Hydromorphone Pharmacokinetic-Pharmacodynamic Fingerprint

Study Overview
=================
Brief Summary
-----------------
The primary objective of the proposed work is development of a high resolution pharmacokinetic-pharmacodynamic (PK-PD) model of hydromorphone for experimental pain stimuli, ventilatory depression, and surrogate biomarkers of opioid effect that will allow the fingerprinting of hydromorphone. This fingerprint will serve as the basis for the development of dosing strategies that efficiently maximize analgesia while minimizing ventilatory depression and sedation. For example, this high-resolution fingerprint will allow precise estimation of an initial hydromorphone target effect site concentration (Ce) from those of effectively administered synthetic opioids with previously determined high-resolution fingerprints (i.e., remifentanil or fentanyl), thereby minimizing underdosing of hydromorphone for analgesia and minimizing side effects.

Detailed Description
-----------------
After 6 h of fasting, each volunteer will have a 20G arterial-line placed in the radial artery for early blood sampling and an 18 G peripheral intravenous catheter placed in the contralateral forearm for drug administration and later blood sampling. Continuously monitored vital signs will include ECG, invasive blood pressure, hemoglobin, O2 saturation, end-tidal CO2, and respiratory rate (from the capnogram) recorded. After baseline PD data acquisition, a bolus of 0.2 mg/kg hydromorphone will be administered over 10 sec via the free-flowing peripheral IV (t=0) and 3 mL arterial blood samples will be obtained at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, and 2 min using a stop-cock and manifold system. Subsequent blood samples will be acquired at 3, 4, 5, 7.5, 10, 15, 20, 25, 30, and 45 min and 1, 1.25, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 20, and 24 h. Although EEG will be acquired continuously, the remaining pharmacologic data will be recorded at discrete times s in the initial 5 min: pupillometry at 1, 2, and 5 min; ventilation at 2 min; temperature analgesia at 3 and 5 min, and sedation level at 4 min. This will allow the ventilation and pupillometry to be acquired in a resting state, thereby limiting distortion of these responses by stimulation. Subsequently, all data will be acquired at all PK time points in the following sequence - ventilation and EEG (simultaneously), pupillometry, modified OAA/S score, and temperature analgesia. After 2 h, once a pharmacologic parameter has returned to baseline for 2 sequential measurements, recording of that parameter will be stopped. During the study, if the volunteer is unable to use the device trigger, due to opioid-induced sedation, the tolerance level for increased temperature will be defined as the temperature at which the volunteer exhibits withdrawal movement of the tested limb. Once all data acquisition has been completed, the volunteer will be allowed to drink clear liquids. Subsequently, the diet will be advanced as tolerated. The volunteer will be monitored hourly (vital signs) in the Clinical Research Unit until all of the blood samples have been acquired.

Official Title
-----------------
A Hydromorphone High Resolution Pharmacokinetic-Pharmacodynamic Fingerprint as the Basis for Identifying Sex Differences in Opioid Pharmacokinetics and Pharmacodynamics

Conditions
-----------------
Pain, Ventilatory Depression

Intervention / Treatment
-----------------
* Drug: hydromorphone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: within 20% of their ideal body weight 21-30 years old ASA I (no systemic disease) No history of PONV (except wisdom teeth extraction) No long term medication use No history of coagulation defect (i.e easy bruising, gum bleeding with teeth brushing, frequent nose bleeds, past documented coagulopathy, etc.) Exclusion Criteria: Inability to place an arterial line A failed urine drug test on admission to the CRU A positive pregnancy test on admission to the CRU A hemoglobin level < 12.5 g/dL on admission to the CRU

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 30 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: hydromorphone<br>open label single arm pharmacokinetic-pharmacodynamic study | Drug: hydromorphone<br>* hydromorphone 0.02 mg/kg<br>* Other names: Dilaudid;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Opioid induced analgesia | A combined PK-PD model for hydromorphone induced analgesia (heat pain tolerance) will be developed | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Opioid induced ventilatory depression | A combined PK-PD model for hydromorphone induced ventilatory depression will be created | 24 hours | 
| Opioid induced miosis | A combined PK-PD model for hydromorphone induced miosis will be developed | 24 hours | 
| Opioid induced EEG changes | A combined PK-PD model for hydromorphone induced EEG effects will be developed | 24 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Intravenous opioids, Patient Controlled Analgesia, volunteer pharmacokinetic-pharmacodynamic study