- Pain reduction with pharmaceuticals in knee osteoarthritis (OA) can result in increased joint loading that may lead to greater odds of disease progression
- Greater knowledge of the mechanisms of the pain-related gait changes in OA is needed
- Combining load-modifying interventions with pharmaceutical pain treatment in knee OA could enhance clinical outcomes
It is estimated that greater than 10% of the world’s population older than 60 yr experiences joint pain associated with osteoarthritis (OA) (1). Pain is the primary reason OA patients seek treatment and the end-point target for all approved treatments. The pathogenic significance of OA knee pain is not well understood. Although exercise is the primary recommended treatment (2), pharmacological pain treatment is still regularly prescribed for pain management. Despite significant interest and effort to improve pain management for OA and to develop novel targets, there has been limited success, with current drug therapies only providing mild to moderate pain relief and patient-specific responses (3). The majority of studies related to management of pain in older adults have focused only on analgesic safety and short-term efficacy (2–16 wk). These studies have not addressed the long-term efficacy (1–8 yr) or potential adverse effects of chronic use on joint health that may result from changes in the magnitude or pattern of loading at the painful site. The relation between pharmaceutical management of OA symptoms and the mechanical environment of the joint for both idiopathic and posttraumatic has only begun to be elucidated. Although clinically beneficial, reduction or removal of pain may interrupt the protective motor system response to nociception and may have negative consequence in OA, in particular for knee and hip OA, which are mechanically mediated. We hypothesize motor system adaptations to joint pain and its treatment may impact OA structural and symptomatic progression, thereby limiting function and efficacy of pharmaceutical pain therapies (Fig. 1). Initial evidence supports a relation between mechanical loading at the knee joint and both structural and symptomatic severity and a potential role of mechanics in structural and symptomatic progression. There is a need for greater knowledge of the different mechanisms for altering knee OA pain (e.g., pharmacological: reducing inflammation or blocking pain pathways; and mechanical: offloading mechanical stress), their individual pathologic significance, and the potential complementary roles of these techniques for balancing the management of OA symptoms and mechanical risk factors for structural and symptomatic progression of the disease.
OA JOINT PAIN: POTENTIAL PROTECTIVE RESPONSE
Pain has an important physiologic role and acts with or stimulates motor system adaptations that may protect tissue from the perceived or actual threat of damage. In the joint, nociceptive nerve fibers are located in the joint capsule, synovial lining, ligaments, menisci, periosteum, and subchondral bone (4). Each of these has been identified as potential sources of pain in knee OA (4,5). Although cartilage changes often are a primary focus of clinical monitoring (radiographic joint space narrowing) of the presence and severity of knee and hip OA, healthy adult cartilage is not normally innervated and not likely a potential source of pain in early OA. However, there is evidence of vascularization and nervous innervation of cartilage at the osteochondral junction as OA progresses, which might contribute to OA pain (6). In response to noxious stimuli within a joint or muscle, a motor system response to remove or reduce the noxious stimuli is expected. This nociception-motor interaction occurs most often without conscious thought. The current theoretical models for the motor response to pain in voluntary movements suggests that activity of muscles that produces a painful movement will be uniformly inhibited, whereas the activity of the antagonist muscle to the painful movement would be facilitated (7) or alternatively, that muscle activity is increased in all muscles regardless of the task (8). Although OA pain is considered nociceptive or inflammatory in nature, a subset of OA pain is thought to be neuropathic in origin (9). This complexity may have implications for both the potential protective response as well as the role of mechanics in exacerbating the pain severity.
Evidence has been provided to support the pain adaptation theories in vivo with experimental pain protocols that use an injection of hypertonic saline to the infrapatellar fat pad. These studies have reported changes consistent with both theories in motor unit recruitment, muscle activity, and muscle force production during controlled, yet simple, activities such as a knee extension task (10). It is proposed that the goal of the motor adaptation is to decrease the displacement, velocity, or force of the painful movement (7,10). The link between the reported changes in muscle function in response to pain during simple activities (11) and those that might be expected during functional activities such as walking (12,13) is not well characterized. There are two experiential pain studies that have aimed to understand the impact of motor system adaptations to acute pain on locomotion (13) and on ambulatory function (14). In walking, with increased pain in the infrapatellar fat pad, there is a reduction in the external knee adduction and flexion moments, along with less knee flexion at initial contract and greater flexion in midstance (13). The changes in gait mechanics do not seem to be isolated to the painful knee joint because a second experimental knee pain study found decreased peak total support, external ankle dorsiflexion, and hip adduction moments in addition to the decreases in external knee flexion moments (12), suggesting a system-level compensatory response.
The experimental pain model can provide some insight to a mechanism for a protective motor system response to joint pain, but there may be limitations in translating the findings to an OA population. OA typically affects middle-aged and older adults, and examining the impact of acute and chronic pain and its treatment on gait mechanics and ambulatory function in an aging population requires special consideration for the comorbid impact of physiologic changes associated with aging (15). Age-related changes in neuromuscular function including decreases in muscle strength and power contribute to changes in gait mechanics and ambulatory function and can be sex specific (16,17). Together, age and knee pain may have significant impact on muscle function, and these factors (age, knee pain, and changes in muscle function) may combine to alter the characteristics of the motor system adaptations to painful stimuli. Thus, to address the need for improved pain management in older adults, it is imperative that we address questions of pain adaptations in older adults to understand the coactive effects of aging with pain on ambulatory function. Gaining a more in-depth understanding of the mechanism leading to normal protective response to experimental pain but also to persistent or chronic joint pain is important because it may be possible to provide supportive technologies and rehabilitation for the response and to predict the potential impact of different pain therapy mechanisms of action on movement patterns.
ROLE OF GAIT MECHANICS IN OA PROGRESSION
OA is at least in part a mechanically mediated disease (a detailed review of the pathways can be found in (18)). In vivo joint mechanics during walking play an important role in joint tissue health and morphology in both healthy and osteoarthritic joints (19). In a healthy joint or an uninjured person, the loads experienced during everyday activity stimulate a positive remodeling response (20) and the tissues adapt to withstand and absorb the applied loads. Cartilage thickness varies across the surface of the joint, and the location of areas of thicker cartilage has been associated with joint kinematics and kinetics during walking (21). At the knee, the sagittal plane angle at heel strike, an instant of rapid high loads, has been associated with the location of thickest cartilage on the tibial plateau (21). The distribution of the loads across the knee as measured by the external knee adduction moment also is important and has been associated with the ratio of cartilage thickness between the medial and lateral compartments of the tibial plateaus (20,22). Although a positive relation between joint loads and cartilage morphology has been identified in healthy joints, this relation changes in individuals at high risk for OA and in those with symptomatic OA (23).
In medial compartment knee OA, numerous prospective studies have supported a causal relationship between knee joint kinetics and the rate of structural progression of medial compartment knee OA over 2–5 yr as measured by radiographic joint space narrowing (24,25), medial compartment cartilage volume (26,27), and tibia and femoral cartilage thickness changes (23,28). In addition, greater coactivation of muscle crossing the knee, an additional factor that will contribute to greater joint loading, also has been related to decreases in cartilage volume over a 12-month period (29). The two surrogate measures of joint loading common in these studies include the peak external knee flexion moment, a surrogate for the total compressive load, and the external knee adduction moment, a surrogate measure for the distribution of load between the medial and lateral compartments (30). A 1% body weight times height change in the peak knee flexion and first peak knee adduction moments results in average reduction of 0.06 unit decrease in the tibia and femoral medial-lateral cartilage thickness ratio over a 5-yr period (23). Similar findings from another study suggest the risk of structural progression of knee OA is increased 6.46 times with a 1% body weight times height increase in the external knee adduction moment (24). Likewise, there also is a sixfold greater risk of clinical progression of OA to total joint replacement (TJR) for every one unit increase in compressive knee loading (25).
Although the magnitude of the joint moments is clearly important, initial work examining the impact of number of loading cycles (steps per day) surprisingly suggests that accounting for the relative cumulative load does not improve the prediction of structural progression (27), but this is consistent with the beneficial findings of exercise as a treatment for knee OA(2). Given this strong evidence for a role of joint kinetics during walking in the progression of radiographic/structural OA and preliminary evidence suggesting gait mechanics also plays a role in the clinical progression to TJR, it is critical to gain knowledge on the mechanism for variation in joint mechanics within the OA population and the potential role of pain and its treatment on these mechanics. In addition, the literature has focused largely on sagittal and frontal plane joint moments and structural progression; a greater focus on the biomechanical variables that may predict progression of symptoms such as the muscle activation patterns (31) or transverse plane motions and moments (32), as well as the interaction with loading cycles (i.e., exercise) is needed.
PAIN-RELATED GAIT ADAPTATIONS IN OA
There is a relatively large body of literature that indicates symptomatic OA patients move differently than asymptomatic or healthy older adults. Many of the differences between asymptomatic or healthy adults and those with symptomatic OA suggest there is motor system response to offload the painful diseased compartment to reduce the displacement and velocity of motion, consistent with a pain adaptation. A consistent finding in the literature is smaller knee flexion angles (33–35) and peak external knee flexion moment in OA patients regardless of structural severity as compared with non-OA controls (33–36). The external knee moments must be balanced by equal and opposite internal moments produced by the knee extensors (30). Smaller peak knee flexion moments and reduced knee extensor function are common findings in individuals with knee pain resulting from experimental protocols (10,13), overuse injury (37), or medial compartment OA (38,39). This common finding in knee pain with and without structural pathology suggests this is a response to noxious stimuli in the joint tissues. Several studies also have reported that OA patients with mild symptomatic severity tend to walk with a smaller first peak knee adduction moment as compared with matched healthy controls and those with more severe disease (35,40). Henriksen et al. (13), 2010 showed that the reduction in the first peak knee adduction moment with experimental knee pain is similar to the magnitude of the difference between healthy and less severe OA patients. Together, the smaller external knee flexion and first peak knee adduction moments in less severe OA patients may contribute to a smaller joint load in the diseased medial compartment (41) and would be consistent with a protective pain adaptation. Changes in the muscle activation pattern that may result in greater cocontraction of muscle crossing the knee can both exacerbate or counteract the impact of knee joint moments on joint loading. Studies indicate that there may be a redistribution of muscle activation between agonist and antagonist muscle and medial and lateral musculature (31,42,43), but the specific contributing factors to altered timing, duration, and intensity of activation previously reported and the implications for joint loading have not been quantified in the same study.
A causal relation between pain and gait alterations in OA patients often is implied in the cross-sectional studies described previously; however, evidence to support this relation in the literature is limited. It’s possible that joint kinetics influences the mechanical stimuli for joint tissue and can be related to the amount of pain. However, it’s also possible that the differences in joint mechanics are a result of a pain adaptation associated with inflammation or a result of structural changes from tissue degeneration. Some studies have reported that there is no association between the knee adduction moment and pain or OA symptomatic severity (31,44). Individuals with more severe structural OA (KL grade 4) tend to have higher magnitude external knee adduction moments than those with less severe OA (33,35,40). Although changes in joint alignment with increases in radiographic severity may explain the lack of an association between pain and the knee adduction moment, conflicting results remain when radiographic OA severity is controlled for. One study reported a negative relation between pain intensities and both the peak adduction moment and adduction moment impulse (45); however, another reported no relation for mild radiographic severity (46). In contrast, for more severe radiographic OA, there seems to be a consensus in the literature for a positive association between the adduction moment or moment impulse and pain severity (45,46), supporting a possible impact of radiographic severity on the moment characteristics. Thus, although initial evidence supports a protective gait adaptation in early stage OA, the relative role of joint pain in the observed gait differences for different OA severities based on structural grading or symptomatic severity needs further study. In addition, the pathologic significance of these alterations in gait also should be addressed to determine the role of joint mechanics and muscle activation pattern in exacerbating the severity of pain-producing pathologies such as synovial inflammation, bone marrow lesions, meniscal pathologies, and vascularization and innervation of cartilage.
Variability in self-reported pain is present even when using the best instruments because of the subjective nature of pain sensation and cognitive interpretation of the information. To more rigorously examine the role of pain in the alterations in neuromuscular and gait outcomes, study designs examining gait changes in response to either increases or decreases in pain using within-subjects analysis are needed. As part of a crossover-designed drug trial, we have previously quantified the repeatability of gait biomechanics in response to successive 2-wk placebo-blinded washouts from analgesic treatments in patients with moderate to severe medial compartment knee OA (Fig. 2) (47). Pain reported after each of the 2-wk placebo periods varied from 39–57 mm on a 100 mm visual analog scale (VAS). The interday repeatability for the knee adduction moment was high, suggesting insensitivity to the small fluctuation in pain. However, interday repeatability of preferred walking speed, maximum ground reaction force, and external knee flexion moments was moderate, suggesting a potential causal relationship between OA pain flares and gait (47). This was a small study, and further investigation using within-subjects study designs to quantify the general and patient-specific neuromuscular and gait responses to fluctuations in pain in the absence of structural changes should be completed.
IMPACT OF PHAMACEUTICAL PAIN TREATMENT ON OA GAIT
There are a small number of studies that have quantified changes in gait mechanics in response to OA pain treatment with pharmaceuticals. Treatments in these studies have included injections of analgesics, analgesics in combination with corticosteroids or hyaluronic acid, and oral administration of pain pharmaceuticals in a variety of forms such as selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics and opioids (48–52). The impact of pain treatment on specific knee joint mechanics variables in these studies has been varied. However, overall, the results suggest that there are beneficial changes to ambulatory function (increased walking speed and greater knee extension at heel strike) (48,50) but greater joint loading (increased knee adduction moment or knee flexion moment) (48,50–52) in response to pharmacologic treatment of OA pain. The reported changes in the knee flexion moment ranged from 0.21% to 0.48% body weight times height. The reported increases in the external first peak knee adduction moment have been smaller, with a high variance in the magnitude of the changes (48–50). The combined 95% confidence interval for a change in the knee adduction moment was 0.03% to 0.36% body weight times height for analgesics or NSAID treatment (48,49). Only one study tested for and found a positive association between the change in pain and the change in knee adduction moment (49). Given there is a reported sixfold increase in the odds of progression to TJR for every unit increase in the knee moments (25), the changes in joint moments with pain treatment could potentially result in a small, yet clinically relevant, increase in risk of both structural and symptomatic disease progression particularly for those individuals who experience the best case response to the pain treatment. It is important to acknowledge that rate of OA progression is not solely driven by mechanics. The impact of altered mechanics or a removal of the protective pain response may be greatest in those individuals who are also obese and have greater systemic inflammation. Results from our prior in vitro study and that of other groups suggest the response of cartilage to loading is negatively impacted by the presence of inflammatory cytokines (53). Prospective studies to quantify the potential adverse effects on joint health that may result from changes in the magnitude or pattern of loading at the painful site with pain fluctuations should be completed in both healthy weight and obese adults.
Although significant biomechanical changes have been reported in studies using pain drugs, and these changes have the potential to confer an increased risk for progression of knee OA, there is considerable variation in the magnitude of the reported changes. This may be a result of variance in intervention type and dosage, reported pain changes, as well as study sample sizes. For example, the response to an intraarticular joint injection of lidocaine, which removes most of the available sensory information from the joint, may have a different impact on the motor system response than an NSAID treatment that targets pain resulting from inflammation in the joint. To address the possibility that drug mechanism of action could impact the biomechanical response to pain treatment, we conducted a small double-blinded placebo-controlled crossover trial using a selective NSAID (celecoxib) and an opioid (oxycodone HCL) as the two active agents (52). Although there were greater increases in walking speed relative to the washout periods for both active drugs as compared with the double-blinded placebo, greater increases in maximum vertical ground reaction force, knee flexion, and total moments were only found for the NSAID condition and not the opioid condition (Fig. 3). This suggests that both the type and source of pain may be important, and it also suggests that the mechanism by which a patient’s interpretation of the nociceptive signal is altered will influence how gait mechanics changes. The selective NSAIDS and opioids have very different targets, with opioids influencing the transmission of the signals going to or within the brain, whereas NSAIDS target the periphery and the inflammatory sources of pain at the site of injury (54). Understanding the impact of the therapeutic mechanism of action of a treatment, the motor-nociception response during dynamic activities is necessary to assess concurrent risks of disease progression and to balance this risk with the potential improvements in physical or muscle function that could accompany a given treatment. As a starting point to garner this information, biomechanical outcomes should be included in phase three and four clinical trials of new therapeutics for OA symptom management.
COMBINING LOAD-MODIFYING INTERVENTIONS WITH PHARMACEUTICALS TO OPTIMIZE TREATMENT
To address the need for improved pain management in OA, it is imperative that we search not only for novel drug targets to improve symptom management but also for alternative treatments that can counteract the potential negative mechanical adverse effects of these drugs. As an alternative to pharmacologic treatment, there has been significant attention on load-modifying devices such as braces or shoes in recent years. The goal of these load-modifying devices is to alter the external knee adduction moment, a surrogate marker of the knee load distribution by changing the lower limb alignment, center of pressure under the foot, or the ground reaction force direction. By offloading the disease medial compartment, there are two suggested benefits: first, there will be a pain reduction and second, there will be a slowing of disease progression. Two recent meta-analyses suggest that, on their own, load-modifying devices may not be enough to achieve clinically relevant changes in symptom or structural severity for patient populations. The first meta-analysis of randomized clinical trials examining efficacy found that with shoe interventions such as lateral wedges or variable-stiffness shoes, there is a moderate effect for a reduction in pain (55). However, this meta-analysis also reports a high heterogeneity in the study findings and subject specific responses to the intervention. This could be attributed to variability in the biomechanical effect of the interventions. A meta-analysis on the biomechanical effect of lateral wedge shoes or insoles found small standardized mean difference from controls shoes in both the peaks of the external knee adduction moment and the adduction angular impulse (56). The biomechanical effects to date have not had a detectable effect on the rate of cartilage thinning (57) and joint space narrowing (58). However, the changes in frontal plane moments (~0.15% body weight times height) may offset a significant percentage of the joint loading increases in response to drug treatments, thus supporting the motor system’s efforts to protect tissue from the perceived or actual threat of damage. The impact of the altered biomechanics on pathologies in other joint tissues has not been examined. We suggest that when combined with pharmacologic treatments, load-modifying devices may offset the potentially negative changes in joint loading and thus play a supporting role in OA clinical management (Fig. 4).
To be able to maximize the biomechanical impact of load-modifying interventions and to understand in whom they may work, it is necessary to understand the biomechanical mechanisms for changes in the sagittal and frontal plane moment. Human movement results from multisegmental motion (multibody system), with many degrees of freedom that must be organized in a coordinated fashion to execute a movement task. To achieve a reduction in the knee adduction moment, a coordinated change in the body segment motion is needed to alter the magnitude or direction of the ground reaction force relative to the center of rotation of the knee joint (59,60). There are numerous methods for quantifying movement coordination. We have applied principal component analysis vector-based representations of body segment (59) or joint kinematics (60) to determine how OA patients may alter movement coordination and to assess how variable-stiffness shoes can produce a reduction in the frontal plane moments. This analysis determines patterns of correlated deviations from the mean motion pattern in all body segments and can therefore pick up such differences that co-vary between several variables, indicative movement coordination. The characteristic features of OA gait that differ from non-OA gait were found in both the sagittal and frontal planes and included asymmetric motion of the symptomatic and contralateral limb suggestive of an unloading of the OA limb; greater knee adduction motion and increased sway in the upper trunk and shoulders; and ground reaction force differences in the medial-lateral and vertical directions indicative of a shift in the resultant force direction. The impact of the variable-stiffness shoe resulted in a similar whole-body change in movement coordination (Fig. 5). The consequences of these changes in movement coordination and joint mechanics within the knee and at adjacent joints in the symptomatic limb as well as those that might occur in the contralateral limb are not well understood in terms of their role in the initiation of OA at the sites. This suggests that greater consideration should be given in future studies for comorbid effects of load-modifying devices. To date, there are a limited number of device designs that have been developed and tested in randomized clinical trials for modifying loading on the knees, and there is significant potential for more development using smart materials and for patient-specific interventions to maximize the biomechanical effects of the load-modifying approaches.
If one of the aims of treatment for OA is to restore the biomechanical function of the joint along with ambulatory function, then it is imperative to identify the underlying cause or mechanism responsible for biomechanical changes and the consequences of clinical management. Combining pharmaceutical intervention with load-modifying devices offers a simple multimodal approach to management of OA symptoms. The load-modifying devices may support the beneficial gait adaptation that can protect the diseased joint, whereas the pharmaceutical interventions would address the inflammation and resulting noxious stimuli that can limit ambulatory function, may contribute to longer term atrophy of important musculature, and reduce overall quality of life for OA patients.
A portion of the work presented was supported by Pfizer Pharmaceuticals.
K.A. Boyer is a consultant with Bayer Consumer Health (<$10,000). Research grants not related to published work received from Bayer Consumer Health, Fossil Inc, and Cole Haan.
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