Trial Outcomes & Findings for Mechanism and Treatment of Sympathetically Maintained Pain (NCT NCT01813149)

Results Overview

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.

Recruitment status

TERMINATED

Study phase

NA

Target enrollment

128 participants

Primary outcome timeframe

Day 1

Results posted on

2021-01-13

Participant Flow

Participant milestones

Participant milestones
Measure	CRPS Patients Patients diagnosed with CRPS that were enrolled in the study. The patients in this group were scheduled to be administered phenylephrine (day 1) and clonidine (day 2) in a sequential manner.	Control Participants Pain-free subjects (i.e. not diagnosed with CRPS) were enrolled in the study. These participants were not administered with phenylephrine or clonidine over the course of the study
Overall Study STARTED	90	38
Overall Study COMPLETED	90	38
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Mechanism and Treatment of Sympathetically Maintained Pain

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	CRPS I n=59 Participants Patients diagnosed with CRPS I.	CRPS II n=31 Participants 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	Control n=38 Participants Pain-free subjects enrolled in the study	Total n=128 Participants Total of all reporting groups
Age, Continuous	47.9 years STANDARD_DEVIATION 11.2 • n=5 Participants	45.7 years STANDARD_DEVIATION 10.6 • n=7 Participants	44.4 years STANDARD_DEVIATION 15.6 • n=5 Participants	46.3 years STANDARD_DEVIATION 12.5 • n=4 Participants
Sex: Female, Male Female	45 Participants n=5 Participants	18 Participants n=7 Participants	24 Participants n=5 Participants	87 Participants n=4 Participants
Sex: Female, Male Male	14 Participants n=5 Participants	13 Participants n=7 Participants	14 Participants n=5 Participants	41 Participants n=4 Participants
Race/Ethnicity, Customized Race · Caucasian	58 Participants n=5 Participants	31 Participants n=7 Participants	38 Participants n=5 Participants	127 Participants n=4 Participants
Race/Ethnicity, Customized Race · Other	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	CRPS Patients n=85 Participants CRPS patients who were enrolled in the study and then injected with phenylephrine	Phenylephrine Non-responders CRPS-affected limbs of phenylephrine non-responders i.e. patients who did not experience prolonged pain in the CRPS-affected limb after administration of phenylephrine
Increased Adrenergic Sensitivity Phenylephrine responders	32 Participants	—
Increased Adrenergic Sensitivity Phenylephrine non-responders	53 Participants	—

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	CRPS Patients n=32 CRPS-affected limbs CRPS patients who were enrolled in the study and then injected with phenylephrine	Phenylephrine Non-responders n=53 CRPS-affected limbs CRPS-affected limbs of phenylephrine non-responders i.e. patients who did not experience prolonged pain in the CRPS-affected limb after administration of phenylephrine
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	0.142 z-score Standard Deviation 0.617
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 Standard Deviation NA Biopsies were collected but nerve bundles in the reticular dermis could not be identified and hence α1-AR immunoreactivity could not be measured. (n=25)	NA z-score Standard Deviation NA Biopsies were collected but nerve bundles in the reticular dermis could not be identified and hence α1-AR immunoreactivity could not be measured. (n=38)

PRIMARY outcome

Timeframe: Day 1

Population: Data on chronic inflammation was not collected

Determine whether heightened expression of cutaneous 1-adrenoceptors is associated with signs of chronic inflammation in patients with sympathetically maintained pain

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 2 weeks after blockade

Population: Data were not collected--no patients were given a topical adrenoreceptor antagonist.

Outcome measures

Outcome data not reported

Adverse Events

Phenylephrine: CRPS Patients

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Clonidine: CRPS Patients

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

CRPS Patients

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Control

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Michael Stanton Hicks, MD

Cleveland Clinic Foundation

Phone: 216-445-3497

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place