Evaluation of Propranolol's Effect on Pain and Inflammation.

Investigation of Analgesic and Anti-inflammatory Effects of Beta-adrenergic Antagonist Propranolol

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01094574

Enrollment

Registered

2010-03-29

Start date

2010-01-31

Completion date

2010-08-31

Last updated

2017-02-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pain Measurement

Brief summary

Previous studies have shown that the beta-adrenergic system plays a role in processing pain and the expression of hyperalgesia. Recent studies have investigated the analgesic effects, and potential anti-hyperalgesic effects (using a model of opioid induced (OIH) hyperalgesia) of propranolol, a beta adrenergic antagonist. We plan to further investigate the analgesic effects, and the potential anti inflammatory effects, of propranolol and compare those effects to alfentanil, an opioid of known effect, and placebo

Detailed description

This study is a double blind-placebo controlled study in which subjects will be exposed to propranolol infusion during one study day, the opioid alfentanil on another day, and placebo infusion during a third study day. The infusion order will be randomized, and the participant and individual conducting the pain testing will both be blinded to the treatment. Propranolol, alfentanil, and placebo infusions will be administered intravenously using a computer-controlled infusion pump that can be set to accurately administer a target plasma concentration of drug. On one study day subjects will receive propranolol at a target concentration of 30ng/ml over 3 hours time. On another study day subjects will receive 100ng/ml alfentanil over 3 hours, and on a third study day subjects will receive placebo (normal saline) using a computer-controlled infusion paradigm. Sites to be evaluated for response to propranolol and placebo will be established in 2 ways. One will use ultraviolet B (UVB) exposure to create a sunburn causing inflammation and pain. The other will be a model of acute injury using an array of micro-needles. Means of evaluation of injured, and non-injured sites will be pain testing (heat and mechanical pain thresholds will be established), interstitial fluid sampling for detection of pro-inflammatory, and pro-nociceptive cytokines, and laser doppler evaluation of tissue perfusion. Subjects will be recruited using flyers. Interested participants will contact the study team, their questions will be answered, and an appointment for screening will be made.

Interventions

DRUGAlfentanil

An infusion of alfentanil 100ng/ml was administered over 3 hours using a programmable infusion pump.

DRUGPropranolol

An infusion of propranolol 30ng/ml was administered over 3 hours using a programmable infusion pump.

DRUGPlacebo

An infusion of normal saline was administered over 3 hours using a programmable infusion pump to mimic the 2 drug arms,

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

BASIC_SCIENCE

Masking

DOUBLE (Subject, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Healthy volunteers

Yes

Inclusion criteria

1) Age 18-65 2) Skin type II-IV according to classification of Fitzpatrick 3) Willing and able to sign an informed consent form and Health Insurance Portability and Accountability Act (HIPAA) authorization and to comply with study procedures

Exclusion criteria

1) History of acute or chronic illness that contraindicate the use of propranolol, may hinder study procedures, or confuse interpretation of the data (e.g. cardiac, dermatological, neurological, psychiatric or addictive diseases) 2) Clinically significant cardiovascular, pulmonary, hepatic or renal diseases 3) Pregnant or breast-feeding 4) Intake of prescription drugs with anti/pro-inflammatory action 5) Intake of prescription drugs with anti/pro-analgesic action 6) Inability to abstain from any anti/pro-inflammatory, or analgesic drugs 48 hours before, or during the study session 7) Inability to obtain at least 6 hours of sleep during the night preceding the study session 8) Known sensitivity or allergy to propranolol or alfentanil 9) Any history of drug or alcohol abuse

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in Heat Pain Threshold During Infusion in Non-Inflamed Skin	Participants underwent the pain testing measures at baseline and at 1 and 2 hours after startingthe drug infusion.	Degrees Centigrade Heat pain was induced with a thermal sensory analyzer (TSA-II, Medoc Advanced Medical Systems, Durham, North Carolina). A thermode was placed in contact with skin on the upper thigh. Starting at a comfortable temperature, the thermode temperature was increased at a measured rate. Study participants pushed a button of a hand-held device at the onset of pain at which point the thermode immediately reduced the temperature. Measurements for analgesia were taken at the sites of non-injured skin. Change form baseline was calculated by subtracting baseline values from the average values obtained 1 and 2 hours after starting the drug infusion.
Change From Baseline in Heat Pain Threshold During Infusion in Inflamed Skin	Participants underwent the pain testing measures at baseline and at 1 and 2 hours after startingthe drug infusion.	Degrees Centigrade Heat pain was induced with a thermal sensory analyzer (TSA-II, Medoc Advanced Medical Systems, Durham, North Carolina). A thermode was placed in contact with skin on the upper thigh. Starting at a comfortable temperature, the thermode temperature was increased at a measured rate. Study participants pushed a button of a hand-held device at the onset of pain at which point the thermode immediately reduced the temperature. Measurements for anti-hyperalgesia were taken at the sites of tissue injury. Change form baseline was calculated by subtracting baseline values from the average values obtained 1 and 2 hours after starting the drug infusion.
Change From Baseline in Mechanical Pain Threshold During Infusion in Non-Inflamed Skin	Participants underwent the pain testing measures at baseline and at 1 and 2 hours after startingthe drug infusion.	A metal rod of 0.24 mm diameter mounted onto 10 different weights (1.0, 2.0, 4.1, 8.2,16.3, 20, 32.7,49.0, 65.3, and 81.3g) will be placed perpendicularly onto the skin. Starting with the lightest probe, consecutively heavier probes will be used until a subject reports pain. Subsequently, the same or the next lighter probe will be used if pain is reported for the preceding stimulus, or the same or the next heavier probe will be used if no pain is reported for the preceding stimulus.The procedure will be repeated until seven perceptional changes (painful/non-painful) are registered. Measurements for analgesia were taken at the sites of non-injured skin. Change form baseline was calculated by subtracting baseline values from the average values obtained 1 and 2 hours after starting the drug infusion.
Change From Baseline in Mechanical Pain Threshold During Infusion in Inflamed Skin	Participants underwent the pain testing measures at baseline and at 1 and 2 hours after startingthe drug infusion.	A metal rod of 0.24 mm diameter mounted onto 10 different weights (1.0, 2.0, 4.1, 8.2,16.3, 20, 32.7,49.0, 65.3, and 81.3g) will be placed perpendicularly onto the skin. Starting with the lightest probe, consecutively heavier probes will be used until a subject reports pain. Subsequently, the same or the next lighter probe will be used if pain is reported for the preceding stimulus, or the same or the next heavier probe will be used if no pain is reported for the preceding stimulus.The procedure will be repeated until seven perceptional changes (painful/non-painful) are registered. Measurements for anti-hyperalgesia were taken at the sites of tissue injury. Change form baseline was calculated by subtracting baseline values from the average values obtained 1 and 2 hours after starting the drug infusion.

Secondary

Measure	Time frame	Description
GMCSF (ng/mL) Change From Baseline During Infusion	Tissue samples were collected at baseline, and 2 and 3 hours after starting the drug infusion.	GMCSF (ng/mL) was measured in interstitial fluid after collecting samples as follows: Microdialysis catheters (very small, custom-made, sterile, semi-permeable, micro-dialysis catheters) were placed after the 1st laser Doppler measurement. Two catheters were placed at an experimentally inflamed skin site on the left leg. A continuous infusion of sterile 1% albumin solution was started using a programmable pump set at a rate of 2.5µl/min. Samples were collected hourly throughout the remainder of the study day. Samples for analysis were collected before, and 2 and 3 hours after starting the drug infusion. Difference form baseline was calculated by subtracting the baseline concentration form the average concentration determined in samples collected during drug infusion.
IL-8 (ng/mL) Change From Baseline During Infusion	Tissue samples were collected at baseline, and 2 and 3 hours after starting the drug infusion.	IL-8 (ng/mL) was measured in interstitial fluid after collecting samples as follows: Microdialysis catheters (very small, custom-made, sterile, semi-permeable, micro-dialysis catheters) were placed after the 1st laser Doppler measurement. Two catheters were placed at an experimentally inflamed skin site on the left leg. A continuous infusion of sterile 1% albumin solution was started using a programmable pump set at a rate of 2.5µl/min. Samples were collected hourly throughout the remainder of the study day. Samples for analysis were collected before, and 2 and 3 hours after starting the drug infusion. Difference form baseline was calculated by subtracting the baseline concentration form the average concentration determined in samples collected during drug infusion.
TNFα (ng/mL) Change From Baseline During Infusion	Tissue samples were collected at baseline, and 2 and 3 hours after starting the drug infusion.	TNFα (ng/mL) was measured in interstitial fluid after collecting samples as follows: Microdialysis catheters (very small, custom-made, sterile, semi-permeable, micro-dialysis catheters) were placed after the 1st laser Doppler measurement. Two catheters were placed at an experimentally inflamed skin site on the left leg. A continuous infusion of sterile 1% albumin solution was started using a programmable pump set at a rate of 2.5µl/min. Samples were collected hourly throughout the remainder of the study day. Samples for analysis were collected before, and 2 and 3 hours after starting the drug infusion. Difference form baseline was calculated by subtracting the baseline concentration form the average concentration determined in samples collected during drug infusion.
IL-12 (ng/mL) Change From Baseline During Infusion	Tissue samples were collected at baseline, and 2 and 3 hours after starting the drug infusion.	IL-12 (ng/mL) was measured in interstitial fluid after collecting samples as follows: Microdialysis catheters (very small, custom-made, sterile, semi-permeable, micro-dialysis catheters) were placed after the 1st laser Doppler measurement. Two catheters were placed at an experimentally inflamed skin site on the left leg. A continuous infusion of sterile 1% albumin solution was started using a programmable pump set at a rate of 2.5µl/min. Samples were collected hourly throughout the remainder of the study day. Samples for analysis were collected before, and 2 and 3 hours after starting the drug infusion. Difference form baseline was calculated by subtracting the baseline concentration form the average concentration determined in samples collected during drug infusion.
Change in Arbitrary Perfusion Units From Baseline During Drug Infusion	Laser doppler images were recorded at baseline and at 2 and 3 hours after starting the drug infusion	Laser Doppler images were recorded at baseline and at 2 and 3 hours after starting the drug infusion to provide measurements of peripheral blood flow as an objective measure of inflammation. Blood flow was quantified by arbitrary perfusion units. Baseline measurements were subtracted from the average measurements obtained 2 and 3 hours after starting the drug infusion.
IL-10 (ng/mL) Change From Baseline During Infusion	Tissue samples were collected at baseline, and 2 and 3 hours after starting the drug infusion.	IL-10 (ng/mL) was measured in interstitial fluid after collecting samples as follows: Microdialysis catheters (very small, custom-made, sterile, semi-permeable, micro-dialysis catheters) were placed after the 1st laser Doppler measurement. Two catheters were placed at an experimentally inflamed skin site on the left leg. A continuous infusion of sterile 1% albumin solution was started using a programmable pump set at a rate of 2.5µl/min. Samples were collected hourly throughout the remainder of the study day. Samples for analysis were collected before, and 2 and 3 hours after starting the drug infusion. Difference form baseline was calculated by subtracting the baseline concentration form the average concentration determined in samples collected during drug infusion.
IL-1β (ng/mL) Change From Baseline During Infusion	Tissue samples were collected at baseline, and 2 and 3 hours after starting the drug infusion.	IL-1β (ng/mL) was measured in interstitial fluid after collecting samples as follows: Microdialysis catheters (very small, custom-made, sterile, semi-permeable, micro-dialysis catheters) were placed after the 1st laser Doppler measurement. Two catheters were placed at an experimentally inflamed skin site on the left leg. A continuous infusion of sterile 1% albumin solution was started using a programmable pump set at a rate of 2.5µl/min. Samples were collected hourly throughout the remainder of the study day. Samples for analysis were collected before, and 2 and 3 hours after starting the drug infusion. Difference form baseline was calculated by subtracting the baseline concentration form the average concentration determined in samples collected during drug infusion.
IL-2 (ng/mL) Change From Baseline During Infusion	Tissue samples were collected at baseline, and 2 and 3 hours after starting the drug infusion.	IL-2 (ng/mL) was measured in interstitial fluid after collecting samples as follows: Microdialysis catheters (very small, custom-made, sterile, semi-permeable, micro-dialysis catheters) were placed after the 1st laser Doppler measurement. Two catheters were placed at an experimentally inflamed skin site on the left leg. A continuous infusion of sterile 1% albumin solution was started using a programmable pump set at a rate of 2.5µl/min. Samples were collected hourly throughout the remainder of the study day. Samples for analysis were collected before, and 2 and 3 hours after starting the drug infusion. Difference form baseline was calculated by subtracting the baseline concentration form the average concentration determined in samples collected during drug infusion.
IL-6 (ng/mL) Change From Baseline During Infusion	Tissue samples were collected at baseline, and 2 and 3 hours after starting the drug infusion.	IL-6 (ng/mL) was measured in interstitial fluid after collecting samples as follows: Microdialysis catheters (very small, custom-made, sterile, semi-permeable, micro-dialysis catheters) were placed after the 1st laser Doppler measurement. Two catheters were placed at an experimentally inflamed skin site on the left leg. A continuous infusion of sterile 1% albumin solution was started using a programmable pump set at a rate of 2.5µl/min. Samples were collected hourly throughout the remainder of the study day. Samples for analysis were collected before, and 2 and 3 hours after starting the drug infusion. Difference form baseline was calculated by subtracting the baseline concentration form the average concentration determined in samples collected during drug infusion.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Alfentanil - Placebo - Propanolol Participant(s) were randomized to receive an intravenous infusion of alfentanil, normal saline, and propanolol on 3 consecutive study days.	1
Propranolol - Placebo - Alfentanil Participants were randomized to receive an intravenous infusion of propanolol, normal saline, and alfentanil on 3 consecutive study days.	1
Placebo - Propanolol - Alfentanil Participants were randomized to receive an intravenous infusion of normal saline, propanolol, and alfentanil on 3 consecutive study days.	2
Alfentanil - Propanolol - Placebo Participants were randomized to receive an intravenous infusion of alfentanil, propanolol, and normal saline on 3 consecutive study days.	2
Propranolol - Alfentanil - Placebo Participants were randomized to receive an intravenous infusion of propanolol, alfentanil, and normal saline on 3 consecutive study days.	2
Placebo -Alfentanil - Propanolol Participants were randomized to receive an intravenous infusion of normal saline, alfentanil, and propanolol on 3 consecutive study days.	2
Total	10

Baseline characteristics

Characteristic	Alfentanil - Placebo - Propanolol	Propranolol - Placebo - Alfentanil	Placebo - Propanolol - Alfentanil	Alfentanil - Propanolol - Placebo	Propranolol - Alfentanil - Placebo	Placebo -Alfentanil - Propanolol	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	1 Participants	1 Participants	2 Participants	2 Participants	2 Participants	2 Participants	10 Participants
Gender Female	0 Participants	0 Participants	1 Participants	0 Participants	2 Participants	0 Participants	3 Participants
Gender Male	1 Participants	1 Participants	1 Participants	2 Participants	0 Participants	2 Participants	7 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	0 / 1	0 / 1	0 / 2	0 / 2	0 / 2	0 / 2
serious Total, serious adverse events	0 / 1	0 / 1	0 / 2	0 / 2	0 / 2	0 / 2

Outcome results

Primary

Change From Baseline in Heat Pain Threshold During Infusion in Inflamed Skin

Degrees Centigrade Heat pain was induced with a thermal sensory analyzer (TSA-II, Medoc Advanced Medical Systems, Durham, North Carolina). A thermode was placed in contact with skin on the upper thigh. Starting at a comfortable temperature, the thermode temperature was increased at a measured rate. Study participants pushed a button of a hand-held device at the onset of pain at which point the thermode immediately reduced the temperature. Measurements for anti-hyperalgesia were taken at the sites of tissue injury. Change form baseline was calculated by subtracting baseline values from the average values obtained 1 and 2 hours after starting the drug infusion.

Time frame: Participants underwent the pain testing measures at baseline and at 1 and 2 hours after startingthe drug infusion.

Arm	Measure	Value (MEAN)	Dispersion
Alfentanil	Change From Baseline in Heat Pain Threshold During Infusion in Inflamed Skin	3.77 degrees centigrade	Standard Deviation 4.77
Propranolol	Change From Baseline in Heat Pain Threshold During Infusion in Inflamed Skin	0.09 degrees centigrade	Standard Deviation 1.31
Placebo	Change From Baseline in Heat Pain Threshold During Infusion in Inflamed Skin	-0.28 degrees centigrade	Standard Deviation 0.93

Primary

Change From Baseline in Heat Pain Threshold During Infusion in Non-Inflamed Skin

Degrees Centigrade Heat pain was induced with a thermal sensory analyzer (TSA-II, Medoc Advanced Medical Systems, Durham, North Carolina). A thermode was placed in contact with skin on the upper thigh. Starting at a comfortable temperature, the thermode temperature was increased at a measured rate. Study participants pushed a button of a hand-held device at the onset of pain at which point the thermode immediately reduced the temperature. Measurements for analgesia were taken at the sites of non-injured skin. Change form baseline was calculated by subtracting baseline values from the average values obtained 1 and 2 hours after starting the drug infusion.

Time frame: Participants underwent the pain testing measures at baseline and at 1 and 2 hours after startingthe drug infusion.

Arm	Measure	Value (MEAN)	Dispersion
Alfentanil	Change From Baseline in Heat Pain Threshold During Infusion in Non-Inflamed Skin	1.01 degree centigrade	Standard Deviation 0.74
Propranolol	Change From Baseline in Heat Pain Threshold During Infusion in Non-Inflamed Skin	0.14 degree centigrade	Standard Deviation 0.26
Placebo	Change From Baseline in Heat Pain Threshold During Infusion in Non-Inflamed Skin	0.01 degree centigrade	Standard Deviation 0.37

Primary

Change From Baseline in Mechanical Pain Threshold During Infusion in Inflamed Skin

A metal rod of 0.24 mm diameter mounted onto 10 different weights (1.0, 2.0, 4.1, 8.2,16.3, 20, 32.7,49.0, 65.3, and 81.3g) will be placed perpendicularly onto the skin. Starting with the lightest probe, consecutively heavier probes will be used until a subject reports pain. Subsequently, the same or the next lighter probe will be used if pain is reported for the preceding stimulus, or the same or the next heavier probe will be used if no pain is reported for the preceding stimulus.The procedure will be repeated until seven perceptional changes (painful/non-painful) are registered. Measurements for anti-hyperalgesia were taken at the sites of tissue injury. Change form baseline was calculated by subtracting baseline values from the average values obtained 1 and 2 hours after starting the drug infusion.

Time frame: Participants underwent the pain testing measures at baseline and at 1 and 2 hours after startingthe drug infusion.

Arm	Measure	Value (MEAN)	Dispersion
Alfentanil	Change From Baseline in Mechanical Pain Threshold During Infusion in Inflamed Skin	29.18 weight in grams	Standard Deviation 19.86
Propranolol	Change From Baseline in Mechanical Pain Threshold During Infusion in Inflamed Skin	-9.07 weight in grams	Standard Deviation 7.95
Placebo	Change From Baseline in Mechanical Pain Threshold During Infusion in Inflamed Skin	-11.00 weight in grams	Standard Deviation 11.55

Primary

Change From Baseline in Mechanical Pain Threshold During Infusion in Non-Inflamed Skin

A metal rod of 0.24 mm diameter mounted onto 10 different weights (1.0, 2.0, 4.1, 8.2,16.3, 20, 32.7,49.0, 65.3, and 81.3g) will be placed perpendicularly onto the skin. Starting with the lightest probe, consecutively heavier probes will be used until a subject reports pain. Subsequently, the same or the next lighter probe will be used if pain is reported for the preceding stimulus, or the same or the next heavier probe will be used if no pain is reported for the preceding stimulus.The procedure will be repeated until seven perceptional changes (painful/non-painful) are registered. Measurements for analgesia were taken at the sites of non-injured skin. Change form baseline was calculated by subtracting baseline values from the average values obtained 1 and 2 hours after starting the drug infusion.

Time frame: Participants underwent the pain testing measures at baseline and at 1 and 2 hours after startingthe drug infusion.

Arm	Measure	Value (MEAN)	Dispersion
Alfentanil	Change From Baseline in Mechanical Pain Threshold During Infusion in Non-Inflamed Skin	10.16 weight in grams	Standard Deviation 17.21
Propranolol	Change From Baseline in Mechanical Pain Threshold During Infusion in Non-Inflamed Skin	-11.22 weight in grams	Standard Deviation 20.65
Placebo	Change From Baseline in Mechanical Pain Threshold During Infusion in Non-Inflamed Skin	-9.53 weight in grams	Standard Deviation 18.75

Secondary

Change in Arbitrary Perfusion Units From Baseline During Drug Infusion

Laser Doppler images were recorded at baseline and at 2 and 3 hours after starting the drug infusion to provide measurements of peripheral blood flow as an objective measure of inflammation. Blood flow was quantified by arbitrary perfusion units. Baseline measurements were subtracted from the average measurements obtained 2 and 3 hours after starting the drug infusion.

Time frame: Laser doppler images were recorded at baseline and at 2 and 3 hours after starting the drug infusion

Arm	Measure	Value (MEAN)	Dispersion
Alfentanil	Change in Arbitrary Perfusion Units From Baseline During Drug Infusion	-234 relative flux	Standard Deviation 191
Propranolol	Change in Arbitrary Perfusion Units From Baseline During Drug Infusion	-217 relative flux	Standard Deviation 123
Placebo	Change in Arbitrary Perfusion Units From Baseline During Drug Infusion	-178 relative flux	Standard Deviation 206

Secondary

GMCSF (ng/mL) Change From Baseline During Infusion

GMCSF (ng/mL) was measured in interstitial fluid after collecting samples as follows: Microdialysis catheters (very small, custom-made, sterile, semi-permeable, micro-dialysis catheters) were placed after the 1st laser Doppler measurement. Two catheters were placed at an experimentally inflamed skin site on the left leg. A continuous infusion of sterile 1% albumin solution was started using a programmable pump set at a rate of 2.5µl/min. Samples were collected hourly throughout the remainder of the study day. Samples for analysis were collected before, and 2 and 3 hours after starting the drug infusion. Difference form baseline was calculated by subtracting the baseline concentration form the average concentration determined in samples collected during drug infusion.