@phdthesis{01JKDQHRMRT85ED3NPDD0BVFHV,
  abstract     = {{Pain (i.e., nociception) is a universal experience, yet this experience varies widely among and even within individuals. Due to internal (i.e., endogenous) pain relieving (i.e., inhibition) and pain enhancing (facilitation) strategies at the spinal cord and brain (i.e., supraspinal), our body is able to modulate pain transmission, consequently modulating the pain experience. In research settings, these strategies are frequently evaluated to determine in which aspects patients with chronic pain differ from healthy, pain-free persons and to evaluate treatment effects. However, endogenous pain modulation and spinal nociception are susceptible to influence by individual factors. On the one hand, such factors need to be identified to be taken into account during evaluation of endogenous pain modulation and spinal nociception. On the other hand, knowledge of individual modifiable factors influencing endogenous pain modulation and spinal nociception might offer potential future treatment strategies for patients with chronic pain.
Therefore, this dissertation aimed to determine which individual factors influence endogenous pain modulation, whether patients with chronic pain show alterations in endogenous pain modulation compared to pain-free persons, wether the outcome on the Central Sensitization Inventory (CSI) correlates with endogenous pain modulation, and which non-conservative and conservative treatments can modulate spinal nociception and endogenous pain modulation. To address these aims, six studies were performed and one study-protocol was developed. Consequently, this dissertation is divided in three major parts, each addressing a research objective:
Part I of this dissertation comprises two chapters, including one cross-sectional study and one systematic review with meta-analysis, and addresses the following research question: Which individual factors influence measures of endogenous pain modulation?
The cross-sectional study described in chapter one showed that up to 10.2% of variation in endogenous pain modulation can be predicted by self-reported physical activity. More precisely, the amount of time an individual reports to spend on physical activity in total, on walking, and on performing moderate physical activity was found predict variation in endogenous pain modulation in healthy persons. However, no significant relation between monitor-based measures of physical activity and endogenous pain modulation were found. These findings are promising, but further research is needed to determine whether physical activity also benefits patients with chronic pain and impaired endogenous pain modulation. Incidentally, this study observed that men exhibited significantly greater endogenous pain modulation than women, despite a lack of significant sex differences in physical activity. Likewise, analysis of the results revealed by chance that endogenous pain modulation significantly improves with age.
The systematic review and meta-analysis described in chapter two provided moderate-quality evidence for the influence of attention on endogenous pain modulation. More precisely, attentional focus directed to the conditioning stimulus results in greater endogenous pain inhibition. Very low quality evidence was found for the influence of intrinsic attention on endogenous pain modulation, demonstrating that more intrinsic attention to pain is associated with less
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efficient endogenous pain modulation. Evidence for the influence of distraction on endogenous pain modulation was rather conflicting. Likewise, conflicting evidence was found for the influence of expectations on endogenous pain modulation. Due to the limited number of studies identified using the systematic search and due to the limited and often conflicting nature of evidence found, more research is needed to unravel the relation between psychological factors and endogenous pain modulation.
Part II of this dissertation entails two chapters, including one systematic review with meta-analysis and one cross-sectional study, and addresses the following research question: Do patients with chronic pain show alterations in spinal nociception , assessed using the nociceptive flexion reflex (NFR), compared to pain-free persons and is the Central Sensitization Inventory (CSI) associated with endogenous pain modulation?
The systematic review and meta-analysis described in chapter three provided low-to-moderate-quality evidence for spinal hyperexcitability as demonstrated by significantly lower NFR threshold, larger NFR area, shorter NFR latency, and lower temporal summation of the NFR in patients with chronic musculoskeletal pain or headache. However, no evidence was found for alterations in NFR duration and NFR magnitude.
The cross-sectional study described in chapter four found no evidence for a correlation between the CSI and measures of endogenous pain modulation, as only one significant yet negligible positive correlation between the CSI and endogenous pain modulation was found. However, several significant, yet weak to moderate, correlations between CSI and questionnaires of anxiety and depressio (i.e., HADS), illness perception (i.e., IPQ), and health-related quality of life (i.e., RAND-36) were identified. This suggests that the CSI is more closely related to psychological features associated with human-assumed central sensitization (HACS) (i.e., anxiety, depression, sleep, fatigue) than measures endogenous pain modulation .
Part III of this dissertation is composed of three chapters, including two systematic reviews with meta-analysis and one study protocol for a randomized controlled trial, and addresses the following research question: Can non-conservative and conservative treatments modulate spinal nociception and endogenous pain modulation?
The systematic review and meta-analysis described in chapter five found low quality evidence for an increase in the NFR threshold and decrease in NFR area and very low quality evidence for an increase in NFR latency following non-conservative treatment. This implies that non-conservative treatment can decrease spinal hyperexcitability, as the NFR occurs at higher stimulus intensities, later, and has a smaller muscle response following treatment. More precisely, non-conservative treatments found to decrease spinal hyperexcitability included surgery, medication targeting the musculoskeletal system, medication targeting the alimentary tract and metabolism, and medication targeting the nervous system. Additionally, very low-to-low quality evidence for the absence of an effect of non-conservative treatment on NFR magnitude and temporal summation of the NFR was found.
In line with chapter five, the systematic review and meta-analysis described in chapter six found low-to-moderate quality evidence showing that conservative therapy decreases the NFR area and NFR magnitude, and
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increases the NFR latency, thereby decreasing spinal hyperexcitability. In contrast, low-to-moderate quality evidence showed no effect of conservative therapy on the NFR threshold in response to single and repetitive stimulation. More precisely, conservative treatments found to decrease spinal hyperexcitability included non-invasive neuromodulation techniques, hypnotic analgesia, progressive muscle relaxation, pain catastrophizing reduction, and repeated eccentric exercise. However, certain treatment effects remained limited to certain subgroups (i.e., either patients or healthy persons) and thus require further research.
Chapter seven describes the protocol for a randomized controlled trial to examine the effects of conservative treatment, namely specific skilled motor training and general exercise training, on endogenous pain modulation and spinal nociception (i.e., as a secondary study aim). The results of this study will contribute to our knowledge of immediate and long-term effects of conservative treatment on spinal nociception and endogenous pain modulation, as well as whether this influence is mediated by physical and psychological factors.
In conclusion, this dissertation provided a clear overview of the individual factors influencing endogenous pain modulation. These factors should be taken into account when performing assessments of endogenous pain modulation. Additionally, these factors might provide potential treatment strategies for patients suffering from chronic pain. Therefore, future research should continue to explore their influence on endogenous pain modulation, including populations with chronic pain. Further research is needed to unravel the constructs of the CSI. A comprehensive update of the evidence was provided for the presence of spinal hyperexcitability in patients with chronic pain. Moreover, measures of spinal nociception were found to be responsive to conservative and non-conservative treatments and can thus be used to monitor treatment effects. More research is needed to examine the effectiveness of the identified conservative and non-conservative treatments when it comes to modulating spinal nociception in patients with chronic pain.}},
  author       = {{Van Oosterwijck, Sophie}},
  keywords     = {{central sensitization,conditioned pain modulation,endogenous pain modulation,human assumed central sensitization,nociception;nociceptive flexion reflex,pain,spinal hyperexcitability,withdrawal reflex,exercise induced hypoalgesia,chronic pain,chronic headache,chronic musculoskeletal pain,Central Sensitization Inventory}},
  language     = {{eng}},
  pages        = {{389}},
  publisher    = {{Ghent University. Faculty of Medicine and Health Sciences}},
  school       = {{Ghent University}},
  title        = {{Endogenous pain modulation and spinal nociception : assessment and treatment in people with and without persistent pain}},
  year         = {{2025}},
}