Healthy
Conditions
Keywords
Cold pain methodology, Healthy male volunteers, gabapentin, Diphenhydramine, morphine
Brief summary
Human experimental pain models are useful in understanding the mechanisms underlying clinical pain conditions and can be used to test the analgesic efficacy of drugs used in the management of pain. Once established these models can be used as mechanism biomarkers in early development clinical studies to establish proof of mechanism for novel compounds. The cold pain model is a mechanistic pain biomarker with potential application in proof of mechanism studies. In this study we aim to set up this cold pain model at a Clinical Research Unit and demonstrate we can effectively screen subjects for this model and examine the effect of morphine, diphenhydramine, and gabapentin in the cold pain model.
Detailed description
Cold pain methodology development
Interventions
DRUGGabapentin
Capsule, single 1200mg dose
DRUGDiphenhydramine
Tablet, single 50mg dose
DRUGMorphine
IV, single 10mg dose
DRUGPlacebo
Placebo formulations (Capsule, tablet, IV to match the active treatments and to be administered in a double-dummy fashion).
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male volunteers having given consent to participate in the study who have no clinically significant anomalies and whose vital signs are within normal range. * Subject having performed the cold pain test reproducibly ie, if the area under the pain-time curve (AUC) must be within 20% during successive tests within one cold pain test screening visit and within 30% between the two cold pain test screening visits.
Exclusion criteria
* Subject who have had a serious adverse reaction or significant hypersensitivity to any of the study drugs. * Subjects with a history of or evidence of any neurological condition which could affect pain sensation. * Subjects with an AUCcpt 0-120 sec in the cold pain test of \<1000 in any of the screening tests (excluding familiarization).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | Pre-dose, 1, 1.5, 2, 4, and 8 hours post-dose | Area under the cold pain test Visual Analog Scale (VAS) time curve (AUCcpt 0 to 120 seconds \[sec\]) averaged over the 120 sec for each time point assessed. Participant adjusted 100 millimeter (mm) electronic VAS with range of no pain (0) to maximum pain (100) at the anchor endpoints of the scale and moderate pain at the midpoint. Pain reported while non-dominant hand was placed in thermostatically controlled water bath at 2±1°C for a maximum of 120 sec. |
| Interpolated Average Pain (0-8 Hours) | Pre-dose to 8 hours post-dose | Interpolated average pain (0 to 8 hours): area under the curve (AUC) of average pain (0 to 120 seconds) recorded at each of the time points taken over 8 hour time period divided by 8. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Abnormal Findings on Electrocardiogram (ECG) | Pre-dose and follow-up visit (at least 7 days after last dosing) | Standard 12-lead ECG performed after subject had rested quietly for at least 10 minutes in a supine position. |
| Number of Participants With Abnormal Haematology, Clinical Chemistry, Urinalysis Results | Pre-dose, follow-up visit (at least 7 days after last dosing) | Standard haematology, clinical chemistry, and urinalysis safety laboratory tests. |
| Number of Participants With Clinically Significant Findings in Vital Signs | Predose, Day 1, Day 2 each treatment period, follow-up visit (at least 7 days after last dosing) | Supine blood pressure measured to nearest millimeter of mercury (mmHg), pulse rate measured with automated device or manually in the brachial/radial artery for at least 30 seconds. |
| Number of Participants With Abnormal Pulse Oxymetry Results | Predose through duration of IV infusion dosing | Pulse oxymetry to monitor percentage of hemoglobin saturated with oxygen during intervenous (IV) infusion dosing (morphine or placebo). |
| Number of Participants With Abnormal Cardiac Monitoring Results | Pre-dose through duration of IV infusion dosing | Continuous cardiac monitoring during intervenous (IV) infusion dosing (morphine or placebo). |
| Number of Participants With Clinically Significant Abnormal Findings on Physical Examination | Pre-dose and follow-up visit (at least 7 days after last dosing) | Full physical examination consisting of an examination of the abdomen, cardiovascular systems, lungs, lymph nodes, mouth, musculoskeletal and neurological systems, skin, extremities, head, ears, eyes, nose, throat and thyroid gland. |
Countries
Belgium
Participant flow
Pre-assignment details
Prior to entering the treatment phases of the study, participants were required to successfully pass cold pain screening tests. Twenty participants were randomized and 19 participants received treatment consisting of a crossover sequence of 4 study drugs administered in sequence I, II, III or IV.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes all participants who initiated in any treatment sequence | 19 |
| Total | 19 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 19 | 18 / 19 | 5 / 19 | 3 / 19 |
| serious Total, serious adverse events | 0 / 19 | 0 / 19 | 0 / 19 | 0 / 19 |
Outcome results
Primary
Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS)
Area under the cold pain test Visual Analog Scale (VAS) time curve (AUCcpt 0 to 120 seconds \[sec\]) averaged over the 120 sec for each time point assessed. Participant adjusted 100 millimeter (mm) electronic VAS with range of no pain (0) to maximum pain (100) at the anchor endpoints of the scale and moderate pain at the midpoint. Pain reported while non-dominant hand was placed in thermostatically controlled water bath at 2±1°C for a maximum of 120 sec.
Time frame: Pre-dose, 1, 1.5, 2, 4, and 8 hours post-dose
Population: Participants for analysis = participants who completed all of the four treatment periods.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gabapentin | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 1 hour | 41.9 mm | Standard Deviation 16.95 |
| Gabapentin | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 4 hours | 41.9 mm | Standard Deviation 16.37 |
| Gabapentin | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | Pre-dose | 45.2 mm | Standard Deviation 16.15 |
| Gabapentin | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 2 hours | 40.4 mm | Standard Deviation 17.71 |
| Gabapentin | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 1.5 hours | 39.4 mm | Standard Deviation 16.21 |
| Gabapentin | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 8 hours | 44.7 mm | Standard Deviation 15.06 |
| Morphine | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 1.5 hours | 26.1 mm | Standard Deviation 18.28 |
| Morphine | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 2 hours | 25.6 mm | Standard Deviation 18.44 |
| Morphine | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 8 hours | 36.7 mm | Standard Deviation 17.14 |
| Morphine | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 1 hour | 28.6 mm | Standard Deviation 16.88 |
| Morphine | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 4 hours | 34.7 mm | Standard Deviation 18.29 |
| Morphine | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | Pre-dose | 45.5 mm | Standard Deviation 16.1 |
| Diphenhydramine | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 4 hours | 44.2 mm | Standard Deviation 17.35 |
| Diphenhydramine | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | Pre-dose | 45.0 mm | Standard Deviation 16.66 |
| Diphenhydramine | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 1 hour | 45.1 mm | Standard Deviation 17.29 |
| Diphenhydramine | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 1.5 hours | 42.3 mm | Standard Deviation 16.67 |
| Diphenhydramine | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 2 hours | 40.5 mm | Standard Deviation 17.22 |
| Diphenhydramine | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 8 hours | 43.8 mm | Standard Deviation 15.08 |
| Placebo | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 1.5 hours | 40.2 mm | Standard Deviation 17.75 |
| Placebo | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 1 hour | 38.4 mm | Standard Deviation 15.69 |
| Placebo | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 4 hours | 44.3 mm | Standard Deviation 16.7 |
| Placebo | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | Pre-dose | 44.9 mm | Standard Deviation 15.16 |
| Placebo | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 8 hours | 44.2 mm | Standard Deviation 14.55 |
| Placebo | Average Pain (0-120 Seconds): Cold Pain Test Visual Analog Scale (VAS) | 2 hours | 39.5 mm | Standard Deviation 16.86 |
Comparison: Pre-dose; mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual. Sample sizing calculated based on results from previous methodology studies performed using the same cold pain test; primary criteria was ability to detect a significant gabapentin effect over placebo.90% CI: [-3.82, 4.38]Mixed Models Analysis
Comparison: Pre-dose; mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-3.53, 4.68]Mixed Models Analysis
Comparison: Pre-dose; mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-3.99, 4.22]Mixed Models Analysis
Comparison: 1 hour post-dose: mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-1.15, 5.44]Mixed Models Analysis
Comparison: 1 hour post-dose: mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-14.48, -7.89]Mixed Models Analysis
Comparison: 1 hour post-dose: mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [2.2, 8.78]Mixed Models Analysis
Comparison: 1.5 hours post-dose: mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-5.53, 4.08]Mixed Models Analysis
Comparison: 1.5 hours post-dose: mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-18.74, -9.13]Mixed Models Analysis
Comparison: 1.5 hours post-dose: mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-2.01, 7.78]Mixed Models Analysis
Comparison: 2 hours post-dose: mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-5.32, 6.96]Mixed Models Analysis
Comparison: 2 hours post-dose: mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-19.14, -7.09]Mixed Models Analysis
Comparison: 2 hours post-dose: mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-4.45, 7.6]Mixed Models Analysis
Comparison: 4 hours post-dose: mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-7.39, 2.32]
Comparison: 4 hours post-dose: mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-14.44, -4.73]Mixed Models Analysis
Comparison: 4 hours post-dose: mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-4.85, 4.85]Mixed Models Analysis
Comparison: 8 hours post-dose: mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-3.23, 4.22]Mixed Models Analysis
Comparison: 8 hours post-dose: mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-11.19, -3.75]Mixed Models Analysis
Comparison: 8 hours post-dose: mixed effect model with random subject effect, fixed period and treatment effects and random subject-by-visit effect as residual.90% CI: [-3.99, 3.45]Mixed Models Analysis
Primary
Interpolated Average Pain (0-8 Hours)
Interpolated average pain (0 to 8 hours): area under the curve (AUC) of average pain (0 to 120 seconds) recorded at each of the time points taken over 8 hour time period divided by 8.
Time frame: Pre-dose to 8 hours post-dose
Population: Participants for analysis = participants who completed all of the four treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Gabapentin | Interpolated Average Pain (0-8 Hours) | 42.2 hours | Standard Error 3.67 |
| Morphine | Interpolated Average Pain (0-8 Hours) | 33.4 hours | Standard Error 3.67 |
| Diphenhydramine | Interpolated Average Pain (0-8 Hours) | 43.6 hours | Standard Error 3.67 |
| Placebo | Interpolated Average Pain (0-8 Hours) | 42.8 hours | Standard Error 3.67 |
90% CI: [-4.24, 3.04]Mixed Models Analysis
90% CI: [-13.07, -5.79]Mixed Models Analysis
90% CI: [-2.8, 4.48]Mixed Models Analysis
Secondary
Number of Participants With Abnormal Cardiac Monitoring Results
Continuous cardiac monitoring during intervenous (IV) infusion dosing (morphine or placebo).
Time frame: Pre-dose through duration of IV infusion dosing
Population: Safety population: all subjects who received at least 1 dose of study medication. Although continuous cardiac monitoring was performed throughout IV dosing, results were not captured for inclusion in the study database.
Secondary
Number of Participants With Abnormal Findings on Electrocardiogram (ECG)
Standard 12-lead ECG performed after subject had rested quietly for at least 10 minutes in a supine position.
Time frame: Pre-dose and follow-up visit (at least 7 days after last dosing)
Population: Safety population: all subjects who received at least 1 dose of study medication. Although individual subject data were collected and monitored, summary statistics were not generated for this outcome measure.
Secondary
Number of Participants With Abnormal Haematology, Clinical Chemistry, Urinalysis Results
Standard haematology, clinical chemistry, and urinalysis safety laboratory tests.
Time frame: Pre-dose, follow-up visit (at least 7 days after last dosing)
Population: Safety population: all subjects who received at least 1 dose of study medication. Although individual subject data were collected and monitored, summary statistics were not generated for this outcome measure.
Secondary
Number of Participants With Abnormal Pulse Oxymetry Results
Pulse oxymetry to monitor percentage of hemoglobin saturated with oxygen during intervenous (IV) infusion dosing (morphine or placebo).
Time frame: Predose through duration of IV infusion dosing
Population: Safety population: all subjects who received at least 1 dose of study medication. Although pulse oxymetry was performed throughout IV dosing, results were not captured for inclusion in the study database.
Secondary
Number of Participants With Clinically Significant Abnormal Findings on Physical Examination
Full physical examination consisting of an examination of the abdomen, cardiovascular systems, lungs, lymph nodes, mouth, musculoskeletal and neurological systems, skin, extremities, head, ears, eyes, nose, throat and thyroid gland.
Time frame: Pre-dose and follow-up visit (at least 7 days after last dosing)
Population: Safety population: all subjects who received at least 1 dose of study medication. Although individual subject data were collected, results were not captured for inclusion in the study database.
Secondary
Number of Participants With Clinically Significant Findings in Vital Signs
Supine blood pressure measured to nearest millimeter of mercury (mmHg), pulse rate measured with automated device or manually in the brachial/radial artery for at least 30 seconds.
Time frame: Predose, Day 1, Day 2 each treatment period, follow-up visit (at least 7 days after last dosing)
Population: Safety population: all subjects who received at least 1 dose of study medication. Although individual listing data for vital signs were collected, summary statistics were not generated for this outcome measure.