search
Back to results

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

Primary Purpose

Hyperalgesia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Propranolol
Placebo to Match Propranolol
Remifentanil
Sponsored by
Stanford University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hyperalgesia

Eligibility Criteria

18 Years - 45 Years (Adult)MaleAccepts Healthy Volunteers

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

Sites / Locations

  • Stanford University School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Propranolol, Then Placebo

Placebo, Then Propranolol

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Full Information

First Posted
October 14, 2010
Last Updated
May 15, 2018
Sponsor
Stanford University
search

1. Study Identification

Unique Protocol Identification Number
NCT01222091
Brief Title
Study on the Effect of a Beta Blocker on Increased Sensitivity to Pain in Humans Caused by Opioids
Official Title
Effect of Beta Blockade on Opioid-Induced Hyperalgesia in Humans
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
February 2009 (undefined)
Primary Completion Date
May 2011 (Actual)
Study Completion Date
June 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Stanford University

4. Oversight

Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hyperalgesia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderOutcomes Assessor
Allocation
Randomized
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Propranolol, Then Placebo
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Placebo, Then Propranolol
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Propranolol
Other Intervention Name(s)
Hemangeol, Inderal, Innopran
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo to Match Propranolol
Intervention Type
Drug
Intervention Name(s)
Remifentanil
Intervention Description
Remifentanil administered intravenously at a plasma concentration of 3 ng/mL.
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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)

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Healthy men, Age between 18 and 45 years Normal weight (according to the table provided by Metropolitan Life Insurance). Exclusion Criteria: Hypersensitivity to opioids or naloxone, History of addictive disease, Significant cardiac, respiratory, gastrointestinal, neurological, dermatological, and psychiatric diseases, Concurrent medication with an analgesic drug, Student and employees affiliated with our laboratory
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dr Larry Fu-nien Chu
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University School of Medicine
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
10490157
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. doi: 10.1007/BF03012978.
Results Reference
background
PubMed Identifier
10910490
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. doi: 10.1097/00000542-200008000-00019.
Results Reference
background
PubMed Identifier
9539228
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. doi: 10.1016/s0306-4522(97)00556-3.
Results Reference
background
PubMed Identifier
9749743
Citation
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.
Results Reference
background
PubMed Identifier
11973202
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. doi: 10.1097/00000539-200205000-00040.
Results Reference
background
PubMed Identifier
11429366
Citation
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.
Results Reference
background
PubMed Identifier
11356895
Citation
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.
Results Reference
background
PubMed Identifier
11027904
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. doi: 10.1016/s0885-3924(00)00191-3.
Results Reference
background
PubMed Identifier
16645459
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. doi: 10.1097/00000542-200605000-00023.
Results Reference
background
PubMed Identifier
17065897
Citation
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.
Results Reference
background
PubMed Identifier
2248388
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. doi: 10.1097/00000542-199012000-00005.
Results Reference
background
PubMed Identifier
9778004
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. doi: 10.1097/00000542-199810000-00011.
Results Reference
background
PubMed Identifier
10686178
Citation
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.
Results Reference
background
PubMed Identifier
11506112
Citation
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.
Results Reference
background
PubMed Identifier
15197245
Citation
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.
Results Reference
background
PubMed Identifier
22365565
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 beta-blocker propranolol in humans. Pain. 2012 May;153(5):974-981. doi: 10.1016/j.pain.2012.01.014. Epub 2012 Feb 22.
Results Reference
result

Learn more about this trial

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

We'll reach out to this number within 24 hrs