Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000407796
Ethics application status
Approved
Date submitted
12/01/2022
Date registered
9/03/2022
Date last updated
9/03/2022
Date data sharing statement initially provided
9/03/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
Assessment of heat sensation following spinal cord injury - a pilot study
Scientific title
Neurophysiological assessment of residual thermonociceptive sensation following spinal cord injury - a pilot study
Secondary ID [1] 305993 0
None
Universal Trial Number (UTN)
Trial acronym
CHEPs
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Spinal cord injury with or without below level neuropathic pain 324618 0
Condition category
Condition code
Anaesthesiology 322068 322068 0 0
Pain management
Injuries and Accidents 322069 322069 0 0
Other injuries and accidents
Neurological 322070 322070 0 0
Other neurological disorders

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
We recruited participants with complete established (greater than or equal to 12 months ) thoracic spinal cord injury who were medically stable. The extent of spinal cord injury (SCI) damage was recorded according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) and classified by the American Spinal Injury Association Impairment Scale - AIS.
Each participant was examined by the same clinician (PW).

Quantitative Sensory Testing (QST)
Quantitative Sensory Testing (mechanical and thermal stimuli) was undertaken to establish the degree of sensory loss or gain in participants with SCI above and below their neurological level of injury (arm, medial knee and dorsum of foot) in comparison with healthy controls. The German Research Network on Neuropathic Pain standardised protocol was used to determine sensory thresholds for cold detection, cold pain, warm detection, warm pain, mechanical detection, mechanical pain, pressure pain and vibration detection.

Contact Heat Evoked Potentials (CHEPs)
Participants were placed in a 22°C±2°C room and asked to keep their eyes open during testing and to fixate on a stationary point to minimise eye movement artefact. Fifteen contact heat stimuli (27 mm diameter thermode, Medoc Pathway System, Ramat Yishai, Israel) using a brief heat pulse (500 ms, 51°C , 70°C/s increasing rate, 40°C/s return rate) were applied in a pseudo random fashion (8-12s intervals) across a small area of skin (7.5x7.5cm) marked at each test site. To reduce peripheral desensitisation the thermode was moved within this area to ensure no two successive stimuli were delivered to the same area of skin. A stimulus-triggered EEG was recorded (V-amp 8, Brain Products GmbH, Munich, Germany) using disposable Ag-AgCl electrodes (bandpass 0.5-35 Hz, sample rate 500 Hz) from Fz, Cz, Pz, T3 and T4 [international 10-20 system, referenced to linked earlobes]. Blink artefacts were monitored by an electrooculogram (EOG) recorded from lateral and infraorbital electrodes. Electrode impedance was maintained below 5 kO by cleaning the skin with alcohol wipes and an abrasive skin prepping gel.
A familiarisation series of 15 stimuli was carried out on the contralateral (generally left) forearm and the same sites used for QST were also used for CHEPs testing. In the SCI-BLNP group, CHEP stimuli were administered within their area of pain if it was not already tested using the routine sites.

Optimising contact heat evoked potential recording
To optimise the acquisition of cortical potentials during CHEP stimulation we tested two baseline temperatures: 38°C and 42°C. All participants were tested with both baselines temperatures at the arm, healthy controls also received both baselines at knee and foot sites. Given their profound loss of sensation, participants with SCIs were tested using the 42°C baseline at test sites below their neurological level of injury.
The effect of pre-treatment with a chemical sensitising agent was also assessed. Three millilitres of capsaicin solution (0.6% (w/v) capsaicin solution in 45% ethanol) was applied to a 7.5 x 7.5 cm gauze patch that was covered and held in place with a transparent film dressing for 15 minutes. CHEP testing series were carried out in the following order: 38°C baseline (where appropriate); 42°C; capsaicin at either 38°C or 42°C (based on the highest temperature required to elicit an evoked potential).
For each test site stimulus-triggered cortical traces (2.5 s including 1s pre stimulation) were recorded from Cz and averaged to produce the final waveform for analysis. Automatic eye-blink detection and correction was used, as was a semi-automated process of trace acceptance or rejection. Each stimulus-linked trace was visually examined and rejected if significant artefact was present (muscular contraction, movement artefact, significantly unstable baseline), otherwise they were included in the analysis. The number of readable traces, out of 15, as well as the number of traces containing an evoked potential were recorded. For the final averaged waveform we recorded presence or absence of an EP, N2-P2 amplitude, and N2 and P2 latency.
Perceived pain intensity of the CHEP stimulus was expressed verbally using the Numerical Rating Scale (NRS-101, where 0 = no pain and 100 = most intense pain imaginable), three seconds after each stimulus to avoid interfering with the EEG recording. If the CHEP stimulus was not felt (NF) this was recorded.
All of the above tests were completed in a single visit of approximately 3 hours.
Intervention code [1] 322390 0
Diagnosis / Prognosis
Comparator / control treatment
Healthy controls participants were required to have a normal physical examination, thermal and vibration detection quantitative sensory testing values, no neurological or psychiatric condition, chronic pain, diabetes mellitus or be taking prescription medications with peripheral or central nervous system effects (i.e. analgesics, psycho-/neuro-pharmaceuticals in particular benzodiazepine, triptane or cortisone preparations). Each participant was examined by the same clinician (PW).

The same tests and procedures were conducted in the healthy control group.
Control group
Active

Outcomes
Primary outcome [1] 329836 0
Evoked potential (EP) detected in response to 15 contact heat stimuli.
Timepoint [1] 329836 0
In response to each stimulus
Secondary outcome [1] 404010 0
Contact heat stimuli felt or not felt
Timepoint [1] 404010 0
3 seconds after each stimulus
Secondary outcome [2] 404011 0
Perceived pain intensity of each stimulus, expressed verbally using the Numerical Rating Scale (NRS-101, where 0 = no pain and 100 = most intense pain imaginable).
Timepoint [2] 404011 0
3 seconds after each stimulus

Eligibility
Key inclusion criteria
1. people with complete spinal cord injury (SCI) without neuropathic pain
2. people with complete SCI and neuropathic pain below the level of their injury and
3. age and gender matched control subjects without SCI or pain

• All subjects are older than 18 years.
• Subjects with SCI have complete thoracic spinal cord injuries (The American Spinal Injury Association (ASIA) impairment scale - Grade A: AIS A). The zone of partial preservation (ZPP) below the level of injury must be above the testing area.
• SCI subjects must be greater than or equal to 3 months following injury and be medically stable. In those subjects with neuropathic pain this must have been present for longer than 3 months and be moderate to severe in intensity (greater than or equal to 4/10).
• SCI subjects in the no neuropathic pain group have not had pain below their injury level since the time of injury.
• Able bodied subjects are to be free of chronic or acute pain, medication and neurological disorder. They are age and sex matched.
• As far as possible, SCI subjects are matched for level and duration of injury.

Below level neuropathic pain is defined as persistent pain in an area of sensory abnormality occurring at least three dermatomes below the neurological level of injury.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Subjects with a mental health condition that may interfere with their ability to be tested psychophysically.
• Subject with intellectual or mental impairment: Participants need to understand the risks and benefits of participating in the study and be able to complete study questionnaires. Altered brain function and alteration of central nervous system function may also impact upon the cortical potentials obtained during the project.
• Subjects with a history of severe dysreflexia are excluded due to the theoretical risk of triggering during stimulation.
• Primary language is other than English: Two elements of the study require the use of standardised instructions the patients are required to understand and follow. The instructions are all in English. Failure to understand the instructions would impact upon the results obtained and affect the quality of the data collected. In addition, participants need to understand the risks and benefits of participating in the study and be able to complete study questionnaires.
• <18 years: Participants need to be of a legal age to consent to take part in the study.

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Sample size:
1. people with complete SCI without neuropathic pain (n = 10)
2. people with complete SCI and neuropathic pain below the level of their injury (n = 10) and
3. age and gender matched control subjects without SCI or pain (n = 10).

Statistical Analysis Plan:
Data are presented as mean and standard deviation (SD) if normally distributed, and median (50th percentile) and interquartile range (25–75th percentiles) if not normally distributed. The Mann-Whitney U-test or Kruskal-Wallis test are applied for unpaired data analyses and the Wilcoxon Signed Rank Sum test and McNemar’s test for paired data. Parametric tests (e.g. Student’s t-test and one way analysis of variance) are applied to normally distributed data. Fisher’s exact test or Chi square test are used to test for differences in the proportions of the responses to the applied tests between the subject groups. Statistical significance is assigned at the P<0.05.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
29/08/2013
Date of last participant enrolment
Anticipated
Actual
7/03/2016
Date of last data collection
Anticipated
Actual
7/03/2016
Sample size
Target
30
Accrual to date
Final
41
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 21318 0
Royal North Shore Hospital - St Leonards
Recruitment postcode(s) [1] 36204 0
2065 - St Leonards

Funding & Sponsors
Funding source category [1] 310335 0
Other Collaborative groups
Name [1] 310335 0
Australian and New Zealand College of Anaesthetists (ANZCA)
Country [1] 310335 0
Australia
Primary sponsor type
Individual
Name
Associate Professor Paul Wrigley
Address
Pain Management Research Institute
Royal North Shore Hospital
Kolling Building, Level 13
3 Reserve Road
St Leonards NSW 2065
Country
Australia
Secondary sponsor category [1] 311530 0
None
Name [1] 311530 0
Address [1] 311530 0
Country [1] 311530 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309995 0
Northern Sydney Local Health District
Ethics committee address [1] 309995 0
Ethics committee country [1] 309995 0
Australia
Date submitted for ethics approval [1] 309995 0
27/07/2012
Approval date [1] 309995 0
24/10/2012
Ethics approval number [1] 309995 0
2019/ETH08417

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 116114 0
A/Prof Paul Wrigley
Address 116114 0
Pain Management Research Institute
Royal North Shore Hospital
Kolling Building, Level 13
3 Reserve Road
St Leonards NSW 2065
Country 116114 0
Australia
Phone 116114 0
+61 413 187 772
Fax 116114 0
+61 2 9463 1050
Email 116114 0
[email protected]
Contact person for public queries
Name 116115 0
Paul Wrigley
Address 116115 0
Pain Management Research Institute
Royal North Shore Hospital
Kolling Building, Level 13
3 Reserve Road
St Leonards NSW 2065
Country 116115 0
Australia
Phone 116115 0
+61 413 187 772
Fax 116115 0
+61 2 9463 1050
Email 116115 0
[email protected]
Contact person for scientific queries
Name 116116 0
Paul Wrigley
Address 116116 0
Pain Management Research Institute
Royal North Shore Hospital
Kolling Building, Level 13
3 Reserve Road
St Leonards NSW 2065
Country 116116 0
Australia
Phone 116116 0
+61 413 187 772
Fax 116116 0
+61 2 9463 1050
Email 116116 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Neither ethics approval nor consent from participants regarding data sharing was obtained.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
14431Study protocol  [email protected]
14432Statistical analysis plan  [email protected]
14433Informed consent form  [email protected]
14435Ethical approval  [email protected]



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.