Osteoarthritis (OA) is the most common form of arthritis and is characterized by joint degeneration and chronic, sometimes severely disabling pain. Standard objective assessment of pathologic changes in the joint is typically accomplished via radiography to evaluate the presence of osteophytes and joint space narrowing. Radiographic evidence, however, has been shown to have variable predictive validity as a marker of subjective clinical pain, with some population-based studies reporting weak correlations between the two (1–3) and others reporting strong correlations (4, 5). The use of more advanced imaging techniques, such as magnetic resonance imaging (MRI), has not clarified the source of pain in OA (6). Some investigations have found that psychological factors, such as depression and anxiety, may partially explain the apparent discordance between objective measures and subjective pain reports (7). However, it is unlikely that such wide variability in population estimates can be attributed to psychological factors alone.
Theorists have therefore proffered that the discrepancy between pain and radiographic changes may be explained by the propensity of some OA patients to develop sensitized central nociceptive circuits that enhance pain during various states of peripheral tissue insult (8, 9). This abnormality, known as central sensitization, is a maladaptive nociceptive process involving complex pain-amplifying neuroplastic alterations at multiple levels of the neuraxis (10). Since central sensitization is correlated with activation of neural circuits that are implicated in the descending facilitation of pain (11) and is therefore a risk factor for the development and maintenance of chronic pain (12), it is important to identify which patients exhibit abnormal responses to relevant painful stimuli.
Hip OA patients with referred pain have been shown to demonstrate hyperalgesia on quantitative sensory testing (QST) in the areas of referred pain, and these psychophysical responses correlate with functional MRI signals in areas associated with central pain modulation, including the anterior cingulate cortex (13). Knee OA patients have been shown to vary in local and diffuse sensitization on QST as a function of reports of clinical pain (14). Further, those reporting severe pain, but not those reporting mild pain, are more sensitive to local pressure stimulation than are healthy controls (14). Together, these findings show that central processes underlie a portion of the variability in the experience of pain in OA and suggest that simple clinical and experimental tools may be applied to identify those most at risk.
Recent reviews highlight the utility of multisite assessment of pain thresholds, assessment of responses to repeated noxious stimuli (e.g., temporal summation), and evaluation of sensitivity to tonic noxious stimulation as indices of sensitization within the central nervous system (15, 16). However, to our knowledge, no study has yet investigated variances in response to QST between groups of knee OA patients who differ with regard to the relative congruence of clinical pain reports and radiographic disease severity. Woolf (16) has noted that the degree of sensitization in OA patients correlates with clinical pain reports but not with radiographic findings, and he suggested that further study of this potential mismatch may help to illuminate individual differences in OA-related symptoms. If subgroups of knee OA patients identified by common symptom profiles can be characterized as having more or less central sensitization, we may be able to better target clinical care, and we may gain a better understanding of factors that contribute to vulnerability or resilience to developing central sensitization over time.
The purpose of this study was to evaluate whether subgroups of knee OA patients defined by the relative congruence of clinical pain and radiographic severity differed on QST measures of central sensitization, after controlling for the potential contribution of psychological factors. We hypothesized that knee OA patients with self reports of elevated levels of clinical pain in the absence of moderate-to-severe radiographic evidence of pathologic changes of knee OA would be hypersensitive to QST measures of central sensitization.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
In the current study, we sought to characterize the QST and psychosocial profiles of subgroups of knee OA patients defined according to the relative congruence of clinical pain and radiographic severity of knee OA. Several novel findings emerged from the analyses. Consistent with our hypotheses, patients with elevated levels of clinical pain in the absence of moderate-to-severe radiographic evidence of pathologic changes were consistently the most pain sensitive across measures distal to the index knee, suggesting evidence of central sensitization. The pattern of findings is evidence against the possibility that QST differences were simply a function of the reporting of high levels of clinical pain. If this were true, the 2 groups with high levels of pain should have been equivalent across measures. Instead, the high pain/low knee OA grade emerged as the most pain-sensitive group. Thus, these findings suggest that central sensitization may be an endophenotype marker of chronic pain in knee OA patients who report high levels of clinical pain in the absence of moderate-to-severe radiographic evidence of pathology, which may help to explain the often-noted phenomenon of minimal-to-modest relationship between self-reported pain and radiographic evidence of pathology in OA.
The group differences in QST measures were independent of psychosocial functioning. Although the high pain/low knee OA grade group reported elevated symptoms of anxiety, depression, and pain catastrophizing relative to the low pain groups, statistical adjustment for these differences did not alter the group effects on QST measures. It is now well-established that pain and emotions share common neurobiologic resources and are bidirectionally related in the course of daily life (39, 40). Therefore, the potential for psychological functioning to explain central sensitization abnormalities in patients with discordant severities of clinical pain and radiographic knee OA may be better evaluated in a prospective study design through which changes in the strength of coupling of pain and cognitive/affective measures can be estimated over time.
Although controlling for sleep disturbance did not diminish the observed group effects, it is notable that 93% of the high pain/low knee OA grade group had comorbid insomnia, as compared to 56% of the low pain/high knee OA grade group. It is difficult to draw any firm conclusions from this finding because the sample was, in part, recruited for the presence of comorbid insomnia. One potential consideration not reflected in our statistical control of sleep disturbance is that other insomnia-related factors that could explain group differences in pain sensitivity, such as inflammation (41), may be at play. The results of the present study should therefore be replicated in an OA study designed without insomnia-specific recruitment strategies to determine if random cases of comorbid insomnia are similarly represented between groups and if QST profiles are altered should different distributions emerge.
The 4 subgroups did not differ significantly in measures of suprathreshold pain sensitivity at affected sites proximal to the index knee. Central sensitization is expected to be evident at both unaffected and affected areas in OA, and recent studies of knee OA patients documented hypersensitivity at anatomic sites corresponding to lesions discovered through imaging (14). However, our grouping system was novel and the findings cannot be directly compared to previous findings, which were based on QST differences between OA patients and healthy controls (see, for example, ref.42), as a function of clinical pain alone (see, for example, ref.14), or only at sites of referred pain (see, for example, ref.13). Inspection of the group mean QST responses at affected sites does in fact suggest that the high pain/low knee OA grade group was hypersensitive relative to both of the low pain groups. Thus, the nonsignificant between-group effect appears to be driven by the similarity of the 2 high pain groups. More work is necessary to determine why the high pain/high knee OA grade group was especially sensitive at affected, but not unaffected, anatomic sites. It is possible that local factors not measured in this study, such as inflammation, introduced additional between-group variance to the QST response at affected sites. In future studies, a more precise pain sensitivity mapping technology, as described by Arendt-Nielsen et al (14), could be applied to more accurately evaluate the group differences we observed in the present study.
Contrary to the results on tests of pain sensitivity, the 4 subgroups were equivalent on the test of CPM. These findings are somewhat unexpected, given several recent studies documenting deficient pain inhibitory processing in patients with painful knee OA (14) and in patients with a variety of idiopathic pain disorders (43–45). It is not clear why the group differences from the present study favored measures of central pain facilitation over pain inhibition. Hypotheses accounting for this discrepancy, such as variability across studies in measurement techniques or neurobiologic system-specific effects for this particular set of subgroups (i.e., opioidergic versus glutamatergic), should be investigated in future studies.
The findings of the current study have potentially important clinical implications. It is of critical interest to the field to identify vulnerability and resilience factors that contribute to, or protect against, the transition from mild arthritis to severe arthritis. The finding that the high pain/low knee OA grade group was more pain sensitive than the other groups raises the question of whether they are in a transitional stage from mild to severe joint pathology. It would be important to know if the patterns of central sensitization observed in this group can be reversed with treatment (e.g., anticonvulsants; selective serotonin and norepinephrine reuptake inhibitors) and whether there is a particular window of opportunity during the course of disease progression when treatments are the most effective. One future direction of research, for example, could be to evaluate whether this subgroup responds differently to analgesic medications or other centrally acting agents relative to other OA patients. Similarly, it would be interesting to evaluate the medical management of low levels of clinical pain in the presence of severe radiographic knee OA and determine what clinical factors (e.g., preventative physical therapy) promote this group's resilience over time. This group demonstrated relatively higher pain thresholds and lower ratings of phasic and tonic noxious stimuli applied at multiple body sites, as well as higher psychosocial functioning. Whether dimensions of neurobiologic resilience, such as a homeostatically balanced mesolimbic dopaminergic system activity (46), or psychosocial resilience, such as healthy affective regulation (see, for example, ref.47), contribute to the pain response in this group remains to be determined and should also be taken up in future investigations.
Several limitations of this study deserve mention. First, the fact that these analyses were performed on a secondary data set limits our explanatory reach in accounting for the specific mechanisms associated with the effects reported here. On a related note, as part of the aims of the parent study, the majority of participants were recruited for the presence of comorbid insomnia. However, we view this as a minor limitation to the generality of the findings, since symptoms of insomnia are highly prevalent in OA, and epidemiologic estimates suggest that as many as 58% of OA patients in the general population experience significant sleep disturbance at least 3 nights per week (48).
The relatively small sample size may have limited power to detect effects, which may account for the lack of significant group effects on QST measures proximal to the index knee. Also owing to the small sample size, we chose to use a median split of WOMAC scores for grouping purposes, rather than select at the extreme ends of the scale. As a result, this may have underestimated the effect sizes due to the similarity of patients whose scores fall at or close to the median.
In conclusion, we identified a subgroup of knee OA patients who display abnormalities in pain processing that are consistent with central sensitization, as well as a subgroup of patients who may be resilient to these abnormalities despite prominent joint degeneration. The findings provide support for the notion that central sensitization is an endophenotype for chronic pain in knee OA and contributes to the ongoing debate surrounding the variable association of clinical pain and radiographic severity of knee OA.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Smith had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Finan, Haque, Haythornthwaite, Smith.
Acquisition of data. Buenaver, Bounds, Hussain, Park, Haque, Campbell, Smith.
Analysis and interpretation of data. Finan, Edwards, Smith.