Background & Aims

Pain is a subjective, multifaceted experience that varies substantially between and within chronic pain patients and is characterized by somatosensory, affective, and cognitive components. Therefore, high and low day-to-day pain severity fluctuations can be observed in different individuals. Interestingly, recent guidelines suggest that patients with high day-to-day baseline pain fluctuations could be excluded from randomized controlled trials (RCTs) using so-called enrichment protocols to enhance homogeneity in a study sample (US FDA, 2019). However, whether high day-to-day fluctuations (“dynamic pain”) or a consistent pain experience (“static pain”) contributes to better or worse therapeutic outcomes is an ongoing debate. Here we explored data from our recently published longitudinal neuroimaging trial (Lee et al., 2024), to identify associations between clinical outcomes and neural nociceptive processing, focusing on the influence of baseline day-to-day pain variability.

Methods

Our longitudinal MRI study included data from fibromyalgia patients (N=61, all female, age (SD)=41.27 (12.54) years) randomized to an 8-week cognitive behavioral therapy (CBT) or a duration-matched education-control (EDU) intervention. We investigated the impact of baseline daily reported pain fluctuations, i.e., standard deviation of pain severity over 7 consecutive days, on baseline brain responses to nociceptive stimuli and clinical outcomes post-intervention. Preceding the intervention, patients underwent an evoked leg cuff pressure pain paradigm during whole-brain fMRI (Siemens Skyra 3T-MRI, TR/TE=1250/33ms, voxel size 2mm3 isotropic, SMS MB acc. factor 5). The task included six left leg cuff stimulations of either non- or moderately-painful pressures (calibrated to individuals’ threshold for 40/100 pain). FMRI analysis focused especially on pain anticipation. Clinical outcomes included the Pain Catastrophizing Scale (PCS), a specific target of CBT, and Brief Pain Inventory.

Results

Greater baseline day-to-day clinical pain fluctuations were associated with greater post-therapy improvement in pain catastrophizing in the CBT (r=-0.32, p=0.02) but not the EDU (r=0.18, p=0.47) group. Furthermore, combining both groups together, greater day-to-day baseline pain fluctuations were related to increased baseline expectations for intervention-related pain relief (r=0.35, p=0.02) as well as lower baseline pain anticipatory BOLD-fMRI activation in nociceptive processing areas (i.e., primary-somatosensory-cortex, insula, and superior-parietal-lobule). The results suggest that greater clinical baseline pain fluctuations may boost CBT treatment effects by influencing nociceptive circuitry recruitment during the anticipation of pain. A potential explanation could be that higher baseline pain fluctuations or the initial “prospect for change” seem to be reflected by a lower neural processing load in preparation for upcoming pain (lower preparatory effort needed).

Conclusions

Importantly, this study highlights the predictive importance of clinical pain variability in longitudinal interventional research involving chronic pain populations. Individual day-to-day pain fluctuations should be considered meaningful and can potentially be used as beneficial modulators to improve outcomes of clinical interventions for chronic pain, particularly non-pharmacological interventions such as CBT. The results of this study provide strong evidence that fluctuations in daily pain should not be considered a bias but rather an important characteristic of chronic pain.

References

US Food and Drug Administration. (2019). Enrichment strategies for clinical trials to support determination of effectiveness of human drugs and biological products. Guidance for industry.

Lee, J., Lazaridou, A., Paschali, M., Loggia, M. L., Berry, M. P., Ellingsen, D. M., Isenburg, K., Anzolin, A., Grahl, A., Wasan, A.D., Napadow, V. & Edwards, R. R. (2024). A Randomized Controlled Neuroimaging Trial of Cognitive Behavioral Therapy for Fibromyalgia Pain. Arthritis & Rheumatology, 76(1), 130-140. https://doi.org/10.1002/art.42672

Presenting Author

Arvina Grahl

Poster Authors

Arvina Grahl

PhD

Spaulding Rehabilitation Hospital/Harvard Medical School

Lead Author

Maya Barton-Zuckerman

Spaulding Rehabilitation Hospital, HMS

Lead Author

Jeungchan Lee

Spaulding Rehabilitation Hospital, HMS

Lead Author

Myrella Paschali

Brigham & Women’s Hospital, HMS

Lead Author

Asimina Lazaridou

Brigham and Women's hospital/Harvard Medical School

Lead Author

Michael P. Berry

Massachusetts General Hospital, HMS

Lead Author

Laura Isaro

Brigham & Women’s Hospital, HMS

Lead Author

Kylie Isenburg

Massachusetts General Hospital, HMS

Lead Author

Alessandra Anzolin

Spaulding Rehabilitation Hospital

Lead Author

Robert Edwards

PhD

Brigham & Women's Hospital/Harvard Medical School

Lead Author

Vitaly Napadow

Spaulding Rehabilitation Hospital

Lead Author

Topics

  • Pain Imaging