Evaluation of Propranolol's Effect on Pain and Inflammation.

• ClinicalTrials.gov Identifier: NCT01094574
• Recruitment Status: Completed
• First Posted: March 29, 2010
• Results First Posted: February 24, 2017
• Last Update Posted: February 24, 2017
• Sponsor: Martin Angst
• Information provided by (Responsible Party): Martin Angst, Stanford University

Study Description

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

Condition or disease	Intervention/treatment	Phase
Pain Measurement	Drug: Alfentanil; Drug: Propranolol; Drug: Placebo	Not Applicable

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Investigation of Analgesic and Anti-inflammatory Effects of Beta-adrenergic Antagonist Propranolol
• Study Start Date: January 2010
• Actual Primary Completion Date: June 2010
• Actual Study Completion Date: August 2010

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Alfentanil; 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.	Drug: Alfentanil; An infusion of alfentanil 100ng/ml was administered over 3 hours using a programmable infusion pump.; Other Name: No other name
Active Comparator: Propranolol; 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.	Drug: Propranolol; An infusion of propranolol 30ng/ml was administered over 3 hours using a programmable infusion pump.; Other Name: No other name
Placebo Comparator: Placebo; 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.	Drug: Placebo; An infusion of normal saline was administered over 3 hours using a programmable infusion pump to mimic the 2 drug arms,; Other Name: Normal Saline

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Heat Pain Threshold During Infusion in Non-Inflamed Skin [ Time Frame: 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.
2. Change From Baseline in Heat Pain Threshold During Infusion in Inflamed Skin [ Time Frame: 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.
3. Change From Baseline in Mechanical Pain Threshold During Infusion in Non-Inflamed Skin [ Time Frame: 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.
4. Change From Baseline in Mechanical Pain Threshold During Infusion in Inflamed Skin [ Time Frame: 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 Outcome Measures :

1. TNFα (ng/mL) Change From Baseline During Infusion [ Time Frame: 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.
2. IL-1β (ng/mL) Change From Baseline During Infusion [ Time Frame: 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.
3. IL-2 (ng/mL) Change From Baseline During Infusion [ Time Frame: 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.
4. IL-6 (ng/mL) Change From Baseline During Infusion [ Time Frame: 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.
5. GMCSF (ng/mL) Change From Baseline During Infusion [ Time Frame: 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.
6. IL-8 (ng/mL) Change From Baseline During Infusion [ Time Frame: 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.
7. IL-10 (ng/mL) Change From Baseline During Infusion [ Time Frame: 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.
8. IL-12 (ng/mL) Change From Baseline During Infusion [ Time Frame: 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.
9. Change in Arbitrary Perfusion Units From Baseline During Drug Infusion [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

United States, California

Stanford University School of Medicine

Stanford, California, United States, 94305

Sponsors and Collaborators

Martin Angst

Investigators

• Principal Investigator: Martin S Angst; Stanford University

More Information

• Responsible Party: Martin Angst, Professor of Anesthesia, Stanford University
• ClinicalTrials.gov Identifier: NCT01094574
• Other Study ID Numbers: SU-10012009-4121; 17743
• First Posted: March 29, 2010
• Results First Posted: February 24, 2017
• Last Update Posted: February 24, 2017
• Last Verified: January 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Individual participant data will not be shared.

Additional relevant MeSH terms:

Propranolol; Alfentanil; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Analgesics, Opioid; Narcotics; Central Nervous System Depressants; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics