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

NCT01222091 | Completed Phase 2 Results

• 1 other identifier: SU-10062010-7050
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Hyperalgesia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (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)

Study Arms (2)

Propranolol, Then Placebo

ACTIVE COMPARATOR

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; Drug: Placebo to Match Propranolol; Drug: Remifentanil

Placebo, Then Propranolol

PLACEBO COMPARATOR

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; Drug: Placebo to Match Propranolol; Drug: Remifentanil

Interventions

Propranolol 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.

Also known as: Hemangeol, Inderal, Innopran

Placebo, Then Propranolol; Propranolol, Then Placebo

Placebo to Match Propranolol DRUG

Placebo, Then Propranolol; Propranolol, Then Placebo

Remifentanil DRUG

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

Placebo, Then Propranolol; Propranolol, Then Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy men,
• Age between 18 and 45 years
• Normal weight (according to the table provided by Metropolitan Life Insurance).

You may not qualify if:

• 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

Sponsors & Collaborators

• Stanford University: lead

Study Sites (1)

Stanford University School of Medicine

Stanford, California, 94305, United States

Location

Related Publications (16)

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  PMID: 10910490 BACKGROUND

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  PMID: 9539228 BACKGROUND

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  PMID: 9749743 BACKGROUND

• 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.

  PMID: 11973202 BACKGROUND

• 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.

  PMID: 11429366 BACKGROUND

• 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.

  PMID: 11356895 BACKGROUND

• 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.

  PMID: 11027904 BACKGROUND

• 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.

  PMID: 16645459 BACKGROUND

• 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.

  PMID: 17065897 BACKGROUND

• 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.

  PMID: 2248388 BACKGROUND

• 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.

  PMID: 9778004 BACKGROUND

• 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.

  PMID: 10686178 BACKGROUND

• 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.

  PMID: 11506112 BACKGROUND

• 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.

  PMID: 15197245 BACKGROUND

• 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.

  PMID: 22365565 RESULT

MeSH Terms

Conditions

Hyperalgesia

Interventions

Propranolol; Remifentanil

Condition Hierarchy (Ancestors)

Somatosensory Disorders; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Propionates; Acids, Acyclic; Carboxylic Acids; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

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

Results Point of Contact

• Title: Dr. Larry Chu
• Organization: Stanford University School of Medicine

lchu@stanford.edu

(650) 723-6632

Study Officials

• Dr Larry Fu-nien Chu

  Stanford University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Anesthesia

Study Record Dates

• First Submitted: October 14, 2010
• First Posted: October 18, 2010
• Study Start: February 1, 2009
• Primary Completion: May 1, 2011
• Study Completion: June 1, 2011
• Last Updated: June 15, 2018
• Results First Posted: June 15, 2018

Record last verified: 2018-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)