Pain sensitivity at rest and during muscle contraction in persons with rheumatoid arthritis: a substudy within the Physical Activity in Rheumatoid Arthritis 2010 study

Pain, tenderness and impaired muscle function are common in persons with rheumatoid arthritis (RA) [1]. Pain is the most common and disabling symptom [2] and is also found to be the main predictor of general health perception in patients with RA [3]. Pain is assumed to be linked to inflammation, but many persons with RA have continued pain despite adequately controlled inflammation [2]. The mechanisms behind non-inflammatory pain in RA, commonly considered as multifactorial, are not fully understood. In RA it might be caused by peripheral mechanisms, such as peripheral joint damage [4], possibly inducing peripheral sensitisation. Central mechanisms might also contribute to pain in RA by amplifying ascending nociceptive signalling due to sensitisation in ascending nociceptive pathways, increased descending facilitation and/or impaired descending inhibitory pathways (i.e., central sensitisation) [4, 5]. Previous findings support the presence of central pain mechanisms in RA. Thus, lower pain thresholds were found in patients with RA compared with healthy control subjects (HC), both at joints and at non-inflamed tissue, in studies using pressure algometry [5, 6]. Furthermore, hypersensitivity to thermal stimuli has been reported at both non-articular and articular sites [7]. Also, a general increase in pain sensitivity was found in patients with long-standing RA (>5 years) compared with those with more recent onset (<1 year) [5]. The data indicated that the generalised alteration of pain processing was due to sensitisation of central nociceptive neurons and/or increased activity in the descending facilitatory pathways, because normal function of conditioning pain modulation was found [5].

Data derived from animal studies indicate an interaction of opioid and serotonergic mechanisms to promote exercise-induced hypoalgesia (EIH) [8]. Also, endogenous opioids have been implicated during EIH in humans, but mainly during high-intensity and long-duration exercise [8, 9]. Recently, a genetic association study in humans showed that genetically inferred increased opioid signalling in combination with decreased serotonergic signalling produced better EIH in HC as well as in patients with fibromyalgia (FM). The study revealed antagonistic interactions between opioid and serotonergic signalling upon EIH [10]. On a behaviour level, exercise activates pain-inhibitory mechanisms in healthy persons with subsequent increase of pain thresholds during muscle contraction [11]. Persons with central sensitisation who were diagnosed with, for example, FM or FM with comorbid chronic fatigue syndrome respond differently [9, 10, 12‐14], owing to a dysfunction of endogenous pain-inhibitory mechanisms during exercise (i.e., dysfunctional EIH). In patients with osteoarthritis (OA) in the hip or knee, we found increased pain sensitivity but normal function of EIH during muscle contractions [15]. These results align with the results of our previous pilot study where pain sensitivity was explored during standardised submaximal static contractions in a small sample of ten postmenopausal women with RA and indicated decreased pain thresholds compared with those in HC, but no dysfunction of segmental or plurisegmental EIH [16]. If these results can be replicated in larger samples including both men and women of different ages, they may offer one explanation for pain reduction following exercise [17]. The aim of the present study was thus to explore pressure pain sensitivity and the function of segmental and plurisegmental EIH in persons with RA compared with HC.

To our knowledge, this is the first study exploring pressure pain sensitivity and activation of EIH in a sample of both men and women with RA and comparing them with HC without major pain. Our main findings indicate that persons with RA have higher pain sensitivity but a normal activation of segmental and plurisegmental EIH. Our results thus confirm those derived from our previous pilot study [15] and offer a possible explanation for pain reduction observed in persons with RA following clinical exercise programmes.

Higher pressure pain sensitivity at muscle tissue in persons with RA at rest as found in the present study suggests involvement of central pain mechanisms (e.g., central sensitisation, including facilitation and/or disinhibition) in RA pain. These findings agree with results of previous studies [5, 16, 29] in which researchers reported decreased pressure pain thresholds at non-inflamed tissue in patients with RA. The present results also confirm the findings of our previous pilot study [16] demonstrating hypersensitivity in postmenopausal women with RA and further support that persons with RA may have dysfunctional pain processing with widespread central sensitisation.

Our findings of higher ratings of global pain at rest and in worst pain in the thigh during contraction among participants with RA compared with HC indicate that persons with RA may experience increased pain during exercise. However, the pain ratings represented a wide range, especially those of ‘worst pain during exercise’. This might be imperative to individualise exercise support, such as in the context of the fear-avoidance model, where pain intensity is suggested to predict disability mediated by fear avoidance [30]. In our recent study, high fear avoidance was correlated with male sex, low income, high pain ratings, poor perceived health, low health-related quality of life and low exercise self-efficacy [31]. Thus, pain is a complex phenomenon, and numerous factors other than pain physiology need to be taken into account when tailoring therapeutic exercise to an individual person with RA.

We found normal activation of pain-inhibitory mechanisms during static contraction, both segmental and plurisegmental, in the participants with RA. Another study exploring endogenous pain modulation in response to submaximal exercise on a bicycle ergometer in RA [14] found a normal decrease in temporal summation of painful stimuli in patients with RA, thus suggesting a decrease in pain-facilitatory mechanisms during dynamic exercise in RA.

In other chronic pain conditions, different responses in pain modulation have been found during exercise. In a previous study assessing patients with hip or knee OA, we found increased pressure pain sensitivity, but a normal function of segmental and plurisegmental EIH, during static contractions [25], which is in accordance with our present findings in persons with RA. In contrast, patients with whiplash-associated disorders were found to have increased temporal summation of pain, suggesting dysfunction in pain-inhibitory mechanisms [32]. Furthermore, patients with FM showed hyperalgesia and no activation of pain-inhibitory mechanisms, segmental or plurisegmental, during static muscle contractions. Rather, an increase in pain sensitivity was seen [10, 13]. Patients with shoulder myalgia showed an activation of the pain-inhibitory mechanisms when contracting a non-painful muscle distant to the pain but a lack of activation when contracting the painful muscle [13]. Thus, on the basis of earlier studies, EIH seems to be normally activated when exercising non-painful but not painful muscles, as well as normally activated in patients with chronic joint pain such as in OA.

In populations with RA, FM is a quite common co-morbidity [33, 34]. One hypothesis presented is that the dysfunction in pain processing in RA has similarities to the dysfunction found in FM [33]. Our results indicate that the dysfunction in pain processing differs between RA and FM; the participants with RA showed augmented pain sensitivity similar to FM but normal activation of the pain-inhibitory mechanisms during muscle contraction. Interestingly enough, the same pattern has been observed in OA [15]. With these results in mind, further exploration of pain processing during a long-term physical activity programme would add important information about the nature of the pain-processing dysfunction in RA.

One strength of our study is its sample, which has to be considered suitable for one including standardised assessments by algometry of PPTs as well as EIH. One limitation is that no disease activity data were available for our study participants. However, our recordings of pain, health-related quality of life and activity limitation, taken together, indicate that disease activity was low to moderate. Another possible limitation is selection bias, with the inclusion of participants with RA being limited to those interested and fit enough to participate in a physical activity support programme. For example, persons with HAQ-DI values > 2 would, by definition, not be able to exercise independently. Thus, our results can be generalised only to populations with RA that are most likely to have a chance to influence their pain sensitivity with exercise. The fairly high dropout rate due to incomplete data was the result of an administrative error and should not influence the external validity of our results. This was also confirmed by the dropout analysis indicating no major differences between those with complete data and those with incomplete data.

Despite our study’s indication that persons with RA might be able to reduce their pain with exercise, the optimal type and dose for adequate pain reduction need to be further explored. Although controlled trials in clinical or research settings are the most frequent study design for evaluating pain reduction by exercise, future studies should also explore the potential effects on pain sensitivity and EIH of physical activity outside health-care contexts.

Our results indicate a generally increased pain sensitivity but normal function of EIH among persons with RA and thus offer one possible explanation for pain reduction observed in this group of patients following clinical exercise programmes. More research is needed to explore the adequate exercise type and dose for optimal response in terms of pain modulation.