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

Hyperalgesia Clinical Trial

Official title:

Effect of Beta Blockade on Opioid-Induced Hyperalgesia in Humans

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01222091
• Other study ID #: SU-10062010-7050
• Status: Completed
• Phase: Phase 2
• Start date: February 2009
• Est. completion date: June 2011

Study information

• Verified date: May 2018
• Source: Stanford University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: June 2011
• Est. primary completion date: May 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Hyperalgesia

Intervention

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.
• Placebo to Match Propranolol

• Remifentanil
Remifentanil administered intravenously at a plasma concentration of 3 ng/mL.

Locations

Country	Name	City	State
United States	Stanford University School of Medicine	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
Stanford University

Country where clinical trial is conducted

United States, 

References & Publications (16)

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. — View Citation

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. — View Citation

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. — View Citation

Chu LF, Cun T, Ngai LK, Kim JE, Zamora AK, Young CA, Angst MS, Clark DJ. Modulation of remifentanil-induced postinfusion hyperalgesia by the ß-blocker propranolol in humans. Pain. 2012 May;153(5):974-81. doi: 10.1016/j.pain.2012.01.014. Epub 2012 Feb 22. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Li X, Angst MS, Clark JD. Opioid-induced hyperalgesia and incisional pain. Anesth Analg. 2001 Jul;93(1):204-9. — View Citation

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. — View Citation

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. — View Citation

Shafer SL, Varvel JR, Aziz N, Scott JC. Pharmacokinetics of fentanyl administered by computer-controlled infusion pump. Anesthesiology. 1990 Dec;73(6):1091-102. — View Citation

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. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Change From Baseline in Size (Area) of Secondary Hyperalgesia After Cessation of Remifentanil Infusion, a Measure of Opioid-induced Hyperalgesia (OIH).	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.	Baseline; 15 min post remifentanil (REM) infusion; 60 min post REM infusion
Secondary	Objective Opioid Withdrawal Scale (OOWS)	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.	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)