Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000911493
Ethics application status
Approved
Date submitted
5/07/2016
Date registered
8/07/2016
Date last updated
24/07/2020
Date data sharing statement initially provided
24/07/2020
Date results information initially provided
24/07/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
Investigating the adrenergic component of pain in patients with complex regional pain syndrome or painful neuropathy
Scientific title
A multi-site study of the role of alpha-1 adrenoceptors for evoking sympathetically maintained pain in patients with complex regional pain syndrome or painful neuropathy
Secondary ID [1] 289610 0
NCT01813149
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
neuropathic pain 299398 0
complex regional pain syndrome 299421 0
Condition category
Condition code
Anaesthesiology 299380 299380 0 0
Pain management
Neurological 299400 299400 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
We will identify patients with an adrenergic component of pain by assessing their response to phenylephrine injected intradermally (0.05 mg injected once only into the affected limb, and 0.05 mg injected simultaneously into the opposite unaffected limb). Phenylephrine will be administered by a pain specialist or by qualified personnel under medical supervision. Phenylephrine may induce pain at the site of injection for 10-40 minutes in symptomatic skin of patients with an adrenergic component of pain but is not expected to induce pain in nonsymptomatic skin. Sensitivity to pinprick stimulation will be investigated at and around the site of injection before and every 10 minutes after the injection for 40 minutes.
At the end of the study, a skin biopsy will be obtained from the affected limb and contralateral limb for comparison, and the distribution of a biomarker (the alpha-1 adrenoceptor) will be examined using immunohistochemistry.
Intervention code [1] 295219 0
Diagnosis / Prognosis
Comparator / control treatment
Phenylephrine is the active treatment and clonidine is the control treatment. Phenylephrine visibly constricts blood vessels. Therefore, to ensure that participants and observers remain double-blind, the vasoconstrictor clonidine will be injected intradermally in a double-blind crossover trial. Specifically, 10 micrograms of clonidine will be injected once only into the affected limb and 10 micrograms will be injected simultaneously into the opposite unaffected limb . Clonidine is not expected to induce pain. The “crossover” injections of phenylephrine and clonidine will be administered at least 1 day apart.
Control group
Active

Outcomes
Primary outcome [1] 298842 0
Numeric pain ratings between 0 (no pain) and 10 (extreme pain) at the site of injection
Timepoint [1] 298842 0
every 5 mins from 5 mins after the injection to 40 minutes after the injection.
Secondary outcome [1] 325386 0
Sensitivity to pinprick will be assessed around the site of injection using a Neuropen (a device that delivers 40 grams of force to the tip of a disposable pin). Patients will rate sharpness between 0 (not at all sharp) and 10 (extremely sharp) to stimuli delivered 1 cm, 2 cm and 3 cm away from the site of injection.
Timepoint [1] 325386 0
Every 10 minutes 10-40 minutes after the injection
Secondary outcome [2] 325509 0
Expression of alpha-1 adrenoceptors in skin biopsy samples from the affected and unaffected limbs will be identified using immunohistochemistry and confocal microscopy. The intensity of staining on target cells (keratinocytes, nerve fibres, blood vessel walls) will be quantified using image J software.
Timepoint [2] 325509 0
Once only at the end of the study.

Eligibility
Key inclusion criteria
meets "Budapest" criteria for complex regional pain syndrome; or meets clinical criteria for other forms of neuropathic pain.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded if they are pregnant or breastfeeding, if they have a medical condition that affects their heart, blood vessels, skin, liver or kidneys that requires regular treatment with medication, if they have a known sensitivity to adrenergic drugs, or have severe hypertension, arrhythmias, hyperthyroidism or hyperglycaemia.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The drug-placebo order is assigned in no predetermined sequence by medical personnel so that neither the assessor nor the participant is aware of the treatment administered during the session.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
At the whim of medical personnel.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
The primary sample will consist of 60 patients with complex regional pain syndrome (CRPS). When compared with the 95% confidence interval of scores in healthy controls, heightened expression of cutaneous alpha-1 adrenoceptors appears to be characteristic of at least 50% of patients with CRPS [Finch et al. Pain Medicine 2014;15:1945-1956]. Based on this preliminary data and on previous reports, we expect that intradermal injection of phenylephrine will increase pain in approximately one-third of patients with CRPS, and hypothesize that cutaneous alpha-1 adrenoceptors will be up-regulated in the majority of this subgroup. To test this hypothesis with power = 0.8 and p<0.05, we estimate that a sample of ~60 CRPS patients will be required. For exploratory purposes, we will collect similar data on smaller, convenience samples of patients with other forms of neuropathic pain.
The mean pain score at the site of injection during minutes 10-40 after the injection of phenylephrine will be used to classify patients into pain responders (with a positive score) and nonresponders (with a score of 0). Differences in the distribution of the alpha-1 adrenoceptor in cutaneous cells will be investigated in Group (responders versus nonresponders) x Side (affected versus contralateral) repeated measures analysis of variance.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
4/03/2013
Date of last participant enrolment
Anticipated
30/06/2017
Actual
1/08/2017
Date of last data collection
Anticipated
30/06/2017
Actual
4/08/2017
Sample size
Target
60
Accrual to date
Final
90
Recruitment in Australia
Recruitment state(s)
WA

Funding & Sponsors
Funding source category [1] 294002 0
Government body
Name [1] 294002 0
NHMRC
Country [1] 294002 0
Australia
Funding source category [2] 294003 0
Charities/Societies/Foundations
Name [2] 294003 0
RSD Association of America
Country [2] 294003 0
United States of America
Primary sponsor type
University
Name
Murdoch University
Address
90 South St, Murdoch WA 6150
Country
Australia
Secondary sponsor category [1] 292822 0
None
Name [1] 292822 0
Address [1] 292822 0
Country [1] 292822 0
Other collaborator category [1] 279064 0
University
Name [1] 279064 0
Johannes Gutenberg-Universitat Mainz
Address [1] 279064 0
Saarstrasse 21, 55122 Mainz, Germany
Country [1] 279064 0
Germany
Other collaborator category [2] 279065 0
University
Name [2] 279065 0
Aarhus University
Address [2] 279065 0
Nordre Ringgade 1, 8000 Aarhus C, Denmark
Country [2] 279065 0
Denmark
Other collaborator category [3] 279066 0
Hospital
Name [3] 279066 0
Cleveland Clinic
Address [3] 279066 0
2049 E 100th St, Cleveland, OH 44195, United States
Country [3] 279066 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295416 0
Murdoch University Human Research Ethics Committee
Ethics committee address [1] 295416 0
90 South Street, Murdoch, 6150 WA
Ethics committee country [1] 295416 0
Australia
Date submitted for ethics approval [1] 295416 0
14/11/2011
Approval date [1] 295416 0
12/12/2011
Ethics approval number [1] 295416 0
2011/233

Summary
Brief summary
A major early component of neuropathic pain is infiltration of immune cells into the injured tissue that release inflammatory mediators. These mediators could either directly, or through the induction of neurotrophic factors, trigger increased alpha-1 adrenoceptor expression on neurons and other cells around the site of injury. In turn, activation of alpha-1 adrenoceptors on fibroblasts and keratinocytes may trigger further release of growth factors and inflammatory mediators. Thus, an upward spiral of alpha-1 adrenoceptor expression on these cells and on regenerating neurons could engender an adrenergic component of inflammation and pain. The aim of this project is to investigate this hypothesis in a large sample of patients with complex regional pain syndrome and in other forms of painful neuropathy. An adrenergic component of pain in the skin will be assessed in response to intradermal injection of the adrenergic agonists phenylephrine and clonidine. In addition, we will investigate the expression of alpha-1 adrenoceptors and inflammatory mediators in skin biopsies of hyperalgesic and control skin. This project may have significant treatment implications, as blocking up-regulation of the alpha-1 adrenoceptor could ultimately prove to be a useful therapeutic strategy for patients with an adrenergic component of pain.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67194 0
Prof Peter Drummond
Address 67194 0
School of Psychology and Exercise Science,
Murdoch University,
90 South Street, Murdoch 6150 WA
Country 67194 0
Australia
Phone 67194 0
+61 8 93602415
Fax 67194 0
Email 67194 0
[email protected]
Contact person for public queries
Name 67195 0
Prof Peter Drummond
Address 67195 0
School of Psychology and Exercise Science,
Murdoch University,
90 South Street, Murdoch 6150 WA
Country 67195 0
Australia
Phone 67195 0
+61 8 93602415
Fax 67195 0
Email 67195 0
[email protected]
Contact person for scientific queries
Name 67196 0
Prof Peter Drummond
Address 67196 0
School of Psychology and Exercise Science,
Murdoch University,
90 South Street, Murdoch 6150 WA
Country 67196 0
Australia
Phone 67196 0
+61 8 93602415
Fax 67196 0
Email 67196 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Drummond PD, Morellini N, Finch PM, Birklein F, Kn... [More Details]

Documents added automatically
No additional documents have been identified.