A Phase III triple-blind randomised placebo-controlled trial to evaluate effectiveness of early treatment with pregabalin to reduce pain severity after whiplash road traffic injury: study protocol for the PRioRTI Trial {1}

Abstract

Background

There are few effective treatments for acute whiplash-associated disorder (WAD) following a road traffic crash. Early clinical features of central sensitisation, for example widespread hyperalgesia, predict poor recovery. Pregabalin’s effects on central sensitisation suggest the potential to prevent or modulate these processes after whiplash injury and prevent later chronic pain. Preliminary evidence indicates that pregabalin provided in the Emergency Department and within 96 hours of injury shows promise to prevent chronic pain. This trial aims to definitively evaluate, in patients at risk for poor recovery following whiplash injury, the effectiveness of early (within 96 hours of injury) pregabalin, compared to placebo, to reduce pain severity.

Methods

The PReventing chronic pain after whiplash Road Traffic Injury (PRioRTI) study is a 12-month randomised, placebo-controlled, triple-blind trial. Individuals with acute WAD (aged 18–70 years) and at risk of poor recovery (pain ≥ 5/10) will be recruited from hospital Emergency Departments in Australia. Participants will be randomly assigned 1:1 to receive pregabalin or placebo. All participants will additionally receive an evidence-based advice booklet. Pregabalin will be commenced at 75 mg bd and titrated to 300 mg bd over 4 weeks, then weaned for 2 weeks. Participants will complete online questionnaires at 6 weeks and 3, 6 and 12 months post-randomisation. The primary outcome will be average pain intensity over 24 hours (0–10 numerical rating scale) at 3 months post-randomisation. Secondary outcomes include disability, patient global impression of recovery, psychological distress, quality of life and the number of adverse events. A cost-effectiveness analysis will be conducted. Potential mediators of treatment effects will be explored. A process evaluation will be conducted to explore barriers and facilitators for future implementation.

Discussion

There are few effective treatments for acute WAD. To address this gap, the PRioRTI trial aims to improve health outcomes by targeting central nociceptive processes very soon after whiplash injury using a readily available medication, pregabalin. If successful, the results of this trial will address an urgent unmet need to reduce pain severity after injury and will have clear implications for the early treatment of patients with whiplash injury.

Trial registration {2a and 2b}

Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12624001359527. Registered 13th November 2024.

Administrative information

Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).

Title {1}	A Phase III triple-blind randomised placebo-controlled trial to evaluate effectiveness of early treatment with pregabalin to reduce pain severity after whiplash road traffic injury. (PRioRTI: Trial).
Trial registration {2a and 2b}.	Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12624001359527. Registered on 13th November 2024.
Protocol version {3}	Protocol version 1.2, 6th February 2025
Funding {4}	This trial is funded by the Medical Research Future Fund (Australia): APP2022935.
Author details {5a}	Michele Sterling1,2,3,4, Scott F Farrell1,2,3,4, Lisa Ferguson1,2,4, Geoffrey Mitchell5, Stephan Schug6, Robert S Ware7, Michael Dinh8,9, Antonio Celenza6, Luke Connelly2,3,10, Paul W Hodges3, David M Klyne3, Rachel Elphinston1,2,3,4, Jane Nikles1, James McAuley11,12, Chung-Wei Christine Lin13 1RECOVER Injury Research Centre, The University of Queensland, Brisbane Australia 2NHMRC Centre of Research Excellence: Better Health Outcomes for Compensable Injury 3The University of Queensland, Centre for Innovation in Pain and Health Research, Brisbane Australia. 4STARS Education and Research Alliance, Surgical Treatment and Rehabilitation Service (STARS), The University of Queensland and Metro North Health, Brisbane Australia 5School of Medicine, The University of Queensland, Brisbane Australia 6 Medical School, University of Western Australia, Perth Australia 7Griffith Biostatistics Unit, Griffith University, Gold Coast, Australia 8Royal Prince Alfed Hospital, Sydney, Australia 9Faculty of Medicine and Health, The University of Sydney, Sydney, Australia 10Centre for the Business and Economics of Health, The University of Queensland, Brisbane Australia 11School of Health Sciences, University of New South Wales, Sydney, Australia 12Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, Australia 13Institute for Musculoskeletal Health, Sydney Local Health District and The University of Sydney, Sydney, Australia
Name and contact information for the trial sponsor {5b}	The University of Queensland. Brisbane QLD 4072 Australia
Role of sponsor {5c}	The sponsor (The University of Queensland) has no role in the study design and will have no role in data collection and analysis, decision to publish, or preparation of the manuscript.

Introduction

Background and rationale {6a}

Road traffic injuries (RTIs) affect 20 to 50 million people globally [1], with 75% being non-catastrophic musculoskeletal injuries, such as whiplash affecting the neck and back [2]. These injuries result in a substantial economic and personal burden in many countries [2–4]. Up to 50% of people with acute musculoskeletal RTI do not recover well but develop chronic pain, associated disability and psychological comorbidities [5, 6].

Current clinical guidelines recommend that patients be screened early for their risk of poor recovery using a validated questionnaire [7], such as the WhipPredict tool that has high accuracy in identifying patients likely to develop chronic pain [8]. Those screened at low risk of poor recovery do well with advice and simple exercises, but this treatment fails for people screened at risk of poor recovery [9]. Recently, better and sustained effects were found when patients at risk of poor recovery were identified, and treatment targeted to a known risk factor [10], in this case posttraumatic stress symptoms [11]. Progression from acute to chronic pain involves many factors and potentially includes central nervous system sensitisation [12]. Clinical features that are presumed to indicate central sensitisation including widespread hyperalgesia and exaggerated spinal cord reflexes are associated with chronic pain development after whiplash injury [13, 14]. Preventing or attenuating the development of sensitivity may improve later health outcomes.

Pregabalin reduces excitability of dorsal horn neurons after tissue or nerve damage, blocking the development of central sensitisation [15]. Pregabalin is effective for neuropathic pain [16], and has positive effects on anxiety [17], indicating potential to ameliorate stress and arousal symptoms that are common after whiplash injury [18]. There is some support for benefits from use in the acute pain stage, where the prevention of later chronic pain has been found in several trials with pre- and peri-operative use of pregabalin, although the evidence is mixed [19]. However, pregabalin has been found to be ineffective in sub-acute to chronic low back and radiating leg pain [20]. Traumatic injuries (e.g. whiplash) show more profound features of central sensitisation than non-traumatic musculoskeletal pain [21]. This is especially the case for patients with acute whiplash, where those at risk of poor recovery show marked early features of central sensitisation compared to those at low risk who recover well [13]. Further, the timing of pregabalin may be important. Very early provision of pregabalin may be a crucial factor to prevent the sensitisation of neural processes. In a feasibility study for this proposed trial, we found promising effects at three months on pain with the administration of pregabalin within 96 hours of whiplash injury, compared to placebo (mean difference: 24.0 [95% confidence interval 26.2 to 21.7] on an 11-point Numerical Rating Scale) [22]. A definitive large trial is needed to confirm or refute these results. Establishing the balance of benefit and harm of pregabalin is particularly important as there are concerns of serious harm associated with the drug and increasing global consumption [23, 24].

We aim to conduct a prospective multicentre randomised placebo-controlled superiority trial, analysed by intention-to-treat, to investigate whether, in patients at risk of poor recovery after whiplash injury, a 6-week course of pregabalin, compared to placebo, can reduce pain severity. We hypothesise that treatment with pregabalin will result in clinically significant less pain at 3 months post-whiplash injury.

Objectives {7}

The primary aim of this trial is to investigate whether, in patients at risk for poor recovery following whiplash injury, a 6-week course of pregabalin, compared to placebo, can reduce pain severity at 3 months.

Secondary objectives are:

• (i)To examine whether pregabalin, in comparison to placebo, improves other clinical outcomes, such as disability and psychological outcomes, as well as evaluating the risk of adverse events.
• (ii)To assess the cost-effectiveness of pregabalin in this patient population over 12 months.
• (iii)To explore potential mechanisms underlying the effects of pregabalin using mediation analysis.
• (iv)To conduct a mixed methods process evaluation to identify and understand the barriers and facilitators to the implementation of pregabalin for acute whiplash injury.

Trial design {8}

This study adopts a 12-month, parallel-group, triple-blind, randomised, superiority, controlled trial design. Individuals with acute (< 96 hours) whiplash injury and at risk of poor recovery will be randomly allocated in a 1:1 ratio into one of two treatment arms (Fig. 1):

1. Pregabalin and advice booklet: Participants in this arm will receive pregabalin titrated as tolerated over 6 weeks and an advice booklet [25].

2. Placebo and advice booklet: Participants in this arm will receive placebo titrated as tolerated over 6 weeks and an advice booklet [25].

Fig. 1.

SPIRIT diagram. D, day; M, month; W, week. *Staff qualitative interviews will be conducted from 6 months post trial commencement, or once 50% of recruitment is complete, whichever is sooner (Phase 1), and from ~ 1.5 years post commencement (Phase 2)

Methods: participants, interventions and outcomes

Study setting {9}

The PRioRTI trial will be conducted in Emergency Departments in Brisbane and Sydney (Australia) and via telehealth with trial nurses and doctors based at The University of Queensland, Brisbane.

Eligibility criteria {10}

Participant inclusion criteria

• Individuals with Grade II WAD [26] within 96 hours of injury presenting to hospital Emergency Departments.

• Currently experiencing pain of ≥ 5/10 on a Numerical Rating Scale (NRS).

• Aged 18–70 years.

• Not admitted as a hospital inpatient.

• Participant can provide written informed consent and is willing to participate for the duration of the trial and to follow trial procedures.

Participant exclusion criteria

• Serious spinal pathology (e.g. fracture or dislocation [Grade IV WAD [26]], metastatic disease)

• Neurological compromise (e.g. Grade III WAD [26]) or peripheral neuropathy.

• A chronic pain condition currently requiring treatment.

• The current use of gabapentin, pregabalin, or other anticonvulsants, or a known hypersensitivity to pregabalin.

• Known renal disease resulting in symptomatic renal insufficiency.

• Those who are pregnant or breastfeeding (females) or attempting conception (females or males).

• A history of psychiatric illness or substance abuse.

• A history of depression or a score of ≥ 15 on the Patient Health Questionnaire-9 (PHQ-9; or a score ≥ 2 for item 9 [regarding suicide and self-harm]),

• Unable to speak and write in English (which is necessary for completing study questionnaires).

Who will take informed consent? {26a}

Participants will be provided with written information and a brief video explaining the trial. Written informed consent will be taken by an Emergency Department doctor.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

This trial does not involve collecting biological specimens for storage.

Interventions

Explanation for the choice of comparators {6b}

The use of placebo as a comparator allows for determination of a genuine effect of pregabalin, over and above the effects of being in a clinical trial. The placebo capsules, containing Avicel® (a pharmaceutically inert microcrystalline cellulose), will be manufactured to be identical in appearance to the active trial investigative medicinal product (pregabalin). Those randomised to the placebo group will receive an intervention kit containing the same number of capsules as those randomised to receive pregabalin, packaged in identical bottles. The placebo medication will be titrated (up and down) based on patient response as per the pregabalin schedule (11a).

Both groups will receive an evidence-based advice booklet in the Emergency Department, Whiplash Injury Recovery: a self-help guide (3rd edition) [25], based on current Australian Guidelines [7]. The booklet provides information about pain, managing stress, reassurance about prognosis, advice to remain active, and on resuming functional daily activities and an exercise program.

Intervention description {11a}

The intervention group will receive the same advice booklet as described. This group will commence 1 pregabalin capsule (75 mg) orally twice daily with the first dose taken immediately on randomisation (prior to discharge from the recruiting Emergency Department). Participants will continue this dose for 3 days after which time the dose could be titrated to 150 mg twice daily if the previous dose is well tolerated. The dose could be further increased to 300 mg twice daily after 11 days if 150 mg twice daily is well tolerated. The dose will be reduced to the previously tolerated level if the higher dose is not well tolerated after 3 days. Participants will be asked to continue taking the medicines (active or placebo) until Day 28 post-randomisation, with a subsequent 14 days of down titration. Participants will be provided with a dose adjustment schedule in the Emergency Department. The Telehealth team (comprising research nurses and trial medical practitioners) will review and monitor participants via telehealth at Days 3, 7, 14, 21, 28, 35, 42 and 49 post-randomisation, with dose titrations scheduled for Days 3, 14, 28 and 35, where possible. The prescription of pregabalin in this way is consistent with our feasibility study [22] and trials of pregabalin for low back pain [20].

Criteria for discontinuing or modifying allocated interventions {11b}

Participants may withdraw from the allocated intervention at any time at their own request for any reason (or without providing any reason), or they may be withdrawn from the intervention by the researchers for safety reasons. In both cases, the reason(s) will be documented. If a participant decides to discontinue the assigned intervention for any reason, the participant’s medication will be down-titrated as appropriate by the Telehealth team. Participants who cease or are withdrawn from the intervention will be encouraged to attend all scheduled trial visits and assessments as outlined in the protocol.

Strategies to improve adherence to interventions {11c}

After discharge from the Emergency Department, participants will self-administer all subsequent doses of the study intervention at home supported by the Telehealth team. In these individual telehealth appointments, the nurse will employ person-centered collaborative care to titrate the medication dose as indicated and answer questions that the participant may have about their care and neck pain condition. Adherence with the trial intervention will be assessed at each telehealth visit. The Telehealth team medical practitioners will provide oversight for all participants during the trial treatment period.

Adherence will be monitored in three ways: (1) daily self-recorded medication intake, (2) the trial Telehealth team will ask about adherence during each review appointment commencing at 3 days post randomisation and (3) counts of returned tablets following treatment completion.

Relevant concomitant care permitted or prohibited during the trial {11d}

Participants (in either group) who experience bothersome pain will be advised that they can take over-the-counter pain relief (e.g. paracetamol). Participants in both groups will be asked where possible not to change current medications (i.e. if they are taking medication for another condition) or start other treatments during the 6-week trial period. The trial Telehealth team will be asked within reason to refrain from suggesting additional or alternative treatments for trial-related problems. They will have the option to down-titrate or cease the study medication. However, if symptoms persist, participants could be asked to see their General Practitioner. The participant’s nominated General Practitioner will be notified in writing of the individual’s participation in the trial (with the participant’s consent) and will also be requested to refrain from referring or suggesting additional treatments within reason and altering treatments for unrelated conditions where possible.

During the trial, the Telehealth team will collect information about names and doses of prescription and over-the-counter medications, as well as any other treatments received (e.g. physiotherapy). At the end of the 6-week intervention period, participants will be permitted to seek further treatment, if necessary (e.g. additional medications, non-pharmacological treatments), and this information will be collected at the follow-up time points.

Participants with high levels of continuing or worsening pain will be advised to notify the trial Telehealth team and visit their usual General Practitioner or return to the Emergency Department for review. No additional prescription for pain relief will be prescribed by the trial Telehealth team.

Provisions for post-trial care {30}

After the completion of the 6-week treatment period, there will be no restriction on the treatment that participants can access, if further care is required. The treatment will be provided outside the trial.

Outcomes {12}

Primary outcome

The primary outcome will be neck pain intensity over the previous 24 hours, using a NRS (0 no pain–10 worst possible pain), measured at 3 months post randomisation.

Secondary outcomes

Trial secondary outcomes are as follows:

• Pain intensity over the last 24 hours (NRS) [27] measured at baseline, 6 weeks and 6 and 12 months post randomisation.

• The Neck Disability Index [28] measured at 6 weeks and 3, 6 and 12 months post randomisation.

• Global perceived recovery (assessed using an 11-point (–5 to + 5) global rating of change scale) [29] measured at 6 weeks and 3, 6 and 12 months post randomisation.

• Depression, Anxiety and Stress Scale-21 (DASS-21) [30] measured at baseline, 6 weeks and 3, 6 and 12 months post randomisation. The anxiety subscale will also be collected at Day 21 and 42 as a mediating variable.

• Posttraumatic Stress Disorder (PTSD) Checklist for DSM-5 (PCL-5) [31] measured at 6 weeks and 3, 6 and 12 months post randomisation.

• The Assessment of Quality of Life 8D (AQoL-8D) [32] measured at baseline, 6 weeks and 3, 6 and12 months post randomisation.

• Adverse events measured at 6 weeks post-randomisation.

• Pain location. Participants are asked to indicate where on a body chart they are experiencing pain/symptoms. Body chart responses will be reported descriptively and collected at baseline, 6 weeks and 3, 6 and 12 months. They will also be collected at Day 21 and Day 42 as a mediating variable.

• A brief 3-item sleep quality survey (problem falling asleep, problem staying asleep, waking too early) [33] measured at Day 21 and Day 42 as a mediating variable.

• Cold hyperalgesia using a validated ice cube test [34]. This test involves placing a small plastic bag with two ice cubes inside on the skin over the neck of the participant for 10 seconds. Participants are asked to rate on a 0–10 numerical rating scale the pain they experienced during the test. A pain rating > 5/10 is indicative of cold hyperalgesia [34]. Participants will perform the test at home under the direction of the Telehealth team. Cold hyperalgesia will be measured at Day 21 and Day 42 as a mediating variable.

• Nociplastic pain will be measured using a study-specific survey that has been developed based on international clinical classification criteria [35]. This survey comprises eight self-report Yes/No questions regarding elements of nociplastic pain (i.e. sensitivity to touch, warmth, cold, and movement; sensitivity to light/sound; fatigue; cognitive problems). Nociplastic pain will be assessed at Day 21 and Day 42 as a mediating variable.

Process evaluation

A subset of clinicians and participants in the clinical trial will be invited to participate in semi-structured qualitative interviews.

Clinician interviews will occur across two phases to examine trial processes which could be improved in relation to trial recruitment and delivery of the trial intervention, as well as explore barriers and facilitators to implementation of the trial intervention. Interviews will be undertaken from 6 months post-trial commencement (or once 50% of recruitment is complete, whichever is sooner [Phase 1]), and at ~ 1.5 years post commencement (Phase 2).

The research team will contact a subset of trial participants after they finish their treatment (6 weeks) and invite them to participate in an interview. The interviews will explore experiences and perceptions of trial participation and trial interventions.

Participant timeline {13}

The participants will follow the timeline as depicted in Fig. 1.

Sample size {14}

Based on pilot trial data and previous trials [10], a standard deviation of the primary outcome, the 11-point NRS of pain severity for patients with neck pain is 2.2. To detect a between-group difference of 1.0 point at 3 months (the minimal clinically important difference for patients with neck pain) with 90% power (alpha = 0.05), outcome data on 206 participants (103/group) is required. To allow for a drop-out of 20% which is more conservative than that of previous trials in acute whiplash (12% drop-out) [10] and pregabalin for low back and leg pain (10%) [20], 258 participants will be recruited. This sample size also has > 80% power to detect a clinically relevant between-group difference of 7.0 on the key secondary outcome, the 100-point NDI (assuming a standard deviation of 18.0).

Recruitment {15}

To facilitate reaching our recruitment target, trial sites have been selected based on reported numbers of potentially eligible participants presenting to the Emergency Department in the year preceding the trial. Collaborative partnerships with Emergency Department healthcare professionals will be established, including physicians, nurses, and allied health staff. Regular communication and training sessions will be conducted to educate new Emergency Department staff about the trial’s objectives, eligibility criteria, and site requirements. The trial Consumer Advisory Group (CAG) will advise on recruitment processes and materials to ensure these are accessible and resonate with the target population.

Recruitment posters with a quick response (QR) code link to trial information (PICF, information video, eligibility criteria, contact information) will be displayed within the Emergency Department to serve as visual aids to raise awareness about the trial.

Assignment of interventions: allocation

Sequence generation {16a}

Randomisation will be in permuted blocks of size 8–10 (block size randomly selected in 1:1 ratio), stratified by trial site. An automatic independent web-based randomisation service (Griffith University Randomisation Service) will generate the randomisation schedule that will be directly supplied to the medication manufacturer, who will prepare the medication/placebo kits according to the schedule. These kits will then be provided to the hospital pharmacies.

Concealment mechanism {16b}

A unique kit number will be displayed on all trial medication/placebo kits. Two researchers at the co-ordinating trial site (UQ) not directly involved in the day-to-day management of the trial will hold the unblinded allocation tables and will be able to link the unique kit number to the intervention group. The investigator responsible for randomisation will not be involved in the other stages of the trial to maintain the blinding process.

Implementation {16c}

An independent statistician will generate the randomisation blocks and schedules. These will be provided to the manufacturer of the medication and placebo who will generate the kits. Blocks will be sent to the trial site pharmacy. The trial pharmacist will allocate the next available kit to the participant and note the unique kit number allocated to the participant in REDCap.

Assignment of interventions: blinding

Who will be blinded {17a}

In this trial, patient participants, care providers in the Emergency Departments, Telehealth staff, research trial staff and data analysts will be blinded to a participant’s allocation to the trial intervention. Success of blinding will be assessed by asking participants to estimate which group they were allocated to at the Day 3 telehealth assessment.

Procedure for unblinding if needed {17b}

To maintain the overall quality and legitimacy of the clinical trial, code breaks will occur only in exceptional circumstances when knowledge of the actual treatment is essential for further management of the participant, or in the case of a Suspected Unexpected Serious Adverse Reaction. Investigators will discuss with the Independent Medical Monitor when the Principal Investigator believes that unblinding is necessary.

The allocation code will be securely maintained by two independent researchers at the coordinating trial site (UQ) not directly involved in the day-to-day management of the trial. Staff holding the allocation code will be provided with a comprehensive Standard Operating Procedure (SOP) for emergency unblinding, detailing the steps to be followed, the individuals involved, and the circumstances under which unblinding is permissible.

Data collection and management

Plans for assessment and collection of outcomes {18a}

The trial will be conducted in accordance with International Council for Harmonisation (ICH) Guidelines for Good Clinical Practice [36] and relevant ethical regulation. Study data will be collected and managed using a regulatory approved electronic data capture system (REDCap) hosted on the University of Queensland server.

Study data will be collected and managed using REDCap electronic data capture tools hosted at The University of Queensland. REDCap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies, providing (1) an intuitive interface for validated data capture; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for data integration and interoperability with external sources.

Demographic and baseline data will be collected in the Emergency Departments, entered into trial case report forms by the trial staff from participant charts and reports, and completed in hard-copy questionnaires by the participant. Hard copies of baseline data collection materials will be available to trial staff in participant packs, and master copies will be available in the trial site file. Emergency Department site staff will scan all completed hard-copy data collection forms and upload into REDCap for data entry by University of Queensland research staff. Data collected at telehealth visits will be entered into REDCap by the Telehealth team.

Data from follow-up questionnaires will be entered by patient participants via email links to the REDCap database.

Site staff will be trained in all trial requirements, standardised measurements, conduct of assessments such as the cold hyperalgesia test and counselling for adherence and the eliciting of information from trial participants in a uniform reproducible manner.

Study instruments

Pain intensity (Numerical Rating Scale, NRS)

The Primary Outcome Measure is the continuous variable neck pain intensity over the previous 24 hours, using a numeric rating scale (NRS, 0 no pain–10 worst possible pain). The NRS is a responsive tool in patients with musculoskeletal neck pain [27]. A mean group difference of 1 point on the 0–10 NRS is a minimally clinically important difference for patients with neck pain [37]. It is a recommended core outcome measure for clinical trials in chronic pain [38] and for trials of WAD [39].

Pain location

Distribution of patient pain and other symptoms (e.g. paraesthesia) will be assessed using a body chart. This is a common pain/symptom assessment method in clinical and research settings for descriptive reporting of patient symptom distribution.

Disability (Neck Disability Index)

Neck pain-related disability is a core outcome domain for WAD [39], and the Neck Disability Index (NDI) is the preferred tool to measure disability according to the WAD core outcome recommendations [39]. The NDI is a reliable and valid 10-item questionnaire that scores on a 0–100% scale, such that 0% is no neck-pain-related disability and 100% is total disability [40]. The NDI is a responsive tool in patients with musculoskeletal neck pain [37]. A clinically meaningful group difference in NDI is 10% [39].

Global impression of recovery scale

Patient overall improvement (perceived recovery, or global impression of recovery) is a core outcome measure for trials of WAD [39]. It will be assessed using an 11-point (–5 to + 5) global rating of change scale [29]. In this scale, 0 represents no change in a patient’s overall condition, negative values denote worsening and positive values denote improvement. This measure has been demonstrated to be valid and reliable in a WAD population [29].

Depression, Anxiety and Stress (DASS-21)

The DASS-21 [30] is a well-validated tool that has three subscales that allow calculation of separate scores for depression, anxiety and stress symptoms; higher scores indicate higher levels of psychological symptoms.

AQoL-8D

The Assessment of Quality-of-Life 8D (AQoL-8D) is a psychometrically sound 35-item questionnaire [32]. Quality of life data will be used in the economic analysis to calculate quality-adjusted life years (QALYs).

PTSD Checklist for DSM-5 (PCL-5)

Post-traumatic stress symptoms will be measured using the PTSD Checklist for DSM-5 (PCL-5), a psychometrically sound 20-item self- report measure that assesses the 20 DSM-5 symptoms of posttraumatic stress disorder [41]. It has previously been used in clinical trials of treatments for WAD [42].

Cold hyperalgesia (ice cube test)

Cold hyperalgesia will be assessed using the ice cube test previously described [34]. This test involves the application of a plastic bag containing two ice cubes which are held against the skin over the neck for 10 s. Participants are asked to rate on a 0–10 NRS the pain experienced during the test. This method has been validated in patients with whiplash through comparison with laboratory-based quantitative sensory testing of cold pain threshold. A pain score of NRS > 5 is consistent with the presence of cold hyperalgesia [34]. The Telehealth team will guide the patient through this test.

Sleep

To assess sleep quality as a potential mediator of treatment effect, we will use the brief sleep survey reported by Beaudoin et al. in a similar population [33]. The survey includes three items: “Over the last few nights, how much of a problem have you had falling asleep?”, “Over the last few nights, how much of a problem have you had staying asleep all night?” and “Over the last few nights, how much of a problem have you had waking up too early in the morning?”. Each item is rated on a 0–4 scale (0 = None, 1 = A little, 2 = Some, 3 = A lot, 4 = Extremely), with the total score ranging 0–12.

Nociplastic pain survey

The presence of nociceptive pain [43] will be measured using a study-specific survey that has been developed based on international clinical classification criteria [35]. This survey comprises eight self-report Yes/No questions regarding elements of nociplastic pain (i.e. sensitivity to touch, warmth, cold and movement, sensitivity to light/sound, fatigue, cognitive problems).

Plans to promote participant retention and complete follow-up {18b}

Participants will meet regularly with the trial Telehealth medical team, and this will promote retention during the intervention period. After completion of the 6-week intervention period, researchers will maintain regular contact through phone calls every 3–4 months to promote participant retention in the study. A trial newsletter will be developed and sent to participants throughout the trial duration. Research staff will encourage participants who have withdrawn from the intervention to complete follow-up outcomes.

Data management {19}

Researchers will be trained before commencing data collection, to maintain the operational procedures shown in the protocol, with the aim of maintaining the consistency and reliability of the data. In addition, standardised forms for collection of dates will be used. A Data Management Plan (DMP) will be developed prior to the trial start to describe how data will be collected, processed and stored. The DMP will be reviewed at least annually and updated to reflect any change in the data management process.

Trial staff will be responsible for ensuring the accuracy, completeness and timeliness of the data reported. The database will have internal quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete or inaccurate.

Confidentiality {27}

Participants will be assigned a unique identifier, and any participant datasets will be identified by this identifier to maintain participant confidentiality. All records that contain names or other personal identifiers, such as locator forms and informed consent forms, will be stored separately from study records identified by code number. Only the study’s research team will have access to the participants’ authorised data in order to contact them for telehealth visits and to send outcome measure questionnaires. Once the trial has closed and prior to locking the database, participant identifiers will be deleted from the database. Any hard copies containing participant identifiers (locator forms, consent forms) will be stored securely at the site and archived as per site protocols for a minimum of 15 years.

Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

See above “ Additional consent provisions for collection and use of participant data and biological specimens {26b}”; there will be no biological specimens collected.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

The primary outcome will be analysed using a mixed-effects linear regression model with random intercepts for individuals to account for the correlation of repeated measures from the same participant. Treatment group and time will be included as fixed effects, with a group-by-time interaction term. We will obtain estimates of the effect of the intervention and 95% confidence intervals by constructing linear contrasts to compare the adjusted mean difference between groups and the 95% confidence interval. Secondary outcomes will be analysed with linear (continuous variables), logistic (binary variables) or Poisson (count variables) models, taking into account repeated measures where necessary. Missing data will be examined for patterns of missingness and addressed using multiple imputation methods if required. The data will be analysed on an intention-to-treat basis. Analyses will be designed and supervised by RW and will be conducted blind to group allocation. A detailed statistical analysis plan will be finalised prior to commencing data analysis.

The economic evaluation will be a trial-based cost utility analysis. The primary cost-effectiveness analysis will be conducted from the perspective of the health sector in which outcomes of the intervention (Quality Adjusted Life Years [QALYs]) will be assessed against health sector costs. A secondary analysis will adopt a societal perspective in which opportunity costs of lost labour and use of non-health care services will be factored into the analysis. A sensitivity analysis will test uncertainty in parameters such as unit costs and effect estimates.

Mechanisms of effect

We will use causal mediation analysis to quantify the mechanisms by which pregabalin may prevent chronic pain. We will investigate 3 hypothesised mediators based on the known mechanisms of pregabalin: its capacity to reduce the likelihood of central sensitisation [44] measured using the pain distribution (body chart), cold hyperalgesia and nociplastic pain survey, facilitate sleep [44] measured with the brief sleep survey, and reduce anxiety [45] measured using the DASS-21 anxiety sub-scale. The mediators will be measured at Day 21 and Day 42 post randomisation. We will evaluate [46] the mediators independently, while assuming independence of the mediators, and [47] the mediators simultaneously as joint mediators, since it is possible that they may affect or interact with each other [48, 49].

Interim analyses {21b}

No interim analyses are planned.

Methods for additional analyses (e.g. subgroup analyses) {20b}

No sub-group analyses are planned.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

Missing data will be examined for patterns of missingness and addressed using multiple imputation methods if required.

Plans to give access to the full protocol, participant level-data and statistical code {31c}

The study protocol, data, statistical code and results will be made available by the corresponding author upon request.

Oversight and monitoring

Composition of the coordinating centre and trial steering committee {5d}

The coordinating centre for this trial is the University of Queensland, with MS serving as the Principal Investigator. The trial management committee (TMG) will comprise the Principal Investigator, Project Manager, Data Manager and any other core research staff involved in decision making of day-to-day trial delivery and conduct. The TMG will meet weekly throughout the trial. The trial steering committee will include the TMG, all other investigators and the consumer advisory group and will meet bi-annually throughout the trial. The consumer advisory committee will comprise three individuals with lived experience of whiplash injury.

Composition of the data monitoring committee, its role and reporting structure {21a}

An independent data monitoring committee (DMC) comprising the medical monitor, an independent biostatistician, qualified person with scientific expertise in the clinical aspects of the road traffic injury has been established. The DMC will review the research protocol, informed consent documents and plans for data safety and monitoring; evaluate the progress of the trial, including periodic assessments of data quality and timeliness, participant recruitment, accrual and retention and other factors that can affect study outcome; consider factors external to the study when relevant information becomes available, such as scientific or therapeutic developments that may have an impact on the safety of the participants or the ethics of the trial; make recommendations to the trial steering committee about continuation, termination, or other modifications of the trial; and ensure the confidentiality of the trial data and the results of monitoring. The DMC will meet biannually throughout the trial.

Adverse event reporting and harms {22}

Adverse events will be recorded at every study visit from time of consent through to 6 weeks post-randomisation. In the event of any serious adverse event, it will be promptly reported to the responsible researcher, communicated to the Research Ethics Committee of Metro North Health, and appropriate measures will be taken.

Frequency and plans for auditing trial conduct {23}

Adherence to ethical guidelines in the study will be overseen by the Ethics Committee of Metro North Health. Progress reports on the trial will be submitted every 12 months to ensure compliance with ethical standards.

Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}

Any modifications to the protocol which may impact on the conduct of the study, potential benefit of the patient or may affect patient safety, including changes of study objectives, study design, patient population, sample sizes, study procedures, or significant administrative aspects will require a formal amendment to the protocol. Such amendment will need to be agreed upon by the trial Steering Committee, approved by the Metro North Health HREC and notified to and approved by Site Governance prior to implementation.

Dissemination plans {31a}

The results of this trial will be published in the ANZCTR. The results will be disseminated through academic conferences and peer-reviewed scientific publications.

Discussion

Chronic pain and disability following whiplash injury create a huge health and economic burden for Australia and many other countries. Current guideline-recommended treatments for acute whiplash injury provide only small to modest effects at best [50, 51]. The early presence of clinical features indicative of sensitised central neural processes, for example, cold and mechanical hyperalgesia, has been shown to be associated with the development of persistent pain, disability and poor mental health [13, 52]. Targeting or preventing the development of central sensitisation may assist in preventing chronic pain and poor health. Based on this tenet, we conducted a feasibility study to evaluate trial procedures and the potential effect of a short course of pregabalin initiated in the early post-injury period compared to placebo [22]. The results of this feasibility trial showed promising effects of pregabalin on pain at 3 and 6 months post-randomisation. Some feasibility issues were encountered including patient recruitment numbers and greater attrition in the placebo group. The proposed PRioRTI Trial aims to provide definitive evidence for the effect of pregabalin to prevent chronic pain after whiplash injury. We have taken steps to address feasibility issues identified in our pilot trial. With respect to patient recruitment, we have included three trial sites of large metropolitan Emergency Departments with an adequate number of whiplash presentations, extended the time frame post-injury for inclusion to 96 hours, and secured funding to be able to employ dedicated research staff at each hospital Emergency Department site. We have also taken steps to minimise attrition including dedicated research staff contact with trial participants and through a regular trial newsletter. We have appointed a Consumer Advisory Group comprising four individuals with lived experience of WAD and have held regular meetings with this group in trial planning and set-up including consultation on patient materials, recruitment processes and measures to minimise attrition. Our Consumer Advisory Group will continue to consult with and advise the research team throughout the life of the trial.

Further improvements to our feasibility trial include the addition of factors that we hypothesise may be causal mechanisms of effect. These include clinical measures of nociplastic pain, sleep and anxiety. Whilst it would be ideal to also include more thorough measures of these processes, for example laboratory measures of central neural processing and sleep, the nature of the trial where recruitment is via the Emergency Department, with follow-ups via telehealth and on-line surveys would place more burden on participants and potentially greater attrition.

If the PRioRTI trial results in improved outcomes for patients at risk of recovery after whiplash injury, this will address a burdensome unmet need in the quest to prevent the development of chronic pain with a treatment that is widely available. It could also guide future global management of acute injury extending beyond whiplash to other conditions with high rates of chronicity after traumatic injury (e.g. orthopaedic injuries).

Trial status

Recruitment for this study commenced in August 2025 and is anticipated to conclude by July 2027. Version 1.2, approved February 2025.

Abbreviations

AQoL-8D

Assessment of Quality-of-Life 8D

CAG

Consumer Advisory Group

DASS-21

Depression, Anxiety and Stress Scale (21 item)

DMP

Data Management Plan

DMC

Data monitoring committee

ICH

International Council for Harmonisation

NRS

Numerical Rating Scale

NDI

Neck Disability Index

PCL-5

PTSD Checklist for DSM-5

PICF

Participant Information and Consent Form

PTSD

Posttraumatic stress disorder

QALYS

Quality Adjusted Life Years

QR

Quick response

RTI

Road traffic injury

SOP

Standard operating procedure

UQ

The University of Queensland

WAD

Whiplash-associated disorder

Authors’ contributions {31b}

MS is the corresponding author of the trial. MS, GM, SS, CL, RSW, MD, AC, LC, PWH, DK, RE, JN and JM designed the trial. MS, SF and LF drafted the protocol. RSW is responsible for the randomisation process and analysis plan. LF, SF, MS and MD are responsible for data collection and monitoring. GM will supervise the trial telehealth team. All authors have reviewed and approved the final manuscript.

Funding {4}

The PrioRti trial is funded by the Medical Research Future Fund (MRFF) Australia, APP 2022935. MS, PH and CL are funded by Investigator Grant fellowships from the National Health and Medical Council Australia (APPs 2017405, 2042003, 1193939).

Data availability {29}

Data obtained through this trial may be provided to qualified researchers with an interest in musculoskeletal pain treatment. Data shared will be coded with no protected health information included. Data requests can be submitted immediately following article publication, and the data will be made accessible for up to 60 months. Extensions will be considered on a case-by-case basis. Access to trial individual patient data can be requested by qualified researchers engaging in independent scientific research and will be provided following review and approval of a research proposal and Statistical Analysis Plan, and execution of a Data Sharing Agreement.

All Principal Investigators will be given access to the cleaned data sets. Project data sets will be housed on the University of Queensland server, and all data sets will be password protected. Principal Investigators will have direct access to their own site’s data sets and will have access to other sites’ data by request. To ensure confidentiality, data dispersed to project team members will be blinded of any identifying participant information.

Declarations

Ethics approval and consent to participate {24}

Ethical approval for this study was granted by the Metro North Health Human Research Ethics Committee B (Project ID 106754; HREC/2024/MNHB/106754) on 12 July 2024, with subsequent ratification from UQ and Griffith University human research ethics committees (Supplementary Material). Written, informed consent to participate will be obtained from all participants.

Consent for publication {32}

The Participant Information and Consent Form for the trial (and equivalent for qualitative interviews of clinicians) have been included as Supplementary Materials.

Competing interests {28}

The authors declare that they have no competing interests.