Trial Outcomes & Findings for Evaluation of Propranolol's Effect on Pain and Inflammation. (NCT NCT01094574)

NCT ID: NCT01094574

Last Updated: 2017-02-24

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 10 participants
• Primary outcome timeframe: Participants underwent the pain testing measures at baseline and at 1 and 2 hours after startingthe drug infusion.
• Results posted on: 2017-02-24

Participant Flow

Participant milestones

Measure	Alfentanil Day 1, Placebo Day 2, and Propranolol Day 3 Day 1: Experimental inflammation, and tissue injury sites were created an infusion of alfentanil 100ng/ml was administered over 3 hours. Day 2: Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours. Day 3: Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump. On all study days data were collected to measure inflammation, pain response, and cytokine levels locally. Experimental inflammation and tissue injury sites were used for pain testing to determine heat and mechanical pain threshold. Interstitial fluid sampling was accomplished with microdialysis. Samples were collected hourly throughout the study day. Laser doppler evaluation of tissue perfusion was made at baseline and again at hours 1, 2 and 3 following initiation of the infusions.	Propranolol Day 1, Placebo Day 2, and Alfentanil Day 3 Day 1: Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours. Day 2: Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump. Day 3: Experimental inflammation, and tissue injury sites were created an infusion of alfentanil 100ng/ml was administered over 3 hours. On all study days data were collected to measure inflammation, pain response, and cytokine levels locally. Experimental inflammation and tissue injury sites were used for pain testing to determine heat and mechanical pain threshold. Interstitial fluid sampling was accomplished with microdialysis. Samples were collected hourly throughout the study day. Laser doppler evaluation of tissue perfusion was made at baseline and again at hours 1, 2 and 3 following initiation of the infusions.	Placebo Day 1, Propranolol Day 2, and Alfentanil Day 3 Day 1: Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump. Day 2: Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours. Day 3: Experimental inflammation, and tissue injury sites were created an infusion of alfentanil 100ng/ml was administered over 3 hours. On all study days data were collected to measure inflammation, pain response, and cytokine levels locally. Experimental inflammation and tissue injury sites were used for pain testing to determine heat and mechanical pain threshold. Interstitial fluid sampling was accomplished with microdialysis. Samples were collected hourly throughout the study day. Laser doppler evaluation of tissue perfusion was made at baseline and again at hours 1, 2 and 3 following initiation of the infusions.	Alfentanil Day 1, Propranolol Day 2, and Palcebo Day 3 Day 1: Experimental inflammation, and tissue injury sites were created an infusion of alfentanil 100ng/ml was administered over 3 hours. Day 2: Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours. Day 3: Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump. On all study days data were collected to measure inflammation, pain response, and cytokine levels locally. Experimental inflammation and tissue injury sites were used for pain testing to determine heat and mechanical pain threshold. Interstitial fluid sampling was accomplished with microdialysis. Samples were collected hourly throughout the study day. Laser doppler evaluation of tissue perfusion was made at baseline and again at hours 1, 2 and 3 following initiation of the infusions.	Propranolol Day 1, Alfentanil Day 2, and Placebo Day 3 Day 1: Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours. Day 2: Experimental inflammation, and tissue injury sites were created an infusion of alfentanil 100ng/ml was administered over 3 hours. Day 3: Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump. On all study days data were collected to measure inflammation, pain response, and cytokine levels locally. Experimental inflammation and tissue injury sites were used for pain testing to determine heat and mechanical pain threshold. Interstitial fluid sampling was accomplished with microdialysis. Samples were collected hourly throughout the study day. Laser doppler evaluation of tissue perfusion was made at baseline and again at hours 1, 2 and 3 following initiation of the infusions.	Placebo Day 1, Alfentanil Day 2, and Propranolol Day 3 Day 1: Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump. Day 2: Experimental inflammation, and tissue injury sites were created an infusion of alfentanil 100ng/ml was administered over 3 hours. Day 3: Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours. On all study days data were collected to measure inflammation, pain response, and cytokine levels locally. Experimental inflammation and tissue injury sites were used for pain testing to determine heat and mechanical pain threshold. Interstitial fluid sampling was accomplished with microdialysis. Samples were collected hourly throughout the study day. Laser doppler evaluation of tissue perfusion was made at baseline and again at hours 1, 2 and 3 following initiation of the infusions.
Overall Study STARTED	1	1	2	2	2	2
Overall Study COMPLETED	1	1	2	2	2	2
Overall Study NOT COMPLETED	0	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Evaluation of Propranolol's Effect on Pain and Inflammation.

Baseline characteristics by cohort

Measure	Alfentanil - Placebo - Propanolol n=1 Participants Participant(s) were randomized to receive an intravenous infusion of alfentanil, normal saline, and propanolol on 3 consecutive study days.	Propranolol - Placebo - Alfentanil n=1 Participants Participants were randomized to receive an intravenous infusion of propanolol, normal saline, and alfentanil on 3 consecutive study days.	Placebo - Propanolol - Alfentanil n=2 Participants Participants were randomized to receive an intravenous infusion of normal saline, propanolol, and alfentanil on 3 consecutive study days.	Alfentanil - Propanolol - Placebo n=2 Participants Participants were randomized to receive an intravenous infusion of alfentanil, propanolol, and normal saline on 3 consecutive study days.	Propranolol - Alfentanil - Placebo n=2 Participants Participants were randomized to receive an intravenous infusion of propanolol, alfentanil, and normal saline on 3 consecutive study days.	Placebo -Alfentanil - Propanolol n=2 Participants Participants were randomized to receive an intravenous infusion of normal saline, alfentanil, and propanolol on 3 consecutive study days.	Total n=10 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Age, Categorical Between 18 and 65 years	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants	2 Participants n=21 Participants	2 Participants n=10 Participants	10 Participants n=115 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Gender Female	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants	0 Participants n=10 Participants	3 Participants n=115 Participants
Gender Male	1 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants	0 Participants n=21 Participants	2 Participants n=10 Participants	7 Participants n=115 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Alfentanil n=10 Participants Experimental inflammation, and tissue injury sites were created, an infusion of alfentanil 100ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Propranolol n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Placebo n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.
Change From Baseline in Heat Pain Threshold During Infusion in Non-Inflamed Skin	1.01 degree centigrade Standard Deviation 0.74	0.14 degree centigrade Standard Deviation 0.26	0.01 degree centigrade Standard Deviation 0.37

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Alfentanil n=10 Participants Experimental inflammation, and tissue injury sites were created, an infusion of alfentanil 100ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Propranolol n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Placebo n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.
Change From Baseline in Heat Pain Threshold During Infusion in Inflamed Skin	3.77 degrees centigrade Standard Deviation 4.77	0.09 degrees centigrade Standard Deviation 1.31	-0.28 degrees centigrade Standard Deviation 0.93

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Alfentanil n=10 Participants Experimental inflammation, and tissue injury sites were created, an infusion of alfentanil 100ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Propranolol n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Placebo n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.
Change From Baseline in Mechanical Pain Threshold During Infusion in Non-Inflamed Skin	10.16 weight in grams Standard Deviation 17.21	-11.22 weight in grams Standard Deviation 20.65	-9.53 weight in grams Standard Deviation 18.75

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Alfentanil n=10 Participants Experimental inflammation, and tissue injury sites were created, an infusion of alfentanil 100ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Propranolol n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Placebo n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.
Change From Baseline in Mechanical Pain Threshold During Infusion in Inflamed Skin	29.18 weight in grams Standard Deviation 19.86	-9.07 weight in grams Standard Deviation 7.95	-11.00 weight in grams Standard Deviation 11.55

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Alfentanil n=10 Participants Experimental inflammation, and tissue injury sites were created, an infusion of alfentanil 100ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Propranolol n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Placebo n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.
TNFα (ng/mL) Change From Baseline During Infusion	4.92 ng/ml Standard Deviation 6.59	5.78 ng/ml Standard Deviation 4.67	2.93 ng/ml Standard Deviation 3.36

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Alfentanil n=10 Participants Experimental inflammation, and tissue injury sites were created, an infusion of alfentanil 100ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Propranolol n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Placebo n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.
IL-1β (ng/mL) Change From Baseline During Infusion	5.39 ng/ml Standard Deviation 4.89	6.99 ng/ml Standard Deviation 6.26	7.53 ng/ml Standard Deviation 11.06

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Alfentanil n=10 Participants Experimental inflammation, and tissue injury sites were created, an infusion of alfentanil 100ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Propranolol n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Placebo n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.
IL-2 (ng/mL) Change From Baseline During Infusion	2.38 ng/ml Standard Deviation 4.43	3.08 ng/ml Standard Deviation 2.52	1.65 ng/ml Standard Deviation 1.91

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Alfentanil n=10 Participants Experimental inflammation, and tissue injury sites were created, an infusion of alfentanil 100ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Propranolol n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Placebo n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.
IL-6 (ng/mL) Change From Baseline During Infusion	344.2 ng/ml Standard Deviation 414.2	214.0 ng/ml Standard Deviation 222.2	153.6 ng/ml Standard Deviation 286.6

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Alfentanil n=10 Participants Experimental inflammation, and tissue injury sites were created, an infusion of alfentanil 100ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Propranolol n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Placebo n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.
GMCSF (ng/mL) Change From Baseline During Infusion	7.85 ng/ml Standard Deviation 7.77	10.75 ng/ml Standard Deviation 5.02	6.48 ng/ml Standard Deviation 6.57

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Alfentanil n=10 Participants Experimental inflammation, and tissue injury sites were created, an infusion of alfentanil 100ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Propranolol n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Placebo n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.
IL-8 (ng/mL) Change From Baseline During Infusion	486.3 ng/ml Standard Deviation 654.9	621.5 ng/ml Standard Deviation 367.0	398.7 ng/ml Standard Deviation 422.6

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Alfentanil n=10 Participants Experimental inflammation, and tissue injury sites were created, an infusion of alfentanil 100ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Propranolol n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Placebo n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.
IL-10 (ng/mL) Change From Baseline During Infusion	0.35 ng/ml Standard Deviation 1.59	0.84 ng/ml Standard Deviation 1.77	-0.01 ng/ml Standard Deviation 2.03

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Alfentanil n=10 Participants Experimental inflammation, and tissue injury sites were created, an infusion of alfentanil 100ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Propranolol n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Placebo n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.
IL-12 (ng/mL) Change From Baseline During Infusion	2.12 ng/ml Standard Deviation 2.77	3.41 ng/ml Standard Deviation 3.58	3.38 ng/ml Standard Deviation 4.88

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Alfentanil n=10 Participants Experimental inflammation, and tissue injury sites were created, an infusion of alfentanil 100ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Propranolol n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of propranolol 30ng/ml was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.	Placebo n=10 Participants Experimental inflammation and tissue injury sites were created, an infusion of normal saline was administered over 3 hours using a programmable infusion pump, and data were collected to measure inflammation, pain response, and cytokine levels locally.
Change in Arbitrary Perfusion Units From Baseline During Drug Infusion	-234 relative flux Standard Deviation 191	-217 relative flux Standard Deviation 123	-178 relative flux Standard Deviation 206

Adverse Events

Alfentanil - Placebo - Propanolol

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Propranolol - Placebo - Alfentanil

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo - Propanolol - Alfentanil

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Alfentanil - Propanolol - Placebo

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Propranolol - Alfentanil - Placebo

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo -Alfentanil - Propanolol

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

Martin Angst, MD, Professor, Dept. of Anesthesia, Stanford SOM

Stanford School of Medicine

Phone: 650-498-5109

Email: ang@stanford.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place