Mechanism and Treatment of Sympathetically Maintained Pain

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.

Study Overview

• Status: Terminated
• Conditions: Complex Regional Pain Syndrome (CRPS)
• Intervention / Treatment: Drug: phenylephrine and clonidine; Other: punch biopsy

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 Type: Interventional
• Enrollment (Actual): 128
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: phenylephrine and clonidine; Subjects will be injected with phenylephrine and clonidine at affected and unaffected sites.	Drug: phenylephrine and clonidine; Subjects will be injected with phenylephrine and clonidine at both affected and unaffected sites.; Other: punch biopsy; Other Names: After local anesthetic, subjects will receive punch biopsy (1/8"diameter and 1/8" deep) from both affected and unaffected sites.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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	Day 1
Decrease in Pain After Topical Adrenoceptor Blockade		2 weeks after blockade

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Collaborators: Murdoch University

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: March 12, 2013
• First Submitted That Met QC Criteria: March 13, 2013
• First Posted (Estimate): March 18, 2013

Study Record Updates

• Last Update Posted (Actual): January 13, 2021
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Complex Regional Pain Syndrome (CRPS)
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases; Autonomic Nervous System Diseases; Complex Regional Pain Syndromes; Reflex Sympathetic Dystrophy; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Protective Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Cardiotonic Agents; Respiratory System Agents; Sympathomimetics; Sympatholytics; Vasoconstrictor Agents; Mydriatics; Nasal Decongestants; Adrenergic alpha-1 Receptor Agonists; Anesthetics; Anesthetics, Local; Clonidine; Phenylephrine; Oxymetazoline
• Other Study ID Numbers: 12-400

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No