Complex Regional Pain Syndrome (CRPS)
Conditions
Keywords
Complex Regional Pain Syndrome (CRPS)
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.
Interventions
DRUGphenylephrine and clonidine
Subjects will be injected with phenylephrine and clonidine at both affected and unaffected sites.
OTHERpunch biopsy
Sponsors
Murdoch University
The Cleveland Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Increased Adrenergic Sensitivity | 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 | 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 | 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 | 2 weeks after blockade | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CRPS I Patients diagnosed with CRPS I. | 59 |
| CRPS II Patients diagnosed with CRPS II. Peripheral nerve injury had been verified surgically or by a confirmatory test in 14 patients with CRPS II (definite nerve lesion), whereas in another 17 patients with CRPS II, a sensory examination and quantitative sensory tests indicated sensory disturbances in an anatomically plausible nerve distribution given the site and nature of the triggering event | 31 |
| Control Pain-free subjects enrolled in the study | 38 |
| Total | 128 |
Baseline characteristics
| Characteristic | CRPS I | CRPS II | Control | Total |
|---|---|---|---|---|
| Age, Continuous | 47.9 years STANDARD_DEVIATION 11.2 | 45.7 years STANDARD_DEVIATION 10.6 | 44.4 years STANDARD_DEVIATION 15.6 | 46.3 years STANDARD_DEVIATION 12.5 |
| Race/Ethnicity, Customized Race Caucasian | 58 Participants | 31 Participants | 38 Participants | 127 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 45 Participants | 18 Participants | 24 Participants | 87 Participants |
| Sex: Female, Male Male | 14 Participants | 13 Participants | 14 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 85 | 0 / 85 | 0 / 5 | 0 / 38 |
| other Total, other adverse events | 0 / 85 | 0 / 85 | 0 / 5 | 0 / 38 |
| serious Total, serious adverse events | 0 / 85 | 0 / 85 | 0 / 5 | 0 / 38 |
Outcome results
Primary
Decrease in Pain After Topical Adrenoceptor Blockade
Time frame: 2 weeks after blockade
Population: Data were not collected--no patients were given a topical adrenoreceptor antagonist.
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
Time frame: Day 1
Population: Data on chronic inflammation was not collected
Primary
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.
Time frame: Day 2, after clonidine injection
Population: After obtaining the mean α1-AR scores for all subjects at the affected/contralateral regions using the process described in the, Outcome Measure Description, we then compared the mean α1-AR score between the subgroup of patients who were classified as either phenylephrine responders or non-responders.Skin biopsies were collected for all patients but nerve bundles in reticular dermis could only be identified in 22 phenylephrine responders/non-responders.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRPS Patients | Expression of α1-adrenoceptors (α1-AR) in Dermal Nerve Bundles in the CRPS-affected Limb of Phenylephrine Responders and Non-responders | Nerve bundles identified in reticular dermis | 1.146 z-score | Standard Deviation 1.009 |
| CRPS Patients | Expression of α1-adrenoceptors (α1-AR) in Dermal Nerve Bundles in the CRPS-affected Limb of Phenylephrine Responders and Non-responders | Nerve bundle not identified in reticular dermis | NA z-score | — |
| Phenylephrine Non-responders | Expression of α1-adrenoceptors (α1-AR) in Dermal Nerve Bundles in the CRPS-affected Limb of Phenylephrine Responders and Non-responders | Nerve bundles identified in reticular dermis | 0.142 z-score | Standard Deviation 0.617 |
| Phenylephrine Non-responders | Expression of α1-adrenoceptors (α1-AR) in Dermal Nerve Bundles in the CRPS-affected Limb of Phenylephrine Responders and Non-responders | Nerve bundle not identified in reticular dermis | NA z-score | — |
Comparison: A t-test to see if expression of α1-AR differs between phenylephrine responders and non-respondersp-value: 0.009t-test, 2 sided
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.
Time frame: Day 1
Population: Data on pain scores were not collected from 5 CRPS patients (not administered phenylephrine \[PE\] per physician decision) of the initial 90 patients. Thus, data from 85 patients were analyzed. Data on control arm not reported because the only purpose for enrolling them in the trial was so that their skin biopsies could be used in immunohistochemistry analyses (see Outcome Measure 2 description). We did not plan to collect pain scores from control arm participants and they weren't administered PE.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CRPS Patients | Increased Adrenergic Sensitivity | Phenylephrine responders | 32 Participants |
| CRPS Patients | Increased Adrenergic Sensitivity | Phenylephrine non-responders | 53 Participants |