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- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
Osteoarthritis (OA) is the most common form of arthritis, and is a major cause of pain and disability in the elderly (1), affecting millions of people in the US (2, 3). OA is the fourth most frequently predicted cause of health problems worldwide in women (4). However, because OA has no cure, therapeutic goals are focused on maximizing function and quality of life while controlling pain and minimizing the potentially harmful side effects of medications and therapies (2, 3). Contemporary pain management has shifted from symptom control to management based on the pathophysiologic mechanisms of pain (5). Control of pain in patients with OA remains challenging, and patients with severe OA of the knee who have failed to respond to an extended course of conservative therapeutic modalities are usually scheduled for total knee replacement (1–3).
We are now beginning to have a better understanding of the concepts of peripheral and central sensitization as they relate to knee OA pain (1). Recently, it has been recognized that constant and intense nociceptive sensory information, generated by painful and inflamed deep somatic structures, produces significant neurochemical and metabolic changes, as well as neurologic reorganization within spinal cord segments (6, 7). These changes include an increased excitability of dorsal horn neurons, which in turn produces pain hypersensitivity in a segmental distribution (6). This increased excitability is also known as central sensitization, and both it and peripheral sensitization cause neurons to respond to stimuli in a more intense fashion or to stimuli that they would not normally respond to (5).
Diagnosis of peripheral and central sensitization is very important because spinal cord neurons that normally would only be activated by noxious stimuli can then be activated by normally or typically non-noxious stimuli (allodynia) (8). Together, these neurochemic changes suggest that pain induces, and is partially maintained by, central sensitization (9). Once these complex mechanisms are present, the rationale for treatment approaches should also target central nervous system structures rather than using antiinflammatory agents alone. In fact, it has been speculated that changes in the central nervous system associated with chronic pain might promote peripheral inflammation (10). Importantly, central sensitization may possibly not be attenuated by reversing inflammation in the peripheral tissue (7), and, therefore, refractory pain may persist even after a total knee replacement. Finally, plastic changes in the spinal cord might induce changes in other central structures, such as the limbic and somatosensory cortex, and this may play an important role in the maintenance of chronic pain (11, 12).
Several studies have already investigated the involvement of central pain modulation in OA (1, 13–16). Bajaj et al described deep hyperalgesia in the tibialis anterior muscle of patients with knee OA (13). Creamer et al demonstrated that the injection of local anesthetic in one knee was followed by pain relief in the contralateral noninjected knee (14). Both studies (13, 14) suggested the possible role of the nervous system in the maintenance of chronic pain in patients with knee OA. Assuming that the spinal nerves might be sensitized, we predicted that the dermatomes, myotomes, and sclerotomes innervated by the sensitized spinal nerve would exhibit areas of hyperalgesia. In order to further investigate the phenomenon in the clinical setting, we performed a cross-sectional study assessing superficial and deep hyperalgesia in patients undergoing total knee replacement due to refractory pain associated with OA, and compared them with healthy controls.
Our goal was to evaluate the presence of nervous system sensitization in these subjects. We hypothesized that nervous system hyperalgesia evaluated by decreased pain threshold to pressure both in superficial and deep structures may be a possible cause of pain in this population, and could be correlated with reduction of functional capacity and quality of life in patients with knee OA.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
Similar to the results observed in our pilot study (27), this study demonstrated that patients with moderate to severe persistent knee pain and disability, which was not relieved by an extended course of nonsurgical treatment, and therefore scheduled for a total knee replacement, had significantly lower pressure pain thresholds (P < 0.001) versus healthy controls (27). We demonstrated that the differential PPT threshold between knee OA patients and healthy controls was constant throughout sites of assessment at the dermatomal, myotomal, and sclerotomal structures. Correlation analysis and multiple linear regression scatterplots determined the relationship between VAS, WOMAC, and SF-36 subscales, and PPT measures (Tables 3 and 4). We found significant correlations between all these measurements (P < 0.01), except for 2 domains of the SF-36: role-emotional and general health. Lower PPT values were correlated with higher pain intensity, higher disability scores, and poorer quality of life.
One strength of this study was its focus on an approach to clinically identify nervous system hyperalgesia in patients with disabling knee OA pain, an issue that has not been addressed sufficiently in the past. A few other studies have directly assessed central sensitization in OA (1, 13–16). Cutaneous and deep hyperalgesia have been demonstrated in the forearm of patients with thumb-base OA (15), and deep hyperalgesia has been shown in the tibialis anterior muscle of patients with knee OA (13). Our study demonstrated a generalized state of hyperalgesia, both in superficial and deep structures, in knee OA patients when compared with healthy controls. This suggests that the peripheral and central nervous system might be involved in the maintenance of the chronic pain state. The clear understanding of the mechanisms involved in how knee OA pain is generated, and how the sensory information is processed from peripheral receptors to cerebral cortex, might provide useful insights that can lead to clinical benefits in the future. Initially, hypersensitivity is found at the site of damage; however when the disease process is not controlled, such as in patients with OA and refractory pain, the central nervous system undergoes plastic changes that are responsible for sustaining chronic pain. It then becomes independent from the peripheral pathologic process.
Usually, repeated stimulation causes most sensory organs to become fatigued and less responsive (28). High-threshold polymodal C fibers involved in nociception, however, show the opposite response (29). In fact, with repeated nociceptive stimulation, nerve endings undergo changes that result in enhanced sensitivity, lowered threshold to stimulation, and prolonged and enhanced response to the stimulation, also known as after-discharge. This phenomenon is called sensitization and it is responsible for sustained pain, tenderness, and segmental and suprasegmental reflex responses (28).
Our findings demonstrated that centrally induced neuroplastic changes measured by a decreased PPT over superficial and deep structures occurred also in sites distant from the knee area. We showed that PPT values were significantly lower in all evaluated structures. It should be underscored that sensitization associated with chronic pain is observed in all levels of the nervous system, from peripheral structures (receptors and nerves) to central structures (spinal cord and brain). In fact, spinal segmental sensitization is a hyperactive state of the spinal cord caused by repeated stimulation of nociceptive receptors from impulses sent by sensitized damaged tissue to the dorsal horn neurons (central nervous system sensitization). The mechanisms of spinal segmental sensitization include neuron hypertrophy and up-regulation of excitatory neurons and of prohyperalgesic peptides, and neurotransmitters at the dorsal horn of the spinal cord. This results in a mismatch of inflammation and pain, as pain does not indicate worsening of inflammation and vice versa.
Knowledge of the segmental distribution of sensory nerve fibers is important in managing patients with pain (28). In humans, the innervation of the skin, muscles, and deep structures is determined embryologically at an early stage of fetal development, and there is little inter-subject variability (30). Each segment of the spinal cord and its corresponding spinal nerves have a consistent segmental relationship that allows the clinician to ascertain the probable spinal level of dysfunction based on the pattern of dermatomal, myotomal, and sclerotomal hyperalgesia (25, 26). We decided to evaluate PPT over anatomic structures innervated by different segmental spinal nerves and divide them into 3 different categories based on the segmental innervations: dermatomal, myotomal, and sclerotomal (28). For the myotomes, we chose to evaluate the PPT over muscles innervated by different spinal nerves. We selected vastus medialis, vastus lateralis, rectus femoris, and adductor longus as muscles innervated by the L2–L3–L4 spinal nerve roots; tibialis anterior and deep peroneus longus by L5–S1 spinal nerves; iliacus for L1–L2; quadrates lumborum for L2–L3; and popliteus for S1–S2 spinal nerve roots. For the dermatomes we followed those described by Keegan and Garrett (19), and the ones described by Bonica (28) for the sclerotomes.
Our data suggested that hyperalgesia over some structures presented a stronger correlation to pain, disability, and quality of life. Of note was that the combined PPT values over the patella tendon, at S2 subcutaneous dermatome and at the adductor longus muscle were the best predictors for VAS and WOMAC pain. A linear increase in VAS (R2 = 0.614) and in WOMAC pain (R2 = 0.608) was observed for the lower values of these 3 combined independent variables, indicating that pain may be influenced by involvement of central sensitization at L3, L4, and S2 spinal segments. Similarly, lower PPT values at the adductor longus muscle, L1–L2 supraspinous ligament, and at the L2 dermatome were associated with poorer SF-36 bodily pain domain. These findings are important due to strong biologic rationale, since knees are predominately innervated by L2, L3, L4, and S2 rather than S1 spinal nerves.
Another possible explanation of our findings is that lower PPT values over a spontaneously painful human skeletal muscle presents significantly elevated levels of substance P, calcitonin gene-related peptide, bradykinin, tumor necrosis factor α, interleukin-1β, serotonin, and norepinephrine versus nonpainful, healthy subjects (31). The concentration of selected inflammatory mediators, neuropeptides, cytokines and catecholamines also differ quantitatively from a remote, uninvolved site (32).
It is also important to note that central plastic changes occur not only in the spinal cord, but also in other structures of the central nervous system. For instance, a previous study evaluated brain areas involved in processing pain in a group of 12 patients with OA using FDG. The results showed that arthritic pain was associated with increased activity in the cingulate cortex, the thalamus, and the amygdale; areas involved with the processing of the emotional aspects of pain. Indeed, the authors suggested in this study that new treatments for pain in arthritis should target central structures (33).
Our study has some limitations. First, we did not measure PPT over thoracic and cervical innervated areas, and therefore cannot evaluate whether central sensitization is systemic or concentrated in areas near or related to the knees. However, our results showed that even when OA was unilateral, both extremities were equally affected in terms of hyperalgesia. Further studies should explore hyperalgesia in distant areas. Second, we did not evaluate changes in sensitization in central structures such as cortical brain areas; therefore, we cannot rule out that hyperalgesia is neither associated with nor a result of brain changes. Finally, the analyses reported in this study were exploratory and hypothesis-generating rather than confirmatory. Further studies are necessary to confirm our findings and fully investigate the mechanisms of the nervous system that enhance patients' reported pain. These insights may then encourage further studies to assess new therapeutic approaches to control pain in knee OA.
Patients should be evaluated for nervous system sensitization before surgical procedures are prescribed to rule out these important and easily-detectable clinical findings. PPT values should be performed at least at the S2 dermatomal level, at the adductor longus muscle, and at the patellar tendon structures. These, when combined showed an inverse correlation with and were the best predictors for VAS and WOMAC pain. Measurements should be performed on both sides for patients with knee OA, because decreased PPT on the nonaffected or on the less-affected side is further evidence for possible nervous system mediated hyperalgesia.
Once central nervous system sensitization is present, the rationale for pain treatment should also target the nervous system structures, rather than using antiinflammatory agents alone. The understanding and clinical identification of nervous system sensitization, and its potential for modulation, may provide exciting and innovative cost effective therapeutic tools to control pain, reduce disability, and improve quality of life in knee OA patients.