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

Effect of Beta Blockade on Opioid-Induced Hyperalgesia in Humans

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.

Study Overview

• Status: Completed
• Conditions: Hyperalgesia
• Intervention / Treatment: Drug: Propranolol; Drug: Placebo to Match Propranolol; Drug: Remifentanil

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 Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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: Inderal; Hemangeol; 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: Inderal; Hemangeol; Innopran; Drug: Placebo to Match Propranolol; Drug: Remifentanil; Remifentanil administered intravenously at a plasma concentration of 3 ng/mL.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)

Collaborators and Investigators

• Sponsor: Stanford University

Publications and helpful links

General Publications

• 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. doi: 10.1097/00000542-200008000-00019.
• 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. doi: 10.1007/BF03012978.
• 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. doi: 10.1016/s0306-4522(97)00556-3.
• Laulin JP, Larcher A, Celerier 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. doi: 10.1046/j.1460-9568.1998.00083.x.
• 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. doi: 10.1097/00000539-200205000-00040.
• Li X, Angst MS, Clark JD. Opioid-induced hyperalgesia and incisional pain. Anesth Analg. 2001 Jul;93(1):204-9. doi: 10.1097/00000539-200107000-00040.
• Celerier 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. doi: 10.1523/JNEUROSCI.21-11-04074.2001.
• 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. doi: 10.1016/s0885-3924(00)00191-3.
• 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. doi: 10.1097/00000542-200605000-00023.
• Troster A, Sittl R, Singler B, Schmelz M, Schuttler J, Koppert W. Modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by parecoxib in humans. Anesthesiology. 2006 Nov;105(5):1016-23. doi: 10.1097/00000542-200611000-00024.
• Shafer SL, Varvel JR, Aziz N, Scott JC. Pharmacokinetics of fentanyl administered by computer-controlled infusion pump. Anesthesiology. 1990 Dec;73(6):1091-102. doi: 10.1097/00000542-199012000-00005.
• 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. doi: 10.1097/00000542-199810000-00011.
• Schmelz M, Schmid R, Handwerker HO, Torebjork 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. doi: 10.1093/brain/123.3.560.
• Koppert W, Dern SK, Sittl R, Albrecht S, Schuttler 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. doi: 10.1097/00000542-200108000-00022.
• 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. doi: 10.1124/jpet.104.070094. Epub 2004 Jun 14.
• Chu LF, Cun T, Ngai LK, Kim JE, Zamora AK, Young CA, Angst MS, Clark DJ. Modulation of remifentanil-induced postinfusion hyperalgesia by the beta-blocker propranolol in humans. Pain. 2012 May;153(5):974-981. doi: 10.1016/j.pain.2012.01.014. Epub 2012 Feb 22.

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (Actual): May 1, 2011
• Study Completion (Actual): June 1, 2011

Study Registration Dates

• First Submitted: October 14, 2010
• First Submitted That Met QC Criteria: October 15, 2010
• First Posted (Estimate): October 18, 2010

Study Record Updates

• Last Update Posted (Actual): June 15, 2018
• Last Update Submitted That Met QC Criteria: May 15, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Sensation Disorders; Somatosensory Disorders; Hyperalgesia; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Propranolol; Remifentanil
• Other Study ID Numbers: SU-10062010-7050

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No