Digital pressure algometer

PPT were examined using a digital pressure algometer (Wagner Instruments, Greenwich, Connecticut, USA). Studies have shown excellent inter‐rater reliability for PPT assessment in healthy individuals at different body regions (Jayaseelan et al. 2021 (link); Waller et al. 2015 (link)). The precise assessment procedure was similar to the study conducted by Tomschi et al. (2022 (link)), with the adjustment that each landmark was assessed twice consecutively. In short, the pressure was constantly increased (10 Newton/s) until the subject verbally indicated that the pressure first became painful. Peak pressure was set at 120 Newton/cm² to avoid the risk of tissue irritation. At each landmark, two measurement series were conducted, and the average value was used for statistical analyses. Higher values indicate a lower level of pain sensitivity.
To ensure standardised assessment of outcomes, the body areas were marked prior to the first measurement series. Landmarks assessed for PPT comprised the rectus femoris muscle (RF) at the centre of the distal third between the patella base and the anterior superior iliac spine (Vaegter et al. 2018 (link)) and the lateral area of the acromial part of the deltoid muscle (DM) (Persson et al. 2004 (link)) as muscular measurement points. The knee joint (KJ) between the medial condyle of the femur and the medial condyle of the tibia (Tomschi, Ransmann, et al. 2024 (link)) and the sternum (ST) two finger widths above the xiphoid process were determined as non‐muscular measurement points (Tomschi et al. 2023 (link)). All PPT measurements were performed in the same presented sequence. PPT assessment of each participant was carried out by the same investigator.

Outcome assessment was performed at baseline, immediately after treatment, and at 3-, 6-, and 12-month follow-up. The primary end point was 12-month follow-up. For details, see the a priori published protocol^{23 (link)} and in Supplement 1.
The primary clinical outcome was mean pain intensity, assessed using the Brief Pain Inventory (BPI)^{24 (link)} item mean pain intensity in the last 24 hours evaluated on an 11-point numeric rating scale (minimal clinically important difference [MCID] = 30% decrease).^{15 (link),25 (link)}Exploratory secondary pain-related outcomes comprised self-reported pain outcomes, including BPI worst and least pain intensity (past 24 hours), BPI pain intensity now (ie, at the time of assessment), BPI pain severity and interference, and symptoms of central sensitization, assessed via the Central Sensitization Inventory (>40 of 100 indicates the presence of central sensitization-related symptoms).^{26 (link),27 (link)} Pressure pain thresholds (MCID = increase >15%²⁸ ) were assessed with a digital pressure algometer (Wagner Instruments) randomly applied at the painful location and 2 remote locations.^{29 (link),30 (link)}Exploratory secondary sleep-related outcomes included data on perceived sleep quality assessed by the Pittsburgh Sleep Quality Index (cutoff = 6 of 21 points; MCID = 3 points^{31 (link),32 (link),33 (link)}); insomnia severity assessed by the Insomnia Severity Index (cutoff = 14 of 28 points; ie, scores ≤14 considered as remittance; MCID = 6 points; ie, reduction ≥6 points qualifies as response^{32 (link),34 (link),35 (link)}); sleep- and insomnia-related cognition, assessed by the Dysfunctional Beliefs and Attitudes About Sleep questionnaire^{36 (link),37 (link)}; sleep propensity measured by the Epworth Sleepiness Scale^{38 (link)}; and mental and physical fatigue assessed by the Brugmann Fatigue Scale.^{39 (link)} Additionally, objective sleep outcomes were assessed using at-home PSG (portable Alice PDX, Philips Respironics Inc) and included sleep-onset latency, wake duration after sleep onset, early-morning awakening, time in bed, total sleep time, sleep efficiency, percentage in rapid eye movement (REM) and non-REM sleep, and number of arousals (eMethods in Supplement 2 provides details).
Other explorative secondary outcomes included depressive symptoms and anxiety (measured with the Hospital Anxiety and Depression Rating Scale, cutoff = 7 of 21 points; MCID = 1.7 points^{40 (link),41 (link),42 (link)}); objective physical activity–related outcomes (recorded over 7 consecutive days using 3-axis accelerometers, GT9X-BT, Actigraph^{43 (link),44 (link)}), including step count and percentage of time in sedentary, light, moderate, and moderate/vigorous physical activity (analyzed using ActiLife6, Actigraph Corporation LLC); health-related QOL (ie, the 36-item Short-Form Health Survey^{45 (link)}); adverse events, classified as serious (led to death, life-threatening, required hospitalization, prolonged hospitalization, and led to prolonged or major disability).

To assess the patients’ subjective pain intensity, the visual analogue scale (VAS) was used; on a 100 mm long line, this runs from 0 points (no pain) to 10 points (maximum pain imaginable) [21 (link)]. This scale has been demonstrated to have good sensitivity and specificity for patients with FM [22 (link)].
Pressure pain thresholds (PPTs) were recorded using a digital pressure algometer (Wagner Instruments, Greenwich, CT, USA) at the 9 points established by the ACR. Bilaterally, three measurements were taken at each point with a 30 s rest period in between, so that the final variable was the arithmetic mean of the three assessments. The reliability for this method of measuring the PPT has been found to be high [23 (link)].