Development of a screening tool to predict the risk of chronic pain and disability following musculoskeletal trauma: protocol for a prospective observational study in the United Kingdom

Introduction Pain is an expected and appropriate experience following traumatic musculoskeletal injury. By contrast, chronic pain and disability are unhelpful yet common sequelae of trauma-related injuries. Presently, the mechanisms that underlie the transition from acute to chronic disabling post-traumatic pain are not fully understood. Such knowledge would facilitate the development and implementation of precision rehabilitation approaches that match interventions to projected risk of recovery, with the aim of preventing poor long-term outcomes. The aim of this study is to identify a set of predictive factors to identify patients at risk of developing ongoing post-traumatic pain and disability following acute musculoskeletal trauma. To achieve this, we will use a unique and comprehensive combination of patient-reported outcome measures, psychophysical testing and biomarkers. Methods and analysis A prospective observational study will recruit two temporally staggered cohorts (n=250 each cohort; at least 10 cases per candidate predictor) of consecutive patients with acute musculoskeletal trauma aged ≥16 years, who are emergency admissions into a Major Trauma Centre in the United Kingdom, with an episode inception defined as the traumatic event. The first cohort will identify candidate predictors to develop a screening tool to predict development of chronic and disabling pain, and the second will allow evaluation of the predictive performance of the tool (validation). The outcome being predicted is an individual’s absolute risk of poor outcome measured at a 6-month follow-up using the Chronic Pain Grade Scale (poor outcome ≥grade II). Candidate predictors encompass the four primary mechanisms of pain: nociceptive (eg, injury location), neuropathic (eg, painDETECT), inflammatory (biomarkers) and nociplastic (eg, quantitative sensory testing). Concurrently, patient-reported outcome measures will assess general health and psychosocial factors (eg, pain self-efficacy). Risk of poor outcome will be calculated using multiple variable regression analysis. Ethics and dissemination Approved by the NHS Research Ethics Committee (17/WA/0421).


EuroQol Five Dimension Scale, 5-level [EQ-5D-5L]
Health-related quality of life will be quantified using the EQ-5D-5L through which 243 possible health states are converted to a single index value of range 0 to 1 where 1 is perfect health, and a visual analogue scale range 0-100, representing 'worst' to 'best' imaginable health state, respectively. 8 The EQ-5D-5L, with each item having 5 possible responses, has improved inter-observer [ICC 2,1 0.57] and test-retest [ICC 2,1 0.69] reliability compared to the previous EQ-5D-3L. 9 In addition, it has less ceiling effects [20.8% reduction] and adequate convergent validity when compared with the WHO-5 [spearman rank 0.38-0.51]. 10 Barthel Index of Activities of Daily Living The Barthel Index of Activities of Daily Living is routinely collected by clinical staff at the hospital, and will be used to evaluate self-care and mobility during activities of daily living. 11 12 It is a 10-item ordinal scale encompassing a range of mobility physical activity tasks. Each item is related to a specific task and rated with a given number of points. A score of '0' is given for least independence/function on that item and scores above that [1 or 2] are given for increasing independence/function [range: 0-20]. The amount of time and physical assistance required to perform each task are used in determining the assigned value of each item. A higher score is associated with a greater likelihood of being able to live at home with a degree of independence following discharge from hospital. With most measurement testing performed in the stroke population, the Barthel Index has demonstrated excellent internal consistency [0. 89-0.90] 13 and is highly responsive in detecting changes 14  ]. This scale has been shown to possess moderate psychometric properties in fibromyalgia patients using a symptom diary. 18 We will aim to assess current pain intensity at baseline, as frequently as every 48-hours while the patient is in hospital up to a maximum of 14 days following recruitment [depending upon patient accessibility and assessor availability], to gain accurate average and rate-of-change data. In addition, we will use the 0-10 NRS to assess average sleep quality, related to the preceding 6-months at the 6 and 12month assessment points, although no psychometric properties have previously been reported for this recall period.

Psychosocial features
The predictive strength of psychosocial factors demonstrated in both primary care, 19 20 and post-trauma pain literature [21][22][23][24] demonstrates the importance of including these domains as candidate predictors.

The Hospital Anxiety and Depression Scales [HADS]
The HADS will be used to measure depression and anxiety, and their role in the manifestation of somatic symptoms. 25 There are 7 items which produce a cumulative score  26 Standard measurement of error in a coronary heart disease population was identified as 1.37 and 1.44 for anxiety and depression scales respectively, and minimal detectable change as 3.80 and 3.99 respectively. 27 The HADS has also demonstrated excellent concurrent validity when compared to various other depression/anxiety scales. 26 Coping Strategies Questionnaire 24  The CSQ-24 will be used to provide an indication of coping strategies used by participants when they are in pain. 28 30 Harland & Georgieff 28 suggested that, since individuals may have a positive score on more than one subscale, the highest scoring subscale should be deemed the dominant coping strategy. 28 However, a recent study in a low back pain cohort, 31 in which individual items from multiple questionnaires were factorised, suggested that diversion, reinterpreting and cognitive coping clustered together as a single factor, representing coping cognitions. By contrast, catastrophizing clustered with pain-related distress items.

Tampa Scale of Kinesiophobia [TSK-11]
The TSK-11 will be used to assess fear of movement or fear of injury or re-injury during movement. 32 It is an 11-item questionnaire, eliminating psychometrically poor items from its original 17-item version, 33  disagree'] [scoring range . Higher scores indicate more fear-avoidance behaviour. The TSK-11 has demonstrated acceptable to good internal consistency in acute and chronic musculoskeletal pain populations. 32 34 Test-retest reliability has been reported as excellent with a high standardised response mean; with good construct validity in relation to changes in disability and pain. 32 The patient's confidence in their ability to perform activities despite their pain will be evaluated using the PSEQ. Developed from the Self-Efficacy Scale, 35 36 It has been used in several large population studies, for example Campbell et al. 31

Impact of Event Scale Revised [IES-R]
The IES-R will be used to measure the subjective stress experienced by the participant following their traumatic event. The IES-R is a 22-item tool [range: 0-88] that consists of 8 intrusion and 8 avoidance items that are derived from the original IES, 37 with an additional 7items assessing hyperarousal. 38 Accordingly, items correspond directly to symptoms of posttraumatic stress disorder. 38

Injury characteristics
Several measures relating to the characteristics of the sustained injury will be taken at baseline, since it is plausible that some of these should possess predictive value. 40 The time of the injury will be gained from hospital records. The location of the injury/injuries will be recorded using an adapted version of previously developed pain drawing software, via a tablet computer. 41 Information relating to the tissues damaged from the injury [e.g. fractures sustained, whether the injury was penetrating, non-penetrating or both, review of available imaging data] will be gathered from hospital records, where possible. Whether the participant received surgery following their admission [where, for what and when], and whether the participant received assisted mechanical ventilation will also be recorded.

Injury Severity Scale [ISS]
The ISS will be retrospectively calculated for each participant, including those who withdraw. The ISS is a numerical score with a range 0-75, that is used to describe the overall severity of injury, and can be used for both multiple and single injuries. The score is calculated, based on the Abbreviated Injury Scale [AIS] scores. 42 43 Higher ISS scores have been associated with increased rates of mortality 42 44 45 and length/cost of hospital stay. 46  recommend any participant with a score of >8 to be referred for rehabilitation.

Pain characteristics
Pain characteristics [e.g. pain intensity, multi-site pain] have long been reported to hold predictive value for long-term pain across a variety of conditions. 19-21 48 49 It is therefore sensible that we include these domains as candidate predictors for post-trauma pain.

Pain intensity
Pain intensity will be measured using an 11-point [0-10] Numerical Rating Scale [NRS], measuring current pain from 'no pain' to 'pain as bad as could be', from the Chronic Pain Grade Scale. 50 We will aim to assess current pain intensity at baseline, as frequently as every 48-hours while the participant is in hospital [depending upon participant accessibility and assessor availability], to gain accurate mean and rate-of-change data. At the 6 and 12 month assessment points, current pain intensity, as well as average and worst pain intensity related to the preceding 6 months, will be collected as part of the Chronic Pain Grade Scale. NRS scales are sensitive, reliable and valid instruments for pain intensity measurement, [51][52][53][54] and have been recommended for use in clinical populations in preference to visual analogue scales or verbal rating scales. 55 A 30% change on a pain NRS score is considered clinically meaningful. [56][57][58][59][60] Pain medication The patient's pain medication [type, dosage and time since trauma] intake will be noted and the Medication Quantification Score [MQS], which is a reliable and validated score for quantifying analgesics, will be calculated to obtain a comparable metric for all different analgesics. [61][62][63] It enables characterisation of analgesics when many different medications are involved and doses are irregular. It will be calculated for each non-opioid and opioid, based on weights assigned by medication class and dosage level [level 1 = sub-therapeutic dosage and/or on demand, level 2 = lower 50% of the therapeutic dose range, level 3 = upper 50% of the therapeutic dose range, level 4 = supra-therapeutic dose] using the 1998 detriment weights. 64 The detriment weights are summed by the dosage level to provide the final score.
These scores will be summed to provide a quantitative index for analgesic usage suitable for statistical analysis.

Pain drawing
All participants will be requested to complete a pain drawing, indicating the spatial distribution of their pain, over two body charts; one reporting a frontal view of the body and one a dorsal view. We will also ask patients to mark their single 'most painful' site on one of these body charts. Pain drawing data will be collected using a custom software application on a tablet computer, and will be analysed with Matlab software, as described previously. 41 The software automatically calculates the number of shaded pixels from the pain drawing, which is defined as pain extent. Summaries of, and relationships between, pre-defined painful body regions will also be evaluated. Conventional pain drawing data will also be collected on paper follow-up questionnaires to assess painful body regions.

The painDETECT questionnaire
It is assumed that all post-trauma patients will have significant nociception at baseline, but given the relatively high proportion of neuropathic pain following traumatic injury, 65 the contribution of other pain-related mechanistic pathways should also be assessed. The painDETECT questionnaire 66 will be used to facilitate the identification of neuropathic pain.
Measurements will also be taken at all follow-up assessment points.

Quantitative sensory testing [QST]
QST methods will be used to assess pain sensibility, throughout which measurements will be concealed from participants. Owing to the clinical heterogeneity of the post-trauma population, precise standardisation of test sites between participants will not be possible.
Instead, we have developed a standardised protocol that will be used to evaluate pain thresholds for multiple stimulus modalities [mechanical pressure, heat and cold] at the same sites in each participant. Each site where multi-modality pain threshold testing is performed will be within the receptive field of the same nerve root using described regions, 72 so that segmental cross-modality excitability may be compared. All pain thresholds will be measured at the same 'local' and 'remote' sites for each participant. We define local sites as being uninjured but within [or, if not accessible, as close as possible to] the same receptive field as the most painful inured tissue [e.g. skin over gastrocnemius in a participant with an ankle fracture]. By contrast, we define remote sites as a distant, accessible, site from the receptive fields in which tissues are injured [e.g. skin over tibialis anterior in a participant without lower limb injury], and on the contralateral side of the body where injured tissue is unilateral.
Where possible, remote sites will be a mirror-image of the local site [to allow for comparison of absolute values], but in a trauma population we are aware that this may not always be possible. For all threshold testing modalities, an ascending method of limits design 73 will be used, whereby stimulus intensity will begin at a low level and gradually increase until the participant first perceives pain. Participants will be instructed to push a button or tell the assessor when the sensation has changed from one of the stimulus alone [e.g. just pressure] to a sensation of both the stimulus and pain [e.g. pressure and pain]. Following a brief demonstration of equipment to familiarise participants, two consecutive assessments will be performed for each modality at each site, and the means used for further analysis. 74 A minimum of 30-seconds inter-stimulus interval will be given between each threshold measurement within a single session. Measurements will be taken at baseline, while the participant is an inpatient in the hospital; we will aim to collect data as frequently as every 48 hours to gain accurate rate-of-change data, but this will depend upon participant accessibility and assessor availability. To ensure pain thresholds are consistently measured at the same sites every session, sites will be labelled using a sterile, skin marking pen [Schuco Ltd, UK].
Because sites cannot be standardised between participants, the rates-of-change of these values will be used as candidate predictive variables, to allow for comparisons between participants.
The order of pain threshold testing will be randomly assigned by modality at each session to avoid order effects.
Thermal [heat and cold] pain thresholds will be measured using skin-contact stimulation, using the same thermode at the same sites, within specified local and remote dermatomes.
Thermal pain threshold assessments will be performed by delivering thermal stimuli directly to the skin through a metal 30x30 mm Peltier thermode, using a TSA-II NeuroSensory Analyzer thermal stimulator and accompanying software [Medoc Ltd, Israel]. To evaluate heat pain threshold, temperature will be gradually increased, at a rate of 1°C/s from a 'neutral' baseline of 32°C, to a maximum temperature of 50.5°C to avoid thermal injury. 75 During each measurement, participants will be instructed to press a button when the stimulus becomes painful, and this will be documented as the threshold value. Once pain threshold is achieved [and recorded], the temperature will return to the baseline value at the same rate [1°C/s]. For cold pain threshold measurements, the temperature will be gradually reduced, at a rate of 1°C/s from the baseline of 32°C, to a minimum temperature of 0°C, 75 before also returning to baseline at a rate of 1°C/s. Pressure pain thresholds will be measured using a digital pressure algometer [Series 7 force gauge, Mark-10 Corporation, USA], providing real-time force measurement and an analogue output that can be linked to a computer. Skin and muscle tissue are simultaneously stimulated during pressure threshold testing; sites will therefore be chosen where a dermatome and myotome are likely to share a common nerve root innervation [e.g. skin over tibialis anterior]. The algometer has a hard rubber circular contact tip of 1.2cm 2 area, with no sharp edges so to avoid an uneven pressure stimulus. 76 In order to preserve hygiene and attend to infection control measures in trauma patients, the contact tip will be covered with a clean, thin disposable covering. The tip will be applied perpendicular to the skin at a constant rate of pressure increase of 50kPa/s [6.0N/s using the 1.2cm 2 tip], until the first onset of pain. For each measurement, pressure will be unloaded immediately once the participant indicates that their pain threshold has been reached. 74 To measure excitability of nociceptive pathways in response to mechanical stimuli, a series of repetitive, pressure stimulus 'pulses' will be applied via the digital algometer, with the aim of provoking temporal summation responses. [77][78][79] A minimum of 2 minutes after all threshold tests have been completed, a series of 10 consecutive pressure pulses will be applied at the remote and local sites [the order of site being randomly assigned]. The peak pressure reached during each pulse will be the mean pressure pain threshold that was measured for that particular site, as described previously. For each pulse, pressure will be gradually increased to the peak value over a period of 5 seconds, maintained at that peak value for 1 second, and then immediately released. A 5 second inter-stimulus interval will be used between pulses, during which the tip of the algometer will remain in contact with the skin. 78 79 Pain intensity from the pulses will be rated on a numerical rating scale [0 being 'no pain' to 10 being 'pain as bad as could be']. In the event that participants indicate that pain has become intolerable, the sequence will be stopped immediately, and the NRS score and number of impulses performed at that point will be noted.

Biomarkers
Serum levels of C-reactive protein [CRP] will be used as a biomarker for inflammation; one of the primary mechanistic pathways that can evoke pain. 80 CRP is an acute-phase response protein produced by hepatocytes and is usually found in concentrations of 0.3 to 1.7 mg/l 81 .
Increased production is due to cytokine-dependent induction of synthesis and elevated levels may be detected within eight hours of a stimulus and can reach 500 mg/1.28. Besides trauma, 82 elevated levels of CRP may be seen in conditions such as autoimmune disease, infection and malignancy. It has also been associated with acute sciatica. 83 The level of CRP usually peaks within 48 hours of the stimulus. In contrast, when the stimulus for increased production completely ceases, the circulating CRP concentration falls rapidly, at almost the rate of plasma CRP clearance. 84 A fall in serial measurements usually indicates resolution of the underlying process, while persisting elevated levels indicates ongoing inflammation. 85 Where possible, measurements of serum CRP will be repeatedly taken on a 48 hour schedule while the participant is an inpatient; absolute and rates of change of CRP values will be used as candidate predictive factors. 86 Plasma cell-free DNA [cfDNA] will be used as an indicator of tissue damage. This includes both nuclear DNA [nDNA] and mitochondrial DNA [mtDNA], which circulate after being released from cells when they are damaged and are thought to be amongst the important initiators of systemic inflammatory responses following tissue injury known as Damage Associated Molecular Patterns [DAMPs]. 87 Clinical outcomes in trauma patients have been related to plasma mtDNA concentration. 88 89 Other work with severe trauma patients has shown that cfDNA values rise to their peak value in the second week post-trauma, and then gradually return to baseline values after approximately 2 months. 90 Where possible, measurements of circulating cfDNA will be repeatedly taken on a 48 hour schedule while the participant is an inpatient; absolute values and rates of change of cfDNA values will be used as candidate predictive factors.