Individual factors and treatment modalities influencing the nociceptive flexion reflex

Chronic pain is a highly prevalent global health problem, which has been linked to numerous physical and mental conditions and contributes to large health care costs and lost productivity. As treatment for chronic pain is often multimodal and expensive, it is essential to deliver an accurate and fast diagnosis. Because pain modulation does not only occur via the supraspinal circuitry but also at the spinal level, a measure of spinal nociception is needed. The quest for a relatively objective measure of spinal nociceptive processes has led to the nociceptive flexion reflex (NFR), a spinally-mediated withdrawal reflex which is elicited by activation of A-delta fibers following noxious stimulation. The NFR is used increasingly as a diagnostic tool in pain research but a more broad use of the reflex is impeded by large between-subject variability. Moreover, a clear overview of which conservative interventions and to what extent they affect spinal nociception does not exist. Therefore, the overall aim of the present dissertation was to gain more insight into individual factors and treatment modalities influencing the NFR. To address this general aim, six studies were performed, which divide the present dissertation into three major parts, each dealing with one major objective: Part I comprises four chapters, including two systematic reviews and two original research studies, and addresses the following research question: What are the individual factors influencing the NFR? The meta-analysis described in chapter one showed higher NFR thresholds in men compared to women. Furthermore, the qualitative analysis provided some evidence indicating that the NFR threshold is increased (i.e., inhibition) during systole, in individuals with higher levels of physical activity (PA), after full-inhalation and exhalation, and during sleep. In contrast, the NFR threshold seemed to be reduced (i.e., facilitation) in the early morning, in overweight individuals, in African Americans compared to non-Hispanic Whites, and during decreased blood glucose levels. Although the evidence was based on one single study, a genetic predisposition to hypertension was shown to affect temporal summation of the NFR. In conclusion, this review pointed out several individual factors that should be taken into account in future studies examining spinal nociception through the NFR. The systematic review described in chapter two provided clear evidence to support the use of the NFR as a stimulation (i.e., test stimulus) and scoring parameter in experimental conditioned pain modulation (CPM) paradigms. Indeed, independent of the sensory modality of the conditioning stimulus, a substantial CPM effect was observed as evidenced by inhibition of the NFR that outlasts the conditioning period by several minutes. Although strong evidence is lacking, future studies examining CPM of the NFR are advised to take into account the potential influence of age and an age-related decline of cognitive inhibitory processes. However, in view of the limited and somewhat conflicting evidence regarding the influence of individual factors on NFR modulation by CPM, more elaborate research is required to be able to provide a clear overview of potential influencing factors, resulting in more accurate CPM paradigms using the NFR as a stimulation and scoring parameter. The cross-sectional study described in chapter three provided preliminary evidence indicating that a physically active lifestyle may reduce spinal nociception in healthy adults, while a sedentary lifestyle enhances spinal nociception. In particular, larger amounts of step counts and higher participation in moderate-to-vigorous intensity activities predicted higher NFR thresholds, indicating that low-threshold activities like walking have the potential to inhibit spinal nociception. Furthermore, spending more time per day on activities of sedentary intensity predicted lower NFR thresholds. This study provided a rationale for considering PA levels evaluated using monitor-based measures when assessing spinal nociceptive processing, and for examining the effects of moderate-to-vigorous intensity exercise programs on spinal nociception. The randomized cross-over study described in chapter four showed that low-to-moderate levels of experimentally induced localized muscle and mental fatigue did not affect the NFR in healthy adults. These results suggest that spinal nociception is resistant to the effects of localized muscle and mental fatigue. The relative robustness of the NFR to fatigue may be beneficial in both clinical and research settings where the influence of confounders complicates the interpretation of test results. Furthermore, the findings possibly help enhance our understanding on why even demanding cognitive/physical exercise-based treatment programs form effective treatment strategies for patients with chronic pain. Part II is composed of one chapter, describing one systematic review, and addresses the following research question: Is there evidence for decreased threshold and increased temporal summation of the NFR in patients with chronic musculoskeletal pain (MSKP) compared to healthy people? The meta-analysis described in chapter five provided low-to-very low quality evidence for the presence of spinal hyperexcitability in patients with chronic MSKP, as demonstrated by lower NFR thresholds in response to single and repetitive (i.e., temporal summation) electrical stimulation. However, future research is needed to address the gap in research on temporal summation of NFR and to address the poor methodological quality in the current body of NFR research. Part III includes one chapter, describing one systematic review, and addresses the following research question: Can the human NFR be modulated by conservative therapy? The meta-analysis described in chapter six provided low quality evidence showing that conservative therapy decreases NFR area and NFR magnitude, and moderate quality evidence for increases in NFR latency. This suggests that conservative interventions can exert immediate central and/or peripheral effects to reduce spinal nociception. The conservative interventions which have been identified in the present review as effective treatment strategies for reducing spinal nociception in pain chronic populations (i.e., repetitive transcranial magnetic stimulation, biofeedback training, cognitive-behavioral therapy, manual therapy) may help prevent and treat chronic pain which is characterized by enhanced spinal nociception. In conclusion, this dissertation provided a clear overview of the individual factors and treatment modalities influencing the NFR. When using the NFR as a valid clinical tool for assessing chronic pain risk, the variables known to influence its assessment should be considered as factors contributing to chronic pain risk. Hence, findings would act as a first step towards the development of NFR-assisted diagnostic criteria to provide chronic pain patients with a more accurate and a much faster diagnosis of biological underpinnings. Furthermore, the identification of modifiable factors influencing the NFR may pave the path for future interventional studies. Indeed, in both therapeutic and preventive approaches it may be of great interest for clinicians to address modifiable factors in a positive way in order to reduce enhanced spinal nociception as evidenced by NFR facilitation. In addition, future studies should examine whether the conservative treatments which have been identified in this dissertation effectively reduce enhanced spinal nociception in chronic pain patients and whether or not they assimilate to reductions in clinical pain and disability