Hyperalgesia
Conditions
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.
Interventions
DRUGPropranolol
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.
DRUGPlacebo to Match Propranolol
DRUGRemifentanil
Remifentanil administered intravenously at a plasma concentration of 3 ng/mL.
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Size (Area) of Secondary Hyperalgesia After Cessation of Remifentanil Infusion, a Measure of Opioid-induced Hyperalgesia (OIH). | Baseline; 15 min post remifentanil (REM) infusion; 60 min post REM infusion | 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
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Half of the participants received propranolol at the first study session and the saline placebo at the second session. The treatment infusions were administered continuously before, during, and after remifentanil infusion. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 23.8 years |
| Height | 178 centimeters |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 10 Participants |
| Weight | 78.8 kilograms |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
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.
Time frame: Baseline; 15 min post remifentanil (REM) infusion; 60 min post REM infusion
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Propranolol | Percent Change From Baseline in Size (Area) of Secondary Hyperalgesia After Cessation of Remifentanil Infusion, a Measure of Opioid-induced Hyperalgesia (OIH). | 15 min post remifentanil infusion | -28 percentage of change |
| Propranolol | Percent Change From Baseline in Size (Area) of Secondary Hyperalgesia After Cessation of Remifentanil Infusion, a Measure of Opioid-induced Hyperalgesia (OIH). | 60 min post remifentanil infusion | -19 percentage of change |
| Placebo | Percent Change From Baseline in Size (Area) of Secondary Hyperalgesia After Cessation of Remifentanil Infusion, a Measure of Opioid-induced Hyperalgesia (OIH). | 15 min post remifentanil infusion | -34 percentage of change |
| Placebo | Percent Change From Baseline in Size (Area) of Secondary Hyperalgesia After Cessation of Remifentanil Infusion, a Measure of Opioid-induced Hyperalgesia (OIH). | 60 min post remifentanil infusion | 141.5 percentage of change |
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.
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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Propranolol | Objective Opioid Withdrawal Scale (OOWS) | 15 min after start of REM infusion | 0.1 units on a scale | Standard Deviation 2 |
| Propranolol | Objective Opioid Withdrawal Scale (OOWS) | 5 minutes after finish of REM infusion | 3 units on a scale | Standard Deviation 4 |
| Propranolol | Objective Opioid Withdrawal Scale (OOWS) | 30 min prior to REM infusion | 1.1 units on a scale | Standard Deviation 2 |
| Propranolol | Objective Opioid Withdrawal Scale (OOWS) | 15 minutes after finish of REM infusion | 2.8 units on a scale | Standard Deviation 4.2 |
| Propranolol | Objective Opioid Withdrawal Scale (OOWS) | 40 min after start of REM infusion | 0.8 units on a scale | Standard Deviation 2 |
| Propranolol | Objective Opioid Withdrawal Scale (OOWS) | 75 minutes after finish of REM infusion | 1.7 units on a scale | Standard Deviation 4 |
| Propranolol | Objective Opioid Withdrawal Scale (OOWS) | Pretreatment | 1.2 units on a scale | Standard Deviation 1.5 |
| Placebo | Objective Opioid Withdrawal Scale (OOWS) | 75 minutes after finish of REM infusion | 1.6 units on a scale | Standard Deviation 2 |
| Placebo | Objective Opioid Withdrawal Scale (OOWS) | Pretreatment | 1.1 units on a scale | Standard Deviation 1.3 |
| Placebo | Objective Opioid Withdrawal Scale (OOWS) | 30 min prior to REM infusion | 1.1 units on a scale | Standard Deviation 1 |
| Placebo | Objective Opioid Withdrawal Scale (OOWS) | 15 min after start of REM infusion | 0.8 units on a scale | Standard Deviation 1 |
| Placebo | Objective Opioid Withdrawal Scale (OOWS) | 40 min after start of REM infusion | 0.5 units on a scale | Standard Deviation 1 |
| Placebo | Objective Opioid Withdrawal Scale (OOWS) | 5 minutes after finish of REM infusion | 1.8 units on a scale | Standard Deviation 2 |
| Placebo | Objective Opioid Withdrawal Scale (OOWS) | 15 minutes after finish of REM infusion | 2.1 units on a scale | Standard Deviation 2.1 |