Abstract
Purpose:
Primary study objectives were to (a) characterize pain and explore differences between adolescents and adults with arthrogryposis multiplex congenita (AMC) and (b) evaluate associations between pain-related outcomes and mobility.
Methods:
People who can walk and with AMC completed pain-related questionnaires.
Results:
Sixty-3 participants (n=28 adolescents; n=35 young adults) were recruited. Pain was reported in the past week by 81% of participants; intensity ratings were similar between age groups. Per McGill Pain Questionnaire, pain severity was significantly lower among adolescents. Adults had a greater number of painful regions compared to adolescents. Greater 7-day average pain intensity, McGill Pain Questionnaire scores, and number of painful regions were associated with reduced functional mobility.
Conclusions:
As most adolescents and young adults with AMC have at least mild pain, and pain is associated with mobility, future longitudinal investigations of pain and its functional consequences are warranted.
Introduction and Purpose
Arthrogryposis Multiplex Congenita (AMC), a condition characterized by joint contractures in 2 or more body areas,1 occurs in up to 1 in 3,000 births.2 More than 68% of individuals with AMC have upper- and lower-limb involvement.3 While most patient cases with AMC have not be linked to a specific genetic cause, there are >400 medical diagnoses that may result in AMC.4 AMC often causes muscle impairments (e.g., weakness, increased fibrotic tissue), but is hallmarked by joint stiffness and deformities that are conservatively and surgically managed, particularly in childhood, to enhance functional independence.5, 6
Chronic pain among individuals with AMC may result from persistent post-surgical pain following corrective procedures, joint pain secondary to abnormal forces from malalignment and/or overuse, and/or psychosocial factors, including poor self-efficacy and inadequate social support.7–9 Nevertheless, pain research among individuals with AMC is limited. Although pain onset may be noted during childhood,10 there is evidence suggesting pain is not a significant issue for children and adolescents with AMC.11 Conversely, in an international study by Nouraei and colleagues of adults with AMC (n=177), ‘regular pain’ was endorsed by 75% of participants, with 88% and 49% reporting joint and muscle pain, respectively.12 Predominant pain regions among adults with AMC included the knees and ankles; 63% reported chronic low back pain.12 Of the sample, 22% were unable to work, with ‘high pain levels’ cited as a primary barrier.12 Based on prior research, future research is warranted to characterize chronic pain among individuals with AMC,12 and particularly among adolescents where research is sparse. Adolescent pain experiences may differ from adult experiences given that psychological and social factors, as well as lived experiences, may differ due to age.
During a break-out session at the 3rd International Symposium on Arthrogryposis held in Philadelphia, Pennsylvania in September of 2018, pain was identified as a key research priority by people with AMC, their caregivers, and clinicians specializing in AMC; participants suggested pain was a critical factor in functional independence and community participation. While pain presence has been associated with severe joint contractures and multiple orthopedic procedures among individuals aged 9 months to 77 years with AMC (n=39),6 research linking pain with functional mobility is sparse in this patient population. Given functional mobility may decline with age, evaluating associations between pain and functional mobility, while considering age as a covariate, seems prudent.
Thus, the primary objectives of this study were to characterize pain and explore differences between adolescents and young adults with AMC, and evaluate associations between pain-related outcomes and functional mobility. We hypothesized pain severity, qualifiers, and extent might differ between adolescents and young adults with AMC, and worse pain-related outcomes would be associated with poorer functional mobility, after considering age as a covariate. Psychometrically-sound outcome measures for evaluating pain-focused interventions among individuals with AMC are needed.5 Furthermore, even though test-retest reliability studies for unidimensional pain ratings among children with chronic pain are lacking, such ratings are commonly used in pediatric clinical practice and clinical trials.13 Hence, as a secondary objective, we sought to establish test-retest reliability for pain-related measures among adolescents and young adults with AMC, with a goal of determining reliable outcome measures for evaluating future therapeutic interventions seeking to mitigate pain in these age groups.
Methods
From March to July of 2019, individuals aged 10-50 years with a diagnosis of AMC per their medical provider, were recruited for this cross-sectional, survey study through print and online advertisements, as well as verbal recruitment at community events held for individuals with AMC. A minimum age of 10 years was set to ensure the cognitive ability of the child to understand pain-related concepts and vocabulary. Additional inclusion criteria included being able to walk within the home (with or without an assistive device) and English-speaking and –reading (due to an inability to secure research staff fluent in other languages). Walking status was a key consideration as individuals with AMC, who are wheelchair-bound, may have differing pain presentations compared to individuals who are walking, due to unique joint loads and reduced activity levels. To enhance external generalizability, no additional exclusion criteria were applied. This project was approved by the Institutional Review Board for Human Subjects Research and was conducted in accordance with the Declaration of Helsinki by an interdisciplinary healthcare team comprised of 3 licensed physical therapists, and a board-certified orthotist, occupational therapist, and pediatric orthopedic surgeon.
Following eligibility screening and the informed consent/assent process, individuals reported demographic information via a standardized questionnaire. Individuals reported whether AMC occurred secondary to a known genetic cause, and regional limb and spinal involvement. Functional mobility was evaluated with the Gillette Functional Assessment Questionnaire (GFAQ), scored 1=’cannot take any steps at all’ to 10=’walks, runs, climbs on level and uneven terrain without difficult or assistance’, which has been shown to be reliable and valid for evaluating walking ability.14 Minors completed paperwork with parental assistance.
Current pain intensity, at the time of survey administration, was assessed with a unidimensional, 0-10 scale (scored 0=’no pain’ to 10=‘worst possible pain’); reliability and validity for other adult populations, but not specifically for adults with AMC, has been previously reported.15 To evaluate 7-day average pain intensity (scored 0=’no pain’ to 10=‘worst imaginable pain’), the Patient-Reported Outcomes Measurement Information System, 29-item (PROMIS-29) was used; test-retest reliability has been previously reported for adults with limb difference (i.e., loss).16 The short-form version of the McGill Pain Questionnaire (MPQ) was used to evaluate sensory and affective descriptors of pain (where higher scores indicate greater severity), and as present pain intensity rated qualitatively (i.e., ‘no pain’ to ‘excruciating pain’).17 If missing data was present for MPQ descriptor items, the participant’s data were excluded. Body diagrams (Figure 1), which have been used in both pediatrics and adults with chronic pain,18, 19 enabled participants to indicate body regions with pain in the past week. Further, given the increased recognition of psychosocial factors as important considerations in the pain experience, the Coping Self-Efficacy Scale (CSES), which has been shown to be reliable and valid among other patient populations,20, 21 was administered. This questionnaire assesses one’s confidence in coping with stressors, with higher scores indicating greater confidence in 3 domains: psychological distress and well-being, ways of coping, and social support.20 For each CSES subscale, in the event of ≤20% missing data, missing item data was imputed from the average score for the completed subscale items; when subscales had missing data for >20% of items, the individual’s data was excluded. Subsets of the sample recompleted the outcome measures 2-10 days later to evaluate between-days, test-retest reliability. Minors completed pain-related measures without parental assistance to reduce reporting bias, given known discrepancies in pain reporting between minors and caregivers.
Figure 1.
Pain Body Diagrams
Statistical Analyses
Descriptive statistics were determined. To evaluate test-retest reliability for continuous pain-related measures, intraclass correlation coefficients (ICCs) with 95% confidence intervals (CIs) were calculated using 2-way mixed-effects models (absolute agreement); standard error of measurements (SEMs) and minimal detectable changes (MDCs) at the 90% and 95% confidence level were computed. ICCs were evaluated as >.900=excellent reliability, .751-.900=good reliability, .501-.750=fair reliability, and ≤.500=poor reliability.22 Weighted kappa was used to evaluate test-retest reliability for ordinal data, i.e., MPQ present pain intensity (‘no pain’ to ‘excruciating pain’). Reliability was considered when selecting variables of interest in subsequent between-group analyses. To explore potential age-group differences, Chi-Square Tests (or Fisher’s Exact when expected cell counts were <5) were used for nominal data, while Mann Whitney U Tests were used for continuous data (p≤.050); effect sizes were calculated, when appropriate.
For linear regression modeling, after considering age as a covariate, with a sample size of n=63, alpha=.05, and f2=.15 (medium effect), power was .86, as calculated using G*Power 3.1 (Heinrich-Heine-Universität Düsseldorf, Germany). Despite removal of outliers, however, the assumption of normality of residuals was not consistently met for linear regression modeling. Linear regression uses ordinary least-squares fitting and can provide misleading results if assumptions are violated. Thus, for the sample, robust linear regression models, which use weighted least-squares fitting and is less affected by outliers, were used to evaluate associations (p<.050). After considering age as a covariate, associations between functional mobility per the GFAQ (dependent variable) and pain-related outcome measures, i.e., pain intensity per the PROMIS, severity per the MPQ score, extent per body diagrams, and coping per the 3 CSES subscales (independent variables), were determined using six, separate robust linear regression models. Coefficients were evaluated to determine the amount of change in functional mobility associated with a 1-unit change in each pain-related measure. Statistical analyses were performed using SPSS Statistics Version 26 (IBM Corp., Armonk, NY, USA).
Results
Participant Characteristics.
In total, 63 participants were included in the study (Table 1). There were no statistically significant differences in participant demographics between adolescent (n=28) and young adult (n=35) subgroups (p>.050). The sample majority was female, Caucasian/white, and had AMC without a known genetic cause. A median of 11 out of 14 possible limb regions were involved. The median number of orthopedic, upper limb and lower limb surgeries was 1 and 5, respectively; 15.9% of the sample had undergone spinal surgery.
Table 1.
Participant Characteristics
| Total Sample (n=63) |
Adolescents (n=28) |
Adults (n=35) |
|
|---|---|---|---|
| Age | n=62 | n=28 | n=34 |
| Yearsa | 20 (14, 32) | 14 (12, 15) | 32 (24, 37) |
|
| |||
| Demographics | |||
| Sex | n=63 | n=28 | n=35 |
| Female | 43 (68.3) | 17 (60.7) | 26 (74.3) |
| Ethnicity | n=63 | n=28 | n=35 |
| Non-Hispanic/Latino | 58 (92.1) | 27 (96.4) | 31 (88.6) |
| Race | n=62 | n=28 | n=34 |
| White/Caucasian | 55 (88.7) | 23 (82.1) | 32 (94.1) |
| Residence | n=63 | n=28 | n=35 |
| United States | 60 (95.2) | 27 (96.4) | 33 (94.3) |
| AMC-Specific | n=63 | n=28 | n=35 |
| Known Genetic Cause | 8 (12.7) | 6 (21.4) | 2 (5.7) |
| Spinal Involvement | 31 (49.2) | 13 (46.4) | 18 (51.4) |
| # of Upper Limb Regions Affected (0-8)a,b | 8 (4, 8) | 8 (4, 8) | 8 (4, 8) |
| # of Lower Limb Regions Affected (0-6)a,c | 6 (3, 6) | 6 (3, 6) | 5 (3, 6) |
|
| |||
| Orthopedic Surgeries | n=63 | n=28 | n=35 |
| History of Spinal Surgery | 10 (15.9) | 5 (17.9) | 5 (14.3) |
| # of Upper Limb Surgeriesa | 1 (0, 3) | 2 (0, 3) | 0 (0, 2) |
| # of Lower Limb Surgeriesa | 5 (3, 8) | 5 (3, 7) | 5 (2, 10) |
|
| |||
| GFAQa | n=63 | n=28 | n=35 |
| 9 (7, 9) | 8 (7, 9) | 9 (6, 9) | |
Abbreviations: AMC, Arthrogryposis Multiplex Congenita; #, number; GFAQ, Gillette Functional Assessment Questionnaire.
Data presented as median (25th, 75th percentile) rather than n (% of sample).
Eight possible upper limb regions affected: right and left hand, wrist, elbow, and shoulder.
Six possible lower limb regions affected: right and left foot/ankle, knee, and hip.
Test-Retest Reliability.
To ensure appropriateness of ICCs since continuous data was not normally distributed, Bland Altman plots were evaluated. Table 2 provides between-days, test-retest reliability results for pain-related measures. Reliability for ‘current’ pain intensity, rated on a 0-10 point scale, was poor (ICC=.444), but good (ICC=.845) for the PROMIS-29 7-day average pain intensity rating. Test-retest agreement was fair [kw=.399 (95%CI: .134, .663); Z=3.096; p=.002] for selection of a MPQ pain intensity descriptor, while MPQ severity scores (0-45 points) had good reliability (ICC=.880). For reporting of number of painful regions (0-59) per body diagrams, test-retest reliability was good (ICC=.757). CSES subscales had fair-to-good test-retest reliability (ICCs: .669-.798). For the PROMIS-29 7-day pain intensity average, the MDC90 and MDC95 were 1.9 and 2.2 points, respectively. For MPQ score, the MDC90 was 3.3 points, while the MDC95 was 3.9 points. MDC90 and MDC95 for pain extent per body diagrams were 5.9 and 7.1 regions, respectively. For the CSES subscales, MDC90 were 20.6-26.2% of the maximal scores, while MDC95 were 24.6-31.2% of maximal scores.
Table 2.
Pain-Related Outcome Measures: Test-Retest Reliability Results
| Time 1 Mean (SD) |
Time 2 Mean (SD) |
ICC (95%CI) |
SEM | MDC90 | MDC95 | |
|---|---|---|---|---|---|---|
| Intensity | ||||||
| Current Pain, 0-10 (n=38) | 1.2 (1.7) | 1.2 (1.8) | .444 (.144, .668) | 1.3 | 3.0 | 3.6 |
| PROMIS 7-day Average Pain, 0-10 (n=24) | 2.7 (2.1) | 2.3 (2.0) | .845 (.677, .930) | 0.8 | 1.9 | 2.2 |
| MPQ Descriptor (n=37)a | ||||||
| No Pain | 22 (59.5%) | 25 (67.6%) | -- | -- | -- | -- |
| Mild | 8 (21.6%) | 6 (16.2%) | -- | -- | -- | -- |
| Discomforting | 6 (16.2%) | 5 (13.5%) | -- | -- | -- | -- |
| Distressing | 1 (2.7%) | 1 (2.7%) | -- | -- | -- | -- |
| Horrible | 0 (0.0%) | 0 (0.0%) | -- | -- | -- | -- |
| Excruciating | 0 (0.0)% | 0 (0.0%) | -- | -- | -- | -- |
|
| ||||||
| Quality/Severity | ||||||
| MPQ Score, 0-45 (n=18) | 3.8 (4.1) | 4.0 (4.0) | .880 (.709, .953) | 1.4 | 3.3 | 3.9 |
|
| ||||||
| Extent | ||||||
| # Regions per Body Diagram, 0-59 (n=26) | 5.5 (5.5) | 5.3 (4.8) | .757 (.528, .884) | 2.5 | 5.9 | 7.1 |
|
| ||||||
| CSES | ||||||
| Psychological Distress & Well-being, 0-150 (n=24) | 120.5 (27.9) | 125.1 (28.9) | .780 (.561, .898) | 13.3 | 30.9 | 36.9 |
| Ways of Coping, 0-50 (n=23) | 39.7 (10.3) | 41.8 (9.3) | .669 (.372, .844) | 5.6 | 13.1 | 15.6 |
| Social Support, 0-60 (n=22) | 47.8 (11.6) | 47.9 (12.4) | .798 (.572, .911) | 5.4 | 12.5 | 15.0 |
Abbreviations: SD, standard deviation; ICC, intraclass correlation coefficient; CI, confidence interval; SEM: standard error of measurement; MDC, minimal detectable change; PROMIS: Patient-Reported Outcomes Measurement Information System; MPQ: McGill Pain Questionnaire; #, Number; CSES, Coping Self-Efficacy Scale.
Data presented as n (% of sample) and evaluated using weighted Kappa given ordinal data.
Pain Results.
Among adolescents, 71.4% reported pain within the past 7 days, while 88.6% of adults reported pain. Average 7-day pain intensity was similar between adolescents, i.e., 2/10, and adults, i.e., 3/10 (U=423.0, p=.348; Table 3). MPQ scores, which are another measure of pain severity,17 however, were significantly greater among adults i.e., 6 points, when compared to adolescents, i.e., 2 points (U=267.0, p=.042), although the effect size was small (r=.256). The most common descriptors of pain were ‘aching’, ‘throbbing’, and ‘tiring-exhausting’, which were endorsed by >40% of the sample and ‘cramping’, ‘tender’, and ‘sharp’, which were endorsed by >30% of the sample. The only age-related difference in pain descriptors, with a medium effect size (X2=12.226, p<.001, φ=.467), was greater endorsement of ‘aching’ among 86.7% of adults versus 42.3% of adolescents with AMC. Adults had a greater number of body regions with pain, i.e., 5 (25th, 75th percentile: 3, 8) as compared to adolescents, i.e., 2 (25th, 75th percentile: 0, 7) with a medium effect size (U=275.0, p=.003, r=.377). The most prevalent regions of pain were the feet, anterior knees, and spine (Table 3). Except for the neck (X2=5.263, p=.018, φ=.278), prevalence rates for the most commonly identified painful regions per body diagrams among adolescents and young adults with AMC were similar (p>.050). There were no significant differences in CSES subscales between age groups (p>.050).
Table 3.
Between-Group Differences in Pain-Related Measures
| Total Sample (n=63) |
Adolescents (n=28) |
Adults (n=35) |
p-value | |
|---|---|---|---|---|
| Intensity | ||||
| PROMIS 7-day Average Pain, 0-10 | 3 (1, 4) | 2 (0, 5) | 3 (2, 4) | .348 |
|
| ||||
| Quality/Severity | ||||
| MPQ Score, 0-45 | n=56 5 (2, 7) |
n=26 2 (0, 7) |
n=30 6 (3, 9) |
.042 |
| Descriptorsa | ||||
| SENSORY | ||||
| Throbbing | 24 (42.9) | 10 (38.5) | 14 (46.7) | .536 |
| Shooting | 11 (19.6) | 3 (11.5) | 8 (26.7) | .155 |
| Stabbing | 12 (21.4) | 5 (19.2) | 7 (23.3) | .709 |
| Sharp | 18 (32.1) | 5 (19.2) | 13 (43.3) | .054 |
| Cramping | 19 (33.9) | 8 (30.8) | 11 (36.7) | .642 |
| Gnawing | 2 (3.6) | 1 (3.8) | 1 (3.3) | 1.000 |
| Hot-Burning | 6 (10.7) | 2 (7.7) | 4 (13.3) | .675 |
| Aching | 37 (66.1) | 11 (42.3) | 26 (86.7) | <.001 |
| Heavy | 10 (17.9) | 3 (11.5) | 7 (23.3) | .310 |
| Tender | 19 (33.9) | 8 (30.8) | 11 (36.7) | .642 |
| Splitting | 4 (7.1) | 1 (3.8) | 3 (10.0) | .615 |
| AFFECTIVE | ||||
| Tiring-Exhausting | 25 (44.6) | 11 (42.3) | 14 (46.7) | .743 |
| Sickening | 2 (3.6) | 1 (3.8) | 1 (3.3) | 1.000 |
| Fearful | 5 (8.9) | 1 (3.8) | 4 (13.3) | .358 |
| Punishing-Cruel | 3 (5.4) | 1 (3.8) | 2 (6.7) | 1.000 |
|
| ||||
| Extent per Body Diagrams | ||||
| Number of Regions, 0-59 | 4 (1, 8) | 2 (0, 7) | 5 (3, 8) | .003 |
| Regions with Highest Prevalence per Body Diagrams b | ||||
| Right Anterior Foot (#29)a | 21 (33.3) | 8 (28.6) | 13 (37.1) | .473 |
| Left Anterior Foot (#30)a | 19 (30.2) | 8 (28.6) | 11 (31.4) | .806 |
| Right Anterior Knee (#23)a | 16 (25.4) | 7 (25.0) | 9 (25.7) | .948 |
| Right Posterior Foot (#59)a | 15 (23.8) | 5 (17.9) | 10 (28.6) | .321 |
| Left Posterior Foot (#58)a | 15 (23.8) | 6 (21.4) | 9 (25.7) | .691 |
| Left Anterior Knee (#24)a | 14 (22.2) | 5 (17.9) | 9 (25.7) | .456 |
| Neck Pain (#32)a | 13 (20.6) | 2 (7.1) | 11 (31.4) | .018 |
| Lower Thoracic Spine (#38)a | 13 (20.6) | 7 (25.0) | 6 (17.1) | .444 |
| Lower Back (#41)a | 12 (19.0) | 4 (14.3) | 8 (22.9) | .389 |
| Right Anterior Ankle (#27)a | 12 (19.0) | 4 (14.3) | 8 (22.9) | .389 |
| Left Anterior Ankle (#28)a | 11 (17.5) | 3 (10.7) | 8 (22.8) | .319 |
| Left Anterior Hip (#15)a | 11 (17.5) | 3 (10.7) | 8 (22.8) | .319 |
|
| ||||
| CSES | ||||
| Psychological Distress & Well-being, 0-150 | n=59 124 (90, 137) |
n=25 124 (85, 134) |
n=34 124 (100, 139) |
.365 |
| Ways of Coping, 0-50 | n=60 40 (31, 46) |
n=26 42 (30, 47) |
n=34 39 (35, 46) |
.976 |
| Social Support, 0-60 | n=57 48 (39, 55) |
n=23 48 (32, 56) |
n=34 49 (41, 54) |
.738 |
Abbreviations: PROMIS, Patient-Reported Outcomes Measurement Information System; MPQ, McGill Pain Questionnaire; #, number; CSES, Coping Self-Efficacy Scale.
Data presented as n (% of sample) rather than median (25th, 75th percentile).
# indicates the corresponding number region for the body diagram provided in Figure 1.
Greater 7-day average pain intensity, MPQ scores, and number of painful regions were associated with reduced functional mobility per the GFAQ (Table 4). Coefficients suggest that for every 1 point increase in 7-day average pain intensity and MPQ score, there was a .23 and .14 point reduction, respectively, in the GFAQ score (Table 4), whereas for every 1 region increase in pain extent, there was a .09 decrease in GFAQ score. Better coping for 2 of 3 CSES subscales was associated with greater functional mobility (Table 4). Coefficients indicate that for each 1-point increase in the CSES Psychological Distress and Well-being and Social Support subscales, there was about a .02 and .05 increase in GFAQ score, respectively.
Table 4.
Associations between Pain-Related Outcome Measures and Functional Mobilitya
| Gillette Functional
Assessment Questionnaire |
||||
|---|---|---|---|---|
| b | Robust SE | t | p-value | |
| PROMIS 7-Day Average Pain Intensity, 0-10 (n=58) | −.231 | .115 | −1.999 | .050 |
| MPQ Score, 0-45 (n=54) | −.140 | .046 | −3.042 | .004 |
| # Regions per Body Diagram, 0-59 (n=55) | −.085 | .023 | −3.628 | .001 |
| Coping Self-Efficacy Scale | ||||
| Psychological Distress & Well-being, 0-150 (n=58) | .017 | .007 | 2.353 | .022 |
| Ways of Coping, 0-50 (n=59) | .036 | .022 | 1.656 | .103 |
| Social Support, 0-60 (n=56) | .049 | .018 | 2.748 | .008 |
Abbreviations: b, slope coefficient; SE, standard error; PROMIS, Patient-Reported Outcomes Measurement Information System; MPQ, McGill Pain Questionnaire; #, Number.
Results presented after considering age as a covariate.
Discussion
AMC may be a rare, but pain with AMC is not rare, as 71.4% of adolescents and 88.6% of adults with AMC experienced pain within the past week (per the PROMIS 7-day average pain rating). While there were no significant differences between adolescents and young adults with AMC when reporting 7-day pain severity using the PROMIS 0-10 scale, adults appear to have greater severity when evaluated with the MPQ. Further, body diagrams suggest adults with AMC report a greater number of painful regions than adolescents. Nevertheless, it is noteworthy that adolescents reported a median of 2 painful sites within the past 7 days. Multisite pain (defined as pain in ≥2 body regions) with AMC may be double that of the general population. Fifty percent of our adolescents had multisite pain (in the past 7 days), while prior research reports about 24% of children and adolescents in the general population report pain in the past month.23 As for adults, previous work among adults, aged 20-59 years, in the general population, has reported about 36% report multisite pain in a given month,24 but 89% of our adults had multisite pain in the past week. For the most commonly affected body regions, i.e., feet, knees, and spine, pain prevalence appears to be generally similar between adolescents and young adults with AMC, but may differ for the cervical spine, where more adults report neck pain (Table 3). Nevertheless, we consider between-group comparisons exploratory in nature given the limited sample size, which might have resulted in Type II error.
This study provides foundational knowledge for future pain research, as it characterizes the pain experience for adolescents and young adults with AMC and can assist with prioritization of pain research. For example, interventional studies addressing foot and anterior knee pain, which are the most commonly affected regions, might be prioritized. Findings also provide reliable measures for use in future interventional studies addressing pain among adolescents and young adults with AMC (i.e., PROMIS-29 7-day average pain intensity rating, MPQ, body diagrams, and CSES). In future clinical trials (and in orthopedic practice) among adolescents and young adults with AMC, MDC values reported in this study may allow determination of whether changes in average pain intensity, severity, and/or extent, surpass measurement error and are indicative of ‘true change’. Furthermore, results suggest pain-related measures are associated with functional mobility, supporting future, longitudinal research assessing whether greater pain severity, multisite pain, and/or worse coping self-efficacy are predictive of long-term mobility limitations among adolescents and young adults with AMC. If pain metrics early in life predict critical long-term outcomes, pain-focused interventions in adolescence and early adulthood would be justified.
Prior work among children, aged 10.9±4.4 years, found pain/comfort per the Paediatrics Outcomes Data Collection Instrument to be 0.5 standard deviations below normative data.11 We found 71.4% of adolescents reported pain with severity similar to young adults with AMC, albeit in fewer body regions. These results among adolescents with AMC align with findings among children with osteogenesis imperfecta, where mild joint pain has been reported, although qualifiers in our study (i.e., ‘throbbing’, ‘cramping’, ‘aching’) appear to be indicative of greater pain severity than those reported with osteogenesis imperfecta (i.e., ‘uncomfortable’, ‘annoying’).25 Among our adults with AMC, pain prevalence is similar to previous reports.10, 12 Further, our results align with a retrospective study of adults with AMC (mean age: 33.2±13.4 years; n=43), suggesting pain is predominantly in the lower-limbs and trunk.10
Pain intensity has been proposed as the ‘most clinically relevant dimension of the pain experience’.26 Given daily fluctuations in chronic pain,13, 27 expectedly, ‘current’ pain intensity test-retest reliability was poor. Conversely, PROMIS 7-day pain intensity ratings had good reliability (ICC=.85; MDC90=1.9) similar to that reported previously among adults with limb loss (ICCs=.85-.89; MDC90=2.0).16 Hence, we would discourage use of ‘current’ pain intensity ratings in clinical practice and research, and instead propose use of the PROMIS 7-day pain intensity rating for adolescents and young adults with AMC, alongside other measures characterizing the pain experience (i.e., MPQ, body diagrams, CSES). Among adolescents and young adults with AMC, changes in 7-day pain intensity ratings of ≥2 points between assessments may be considered ‘true change’ surpassing measurement error.
Our data suggest pain may be functionally limiting, as increased 7-day average pain intensity, greater MPQ severity, and a greater number of pain locations per body diagrams, were associated with worse functional mobility, after considering age as a covariate. For example, an individual with AMC reporting a 4.5-point increase in their 7-day average pain rating might be expected to have a 1-level reduction in their GFAQ functional-mobility classification. These findings expand on prior research among adults (n=50) with AMC (mean age: 42.4±13.6 years), which found pain to impact standing and walking among 30% and 48% of participants, respectively.28 Future research may consider additional covariates, including activity level, extent of lower-extremity involvement, and mental health, when evaluating relationships between pain and functional mobility.
Prior pediatric chronic pain research suggests psychosocial factors, such as coping, may be critical prognostic indicators.29 It has been previously suggested individuals with AMC cope well,30 which is supported by our CSES subscale scores. That said, poorer coping was associated with worse functional mobility, exemplifying how enhancing coping might be effective for improving functional mobility among individuals with AMC. For example, a perceived increase in social support, as exemplified by a 21-point increase in the relevant CSES subscale may be accompanied by a 1-level increase in functional mobility per the GFAQ.
Study strengths include evaluation of pain beyond ‘current’ intensity, reporting of test-retest reliability for a set of pain-related measures, and inclusion of adolescents with AMC (as most pain research has been among adults), yet, we acknowledge some limitations. First, in cases where imputation of missing data was not possible, participant data was excluded. Second, recall bias is possible, as we relied on self-report without medical record corroboration. Similarly, without medical records access, we were unable to verify the AMC diagnosis, nor whether individuals had a known genetic cause resulting in AMC. Third, we did not capture region-specific pain intensities or pain medication data. Fourth, given the limited number of participants with AMC with a known genetic cause, we did not conduct subtype analyses, although prior AMC research suggests pain-related differences would be unlikely.10 Finally, our cross-sectional design precludes establishing cause-and-effect relationships between pain outcomes and mobility.
Conclusions
As the majority of adolescents and young adults with AMC have at least mild pain and pain is associated with reduced functional mobility, future longitudinal investigations of pain and its functional consequences are warranted for these individuals. Test-retest reliability for possible outcome measures for such investigations is provided.
Grant support:
Eunice Kennedy Shriver National Institute of Child Health and Human Development [grant number: T32HD007490].
At the time this manuscript was written, Dr. Beisheim-Ryan was a graduate student within the Biomechanics and Movement Science PhD program at the University of Delaware in Newark, Delaware, USA.
Conflict of Interest statement:
Dr. Sions received a private donation from Run with Jack to the University of Delaware to support this study. Dr. Beisheim-Ryan received personal funding from the Foundation for Physical Therapy Research through Promotion of Doctoral Studies I and II scholarships. Dr. Nichols has received honoraria from Orthopediatrics, Smith and Nephew, and Orthofix, but outside the submitted work. For the remaining authors, none were declared.
Footnotes
Publisher's Disclaimer: Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the funding sources’ official views. Funders were not involved in data acquisition and/or the decision to publish.
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