Mechanism and Treatment of Sympathetically Maintained Pain

Complex Regional Pain Syndrome (CRPS) Clinical Trial

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01813149
• Other study ID #: 12-400
• Status: Terminated
• Phase: N/A
• Start date: August 2012
• Est. completion date: December 2016

Study information

• Verified date: December 2020
• Source: The Cleveland Clinic
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 128
• Est. completion date: December 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Complex Regional Pain Syndrome (CRPS)
• Complex Regional Pain Syndromes
• Reflex Sympathetic Dystrophy

Intervention

Drug:
• phenylephrine and clonidine
Subjects will be injected with phenylephrine and clonidine at both affected and unaffected sites.

Other:
• punch biopsy

Locations

Country	Name	City	State
United States	Cleveland Clinic	Cleveland	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
The Cleveland Clinic	Murdoch University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Expression of a1-adrenoceptors (a1-AR) in Dermal Nerve Bundles in the CRPS-affected Limb of Phenylephrine Responders and Non-responders	Expression of a1-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 a1-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 a1-AR immunoreactivity (i.e. higher expression of a1-AR) compared with other samples in the run, and negative scores represent less than average a1-AR immunoreactivity. Normalized scores were averaged across multiple runs for each patient or control to obtain a mean a1-AR score.	Day 2, after clonidine injection
Primary	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
Primary	Decrease in Pain After Topical Adrenoceptor Blockade		2 weeks after blockade