Feasibility and reliability of a quantitative sensory testing protocol in youth with acute musculoskeletal pain post-surgery or post-injury

Abstract

Quantitative sensory testing (QST) is increasingly used in pediatric chronic pain; however, assessment in youth with acute musculoskeletal (MSK) pain is limited. This study evaluated the feasibility, reliability, and sources of variability of a brief QST protocol in two clinical samples of youth with acute MSK pain. Participants were 277 youth (M_age=14.5 years, SD=2.0, range=11–18 years, 59% female, 83% non-Hispanic) across 3 geographic study sites who completed a QST protocol assessing pressure and thermal pain sensitivity, temporal summation of pain (TSP), and conditioned pain modulation (CPM) 8-weeks post MSK surgery (n=100) or within 4-weeks following an acute MSK injury (n=177). High feasibility was demonstrated by protocol completion rates ranging from 97.5%−100% for each task, with 95.3% of youth completing all tasks. Reliability was high, with reliability coefficients > 0.97 for 7 out of 8 QST parameters and minimal influence of examiner or participating site effects. Younger youth had lower pressure and heat pain thresholds (11–12 vs. 13–18 years, d=−0.80 to −0.56) and cold pain tolerance (d=−0.33). Hispanic youth had higher pressure and heat pain thresholds (d=0.37–0.45) and pain ratings for cold pain tolerance (d=0.54) compared to non-Hispanic youth. No significant differences were observed in QST values by sex or personal contextual factors at time of assessment (momentary pain, menstrual period, use of pain medications). Overall findings demonstrate feasibility of a brief QST protocol with youth with diverse acute MSK pain and data provide initial support for the reliability of this QST protocol for multisite research studies.

1. Introduction

Musculoskeletal (MSK) pain is common in both adult and pediatric populations. The annual incidence of MSK pain in any bodily location among community samples of youth is as high as 38%[19]. Chronic MSK pain is also highly prevalent[11; 13; 21; 28; 30; 38], with a 12-month prevalence of 27%[39], contributing to 8.71 million annual outpatient visits among adolescents in the US[18]. The prevalence of MSK pain among adolescents has increased over the past several decades[22; 42], highlighting the importance of preventing and reducing the impact of MSK pain among youth. Identifying youth with acute MSK pain who are at elevated risk for persistence of pain is an important step toward preventing long-term pain and disability.

Quantitative sensory testing (QST) is a series of non-invasive tasks in which mechanical, thermal, and/or other sensory stimuli are applied to quantify self-reported sensory perception. QST measures of pain sensitivity and modulation have been identified as potentially important pain biomarkers[14], with potential for identifying youth with acute MSK pain at risk of pain persistence[2; 48]. To our knowledge, only one prior study has applied QST methodologies in youth with acute MSK pain, testing conditioned pain modulation (CPM) among a sample of adolescents with new-onset MSK pain[27].

The German Research Network on Neuropathic Pain (DFNS) QST protocol has demonstrated strong validity among healthy children aged 6–16 years[8]. However, the four- hour protocol duration limits feasibility. Among adolescents with chronic pain[31; 32; 44–46; 50; 52], there is significant heterogeneity in QST protocols used, particularly for dynamic QST modalities (e.g., temporal summation of pain [TSP] and CPM), and feasibility and reliability have been minimally examined. A feasible and reliable QST protocol is a first step in implementing QST in acute MSK pain samples. There is also a clear need to standardize QST protocols for facilitating comparison of findings across studies and combining data from different laboratories. A recent systematic review of adult studies revealed inconsistent associations between QST and clinical MSK pain, with variation in QST protocols highlighted as the major reason for inconsistencies[20; 34; 36].

In addition to feasibility and reliability, identifying contributors to individual variability in QST profiles is important for comparing and interpreting group differences. Sociodemographic characteristics and personal contextual factors such as concurrent pain, medications, and menstrual cycle may influence QST values[34; 37] and therefore need to be evaluated in research examining prognostic value of QST in acute MSK pain.

The objectives of the current study were to (1) evaluate the feasibility of a standardized brief QST protocol developed for youth with MSK pain tested among two clinical samples of youth with acute MSK pain (Post-MSK Surgery Sample, Post-MSK Injury Sample) across 3 study sites, (2) describe the reliability of QST measurements across examiners and study sites, and (3) investigate sources of individual variability in QST parameters by demographic (age, sex, ethnicity) and personal contextual factors (momentary pain, menstrual cycle, analgesic use). An exploratory aim examined potential associations between QST and acute MSK pain characteristics.

2. Methods

Data were collected as part of two ongoing longitudinal studies examining the transition from acute to chronic MSK pain among youth at three pediatric specialty hospitals in the Western United States (Site A, Site B, and Site C). Studies were approved by the Institutional Review Boards at the three sites. Participants in these studies were recruited from two acute MSK pain samples—youth undergoing spinal fusion surgery (Post-MSK Surgery Sample, Study 1) and youth with new-onset acute MSK pain (Post-MSK Injury Sample, Study 2). Baseline demographic data, as well as QST and questionnaire data collected at the acute post-MSK surgery/injury timepoint were included in the present analyses. Specifically, we included the acute time point following insult (i.e., around 8-weeks post-MSK surgery and within 4-weeks post-MSK injury) to reflect the acute to subacute phase of MSK pain. Parents reported baseline demographic characteristics. Youth completed the QST protocol and provided self-report on acute pain at 8-weeks post-surgery for the Post-MSK Surgery Sample (Study 1, Site A and Site B), or within 4-weeks of injury for the Post-MSK Injury Sample (Study 2, Site A and Site C). Study data were collected and managed using REDCap electronic data capture tools hosted at the research institution at each study site[23; 24]. This is the first paper reporting QST protocol and data from these 2 longitudinal studies. Three papers have been published using data from the Post-MSK Injury sample[3; 25; 26]; none utilized QST in aims or analyses.

2.1. Participants

Sample 1 participants were youth aged 10–18 years undergoing spinal fusion surgery for idiopathic scoliosis, juvenile scoliosis, spondylolisthesis, and kyphosis. Exclusion criteria were: chronic medical condition requiring daily medication, recent psychiatric admission, history of prior major surgery (e.g., spine or cardiac surgery), parent or child non-English/Spanish speaking, or severe developmental delay or cognitive impairment. In addition, we excluded youth currently receiving treatment for chronic pain.

Sample 2 participants were youth aged 11–17 years with acute MSK pain in the legs, back or neck regions (e.g., sprain, fall, sports injury, non-displaced fracture) receiving ambulatory treatment at the emergency department or outpatient clinic (e.g., orthopedics, primary care). Youth with pain associated with infection or disease process, flesh wound/laceration, self-injury, moderate to severe head injury, or requiring surgery were excluded. Additional exclusion criteria were: prior injury at the MSK pain site in the past 2 years, history of prior major surgery or major hospitalization (>1 week), psychiatric admission in the past year, parent or child unable to understand written or spoken English, or severe developmental delay or cognitive impairment.

2.2. QST procedures

2.2.1. QST Examiner Training

Each clinical research associate (examiner) at the 3 study sites completed standardized training consisting of: an 8-hour workshop on QST procedures and techniques with the study P.I. and study manager (i.e., task and protocol training), 20-hours of training and independent practice over 5 weeks, an initial proficiency assessment in which the research associate conducted a supervised mock QST testing to identify skills that needed additional practice, and a final mock QST testing demonstration to confirm that the procedures were mastered. At minimum, research associates were required to either conduct two QST testing procedures per month or conduct one testing and observe an additional testing per month. Proficiency evaluations were conducted every 6 months to ensure consistent conduct of QST procedures and adherence to the research protocol. Each clinical research associate maintained a record of their training and proficiency.

2.2.2. QST Procedures

Prior to beginning the QST assessment, participants were given scripted instructions, told what to expect, and taught how to use the pain-rating scale. Participants were also asked whether they were left-handed or right-handed. Each participant completed the QST battery with one of the 15 research associates, without the presence of their parent. Research associates followed a standardized script throughout the protocol. During breaks, participants waited in a quiet private area without access to electronic devices or family members. See Figure 1 for the order of QST tasks and breaks and the anatomic location of each QST task. The QST assessment procedure (including participant instructions and breaks) takes 50–55 min to complete. Across all tasks, reasons for missing data were noted by the clinical research associate as free text. Procedures for individual tasks are described below.

Figure 1.

Description of the brief QST protocol applied among two samples of youth with acute musculoskeletal (MSK) pain.

2.2.2.1. Pressure Task

Pressure stimuli were applied to both the forearm and trapezius, with sites chosen based on accessibility and relevance to MSK pain. Participants were sitting close to a table, with their legs uncrossed and planted on the floor and their arm on the table. Pressure stimuli were produced by using the computerized pressure algometer, AlgoMed (Medoc). The rubber tip of 1 cm² was applied to the dorsal forearm with the participant’s arm palm down, 2 cm distal to the elbow crease at the maximal prominence of the extensor digitorum muscle body, based on higher reproducibility in adults of pressure thresholds over the muscle body[40] (see Figure 2). Increasing pressure was applied at a rate of 35 kPa/sec to a ceiling pressure of 1000 kPa. Participants were asked to press a trigger (using their nondominant hand) once the pressure stimulus became painful, specifically “You need to push the button on this controller when the pressure becomes painful to you”. Pressure tests were repeated for 4 trials with a 10-second break between trials. After each trial the algometer was moved to an adjacent location to prevent sensitization. The first trial was removed, the mean pressure threshold of all available remaining trials was computed to yield pressure pain threshold at the forearm (PPT_forearm; kPa). Immediately after completing the pressure task, participants were asked “How much pain did you feel during the pressure activity?” using an 11-point numerical rating scale (NRS) to verify that they had experienced pain when pressing the button.

Figure 2.

Assessment of pressure pain threshold (PPT) at the forearm. (A) The rubber tip was applied to the dorsal forearm with the participant’s arm palm down, 2 cm distal to the elbow crease at the maximal prominence of the extensor digitorum muscle body. (B) Algometer was held perpendicular to the site of pressure, and the angle was directed to the middle of the arm (not toward edge) to prevent slipping or pushing of participant’s muscle.

For the pressure task performed at the trapezius, C7 spinous process and the spine of the scapula were located. The rubber tip was applied to the biggest bulge of the interceding muscle body which is about 3 fingers lateral of the spinous process and 2 fingers medial from edge of shoulder (see Figure 3). Participants pressed the trigger (using their nondominant hand) once the pressure stimulus became painful following the same cue as the forearm task. Trapezius pressure tests were similarly repeated for 4 trials with a 10-second break between trials. After each trial the algometer was moved to an adjacent location to prevent sensitization. The first trial was removed, the mean pressure threshold of all available remaining trials was computed to yield pressure pain threshold at the trapezius (PPT_trapezius; kPa). To verify they experienced pain during the stimulus, participants were asked “How much pain did you feel during the pressure activity?” using the same 11-point NRS.

Figure 3.

Assessment of pressure pain threshold (PPT) at the trapezius. (A) The rubber tip was applied to the biggest bulge of the interceding muscle body which is about 3 fingers lateral of the C7 spinous process and 2 fingers medial from the spine of the scapula. (B) Algometer was held perpendicular to the site of pressure.

2.2.2.2. Temporal Summation of Pain (TSP) Task

Participants underwent an assessment of mechanical temporal summation of pain using weighted pinprick stimulators. The TSP protocol was based on previous studies of adult populations including women with postsurgical pain and patients with MSK pain [15–17]. Punctate mechanical stimuli were delivered to the dorsal surface of the middle finger of the dominant hand using a set of weighted pinprick stimulators (between 8mN and 512mN) used by the German Research Network on Neuropathic Pain, for the assessment of temporal summation of pain (TSP)[41]. We started with the lowest force and determined the highest force stimulator (128 or 256 mN for most participants) that produced pain equal to 1 on a 0 to 10 NRS for pain intensity. If participants did not rate any stimulus at 1/10, the pinprick stimulator with the next higher pain rating (2, 3, etc.) was selected; if participants rated 0 pain for all stimulators, the 5^th pinprick stimulator was selected. We then applied a train of 10 stimuli with the selected pinprick stimulator at the rate of 1 stimulus per second (see Figure 4). Participants rated the pain intensity (0–10 NRS) of the first, fifth, and tenth stimulus. We quantified the magnitude of TSP as the difference in the pain rating between the tenth to the first stimulus as has been done in previous studies[15; 17].

Figure 4.

Assessment of temporal summation of pain (TSP). Punctate mechanical stimuli were delivered to the dorsal surface of the middle finger of the dominant hand for 10 times.

2.2.2.3. Heat Task and Conditioned Pain Modulation (CPM)

Youth participated in the heat task during which heat thermal stimuli were produced by an FDA approved QSense System (Thermal Sensory Analyzer 2001, QSense CPM, Medoc Ltd, Advanced Medical Systems, Ramat Yishai, Israel) with a 30 × 30 mm Peltier contact thermode applied to the dominant inner forearm. Baseline temperature was 32°C with a maximum temperature of 50°C. The temperature increased linearly at 1.5°C/second from baseline and participants were asked to press a trigger (using their dominant hand) when the heat stimulation became painful. Temperature then decreased to baseline at a rate of 1°C/second. Consistent with previous studies[27; 52], two practice heat stimuli were delivered to ensure that participants understood the instructions, familiarized with heat stimulation, and practiced terminating the stimulation when pain threshold was reached. After that thermode was moved distally to the adjacent forearm to avoid repeated stimulation of a single area. The heat stimuli were repeated 4 times with a 10-second break between trials. Consistent with the calculation of PPT, the first trial was removed, and the mean temperature of all available remaining trials was computed to yield heat pain threshold (HPT), which also served as baseline for the CPM task. Immediately after the heat task, participants were again asked “how much pain did you feel during the heat activity?” using the 11-point NRS to verify that they felt pain.

Following the heat sensitivity procedure above, the thermode was once again moved distally to adjacent forearm for heat pain testing under conditioning stimulus for assessing CPM, consistent with prior studies of CPM assessment[27; 52]. A 10°C water bath apparatus was used as the conditioning stimulus, based on guidelines for the cold pressor task for use with children and a prior CPM study in adolescents[6; 51]. Participants immersed their non-dominant hand (just above the wrist) in the 10°C water bath for 2 minutes (or less if not tolerated). Three heat stimuli were delivered to the dominant arm after the hand was in cold water for 5 seconds, with the participants pressing the trigger to indicate heat pain threshold (see Figure 5). Participants also rated pain intensity from the cold water using the 11-point NRS after completing the final trial. We used the mean temperature of all available heat trials to calculate HPT under conditioning stimulus. We calculated CPM index as the ratio of the HPT during conditioning stimulus relative to the HPT at baseline (heat pain sensitivity), with greater values indicating more efficient inhibitory pain modulation.

Figure 5.

Assessment of conditioned pain modulation (CPM). Heat pain was used as the test stimulus (applied in the dominant hand) and cold pressor (10°C) was used as the conditioning stimulus (applied in the non-dominant hand).

2.2.2.4. Cold Pressor Tolerance Task

Participants underwent a cold pressor task with 8°C cold water using a cooling unit with a finger guard and an immersion circulator (Cole Parmer Ltd, Vernon Hills, Illinois, USA), to assess pain tolerance. The temperature was chosen based on the recommendation of using water temperature <10°C for assessing cold water pain tolerance in older children[7]. Participants were asked to immerse their dominant hand up to the wrist in the cold water bath (using the instruction “Please keep your hand open and relaxed”) and were instructed to remove their hand when they could no longer tolerate the cold (tolerance time was counted) (see Figure 6). Maximum immersion time was 4 minutes which was not told to participants. We chose 4 minutes as the maximum immersion time based on the systematic review of contemporary use of the CPT task in pediatric pain research[7] which provided an update to von Baeyer et al’s earlier recommendations[51]. Participants rated the maximum pain felt (0–11 NRS) during the cold-water task within 5 seconds of withdrawal. Immersion time (cold pressor tolerance, CPT, measured in in seconds) and maximum pain rating for the cold pressor (cold pain rating, CPR, measured by the 0–10 NRS) were used as measures of cold pain sensitivity. Participants also rated pain intensity (0–11 NRS) at 15 seconds after withdrawal from the cold water, which was deemed as cold pressor painful after-sensations (PAS).

Figure 6.

Assessment of cold pressor tolerance (CPT). Participants immersed their dominant hand up to the wrist in the cold water bath (8°C) for up to 4 minutes.

2.3. Questionnaire measures

2.3.1. Sociodemographic Factors

Participant age was categorized into 11–12 years vs. 13–18 years, consistent with previous literature and the definition of pre- and post-adolescence[8; 10]. Sex (male vs. female) and gender identity (male, female, non-binary or transgender) were based on youth self-report. Both youth and parents’ race (Asian, American Indian or Alaska Native, Black, White, Multiracial, and others) and ethnicity (Hispanic or Latino, Non-Hispanic/Latino), and household income (<$24,999, $25,000–49,999, $50,000–149,000, ≥$150,000) were based on parent report.

2.3.2. Contextual Factors

Information on present pain, analgesic use, and menstrual cycle (for females) was collected right before QST assessment. Participants were asked if they were experiencing “any pain right now”, and if so, to rate their pain intensity (0–10 NRS). For analgesic use, youth were asked whether they took any pain medications on the lab day, and if so, the type of medications taken. Females were asked whether they were on their menstrual period during the day of the QST assessment with responses coded as yes/no.

2.3.3. MSK Pain Characteristics

MSK pain was assessed via ratings of pain intensity, pain frequency, and pain locations. For pain intensity, participants were asked to provide ratings of each: usual pain intensity, pain intensity at rest, and pain intensity when moving (a relevant feature of MSK pain) during the past 7 days, using 0–10 NRS. For pain frequency, participants were asked how many days they had aches or pains during the past 7 days with response options being: not at all, 1 day per week, 2–3 days per week, 4–6 days per week, and daily. For both pain intensity and pain frequency measures, youth in the Post-MSK Injury Sample were specifically prompted to report pain at the location of their injury (e.g., back, knee), while youth in the Post-MSK Surgery Sample were asked to report on pain without prompting a specific location. For number of pain locations, participants indicated where they experienced pain in the past 7 days using the Peds-CHOIR self-report body map with 74 sites, including 36 anterior sites and 38 posterior sites[5].

2.3.4. Pain Interference

Participants completed the PROMIS Pediatric pain interference scale which assess impact of pain on daily activities, including physical, psychological, and social functioning, during the past 7 days[49]. The Post-MSK Surgery Sample participants completed the 8-item short form measure and Post-MSK Injury Sample participants completed the 4-item short form measure from the PROMIS Pediatric Profile v2.0 (https://www.healthmeasures.net/index.php?option=com_instruments&view=measure&id=764&Itemid=992). We calculated T-scores with a higher T-score indicating a higher level of pain interference.

2.4. Statistical Analyses

Sample characteristics (for individual samples and the combined sample) were described using means, standard deviations (SDs), medians, percentiles (25^th, 75^th), and number and percentages. The distributions of QST parameters were described using mean (SD) and median (25^th–75^th), for individual samples as well as for the combined sample. Normality was determined via Shapiro-Wilk tests, skewness of data, and visual examination of quantile-quantile (Q-Q) plots. Given the skewed distribution of pressure pain thresholds (PPT), we calculated the logarithmically transformed PPTs (base 10), consistent with previous literature[8]. To determine whether QST parameters from the 2 acute MSK pain samples could be combined for analysis, we compared the between-sample differences in the QST values using 2-sample t tests for normally distributed variables and Wilcoxon rank-sum tests for non-normally distributed variables.

To assess the feasibility of our QST protocol, we calculated the completion rate indicated by the percentage of usable QST values (at least 1 available trial per measure for tasks with repeated trials) out of the number of participants who participated in a specific QST task, for each task and for the entire QST battery (consisting of pressure task in both the forearm and trapezius, TSP, heat and CPM task, CPT task), within each sample and by study site. We assessed the reasons for not completing a specific QST task, and grouped them into one of the categories: participant conditions that prohibited completing the task (e.g., participant had injury at the QST testing location or had scars on the arm, participants refused to complete a certain task), participant errors (e.g., participant did not understand or did not follow the instructions), or equipment/examiner errors (e.g., equipment malfunction, research associate unable to generate appropriate pressure slope with algometer).

To assess the reliability of individual tasks, we employed the multilevel modeling technique to decompose the variance in the QST values into variance due to research study site effect (3 geographic sites in total), examiner effect (15 examiners in total), and individual differences (at the participant level); we controlled for the 2 study samples as a fixed effect. We calculated the reliability coefficient for each individual QST task as the variance in the QST values due to participant differences relative to the variance in the QST values due to the participant differences, examiners, and study sites[1], with a higher reliability coefficient indicating less influence by lab and examiner effects, and therefore, more reliable QST assessment.

To examine sources of variability in QST values by sociodemographic and contextual factors, we compared QST values according to age (11–12 years vs. 13–18 years), sex (male vs. female), ethnicity (Hispanic vs. non-Hispanic), momentary pain at time of QST assessment (yes vs. no), menstrual cycle (currently menstruating yes vs. no, for girls), and use of analgesics (yes vs. no) on the lab day. For menstrual cycle, we only compared QST differences among girls who already had their first menstrual period (n = 134). We divided analgesics into opioid and non-opioid medications (in our sample, none of the participants used opioid medications on the lab day). We described QST differences using effect sizes (Cohen’s d), with d = 0.2 as a small effect, d = 0.5 as a medium effect, and d = 0.8 as a large effect[12]. For multiple testing, we used the Benjamini-Hochberg procedure to control the false positive rate (FDR) at 0.05[4].

Lastly, we described the Spearman correlations between each QST parameter and MSK pain characteristics, including the number of pain body sites (a count variable), pain frequency (1–5 with increasing frequencies), self-reported MSK pain intensity (usual pain intensity, pain intensity at rest, pain intensity when moving), and pain interference (PROMIS T-score). Spearman correlations were used because not all QST parameters and clinical pain variables were normally distributed. All data management and statistical analyses were conducted in SAS v.9.4 (SAS Inc., Cary, NC, USA).

3. Results

3.1. Participant characteristics and descriptive data

Data from 277 youth were included in our analyses, with 100 (36%) from the Post-MSK Surgery Sample and 177 (64%) from the Post-MSK Injury Sample. Participants were aged 11–18 years (age mean = 14.5, SD = 2.0), 59% were female, 68% were White, and 81% were non-Hispanic. There were more female participants in the Post-MSK Surgery Sample (80%) than the Post-MSK Injury Sample (47%) due to female predominance of the surgery type. See Table 1 for complete participant characteristics.

Table 1.

Characteristics of the study sample (n = 277)

Characteristics	Total (n = 277)	Post-MSK Surgery Sample (n = 100)	Post-MSK Injury Sample (n = 177)	P for sample differencea
Age (years): mean (±SD)	14.5 (±2.0)	14.5 (±2.0)	14.4 (±1.9)	0.67
Child sex				<0.0001
Male	113 (40.8%)	20 (20.0%)	93 (52.5%)
Female	164 (59.2%)	80 (80.0%)	84 (47.5%)
Child gender identity				<0.0001
Male	112 (40.4%)	20 (20.0%)	92 (52.0%)
Female	161 (58.1%)	77 (77.0%)	84 (47.5%)
Transgender or gender non-conforming	4 (1.4%)	3 (3.0%)	1 (0.6%)
Parent race				0.006
American Indian/Alaska Native	3 (1.1%)	1 (1.0%)	2 (1.1%)
Asian	25 (9.2%)	15 (15.3%)	10 (5.7%)
Black	14 (5.1%)	3 (3.1%)	11 (6.3%)
White	203 (74.6%)	76 (77.6%)	127 (73.0%)
Multiracial	14 (5.1%)	1 (1.0%)	13 (7.5%)
Other	13 (4.8%)	2 (2.0%)	11 (6.3%)
Parent ethnicity				0.41
Hispanic or Latino	40 (15.0%)	17 (17.3%)	23 (13.6%)
Non-Hispanic	227 (85.0%)	81 (82.7%)	146 (86.4%)
Child race				0.10
American Indian/Alaska Native	2 (0.7%)	0	2 (1.2%)
Asian	20 (7.4%)	11 (11.1%)	9 (5.2%)
Black	16 (5.9%)	3 (3.0%)	13 (7.6%)
White	184 (67.9%)	72 (72.7%)	112 (65.1%)
Multiracial	35 (12.9%)	10 (10.1%)	25 (14.5%)
Other	14 (5.2%)	3 (3.0%)	11 (6.4%)
Child ethnicity				0.57
Hispanic or Latino	53 (19.4%)	21 (21.2%)	32 (18.4%)
Non-Hispanic	220 (80.6%)	78 (78.8%)	142 (81.6%)
Household annual income				0.37
Less than $24,999	22 (8.2%)	9 (9.5%)	13 (7.5%)
$25,000 – 49,999	38 (14.1%)	15 (15.8%)	23 (13.2%)
$50,000 – $149,999	102 (37.9%)	40 (42.1%)	62 (35.6%)
$150,000 or more	107 (39.8%)	31 (32.6%)	76 (43.7%)

MSK = musculoskeletal; SD = standard deviation

Missing values were not included in the calculation of percentages.

^aSignificance testing for the difference in sample characteristics between the Post-MSK Surgery Sample and the Post-MSK Injury Sample.

Distributions of QST parameters among the individual and combined samples are described in Table 2 (also see Supplemental Table 1 for Skewness, Kurtosis, and normality testing of all QST parameters). Overall, QST values were similar between two samples, except for a lower CPT for the Post-MSK Surgery Sample compared with the Post-MSK Injury Sample (median = 30s and 42s, respectively, Wilcoxon rank-sum Z = −3.29, P = 0.001). Because there were overall minimal group differences in QST measures between the two study samples, we combined samples for aim 2 and 3 analyses. Mean pain intensity ratings during the TSP task were 1.4 (SD = 1.3), 2.5 (SD = 1.6), and 3.3 (SD = 2.0), at 1^st, 5^th, and 10^th stimulus respectively. There was no statistical difference in pain intensity ratings between samples at any of these stimuli. CPM effect was small in the combined sample (CPM index mean = 101.3, SD = 5.6). We also compared the HPT with and without the conditioning stimulus using a paired t-test. The mean temperature increase with the conditioning stimulus was 0.46°C (t = 3.26, P = 0.001), indicating an overall CPM effect.

Table 2.

QST parameters in the combined sample, the Post-MSK Surgery Sample, and the Post-MSK Injury Sample (n = 277)

QST parameter	Mean (±SD) or Median (25th–75th)
	Total (n = 277)	Post-MSK Surgery Sample (n = 100)	Post-MSK Injury Sample (n = 177)	P for sample difference a
Pressure pain threshold (forearm, raw value)	165 (120–209)	172 (124–204)	161 (119–214)	0.57
Pressure pain threshold (forearm, log10)	2.20 (±0.21)	2.21 (±0.21)	2.20 (±0.21)
Pressure pain threshold (trapezius, raw value)	175 (127–236)	170 (126–218)	176 (127–260)	0.69
Pressure pain threshold (trapezius, log10)	2.24 (±0.23)	2.23 (±0.24)	2.24 (±0.23)
Heat pain threshold	43.5 (±3.6)	43.9 (±3.7)	43.3 (±3.6)	0.24
Cold pain tolerance (ss)	40 (22–122)	30 (17–74)	42 (28–176.5)	0.001
Cold pain rating	5.8 (±2.2)	5.6 (±2.1)	5.9 (±2.2)	0.25
Painful after-sensations	3.5 (±2.3)	3.5 (±2.3)	3.4 (±2.3)	0.83
Temporal summation of pain	1.9 (±1.5)	1.8 (±1.4)	1.9 (±1.6)	0.84
Conditioned pain modulation index	101.3 (±5.6)	100.6 (±5.4)	101.7 (±5.7)	0.12

MSK = musculoskeletal; QST = quantitative sensory testing.

^aSignificance testing for the difference in QST parameters between the Post-MSK Surgery Sample and the Post-MSK Injury Sample.

3.2. Feasibility of the brief QST protocol

Table 3 shows results for the completion rate of individual QST tasks as well as for all tasks. Across study sites, the completion rate for individual QST tasks ranged from 88.6% for the CPM task (Site B) to 100% for multiple tasks (at multiple study sites). For the Post-MSK Surgery Sample, the completion rate ranged from 94.0% for the CPM task to 100% for the pressure task (at the forearm) and the TSP task, with 92.0% of the participants completing all QST tasks. For the Post-MSK Injury Sample, the completion rate ranged from 97.7% for the TSP task to 100% for the pressure task (at the forearm), with 97.2% of the participants completing all QST tasks. Combining samples, completion rates ranged from 97.5% for the CPM task to 100% for the pressure task (at the forearm), with 95.3% of all participants completing all QST tasks.

Table 3.

Feasibility of the QST protocol across 2 study samples and 3 participating sites for acute MSK pain among youth (n = 277)

Completion ratea	Post-MSK Surgery Sample			Post-MSK Injury Sample			Total (n = 277)
	Site A (n = 56)	Site B (n = 44)	Total (n = 100)	Site A (n = 95)	Site C (n = 82)	Total (n = 177)
Pressure task (forearm)	56 (100%)	44 (100%)	100 (100%)	95 (100%)	82 (100%)	177 (100%)	277 (100%)
Pressure task (trapezius)	55 (98.2%)	44 (100%)	99 (99.0%)	94 (98.9%)	80 (97.6%)	174 (98.3%)	273 (98.6%)
Heat task	55 (98.2%)	43 (97.7%)	98 (98.0%)	94 (98.9%)	82 (100%)	176 (99.4%)	274 (98.9%)
Cold pressor task	56 (100%)	41 (93.2%)	97 (97.0%)	94 (98.9%)	82 (100%)	176 (99.4%)	273 (98.6%)
Temporal summation of pain	56 (100%)	44 (100%)	100 (100%)	94 (98.9%)	79 (96.3%)	173 (97.7%)	273 (98.6%)
Conditioned pain modulation	55 (98.2%)	39 (88.6%)	94 (94.0%)	94 (98.9%)	82 (100%)	176 (99.4%)	270 (97.5%)
All tasksb	54 (96.4%)	38 (86.4%)	92 (92.0%)	92 (96.8%)	80 (97.6%)	172 (97.2%)	264 (95.3%)

MSK = musculoskeletal; QST = quantitative sensory testing.

^aCompletion rate for each task was calculated as the number of participants with effective QST data out of the number of participants who participated in that task.

^bCompletion rate for all QST tasks was calculated as the number of participants with effective QST data for the pressure tasks (at the forearm and trapezius), heat task, cold pressor task, TSP task, and CPM task, out of the number of participants who attended laboratory visit for QST assessment.

For the 4 participants who did not complete the pressure pain task at the trapezius (1.4%), 3 were due to prohibiting participant conditions and 1 due to equipment/examiner errors. For the 4 participants who did not complete the TSP task (1.4%), all were due to participant errors. For the 3 participants who did not complete the heat task (1.1%), 2 were due to prohibiting participant conditions and 1 due to equipment failure. For the 7 participants who did not complete the CPM task (2.5%), 4 were due to prohibiting participant conditions, 1 due to participant error, and 2 due to equipment failure. For the 4 participants who did not complete the cold pressor tolerance task (1.4%), all were due to prohibiting participant conditions. One participant experienced an unanticipated problem related to the QST testing, sustaining a burn to the skin related to Qsense malfunction. See Supplemental Table 2 for more details.

3.3. Reliability of QST parameters

Table 4 shows the reliability of QST parameters across study sites. When sample effect was controlled for, study sites and laboratory examiners explained minimal variance in the QST values, with the majority of the variance explained by participant individual differences. Reliability coefficients ranged from 78.0% for PPT_forearm to 100% for HPT, CPT, CPR, PAS, and TSP. Of the 8 QST parameters examined, 7 had reliability index > 0.97.

Table 4.

Reliability coefficient of QST tasks across samples, participant sites, and laboratory examiners for acute MSK pain among youth (n = 277)

QST parameter	Site variance	Examiner variance	Participant variance	Reliability coefficienta
Pressure pain threshold (forearm, log10)	0	0.01079	0.03827	78.0%
Pressure pain threshold (trapezius, log10)	0	0.001226	0.05380	97.8%
Heat pain threshold	0	0	13.2005	100%
Cold pain tolerance (ss)	0	0	6895.17	100%
Cold pain rating	0	0	4.6265	100%
Painful after-sensations	0	0	5.2219	100%
Temporal summation of pain	0	0	2.2975	100%
Conditioned pain modulation index	0.3408	0	30.5993	98.9%

MSK = musculoskeletal; QST = quantitative sensory testing.

^aMultilevel modeling calculated the reliability coefficient for individual QST task as the variance in the QST values due to individual participants relative to the variance in the QST values due to the individual participants, examiners, and participating sites; the sample effect (Post-MSK Surgery Sample vs. Post-MSK Injury Sample) was controlled as a fixed effect.

3.4. Influence of demographic and contextual laboratory factors on QST values

Differences in QST values by participant demographic factors and contextual laboratory factors are described in Table 5. After Benjamini-Hochberg correction of multiple comparisons, compared with younger youth (11–12 years), older youth (13–18 years) had significantly higher PPT_forearm, PPT_trapezius, and HPT with effect sizes of medium magnitude (d’s ranging between 0.56–0.80), as well as higher CPT (d = 0.33). No significant differences were observed between male and females in QST values. Hispanic youth had significantly higher PPT_forearm, PPT_trapezius, HPT, and CPR than non-Hispanic youth, with effect sizes ranging from 0.37 for PPT_forearm to 0.54 for CPR. See Supplemental Table 3 for QST values across age, sex, and ethnicity subgroups.

Table 5.

Differences in QST parameters (indicated by effect size) by demographic factors for acute MSK pain among youth

QST parameter	Age: 13–18 (204) vs. 11–12 (72)	Sex: female (164) vs. male (113)	Ethnicity: Hispanic (53) vs. Non-Hispanic (220)
Pressure pain threshold (forearm, log10)	0.56*	−0.32	0.37*
Pressure pain threshold (trapezius, log10)	0.80*	−0.05	0.40*
Heat pain threshold	0.65*	0.15	0.45*
Cold pain tolerance (ss)	0.33*	−0.29	−0.16
Cold pain rating	−0.09	0.06	0.54*
Painful after-sensations	0.17	0.25	0.32
Temporal summation of pain	−0.26	−0.04	0.07
Conditioned pain modulation index	−0.05	−0.10	−0.20

QST = quantitative sensory testing; MSK = musculoskeletal.

^*Significant after Benjamini-Hochberg Procedure controlling false positive rate at 0.05.

QST values according to personal contextual factors are described in Table 6. There were no statistically significant differences in the QST values by momentary pain, menstrual period, or use of pain medication after Benjamini-Hochberg correction of multiple comparisons. Based on effect sizes, girls on menstrual period had lower PPT_trapezius (d = −0.63) in comparison to girls not on menstrual period, and youth who used non-opioid pain medications on the day of QST assessment had lower TSP (d = −0.49) and CPM (d = −0.45) as compared to those not using pain medications. See Supplemental Table 4 for QST values across subgroups of momentary pain, menstrual period, and medication use on the lab day.

Table 6.

Differences in QST parameters (indicated by effect size) by contextual laboratory factors for acute MSK pain among youth

QST parameter	Momentary paina: Yes (86) vs. No (191)	On menstrual periodb: Yes (18) vs. No (116)	Medication usec: Yes (15) vs. No (262)
Pressure pain threshold (forearm, log10)	−0.14	−0.37	0.16
Pressure pain threshold (trapezius, log10)	0.09	−0.63	0.19
Heat pain threshold	−0.18	0.14	0.02
Cold pain tolerance (ss)	0.01	−0.07	0.06
Cold pain rating	−0.00	0.19	0.03
Painful after-sensations	0.15	0.35	−0.03
Temporal summation of pain	−0.13	0.04	−0.49
Conditioned pain modulation index	0.31	−0.17	−0.45

QST = quantitative sensory testing; MSK = musculoskeletal.

^aMomentary pain refers to a “yes” answer to the question: “Are you in any pain right now” asked right before QST assessment.

^bAnalyses were performed for girls who already had their first menstrual period.

^cMedication included Ibuprofen, Acetaminophen, and Naproxen.

3.5. Associations between QST parameters and clinical acute MSK pain characteristics

According to bivariate correlation analyses (Table 7), PPT_trapezius, CPR, and PAS were associated with MSK pain intensity including usual pain and pain with moving, while PAS was additionally associated with MSK pain disability. Overall, TSP and CPM were not associated with any acute MSK pain characteristics. Neither number of pain locations nor pain frequency were associated with QST parameters.

Table 7.

Spearman correlations between QST parameters and acute MSK pain characteristics

QST parameter	Number of pain body sites	Pain frequency	Usual pain intensity	Pain intensity at rest	Pain intensity when moving	Pain interference
Pressure pain threshold (forearm, log10)	−0.00	−0.01	0.10	0.07	0.06	0.07
Pressure pain threshold (trapezius, log10)	−0.02	0.04	0.17**	0.05	0.15*	0.09
Heat pain threshold	0.06	−0.00	0.09	0.06	0.07	0.06
Cold pain tolerance (ss)	0.05	0.06	−0.11	−0.05	0.09	0.00
Cold pain rating	−0.04	0.01	0.17**	0.05	0.14*	0.11
Painful after-sensations	0.03	0.05	0.19**	0.09	0.13*	0.20***
Temporal summation of pain	0.09	0.06	0.10	0.03	0.02	0.03
Conditioned pain modulation index	0.01	0.05	−0.03	0.05	0.08	0.00

QST = quantitative sensory testing; MSK = musculoskeletal.

^*p<0.05

^**p<0.01

^***p<0.001.

Because analyses were exploratory, multiple testing corrections were not made.

4. Discussion

This study presents a brief, reliable and valid QST protocol that can be used with youth with acute MSK pain post-surgery or post-injury. Results demonstrate feasibility of the protocol as indicated by excellent completion rate in 2 acute MSK pain samples and show that the protocol can be consistently and reliably implemented across multiple geographical study sites with rigorous training and monitoring procedures. Significant and meaningful differences were observed in QST values by age, suggesting that age needs to be considered when interpreting QST results. Ethnicity was also associated with QST values, warranting further study. Small correlations were seen between experimental and clinical pain.

The brief QST protocol developed by our team carefully considered developmental appropriateness, relevance to MSK pain, and reducing participant burden/fatigue, which may extend the usability of QST among pediatric MSK populations. Indeed, a key strength of our brief QST protocol is shown by completion rates with fewer than 5% of the participants not completing the entire QST tasks, indicating that our protocol is highly feasible among youth after MSK surgery or post MSK injury. Despite the increasing application of QST among children and adolescents with recurrent or chronic pain, prior assessment procedures have been highly variable with respect to the testing modalities, testing sites, task order, task-specific parameters (e.g., the temperature setting), and instructions[31; 32; 35; 44–47; 50; 52], potentially explaining differences in QST findings across studies, and hindering the mechanistic understanding of QST for pediatric pain. Our study filled an important gap by contributing comprehensive multisite QST data for youth with acute MSK pain, serving as the foundation for future longitudinal QST monitoring to examine QST as a biomarker predicting prognosis and trajectories of MSK pain.

Results revealed that for the most part QST values were subject to minimal influence of different participating sites and laboratory examiners, likely due in part to the rigorous standardized training implemented across participating sites. The exception was PPT_forearm for which the reliability coefficient was lower. Examiner effect explained about 22% of the variance in PPT_forearm. This is likely because the PPT_forearm is a challenging task to administer particularly related to difficulty in pinpointing the correct location in the forearm to apply the algometer in youth with different sized arms related to age, weight and body mass. This speaks to the importance of rigorous laboratory training which should be implemented in future QST protocols for improving reliability of QST assessment.

When comparing QST values in our sample with published QST data from other pediatric samples, PPT_forearm in our acute MSK pain sample appeared to be lower than the PPT measured at the hand in a sample of healthy adolescents 13–16 years of age reported by the German Research Network on Neuropathic Pain[8]. The difference could be attributed to different PPT protocols. This may also suggest that sensory perturbation by surgery/injury could lead to increased pain sensitivity. Compared with a sample of participants with chronic pain (mostly MSK pain) in Europe, our sample had higher pain sensitivity indicated by lower PPT_trapezius, lower HPT, and lower CPT. It is unknown exactly why these differences emerged but it could be due to protocol differences, older age of participants in the chronic pain sample, or related to the differences with risk for onset vs. maintenance of chronic pain[45].

We observed significant effect of age on QST values, with older adolescents (13–18 years) having higher pressure and heat pain thresholds and higher cold pain tolerance than the younger age group (11–12 years). This builds on QST data from healthy children and adolescents reported by the German Research Network on Neuropathic Pain which found marginal differences in QST measures between older children (9–12 years) and adolescents (13–16 years)[8]. This could indicate that perturbations (i.e., acute MSK pain) magnify age differences in pain sensitivity. The lack of meaningful difference in QST values by sex in our study is consistent with the German Research Network on Neuropathic Pain report which similarly found minimal or negligible impact of sex on QST values among healthy children and adolescents[8; 9]. These findings are in contrast to another study showing greater pain sensitivity across QST modalities among female adolescents as compared to males in healthy and chronic pain samples[45]. Because healthy and chronic pain samples were combined in their analyses, it is unknown whether the sex differences in QST found were potentially driven by the chronic pain sample[45]. Regarding ethnicity, in our study, Hispanic youth had higher pain thresholds and higher pain ratings for the cold pressor task, which is partially congruent with results from adult populations which found greater experimental pain ratings among racial and ethnic minoritized groups but no differences in threshold measures[33]. Our study was not powered to examine differences by race and ethnicity, moreover we did not assess relevant factors such as experience of racism, which may underlie this finding. Future studies should consider the differences in QST values across different racial and ethnic groups in the context of acute MSK pain and investigate relevant mechanisms involved.

Regarding contextual factors, pain at time of QST assessment and pain medications taken on the day of the laboratory visit did not appear to influence QST values in our study, indicating that QST measures are not affected by spontaneous pain. Although girls on menstrual period at time of QST assessment appeared to have lower PPT, larger samples are needed to confirm this. Indeed, the effect of menstrual phase on somatosensory function in the context of acute pain remains largely unknown. One study found greater pinprick pain and incision-induced pain and mechanical hyperalgesia in the luteal phase compared with the follicular phase among healthy women[37]. It is possible menstruation could be a time of potential heightened pain sensitivity, due to hormonal influences or other clinical pain such as dysmenorrhea which is common among adolescent girls and associated with greater pain sensitivity[35; 43].

In terms of clinical pain characteristics, small correlations were found between PPT_trapezius, CPR, PAS and clinical pain intensity and pain interference. TSP and CPM were not associated with any acute MSK pain characteristics. In adult populations, QST has been shown to prospectively predict pain and disability across a range of MSK conditions, with dynamic QST such as TSP and CPM showing the strongest associations[20]. It is possible that QST could longitudinally predict the prognosis of acute MSK pain among youth, and it would be of great interest to explore similarities and differences across age groups in the associations between QST-assessed measures of pain processing and clinical MSK pain outcomes.

Several limitations must be acknowledged. First, although our reliability coefficients for individual QST parameters demonstrated consistent laboratory practice which may ensure data quality, test-retest reliability was not examined and thus, the stability of QST measures for acute MSK pain is unknown. Second, despite being a multisite study, our samples were based on one region of the United States which lack geographical representation. Moreover, participants were recruited from urban academic hospitals which may have introduced sampling bias as only families with access to health care and able to attend the laboratory visit were included. Third, we only used one paradigm in the assessment of CPM. It has been suggested multiple CPM protocols could be administered to participants for comparison[53], and this can be a future research direction with pediatric acute pain samples. Fourth, QST was performed at 8-weeks in the Post-MSK Surgery Sample and within 4-weeks of injury onset in the Post-MSK Injury Sample; different time points of assessment could contribute to differences in QST values between samples, although such differences were overall not observed in our study. Fifth, we did not pre-register our protocol via platforms such as Open Science Framework which is increasingly encouraged in pain research[29].

In summary, QST assessment using a brief protocol adapted for youth with MSK pain demonstrated good feasibility and reliability among youth with post-surgery or post-injury acute MSK pain, and proved to be appropriate for multisite research studies. Age and ethnic background are associated with individual differences in QST. Future studies should consider potential influence of other sociodemographic and contextual factors on QST measures, and examine the prognostic utility of QST in predicting MSK pain outcomes among youth including the transition from acute to chronic pain.