Chronic Pain in the Rheumatic Diseases
Dr. Khaled Sorour, MD
Pain is defined as an unpleasant sensory and emotional experience results from activation of sensory receptors (nociceptors) specialized to detect actual or impending tissue damage.Musculoskeletal diseases causing pain are common with prevalence 13.5% - 47% of the general population which represent a considerable burden to the individual and society. Rheumatic pain was previously categorized as nociceptive, on the ground that
the pain was related to inflammation, structural changes or reflecting tissue damage. Neurogenic pain was believed to be associated with specific nerve damage. Distinction between nociceptive and neurogenic pain , particularly in arthritic disease no longer exists with clear evidence of overlap .Development of chronic pain is a complex process, implying response of peripheral tissue damage and transduction of information in peripheral and central nervous system.
Inflammation activates the afferent neurons and the silent nociceptors start firing . This process is called peripheral sensitization . Inflammatory molecules eg PGE2, LTC4, TNF, IL6 and bradykinin produced at the local site , initiate a response in the first order somatosensory neuron which is relayed via the dorsal horn in the spinal cord to the brain .
This inflammatory environment lowers the firing threshold of high-threshold nociceptors to mechanical, thermal or chemical stimuli. Under normal circumstances joint structures are not sensitive to strong pressure. In contrast, diseased joints that have been primed by inflammatory molecules, develop sensitivity even to benign movements.
Pain often modifies the way the central nervous system works , so that a patient becomes more sensitive and gets more pain with less provocation . That is called “central sensitization”. Central pain can be due to neurotransmitters imbalance like norepinephrine, serotonin
,GABA (-aminobutyric acid) , substance P and nerve growth factor ( NGF) which regulates the expression of neuropeptides.Central pain is a widespread pain in different regions of the body as in fibromyalgia . Usually no structural abnormalities can be identified. The limbic system is a complex structure includes the hypothalamus, the hippocampus, the amygdala and the cingulate gyrus . It is responsible for emotional life, behavior and formation of long-term memories.
Pain experience can be enhanced or diminished by the emotional state, degree of anxiety, attention and distraction , past experiences and memories. Patients cope with pain in different ways with some demonstrating better coping skills whereas others tend to amplify severity of symptoms. Patients having central pain may complain of electrical sensations, burning pain , coldness, numbness or itching.
Descending pain modulatory system:
Centers in the midbrain and medulla containing high concentrations of cannabinoid and opioid receptors which have inhibitory effects . Opioid receptors and endogenous opioids
are involved in descending inhibitory modulation . Descending pathways inhibit pain transmission and utilising noradrenaline and serotonin as neurotransmitters.
Peripheral and central sensitization contributes to pain chronicity.Chronic pain in rheumatic diseases is a combination of pain arising from tissue destruction and is sustained by
activation of neurogenic mechanisms.
Pain assessment :
Pain is subjective and depends on emotion, cognition and behavior. Assessment of pain is required before the initiation of treatment to record efficacy of therapy.
management of chronic
Pain should be considered independent disease entity, carrying the same importance as the underlying rheumatic disease. First obtain a correct diagnosis; rheumatic diseases may be grouped into three broad categories of inflammatory, degenerative and soft tissue processes , there may be considerable overlap within an individual patient. In inflammatory arthritis, the first goal of treatment must be to control the disease , reduce the inflammatory activity and prevent chronic joint damage. DMARDs like MTX , sulfasalazine, leflunomide and biologicals reduce disease activity and maintain remission . Reduced disease activity is associated with reduced pain and improvement of function. Chronic pain is not a symptom in isolation , but co-associates with fatigue , sleep disturbance and mood changes including depression and anxiety. Fatigue is almost present in all patients with chronic pain . Some causes of fatigue may include inadequate control of the underlying systemic disease , adverse effects of medications including adjuvants or a symptom of depression. Sleep disturbance should not immediately be treated with the prescription of a sleeping pill , but rather explored regarding its specifics and underlying causes. The cause of sleep disturbance may be multifactorial due to inadequate pain control, presence of restless leg syndrome or due to the underlying depression. Depression and anxiety are commonly associated with all chronic pain and may aggravate pain and exacerbate a preexisting depressive condition.
Management of chronic rheumatic pain
Effective management of chronic rheumatic pain is not simply prescription of analgesic pills but depends on multimodal approach including nonpharmacological as well as pharmacological treatments . Should be the first step in management of chronic pain in rheumatic diseases. Drug treatment alone is not an ideal solution for pain care. Reassurance and simple explanation is required for all patients. Cognitive behavioral therapy , relaxation exercise and the use of different physical modalities have been shown to be useful and effects on both the physical and mental status in patients with chronic pain.
Treatment of pain has mostly focused on the use of analgesics and NSAIDs which are the most common pain relief medicine in the world.
Remains the most commonly used analgesic for the management of musculoskeletal pain .The mechanism of action through it’s effect on COX-1 and COX-2 enzymes in the brain . Peripheral inhibition of the enzymes is unlikely to result in clinical anti-inflammatory effect . The safety profile of the drug is below 2000 mg /day, but there is a risk of liver toxicity when higher doses are used for prolonged periods.
Traditional NSAIDs and COX-2 selective inhibitors have an important role in pain management .These agents have an adverse effects on the GIT, kidneys, liver and CV system . Their use is recommended to be at the lowest dose required and for the shortest period of time to reduce the side effect profile. Topical NSAIDs provide an alternativeto oral treatments for patients with musculoskeletal conditions.It has a strong potential for (temporally) decreasing peripheral nociceptive input. The effect of topical NSAIDs is of short duration only . Interventions like local corticosteroid injections into joints or soft tissues and surgical intervention with joint replacement for severe damage of hips and knees may be useful .
Pain modulators affecting
descending inhibitory pathways:
Defined as agents whose primary function is not pain relief, but have pain modulatory effects as an associated feature. Initially used in the management of neuropathic pain, they have been shown to have effect in fibromyalgia and other painful musculoskeletal conditions . The two drug classes that have been studied for analgesic effects are the anticonvulsants and antidepressants.
Pregabalin and gabapentin are the second anticonvulsant generation . They are better tolerated having a fewer adverse events compared with the first generation e.g. carbamazepine. Pregabalin and gabapentin have a similar site of action with a high-affinity binding site in brain membranes , with pregabalin showing more potency. They have good bioavailability and are excreted by the kidney with gabapentin dose 2400- 3600 mg/day while the he maximal dose of pregabalin is 600 mg/day.
Independent of their impact on mood , antidepressants affect pain within 2 weeks of treatment initiation . The major mechanism of action is to affect descending pain inhibitory pathways in the brain stem and spinal cord mediated by norepinephrine and serotonin . Their effect may include impact on opioid mechanisms. Tricyclic antidepressants have shown efficacy in the treatment of pain syndromes, especially fibromyalgia. They have multiple side effects including dry nose, blurry vision ,constipation , urinary retention, cognitive and/or memory impairment . Development of new antidepressants with less side effects e g the selective serotonin and norepinephrine reuptake inhibitors ( SNRI ) as duloxetine which was approved for treatment of fibromyalgia
Dopaminergic agents :
Recent insights have demonstrated a central role for dopaminergic neurotransmission in modulating pain perception within supraspinal regions including basalganglia, insula, anterior cingulate cortex and thalamus.Dopamine help in regulating emotions and movement. Decreased of dopamine level contributes to the painful symptoms that may occur in Parkinson's disease and also in painful conditions including burning mouth syndrome , fibromyalgia , allodynia and restless legs syndrome.
Opioid analgesics exert their effects by binding to opioid receptors in the brain , spinal cord & GIT. They offer the best analgesia for any pain, with limited use due to their side effects as well as concerns for long-term safety . Their use to ameliorate chronic rheumatic pain is still controversial . Endogenous opioids as dynorphins , endorphins enkephalins , endomorphins and nociceptin are released in response to pain , following exercise & mediate the placebo response.
Cannabinoid analgesics :
Cannabinoid receptors located throughout the body in the nervous system and in
peripheral sites including the skin , joint tissue and cartilage and are involved in a variety of physiological processes including appetite, mood and pain-sensation . Activation of cannabinoid receptors results in inhibition of pain. Drugs with cannabinoid modulating effects was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis and in 2007 for intractable cancer pain.
Remission of rheumatic diseases can be achieved with the use of DMARDs or biologics but treatment of pain still to be a challenge in every day practice . Pain should be considered independent disease entity, carrying the same importance as the underlying rheumatic disease. Optimal pain management for the rheumatic patient will be multimodal with incorporation of pharmacological and nonpharmacological and modalities . Rheumatic pain is no longer believed to be entirely dependent upon the inflammatory prostaglandin cascade , other drugs may offer an advantage. Activation of descending inhibitory mechanisms is believed to be the mechanism of action for pain relief for many drugs treatment.There has been recent interest in the use of antiparkinson drugs in the treatment of chronic pain particularly fibromyalgia