摘要
目的：确定负荷运动是否对膝关节骨性关节炎患者产生镇痛作用。
方法：十一名膝关节骨性关节炎患者(65.9±10.4岁),和11名老年健康受试者 (61.3±8.2岁)和11名年轻健康受试组(25.0±4.9岁) 进行了上下半身负荷运动的比较。测量了八个部位基线和运动后压痛阈值，并测量了膝关节的压力耐受力。
结果：所有三组患者在运动后的压痛阈值增加，表明疼痛敏感性降低。对青年和老年健康人群来说，运动镇痛效应是在上半身或下半身负荷运动后发生的。但是只有上半身负荷运动能显著提高膝骨性关节炎患者的压痛阈值，而在下半身运动时，压痛阈值变化不显著。无论是上半身还是下半身运动，压力耐受性均不变。
结论：剧烈的上半身或下半身运动能明显降低健康个体的疼痛敏感性。负荷运动后疼痛敏感性下降可以归因于疼痛阈值的改变，而不是疼痛耐受性。膝骨性关节炎患者在运动性镇痛后，疼痛敏感性降低仅在上半身运动后明显。
引言
运动一直被认为是膝骨关节炎的主要治疗方式。它可以改善疼痛和功能，但其潜在的机制尚未明确。一种可能机制是关节负荷和稳定性的调节，许多研究表明，膝骨性关节炎患者股四头肌肌力降低。因此，迄今为止运动研究主要集中在神经机械性因素，通过探究增加腿部力量提高关节负荷能力，进一步减少症状。虽然这一假说已经在人类和动物研究中进行了研究，但它仍然是推测性的。最近的研究表明膝关骨性关节炎的力量训练干预可以改善症状，但不伴随关节力矩或负荷的变化。这些发现表明除了神经肌肉变化以外的机制可能能够解释力量训练后症状的缓解。
外周和中枢敏感性与膝骨关节炎疼痛体验有关。运动已经被证明能暂时降低健康人群的疼痛敏感性，这被称为运动镇痛。运动镇痛公认的机制为内源性阿片类物质的释放，可能有多种因素参与了这种现象。迄今为止，大多数研究都集中在健康人群，但也有越来越多的证据表明，运动镇痛可能发生在处于慢性疼痛状态情况下，但也不全是如此。有氧运动是运动镇痛最常用的研究方法，已被证明有长达30分钟的镇痛反应，而负荷训练镇痛效应已被证实能长达20分钟。
虽然运动镇痛持续时间相对较短，但了解剧烈运动对膝骨关节炎疼痛感的影响可能有助于深入研究长期锻炼减轻疼痛的方法。也有一些不太明确的证据表明，慢性运动甚至一般水平的体力活动可以减少疼痛的敏感性。从现有对膝骨关节炎患者的研究中很难确定慢性运动后疼痛减轻是通过直接影响疼痛敏感性还是对运动的适应性改变起作用的。如果运动镇痛确实发生在膝骨关节炎患者，它将提供证据表明运动可以直接影响疼痛敏感性。
最常用的评估运动镇痛的方法是通过定量感觉测试。这包括实验性地将个体暴露在可量化的伤害性刺激中，并记录反应，如痛阈或强度。虽然定量感觉测试能否反映临床疼痛有些质疑，但研究表明定量感觉测试在膝骨关节炎患者中使用是可靠的，可以区分OA患者和健康对照者。定量的感觉测试正在越来越多地用于膝关节骨性关节炎的研究，比现有的问卷调查更适合于急性干预反应（如运动）时检测疼痛的短暂变化。
本次调查的主要目的是确定是负荷运动是否增加膝骨性关节炎患者的压力疼痛的阈值和耐受性，如果答案是肯定，这种影响是全身性的还是仅仅局限于运动的肢体。第二个目的是确定在同年龄的健康个体中（还有年轻的健康的群体）这种效应是否相似，以研究运动镇痛的潜在年龄差异。
讨论
这项研究观察了单纯负荷运动对膝骨关节炎患者、年轻健康受试者和老年健康受试者的压痛阈值、疼痛耐受度的效应。研究结果显示短暂负荷运动显著降低膝骨关节炎患者、年轻健康受试者和老年健康受试者的压痛阈值，进一步为膝骨关节炎患者负荷运动后出现运动镇痛（exercise-induced analgesia，EIA）效应提供了证据。
膝骨关节炎组的运动镇痛只出现在上半身运动后，在下半身运动后膝骨关节炎组压痛阈值无明显改变。这可能是因为下半身运动后，膝骨关节炎组个体疼痛阈值有较大的变异度，其中一些受试者压痛阈值提高，而另外一些压痛阈值下降（ 81%—-12%）。这种变异度可能和某些受试者症状恶化有关，尽管试验中采取的运动为中等强度的。压痛阈值没有统计学上的意义也可能是因为研究样本量小的缘故，但是膝骨关节炎患者的下半身运动对压痛阈值的效应强度也比较小。膝骨关节炎患者下半身较弱的运动强度产生相对较小的效应，导致反应上的巨大变异，表明运动镇痛机制容易受到个体特别因素的干扰。
上半身负荷运动后，下半身的压痛阈值显著地增加。同样地，下半身压痛阈值在上半身负荷运动后也增加，这些现象不仅仅出现在膝骨关节炎组。这些结果表明运动会导致疼痛敏感度的短暂下降，而且疼痛敏感度的下降甚至出现在非运动的肢体，支持了先前的研究结论——等长收缩运动产生全身的镇痛效应。
运动后的全身镇痛效应表明其机制是由中枢调节或参与的。疼痛处理高度复杂，发生在外周、脊髓、脊髓上层次，受下行抑制和易化疼痛路径调节。运动诱导疼痛可能是下行抑制路径活动增强的结果，下行抑制路径主要受内生阿片肽、大麻素类、五羟色胺等神经递质调节。但是一些慢性疼痛状态如纤维肌炎、肩肌痛、慢性疲劳综合征，当活动疼痛的肌肉时，没有表现出镇痛效应，本研究也符合这一点，在本研究中对膝骨关节炎组实施下半身运动方法后没有使下半身和上半身压痛阈值增加。慢性疼痛患者没有运动镇痛的效应可能和中枢敏化相关，中枢敏化是一种普遍现象，伴随再许多慢性疼痛状态中。
中枢敏化是通过下行抑制和易化疼痛机制相互作用阻断慢性疼痛病人的运动诱镇痛效应。例如，膝骨关节炎患者锻炼膝关节时，已经敏化的伤害感受器增加易化驱动要超过抑制驱动，这便引起了疼痛感受度的敏感，就像本研究中膝骨关节炎组几位受试者所感受的那样。相反运动不受疼痛影响的肢体如上肢或者健康组受试者的任一肌肉不会促进疼痛加重和疼痛抑制，最终引发镇痛效应。慢性疼痛状态运动镇痛效应缺失另外一个可能原因是在膝关节处与负荷运动实施有关的伤害性输入，触发了抑制性输入的关闭或下降，因此不会有镇痛效应。无论何种原因，因此膝骨关节炎或者其他慢性疼痛有运动诱导镇痛效应还是没有都是高度个体化的。正如本项研究，膝骨关节炎组对下半身运动的反应变异很大。
在多组运动后，膝骨关节炎组、老年健康组、年轻健康组压痛忍受度都没有改变。疼痛忍受度测试是在5分钟内进行，要求受试者每30s评估他们的疼痛，这项测试需要在限定的时间里连续对疼痛监测和评估，因此较压力疼痛测试需要更大认知处理能力，许多种因素如环境、注意力、期待、恐惧、焦虑和过去疼痛体验影响到人体疼痛处理、疼痛忍受度结果测试。例如，集中注意力关注疼痛刺激会增强疼痛的感受，而分散注意力会减弱疼痛的感受。评估期间不能分散一丝注意力，要求每30s报告疼痛程度可能就增加受试者对疼痛刺激的关注，扩大疼痛的感受。在5min压痛测试期间，受试者对恐惧的担心也会加重受试者疼痛的感受。其他与恐惧、焦虑和先前疼痛经历相关高度个体化的认知处理也会促进疼痛忍受结果。在各种复杂因素下的疼痛敏感性测试较简单的疼痛阈值测量实施起来显得非常不严谨。
尽管膝骨关节炎病人疼痛经历可能涉及心理因素，如恐惧和焦虑，但本组疼痛忍受度测量仍不受影响。以前几份研究报告了膝骨关节炎患者整体自我评估疼痛随着运动训练而下降，但是这些研究并没有评估疼痛经历哪一方面受到影响。某种程度上来说，和我们的研究结果相反，先前的研究结果为健康受试者缓慢训练可以增加疼痛忍受度，而痛阈并没有增加。也许是因为长期锻炼提高受试者疼痛忍受度，而短暂的运动训练的即时效应是调节痛阈的。总的来说，剧烈锻炼可以降低膝骨关节炎疼痛敏感度，表明了疼痛敏感度下降可能是慢性锻炼适应性反应的部分。
这项研究的局限之一就是运动训练的镇痛效应持续时间仍不确定。以前的研究表明有氧运动后镇痛效应可长达30min，而负荷运动后镇痛效应持续时间较短。在这项研究中，疼痛测量是在运动后即刻进行的，随后测量也没有跟进。重复进行疼痛测量来评估镇痛效应会是非常有趣的事。另外一个局限是研究纳入的样本量较小，以致组间没有出现统计学意义上差别。
这项研究结果可能有临床意义。首先，锻炼患肢应该采取具有个性化的方案，因为在膝骨关节炎组部分患者负荷运动采取最大负荷的60%时是可以降低疼痛敏感性的，而另外部分患者疼痛敏感性却提高到了。下半身锻炼时疼痛容忍度低的膝骨关节炎患者，采取保守的锻炼方案可能有助于减少症状恶化的风险。其次有一个关键的发现，锻炼健康的肢体或许能产生全身镇痛反应，尽管这种镇痛效应持续时间尚不清楚。正如在引言中指出，对膝骨关节炎患者进行定量感觉检查是可靠的，可以区分出健康组、膝骨关节炎组，定量感觉检查也和WOMAC评分有一定的关联。当从试验诱导的疼痛变化去推断临床意义还是应该谨慎的。尽管有这些局限性，对于那些下半身运动耐受性差的人刚开始进行运动干预时，采取上半身运动或许可以诱发出镇痛效应。
原文：
Summary
Objective To determine whether a single bout of resistance exercise produces an analgesic effect in individuals with knee osteoarthritis (OA).Design Eleven participants with knee OA (65.9 ± 10.4 yrs), and 11 old (61.3 ± 8.2 yrs) and 11 young (25.0 ± 4.9 yrs) healthy adults performed separate bouts of upper and lower body resistance exercise. Baseline and post-exercise pressure pain thresholds were measured at eight sites across the body and pressure pain tolerance was measured at the knee.Results Pressure pain thresholds increased following exercise for all three groups, indicating reduced pain sensitivity. For the young and old healthy groups this exercise-induced analgesia (EIA) occurred following upper or lower body resistance exercise. In contrast, only upper body exercise significantly raised pain thresholds in the knee OA group, with variable non-significant effects following lower body exercise. Pressure pain tolerance was unchanged in all groups following either upper or lower body exercise.Conclusion An acute bout of upper or lower body exercise evoked a systemic decrease in pain sensitivity in healthy individuals irrespective of age. The decreased pain sensitivity following resistance exercise can be attributed to changes in pain thresholds, not pain tolerance. While individuals with knee OA experienced EIA, a systemic decrease in pain sensitivity was only evident following upper body exercise.
Keywords；Osteoarthritis Pain Resistance exercise
Introduction
Exercise has long been regarded as a primary treatment modality for knee osteoarthritis (OA)1,2. It improves both pain and function, but the underlying mechanisms have not been clearly identified3. One proposed mechanism is modulation of joint loading and stability, with a number of studies having demonstrated individuals with knee OA display reduced quadriceps strength4–6. Therefore, research to date has focused predominantly on neuromechanical factors by exploring the notion that increased leg strength improves joint loading, leading to symptom reduction7–9. While this hypothesis has been investigated in human and animal studies it remains speculative3. Moreover, recent studies have demonstrated that strength training interventions for knee OA may improve symptoms with no accompanying change in joint moments or loads10–12. These findings suggest that mechanisms other than neuromuscular changes might contribute to symptom reduction following strength training.
Sensitisation, both peripherally and centrally, has been implicated in the pain experience of knee OA13–15. Exercise has been shown to transiently decrease pain sensitivity in healthy populations, which is termed 'exercise-induced analgesia’ (EIA)16,17. With EIA, the threshold at which a stimulus, such as mechanical, thermal or electrical stimulus, is deemed to be painful is typically elevated following a bout of exercise; hence pain sensitivity is reduced. The most accepted mechanism underlying EIA is the release of endogenous opioids16,18, although multiple factors have been implicated in this phenomenon19–21. The majority of research to date has focused on healthy populations, but there is growing evidence that EIA may occur in some chronic pain conditions yet be absent in others21,22.
Aerobic exercise, the most commonly studied modality with respect to EIA, has been shown to cause an analgesic response lasting up to 30 min, whilst the analgesic response to resistance training has been shown to last up to 20 min16,17. Although the duration of EIA is only relatively brief, understanding the way in which acute exercise influences the pain sensation in OA may provide insight into the means by which exercise can reduce pain in the longer term. There is also evidence, though less conclusive, that chronic exercise23,24 or even generally elevated levels of physical activity25,26 can reduce pain sensitivity. It is difficult to ascertain from existing studies of people with OA whether observed reductions in pain after chronic exercise were mediated by a direct influence on pain sensitivity or via other adaptations to exercise. If EIA does occur in people with OA, it would provide evidence that exercise can influence pain sensitivity directly.
The most common method for assessing EIA is via quantitative sensory testing20,27,28. This involves experimentally exposing an individual to a quantifiable noxious stimulus and recording a response, such as pain threshold or intensity. Whilst there is some conjecture as to whether quantitative sensory testing reflects clinical pain, studies have shown that quantitative sensory testing is reliable in people with knee OA29 and can differentiate between people with OA and healthy controls13,14,30. Imamura et al. demonstrated that pressure pain thresholds both at the knee and at non-affected sites had a significant correlation with the Western Ontario and McMaster Osteoarthritis Index (WOMAC)31 pain and physical activity scores (r2 > 0.6, P < 0.001)32. Quantitative sensory testing is being increasingly used in studies of knee OA17,21,33,34 and is more suitable than existing questionnaires for detecting transient changes in pain in response to acute interventions, such as exercise.
The primary aim of this investigation was to determine whether resistance exercise increased the threshold and tolerance of pressure pain in individuals with knee OA and, if so, whether this effect was systemic or confined to the exercising limbs. A secondary aim was to determine if this effect was similar in apparently healthy individuals of the same age, as well as a young healthy cohort, to examine potential age-related differences in EIA.
Discussion
This study examined the effects of a single bout of exercise on pressure pain threshold and pain tolerance in individuals with knee OA and young and old healthy adults. An acute bout of resistance exercise significantly increased mean pressure pain thresholds in individuals with knee OA and young and old healthy adults. These results provide evidence of EIA in individuals with knee OA following resistance exercise.
The EIA in the knee OA group occurred after upper body exercise only, with no apparent change in pressure pain threshold in the knee OA group following lower body exercise. This may be explained by the large degree of variability in the individual pain thresholds in the knee OA group following the bout of lower body exercise. In some participants, pressure pain thresholds increased, whilst in others these decreased ( 81% to −12%). This variability may be associated with symptom exacerbation in some individuals despite the modest intensity of the exercise. While the absence of a statistically significant difference in pressure pain thresholds may be attributed to the small sample size of this study, the magnitude of the effect of lower body exercise on pressure pain thresholds was notably smaller for people with knee OA. The comparatively smaller effect size for lower body exercise in the people with knee OA is indicative of the large variability in the response and suggests that the mechanisms underlying EIA were disrupted by individual-specific factors.
Notably, lower body pressure pain thresholds increased following a single bout of upper body resistance exercise. Likewise, upper body pressure pain thresholds increased following a bout of lower body resistance exercise, though not for the knee OA group. These results suggest that exercise produced an immediate reduction in pain sensitivity, even in non-exercised limbs and supports previous research showing a systemic analgesic effect using isometric contractions20,33,34,41. The evidence of a systemic analgesic effect of exercise is, to our knowledge, the first such demonstration following traditional, dynamic resistance exercise in any population.
A systemic analgesic effect post-exercise suggests that the mechanisms underlying EIA are in part, centrally mediated. Pain processing is highly complex and occurs at peripheral, spinal and supraspinal levels and is modulated by descending inhibitory and facilitatory pain pathways42. It is believed that EIA is the result of increased activity in the descending inhibitory pathways mediated by neurotransmitters thought to include endogenous opioids, primarily, and possibly cannabinoids and neurotransmitters such as serotonin and norepinephrine among others17,21. However in chronic pain conditions such as fibromyalgia, shoulder myalgia, chronic fatigue syndrome and chronic whiplash associated disorders, an analgesic effect has been shown to be absent when exercising painful muscles40,43. Consistent with this, neither upper nor lower body pressure pain thresholds were increased for the knee OA group after performing lower body exercise. The absence of EIA in chronic pain patients may be associated with central sensitisation, a common phenomenon accompanying many chronic pain conditions44.
One way in which central sensitisation may disrupt EIA in people with chronic pain is via an interaction between the inhibitory and facilitatory pain mechanisms. For example, when the knee is exercised in individuals with knee OA the already sensitised nociceptors increase the facilitatory drive more than the accompanying inhibitory drive. This results in a net increase in pain sensation, which several participants in the knee OA group in the present study experienced. In contrast exercising the non-affected limbs, such as the upper body or indeed any muscle of the healthy group, does not facilitate the pain pathways to the same extent as the concurrent inhibition, resulting in an analgesic response. Another possible explanation for the absence of the analgesic effect in chronic pain conditions is that the noxious input associated with performing a resistance exercise at the knee, acts to shut down or decrease the inhibitory inputs, thereby diminishing the analgesic response. Regardless of the cause, the EIA or lack thereof in knee OA (or other conditions) appears to be highly individualised. As seen in the present study, there was a wide variance in response of the OA group to the lower body exercise.
Following the bouts of exercise, pressure pain tolerance was unchanged in the OA, old healthy and young healthy groups (Fig. 3). Our measure of pain tolerance was conducted over a 5 min period during which participants were asked to rate their pain every 30 s. This task required a greater degree of cognitive processing than the threshold testing, due to constant monitoring and rating of the pain over an extended time period. Many factors including context, attention, expectation, fear, anxiety and past pain experiences can influence pain processing and may have influenced our pain tolerance results. For example, attention to a painful stimulus influences pain perception45, while distraction from a painful stimulus can attenuate pain perception46. Reporting the pain ratings every 30 s in the absence of any distraction may have increased the participants' attention to the painful stimulus, augmenting pain perception. Threat expectancy during the 5 min pressure pain test may have influenced the participants' perception of the pain37. Other highly individualised cognitive processes associated with fear, anxiety and previous pain experiences may also have contributed to the pain tolerance results47. It appears that a test of pain sensitivity under greater influence of higher processing is less sensitive to exercise than simple measures of pain threshold.
Although the pain experience of people with knee OA can involve psychological factors, such as fear and anxiety48, the pain tolerance measure was still unaffected in this group. Studies that have shown global self-reported pain to decrease with exercise training in individuals with OA1,2 have not assessed which aspect of the pain experience is affected. Somewhat in contrast to our results are previous findings that in healthy individuals chronic training increases pain tolerance but not pain threshold24. It may be that long-term training increases an individual's pain tolerance, whilst the immediate effects of a single exercise bout modulate pain thresholds. Regardless, the demonstration that acute exercise can reduce pain sensitivity in people with knee OA hints at the possibility that a reduction in pain sensitivity may be part of the adaptive response to chronic exercise.
A limitation of this study is uncertainty regarding the duration of the analgesic response to exercise. It has been shown that analgesia following aerobic exercise can last as long as 30 min, while the effect following resistance exercise is of shorter duration16,17. In this study, pain was measured immediately following exercise, with no follow up measures. It would be of interest to measure how long the analgesic response lasted with repeated measures after exercise. A further limitation was the small sample size, which may have contributed to the lack of between-group differences13 and some within-group effects lying on the margin of statistical significance.
The findings of this study may have clinical implications. Firstly, individualised prescription should be recommended for knee OA since exercising the affected limb at 60% 1RM reduced pain sensitivity in some of the knee OA group yet increased sensitivity in others. For knee OA patients with a low tolerance for lower-body exercise, conservative individualised exercise prescription is likely to reduce the risk of symptom exacerbation. Secondly, and a key finding of this study, exercising unaffected limbs may produce a systemic analgesic response without the risk of symptom flare up, though the duration of this effect is unclear and the analgesic response was measured for experimentally induced pain rather than specific clinical symptoms of knee OA. As noted in the introduction, quantitative sensory testing is reliable in individuals with knee OA29, can distinguish between individuals with knee OA and healthy controls13,14,30 and also correlates with WOMAC scores32. Despite this evidence, caution should be taken when inferring clinical significance from a change in experimentally induced pain. Notwithstanding these limitations, for those individuals with a poor tolerance of lower-body exercise, such as people just commencing an exercise intervention, upper-body exercise may be prescribed to evoke an analgesic response. It remains to be determined if and how this acute effect of resistance exercise on pain sensation may manifest as an adaptation to chronic exercise.
