The Effect of S-ketamine on Pharmacokinetics of Morphine, Hydromorphone, and Buprenorphine
Conditions
Keywords
S-ketamine, hepatic UGT2B7 enzyme, pharmacokinetic interaction, morphine, hydromorphone, buprenorphine
Brief summary
S-ketamine is often administered as a part of multimodal analgesia to reduce postoperative pain and postoperative opioid consumption. Current data indicates that ketamine may be useful for patients with prior use of opioids whereas the benefit for opioid-naive patients is less clear. However, different opioids have variable pharmacokinetic characteristics. Therefore, it is important to evaluate S-ketamine's effect on the pharmacokinetics of opioids.
Detailed description
S-ketamine is often used as a part of multimodal analgesia to reduce postoperative pain and opioid consumption, in part by mitigating opioid tolerance and opioid-induced hyperalgesia. However, there are mixed results concerning the effect of ketamine for this indication. Different opioids have various pharmacokinetic characteristics. Ketamine is known to inhibit the liver UGT2B7-enzyme, that is responsible for e.g., morphine metabolism. Therefore, it is important to investigate whether there is a clinically important pharmacokinetic interaction between S-ketamine and opioids metabolized via liver UGT2B7 enzyme. These opioids include morphpine, hydromorphone and buprenoprhine.
Interventions
DRUGS-ketamine
S-ketamine infusion 0.29 mg/kg/h for 4 hours
Sponsors
Elina Brinck
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This is a double-blind study. Study participants, investigators, care providers and personnel collecting samples are blinded. Personnel preparing study drugs will not participate on conducting the study. On the first phase of the study, study participants will be administered one of the study drug infusions (either S-ketamine or placebo). The order of the study drug is random. On the second phase, study participants will be administered the other study drug (S- ketamine or placebo) that she/he did not receive on the first phase.
Intervention model description
This is a cross-over study with two phases on 12 healthy volunteers. Study participants will be administered S-ketamine 0.29mg/kg/h intravenously or placebo (NaCl 0.9%) for 4 hours. 30 minutes after the initiation of the study drug infusion, each subject will be given single boluses of morphine 0.01mg/kg, hydromorphone 0.002mg/kg and buprenorphine 0.003mg/kg IV. We will analyze pharmacokinetic parameters (Cmax, tmax, AUC, t1/2) for morphine, hydromorphone, and buprenorphine. The aim of the study is to evaluate whether S-ketamine has a pharmacokinetic interaction with the opioids (morphine, hydromorphone, buprenorphine) known to be metabolized via liver UGT2B7 enzyme.
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* written informed consent * age 18-45 years * healthy * Normal values in the following laboratory assessments: Hb, P-ALAT, P-AFOS, P-GT, P-creatinine, P-K, P-Na, chemical sample for urine (U-KemSeul). Pregnancy test (P-hCG-tot) must be negative. * Urine sample for detection of any illegal drugs must be negative (U-Huum-PS) * Normal EKG * Normal blood pressure * No prior use of illicit drugs
Exclusion criteria
* Tendency/predisposition to illicit drug use, illicit drug use in history * Abnormal EKG * smoking * use of oral contraceptives * pregnancy, lactation * participating in a less tha 3 months ago * Blood donation less than 3 months ago * The subject's peripheral veins are hardly visible (predisposing difficulties in cannulation) * weight less than 50 kg, body mass index (BMI) less than 18,5 or over 30
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area under the plasma concentration versus time curve (AUC) of morphine, hydromorphone and buprenorphine after intravenous S-ketamine infusion. | Time points for the measurements after the initiation of S-ketamine infusion: 0 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes and 210 minutes | We aim to investigate whether there is a clinically significant pharmacokinetic interaction between S-ketamine and morphine, S-ketamine and hydromorphone and S-ketamine and buprenorphine. |
| Peak plasma concentrations (Cmax) of morphine, hydromorphone and buprenorphine after intravenous S-ketamine infusion | Time points for assessing peak plasma concentrations (Cmax) for morphine, hydromorphone and buprenorphine are the following: 0 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 210 minutes after the initiation of S-ketamine infusion. | We aim to investigate whether there is a clinically significant pharmacokinetic interaction between S-ketamine, morphine, S-ketamine and hydromorphone and S-ketamine and buprenorphine. |
| Half-life time (t1/2) of morphine, hydromorphone and buprenorphine concentrations after intravenous S-ketamine infusion. | Time points for assessing half-life time of morphine, hydromorphone and buprenorphine are 0 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes and 210 minutes after initiation of S-ketamine infusion. | We aim to investigate whether there is a clinically significant pharmacokinetic interaction between S-ketamine, morphine, S-ketamine and hydromorphone and S-ketamine and buprenorphine. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The effect of S-ketamine infusion on cortisol release. | Time points for assessments: 30 minutes, 120 minutes, 240 minutes, 360 minutes, 480 minutes and at Day1 after the intiation of S-ketamine infusion | We measure cortisol levels (nmol/l) during and after intravenous S-ketamine infusion. |
| The effect of S-ketamine on brain-derived neurotrophic factor (BDNF) release | Time points for assessments: 30 minutes, 120 minutes, 240 minutes, 360 minutes, 480 minutes and at Day1 after the intiation of S-ketamine infusion | We measure BDNF plasma levels (ng/ml) during and after intravenous S-ketamine infusion . |
| The effect of S-ketamine infusion on thrombocyte aggregation. | At 2 hours after initiation of S-ketamine infusion. | We evaluate the effect of intravenous S-ketamine infusion on thrombocyte aggregation by using Platelet Function Analyzer (PFA), a method that is based on the property of platelets to adhere upon shear stress conditions and aggregate in consequence of agonist presence in the system. We assess the clotting time. Unit of analysis is seconds (s). |
| The effect of S-ketamine on vascular endothelial growth factor (VEGF) release | Time points for assessments: 30 minutes, 120 minutes, 240 minutes, 360 minutes, 480 minutes and at Day1 after the intiation of S-ketamine infusion. | We measure VEGF levels (ng/l) during and after intravenous S-ketamine infusion. |
| The effect of S-ketamine infusion on prolactin release. | Time points for assessments: 30 minutes, 120 minutes, 240 minutes, 360 minutes, 480 minutes and at Day1 after the intiation of S-ketamine infusion | We measure prolactin levels (mU/l) during and after intravenous S-ketamine infusion. |
Contacts
Primary ContactElina CV Brinck, MD, PhD
Backup ContactTuomas Lilius, MD, PhD
Outcome results
None listed