Study on the Effect of a Beta Blocker on Increased Sensitivity to Pain in Humans Caused by Opioids

• Sponsor: Stanford University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01222091
• Collaborator: (none)
• Enrollment: 10
• Location: 1
• Arms: 2
• Duration (Months): 27.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This research study explores whether a beta-blocker (propranolol) can prevent a person from becoming more sensitive to pain after administration of an opioid (remifentanil). Beta blockers inhibit the sympathetic (fight or flight) response and are often used to treat angina and high blood pressure. In a previous study in human volunteers, the investigators demonstrated an increased sensitivity to pain after a 60-minute infusion of the opioid remifentanil. The goal of this study is to identify a possible inhibitor of this phenomenon.

Condition or Disease	Intervention/Treatment	Phase
Hyperalgesia	Drug: Propranolol; Drug: Placebo to Match Propranolol; Drug: Remifentanil	Phase 2

Detailed Description

Recent evidence suggests that opioid therapy may cause a biphasic response, i.e. initial pain relief followed paradoxically by a longer lasting hypersensitivity to pain. Recent genetic analysis in mice suggests that beta adrenergic receptor antagonists reduce opiate-induced hyperalgesia (OIH). The purpose of this study is to determine the analgesic and antihyperalgesic properties of the beta-blocker propranolol on remifentanil-induced hypersensitivity in humans.

The investigators want to determine the analgesic and antihyperalgesic properties of the beta-blocker propranolol on remifentanil-induced hypersensitivity in humans. The investigators hope to learn whether the administration of beta-blocker propranolol will significantly diminish the hyperalgesic response after administration of an opioid.

The primary outcome measure for this study is change in size (area) of secondary hyperalgesia after cessation of remifentanil infusion, a measure of OIH.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of Beta Blockade on Opioid-Induced Hyperalgesia in Humans
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Propranolol, Then Placebo Propranolol, a beta blocker, or placebo to match, will be given to test whether or not it could modulate the expression of remifentanil-induced postinfusion hyperalgesia (RPH) during two pain test including: mechanically evoked pain to map the size of the hyperalgesic skin region caused by electrical stimulation and heat pain.	Drug: Propranolol; Propranolol administered intravenously, initially set to target plasma concentration of 5 ng/mL, titrated upward in 5 ng/mL intervals until a final concentration of 15 ng/mL is achieved.; Other Names: Hemangeol Inderal Innopran ; Drug: Placebo to Match Propranolol; Drug: Remifentanil; Remifentanil administered intravenously at a plasma concentration of 3 ng/mL.
Placebo Comparator: Placebo, Then Propranolol Propranolol, a beta blocker, or placebo to match, will be given to test whether or not it could modulate the expression of remifentanil-induced postinfusion hyperalgesia (RPH) during two pain test including: mechanically evoked pain to map the size of the hyperalgesic skin region caused by electrical stimulation and heat pain.	Drug: Propranolol; Propranolol administered intravenously, initially set to target plasma concentration of 5 ng/mL, titrated upward in 5 ng/mL intervals until a final concentration of 15 ng/mL is achieved.; Other Names: Hemangeol Inderal Innopran ; Drug: Placebo to Match Propranolol; Drug: Remifentanil; Remifentanil administered intravenously at a plasma concentration of 3 ng/mL.

Outcome Measures

Primary Outcome Measures

1. Percent Change From Baseline in Size (Area) of Secondary Hyperalgesia After Cessation of Remifentanil Infusion, a Measure of Opioid-induced Hyperalgesia (OIH). [Baseline; 15 min post remifentanil (REM) infusion; 60 min post REM infusion]

   A slightly modified version of a previously described model of secondary hyperalgesia was used. Two copper wires contained in a microdialysis catheter were inserted in parallel over a length of 5 mm into the dermis of the right volar forearm. The wires were connected to a constant current stimulator controlled by a pulse generator to deliver rectangular and monophasic pulses with a duration of 0.5 mg at 2 Hz. Over a period of 15 min, the current was increased by targeting a pain rating of 5 on an 11-point numeric rating scale (0 = no pain and 10 = maximum tolerable pain) until the hyperalgesic area surrounding the stimulation site was fully established. Once the area was established, the current was held constant. Percent change from baseline in size (area) of secondary hyperalgesia after cessation of remifentanil infusion was calculated per group.

Secondary Outcome Measures

1. Objective Opioid Withdrawal Scale (OOWS) [Pretreatment [90 min prior to 60-min REM infusion]; 30 min prior to 60-min REM infusion; 15 and 40 min after start of 60-min REM infusion; 5, 15, and 75 minutes after finish of 60-min REM infusion)]

   OOWS: Is a 13-item instrument of documenting physically observable signs of withdrawal, which are rated as present (1) or absent (0) during the observation period. Maximum score = 13, minimum score = 0. Lower scores correspond to fewer symptoms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Healthy men,

2. Age between 18 and 45 years

3. Normal weight (according to the table provided by Metropolitan Life Insurance).

Exclusion Criteria:

1. Hypersensitivity to opioids or naloxone,

2. History of addictive disease,

3. Significant cardiac, respiratory, gastrointestinal, neurological, dermatological, and psychiatric diseases,

4. Concurrent medication with an analgesic drug,

5. Student and employees affiliated with our laboratory

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University School of Medicine	Stanford	California	United States	94305

Sponsors and Collaborators

• Stanford University

Investigators

• Principal Investigator: Dr Larry Fu-nien Chu, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Avram MJ, Krejcie TC, Henthorn TK, Niemann CU. Beta-adrenergic blockade affects initial drug distribution due to decreased cardiac output and altered blood flow distribution. J Pharmacol Exp Ther. 2004 Nov;311(2):617-24. Epub 2004 Jun 14.
• Célèrier E, Laulin JP, Corcuff JB, Le Moal M, Simonnet G. Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: a sensitization process. J Neurosci. 2001 Jun 1;21(11):4074-80.
• Chia YY, Liu K, Wang JJ, Kuo MC, Ho ST. Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth. 1999 Sep;46(9):872-7.
• Compton P, Charuvastra VC, Kintaudi K, Ling W. Pain responses in methadone-maintained opioid abusers. J Pain Symptom Manage. 2000 Oct;20(4):237-45.
• Drover DR, Lemmens HJ. Population pharmacodynamics and pharmacokinetics of remifentanil as a supplement to nitrous oxide anesthesia for elective abdominal surgery. Anesthesiology. 1998 Oct;89(4):869-77.
• Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, Fletcher D, Chauvin M. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000 Aug;93(2):409-17.
• Koppert W, Dern SK, Sittl R, Albrecht S, Schüttler J, Schmelz M. A new model of electrically evoked pain and hyperalgesia in human skin: the effects of intravenous alfentanil, S(+)-ketamine, and lidocaine. Anesthesiology. 2001 Aug;95(2):395-402.
• Larcher A, Laulin JP, Celerier E, Le Moal M, Simonnet G. Acute tolerance associated with a single opiate administration: involvement of N-methyl-D-aspartate-dependent pain facilitatory systems. Neuroscience. 1998 May;84(2):583-9.
• Laulin JP, Larcher A, Célèrier E, Le Moal M, Simonnet G. Long-lasting increased pain sensitivity in rat following exposure to heroin for the first time. Eur J Neurosci. 1998 Feb;10(2):782-5.
• Laulin JP, Maurette P, Corcuff JB, Rivat C, Chauvin M, Simonnet G. The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance. Anesth Analg. 2002 May;94(5):1263-9, table of contents.
• Li X, Angst MS, Clark JD. Opioid-induced hyperalgesia and incisional pain. Anesth Analg. 2001 Jul;93(1):204-9.
• Liang DY, Liao G, Wang J, Usuka J, Guo Y, Peltz G, Clark JD. A genetic analysis of opioid-induced hyperalgesia in mice. Anesthesiology. 2006 May;104(5):1054-62.
• Schmelz M, Schmid R, Handwerker HO, Torebjörk HE. Encoding of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve fibres. Brain. 2000 Mar;123 Pt 3:560-71.
• Shafer SL, Varvel JR, Aziz N, Scott JC. Pharmacokinetics of fentanyl administered by computer-controlled infusion pump. Anesthesiology. 1990 Dec;73(6):1091-102.
• Tröster A, Sittl R, Singler B, Schmelz M, Schüttler J, Koppert W. Modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by parecoxib in humans. Anesthesiology. 2006 Nov;105(5):1016-23.

• Responsible Party: Larry Fu-nien Chu, Professor of Anesthesia, Stanford University
• ClinicalTrials.gov Identifier: NCT01222091
• Other Study ID Numbers: SU-10062010-7050
• First Posted: Oct 18, 2010
• Last Update Posted: Jun 15, 2018
• Last Verified: May 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Hyperalgesia; Propranolol; Remifentanil

Study Results

Participant Flow

Arm/Group Title	Propranolol, Then Placebo	Placebo, Then Propranolol
Arm/Group Description	Half of the participants received propranolol at the first study session and the saline placebo at the second session. The treatment infusions were administered continuously before, during, and after remifentanil infusion.	Half of the participants received saline placebo at the first study session and propranolol at the second session. The treatment infusions were administered continuously before, during, and after remifentanil infusion.
Period Title: Overall Study
STARTED	5	5
COMPLETED	5	5
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	Half of the participants received propranolol at the first study session and the saline placebo at the second session. The treatment infusions were administered continuously before, during, and after remifentanil infusion.
Overall Participants	10
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	23.8
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	10 100%
Weight (kilograms) [Mean (Full Range) ]
Mean (Full Range) [kilograms]	78.8
Height (centimeters) [Mean (Full Range) ]
Mean (Full Range) [centimeters]	178

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Size (Area) of Secondary Hyperalgesia After Cessation of Remifentanil Infusion, a Measure of Opioid-induced Hyperalgesia (OIH).
Description	A slightly modified version of a previously described model of secondary hyperalgesia was used. Two copper wires contained in a microdialysis catheter were inserted in parallel over a length of 5 mm into the dermis of the right volar forearm. The wires were connected to a constant current stimulator controlled by a pulse generator to deliver rectangular and monophasic pulses with a duration of 0.5 mg at 2 Hz. Over a period of 15 min, the current was increased by targeting a pain rating of 5 on an 11-point numeric rating scale (0 = no pain and 10 = maximum tolerable pain) until the hyperalgesic area surrounding the stimulation site was fully established. Once the area was established, the current was held constant. Percent change from baseline in size (area) of secondary hyperalgesia after cessation of remifentanil infusion was calculated per group.
Time Frame	Baseline; 15 min post remifentanil (REM) infusion; 60 min post REM infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Propranolol	Placebo
Arm/Group Description	Half of the participants received propranolol at the first study session and the saline placebo at the second session. The treatment infusions were administered continuously before, during, and after remifentanil infusion.	Half of the participants received propranolol at the first study session and the saline placebo at the second session. The treatment infusions were administered continuously before, during, and after remifentanil infusion.
Measure Participants	10	10
15 min post remifentanil infusion	-28	-34
60 min post remifentanil infusion	-19	141.5

2. Secondary Outcome

Title	Objective Opioid Withdrawal Scale (OOWS)
Description	OOWS: Is a 13-item instrument of documenting physically observable signs of withdrawal, which are rated as present (1) or absent (0) during the observation period. Maximum score = 13, minimum score = 0. Lower scores correspond to fewer symptoms.
Time Frame	Pretreatment [90 min prior to 60-min REM infusion]; 30 min prior to 60-min REM infusion; 15 and 40 min after start of 60-min REM infusion; 5, 15, and 75 minutes after finish of 60-min REM infusion)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Propranolol	Placebo
Arm/Group Description	Half of the participants received propranolol at the first study session and the saline placebo at the second session. The treatment infusions were administered continuously before, during, and after remifentanil infusion.	Half of the participants received propranolol at the first study session and the saline placebo at the second session. The treatment infusions were administered continuously before, during, and after remifentanil infusion.
Measure Participants	10	10
Pretreatment	1.2 (1.5)	1.1 (1.3)
30 min prior to REM infusion	1.1 (2)	1.1 (1)
15 min after start of REM infusion	0.1 (2)	0.8 (1)
40 min after start of REM infusion	0.8 (2)	0.5 (1)
5 minutes after finish of REM infusion	3 (4)	1.8 (2)
15 minutes after finish of REM infusion	2.8 (4.2)	2.1 (2.1)
75 minutes after finish of REM infusion	1.7 (4)	1.6 (2)

Adverse Events

Arm/Group Title	Propranolol		Placebo
Arm/Group Description	Half of the participants received propranolol at the first study session and the saline placebo at the second session. The treatment infusions were administered continuously before, during, and after remifentanil infusion.		Half of the participants received propranolol at the first study session and the saline placebo at the second session. The treatment infusions were administered continuously before, during, and after remifentanil infusion.
All Cause Mortality
	Propranolol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Propranolol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Propranolol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)

Limitations/Caveats

Local anesthetic properties of propranolol; electrical burn pain model not useful for fully reproducing clinical sources of pain.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.