damage, there can be a neurological component as well to pain in inflammatory arthritis. Therefore, it is important to identify the underlying cause and the precise mechanism of pain in a particular patient for choosing the right modality of management. After conventional nonpharmacological and pharmacological measures, and before major surgical procedures, interventional pain management techniques hold an important place in management of pain. These procedures which are mostly percutaneous are reasonably safe and highly efficacious.
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Conflicts of interest
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]