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Mechanism and Treatment of Sympathetically Maintained Pain

Primary Purpose

Complex Regional Pain Syndrome (CRPS)

Status
Terminated
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
phenylephrine and clonidine
punch biopsy
Sponsored by
The Cleveland Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Complex Regional Pain Syndrome (CRPS) focused on measuring Complex Regional Pain Syndrome (CRPS)

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • CRPS patients

Exclusion Criteria:

  • <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

Sites / Locations

  • Cleveland Clinic

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

phenylephrine and clonidine

Arm Description

Subjects will be injected with phenylephrine and clonidine at affected and unaffected sites.

Outcomes

Primary Outcome Measures

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.
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.
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
Decrease in Pain After Topical Adrenoceptor Blockade

Secondary Outcome Measures

Full Information

First Posted
March 12, 2013
Last Updated
December 16, 2020
Sponsor
The Cleveland Clinic
Collaborators
Murdoch University
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1. Study Identification

Unique Protocol Identification Number
NCT01813149
Brief Title
Mechanism and Treatment of Sympathetically Maintained Pain
Study Type
Interventional

2. Study Status

Record Verification Date
December 2020
Overall Recruitment Status
Terminated
Why Stopped
Study halted prematurely and will not resume; participants are no longer being examined or receiving intervention. There is no data collected
Study Start Date
August 2012 (undefined)
Primary Completion Date
June 2016 (Actual)
Study Completion Date
December 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The Cleveland Clinic
Collaborators
Murdoch University

4. Oversight

Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Complex Regional Pain Syndrome (CRPS)
Keywords
Complex Regional Pain Syndrome (CRPS)

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
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)
Allocation
N/A
Enrollment
128 (Actual)

8. Arms, Groups, and Interventions

Arm Title
phenylephrine and clonidine
Arm Type
Experimental
Arm Description
Subjects will be injected with phenylephrine and clonidine at affected and unaffected sites.
Intervention Type
Drug
Intervention Name(s)
phenylephrine and clonidine
Intervention Description
Subjects will be injected with phenylephrine and clonidine at both affected and unaffected sites.
Intervention Type
Other
Intervention Name(s)
punch biopsy
Other Intervention Name(s)
After local anesthetic, subjects will receive punch biopsy (1/8"diameter and 1/8" deep) from both affected and unaffected sites.
Primary Outcome Measure Information:
Title
Increased Adrenergic Sensitivity
Description
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.
Time Frame
Day 1
Title
Expression of α1-adrenoceptors (α1-AR) in Dermal Nerve Bundles in the CRPS-affected Limb of Phenylephrine Responders and Non-responders
Description
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.
Time Frame
Day 2, after clonidine injection
Title
Expression of Pain Association With Chronic Inflammation in Patients With Sympathetically Maintained Pain
Description
Determine whether heightened expression of cutaneous 1-adrenoceptors is associated with signs of chronic inflammation in patients with sympathetically maintained pain
Time Frame
Day 1
Title
Decrease in Pain After Topical Adrenoceptor Blockade
Time Frame
2 weeks after blockade

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: CRPS patients Exclusion Criteria: <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
Facility Information:
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States

12. IPD Sharing Statement

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Mechanism and Treatment of Sympathetically Maintained Pain

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