Complex Regional Pain Syndrome (CRPS)NCT01813149
Mechanism and Treatment of Sympathetically Maintained Pain
A study testing phenylephrine and clonidine and punch biopsy in people with Complex Regional Pain Syndrome (CRPS), run by The Cleveland Clinic at 1 site in United States.
Trial summary
40 CRPS patients will be recruited over a three-year period (target of 160 patients at all sites). Assessment of exclusion criteria will be undertaken during initial recruitment. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Complex Regional Pain Syndrome (CRPS)
- What is being tested?
- phenylephrine and clonidine and punch biopsy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 128 participants
- Where
- 1 siteUnited States
- Study dates
- Aug 2012to Dec 2016
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- CRPS patients
Who cannot join
- <18 years
- a second chronic pain syndrome that would interfere with pain rating
- psychiatric comorbidity
- pain in both hands or feet
- pregnancy or breastfeeding
- sympathectomy in the affected limb
- use of topical medication
- known sensitivity to alpha 1- adrenoceptor agonists or other contraindications
Trial locations and contacts
1 site in 1 country.
About this study
40 CRPS patients will be recruited over a three-year period (target of 160 patients at all sites). Assessment of exclusion criteria will be undertaken during initial recruitment. Exclusion criteria are: <18 years; a second chronic pain syndrome that would interfere with pain rating; psychiatric comorbidity; pain in both hands or feet; pregnancy or breastfeeding; sympathectomy in the affected limb; use of topical medication; known sensitivity to alpha 1- adrenoceptor agonists or other contraindications. Patients will maintain their regular oral medications throughout the study period.
Assessment of sympathetically maintained pain (SMP) will require an intradermal dose of Phenylephrine to rekindle SMP and mechanical hyperalgesia. Clonidine will be used to control for affects of algometer fiction and may inhibit SMP by inhibiting the release of more norepinephrine from sympathetic nerve terminals. Skin biopsies will be obtained under sterile conditions from a site of mechanical or thermal hyperalgesia using a 3mm diameter skin biopsy punch under local anesthesia. Samples from a mirror image site on the contralateral body side will also be taken.
Read the detailed description
Patients diagnosed with CRPS and control subjects will be enrolled in the study. The CRPS participants will be administered with phenylephrine (day 1) and clonidine (day 2). The control participants will not receive any intervention.
The aim of this study is to determine if expression of α1-adrenoceptors (α1-AR) altered in the skin of a subgroup of patients whose pain is associated with increased adrenergic sensitivity after nerve trauma. Increased adrenergic sensitivity will be determined by assessing pain in patients after administration of phenylephrine on day 1. Expression of α1-AR will be determined by taking skin biopsies on day 2 after administration of clonidine. Then, we will compare the expression of α1-AR in patients who were classified as having increased adrenergic sensitivity versus those who were not.
- Conditions
- Complex Regional Pain Syndrome (CRPS)
- Being tested
- phenylephrine and clonidine, punch biopsy
- Keywords
- Complex Regional Pain Syndrome (CRPS)
- Medical subject headings
- Complex Regional Pain Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
phenylephrine and clonidineDrug
Subjects will be injected with phenylephrine and clonidine at both affected and unaffected sites.
punch biopsyOther
Also called After local anesthetic, subjects will receive punch biopsy (1/8"diameter and 1/8" deep) from both affected and unaffected sites.
| Study group | Role | What they receive |
|---|---|---|
| phenylephrine and clonidine | Experimental | Subjects will be injected with phenylephrine and clonidine at affected and unaffected sites. Receives: Drug: phenylephrine and clonidine; Other: punch biopsy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Increased Adrenergic Sensitivity
To investigate adrenergically evoked pain, 50 mg of the a1-AR agonist phenylephrine in 0.1 mL normal saline (equivalent to 2.5mMconcentration was injected intradermally into the most painful region of the dorsal and or foot and into a mirror-image site in the contralateral limb. Pain induced by the intradermal injection of phenylephrine into the contralateral limb of patients with CRPS usually resolved within 5 to 10 minutes. Therefore, pain that persisted for 15 minutes or longer (in the CRPS-affected limb) was considered to be atypical.
Using this criterion, subjects who reported prolonged pain (a sign of adrenergic sensitivity) following the phenylephrine injection were classified as phenylephrine responders and those who didn't were classified as phenylephrine non-responders.
Measured: Day 1
Expression of α1-adrenoceptors (α1-AR) in Dermal Nerve Bundles in the CRPS-affected Limb of Phenylephrine Responders and Non-responders
Expression of α1-AR was determined from the skin biopsies using immunohistochemistry. Nerve bundles in the reticular dermis were identified in the affected limb of 25 patients with CRPS [only 22 of these were classified as phenylephrine responders/non-responders], in the contralateral limb of 21 patients with CRPS, and in 12 controls. Samples were processed in batches containing sections from 10 controls and from the affected and contralateral limbs of 10 patients. The α1-AR immunoreactivity (a measure of the expression of receptors) scores were transformed into standard units with a mean of 0 and a SD of 1 (ie, Z-scores). Positive scores represent greater than average α1-AR immunoreactivity (i.e. higher expression of α1-AR) compared with other samples in the run, and negative scores represent less than average α1-AR immunoreactivity. Normalized scores were averaged across multiple runs for each patient or control to obtain a mean α1-AR score.
Measured: Day 2, after clonidine injection
Expression of Pain Association With Chronic Inflammation in Patients With Sympathetically Maintained Pain
Determine whether heightened expression of cutaneous 1-adrenoceptors is associated with signs of chronic inflammation in patients with sympathetically maintained pain
Measured: Day 1
Decrease in Pain After Topical Adrenoceptor Blockade
Measured: 2 weeks after blockade
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Mar 2013 (estimated)
- Study startAug 2012
- Primary completionJun 2016
- Study completionDec 2016
Why it stopped: Study halted prematurely and will not resume; participants are no longer being examined or receiving intervention. There is no data collected
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Complex Regional Pain Syndrome (CRPS)Studies of the same condition, open and under way.
- More trials run by The Cleveland ClinicThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- This is best thought of as a single-arm study because the primary purpose for recruiting control patients is to use their skin biopsies as controls when running immunohistochemistry tests for determining α1-adrenoceptors (α1-AR) expression in CRPS patients. The primary outcomes are concerned with making comparisons between subgroups of CRPS patients, and not between CRPS patients and control patients.
- Masking
- None (open label)
- Enrolment
- 128 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Cleveland Clinic
- Sponsor type
- University, hospital or other
- Collaborators
- Murdoch University
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01813149
- Sponsor's protocol ID
- 12-400
- Status last verified
- Dec 2020
- First submitted
- 12 Mar 2013
- Last updated
- 13 Jan 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mechanism and Treatment of Sympathetically Maintained Pain
- ClinicalTrials.gov ID
- NCT01813149
- Acronym / sponsor ID
- 12-400
- Conditions
- Complex Regional Pain Syndrome (CRPS)
- Keywords
- Complex Regional Pain Syndrome (CRPS)
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study halted prematurely and will not resume; participants are no longer being examined or receiving intervention. There is no data collected
- Enrolment
- 128 participants (actual)
- Lead sponsor
- The Cleveland ClinicUniversity, hospital or other
- Collaborators
- Murdoch University
- Study start
- Aug 2012
- Primary completion
- Jun 2016 (actual)
- Study completion
- Dec 2016 (actual)
- First posted
- 18 Mar 2013 (estimated)
- Results
- Posted 13 Jan 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
40 CRPS patients will be recruited over a three-year period (target of 160 patients at all sites). Assessment of exclusion criteria will be undertaken during initial recruitment. Exclusion criteria are: <18 years; a second chronic pain syndrome that would interfere with pain rating; psychiatric comorbidity; pain in both hands or feet; pregnancy or breastfeeding; sympathectomy in the affected limb; use of topical medication; known sensitivity to alpha 1- adrenoceptor agonists or other contraindications. Patients will maintain their regular oral medications throughout the study period.
Assessment of sympathetically maintained pain (SMP) will require an intradermal dose of Phenylephrine to rekindle SMP and mechanical hyperalgesia. Clonidine will be used to control for affects of algometer fiction and may inhibit SMP by inhibiting the release of more norepinephrine from sympathetic nerve terminals. Skin biopsies will be obtained under sterile conditions from a site of mechanical or thermal hyperalgesia using a 3mm diameter skin biopsy punch under local anesthesia. Samples from a mirror image site on the contralateral body side will also be taken.
Detailed description
Patients diagnosed with CRPS and control subjects will be enrolled in the study. The CRPS participants will be administered with phenylephrine (day 1) and clonidine (day 2). The control participants will not receive any intervention.
The aim of this study is to determine if expression of α1-adrenoceptors (α1-AR) altered in the skin of a subgroup of patients whose pain is associated with increased adrenergic sensitivity after nerve trauma. Increased adrenergic sensitivity will be determined by assessing pain in patients after administration of phenylephrine on day 1. Expression of α1-AR will be determined by taking skin biopsies on day 2 after administration of clonidine. Then, we will compare the expression of α1-AR in patients who were classified as having increased adrenergic sensitivity versus those who were not.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- This is best thought of as a single-arm study because the primary purpose for recruiting control patients is to use their skin biopsies as controls when running immunohistochemistry tests for determining α1-adrenoceptors (α1-AR) expression in CRPS patients. The primary outcomes are concerned with making comparisons between subgroups of CRPS patients, and not between CRPS patients and control patients.
| Arm | Type | Receives |
|---|---|---|
| phenylephrine and clonidine | Experimental | Drug: phenylephrine and clonidine, Other: punch biopsySubjects will be injected with phenylephrine and clonidine at affected and unaffected sites. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- CRPS patients
Key exclusion criteria (8 listed)
- <18 years
- a second chronic pain syndrome that would interfere with pain rating
- psychiatric comorbidity
- pain in both hands or feet
- pregnancy or breastfeeding
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| phenylephrine and clonidineSubjects will be injected with phenylephrine and clonidine at both affected and unaffected sites. | Drug | phenylephrine and clonidine |
| punch biopsyAlso: After local anesthetic, subjects will receive punch biopsy (1/8"diameter and 1/8" deep) from both affected and unaffected sites. | Other | phenylephrine and clonidine |
Primary outcome
Increased Adrenergic Sensitivity
Time frame: Day 1
To investigate adrenergically evoked pain, 50 mg of the a1-AR agonist phenylephrine in 0.1 mL normal saline (equivalent to 2.5mMconcentration was injected intradermally into the most painful region of the dorsal and or foot and into a mirror-image site in the contralateral limb. Pain induced by the intradermal injection of phenylephrine into the contralateral limb of patients with CRPS usually resolved within 5 to 10 minutes. Therefore, pain that persisted for 15 minutes or longer (in the CRPS-affected limb) was considered to be atypical. Using this criterion, subjects who reported prolonged pain (a sign of adrenergic sensitivity) following the phenylephrine injection were classified as phenylephrine responders and those who didn't were classified as phenylephrine non-responders.
Expression of α1-adrenoceptors (α1-AR) in Dermal Nerve Bundles in the CRPS-affected Limb of Phenylephrine Responders and Non-responders
Time frame: Day 2, after clonidine injection
Expression of α1-AR was determined from the skin biopsies using immunohistochemistry. Nerve bundles in the reticular dermis were identified in the affected limb of 25 patients with CRPS [only 22 of these were classified as phenylephrine responders/non-responders], in the contralateral limb of 21 patients with CRPS, and in 12 controls. Samples were processed in batches containing sections from 10 controls and from the affected and contralateral limbs of 10 patients. The α1-AR immunoreactivity (a measure of the expression of receptors) scores were transformed into standard units with a mean of 0 and a SD of 1 (ie, Z-scores). Positive scores represent greater than average α1-AR immunoreactivity (i.e. higher expression of α1-AR) compared with other samples in the run, and negative scores represent less than average α1-AR immunoreactivity. Normalized scores were averaged across multiple runs for each patient or control to obtain a mean α1-AR score.
Expression of Pain Association With Chronic Inflammation in Patients With Sympathetically Maintained Pain
Time frame: Day 1
Determine whether heightened expression of cutaneous 1-adrenoceptors is associated with signs of chronic inflammation in patients with sympathetically maintained pain
Decrease in Pain After Topical Adrenoceptor Blockade
Time frame: 2 weeks after blockade
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jan 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing phenylephrine and clonidine and punch biopsy in people with Complex Regional Pain Syndrome (CRPS), run by The Cleveland Clinic at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 13 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Jan 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Increased Adrenergic Sensitivity (time frame: Day 1). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jan 2021.