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

NCT ID: NCT01222091

Last Updated: 2018-06-15

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

10 participants

Study Classification

INTERVENTIONAL

Study Start Date

2009-02-28

Study Completion Date

2011-06-30

Brief Summary

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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

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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.

Conditions

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Hyperalgesia

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Outcome Assessors

Study Groups

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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.

Group Type ACTIVE_COMPARATOR

Propranolol

Intervention Type DRUG

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

Intervention Type DRUG

Remifentanil

Intervention Type DRUG

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

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.

Group Type PLACEBO_COMPARATOR

Propranolol

Intervention Type DRUG

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

Intervention Type DRUG

Remifentanil

Intervention Type DRUG

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

Interventions

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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.

Intervention Type DRUG

Placebo to Match Propranolol

Intervention Type DRUG

Remifentanil

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

Intervention Type DRUG

Other Intervention Names

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Hemangeol Inderal Innopran

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Maximum Eligible Age

45 Years

Eligible Sex

MALE

Accepts Healthy Volunteers

Yes

Sponsors

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Stanford University

OTHER

Sponsor Role lead

Responsible Party

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Larry Fu-nien Chu

Professor of Anesthesia

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Dr Larry Fu-nien Chu

Role: PRINCIPAL_INVESTIGATOR

Stanford University

Locations

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Stanford University School of Medicine

Stanford, California, United States

Site Status

Countries

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United States

References

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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.

Reference Type BACKGROUND
PMID: 10490157 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 10910490 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 9539228 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 9749743 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 11973202 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 11429366 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 11356895 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 11027904 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 16645459 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 17065897 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 2248388 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 9778004 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 10686178 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 11506112 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 15197245 (View on PubMed)

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.

Reference Type RESULT
PMID: 22365565 (View on PubMed)

Other Identifiers

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SU-10062010-7050

Identifier Type: -

Identifier Source: org_study_id

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