Influence of Diabetes on Tramadol Pharmacokinetics

Study Overview
=================
Brief Summary
-----------------
This study aimed to investigate the influence of uncontrolled type 1 and type 2 diabetes mellitus (DM) on the kinetic disposition, metabolism and pharmacokinetics-pharmacodynamics of tramadol enantiomers in patients with neuropathic pain. Thus, nondiabetic patients (control group, n = 12), patients with type 1 DM (n = 9), and patients with type 2 DM (n = 9), all with neuropathic pain and phenotyped as extensive metabolizers of cytochrome P450 2D6 (CYP2D6) who were treated with a single oral dose of 100 mg racemic tramadol were investigated.

Detailed Description
-----------------
Tramadol is a centrally acting analgesic that effectively relieves acute and chronic pain, including neuropathic pain in diabetic patients. The drug is available in clinical practice as a mixture of the (+)-tramadol and (-)-tramadol enantiomers. Tramadol is metabolized by CYP2D6 to O-desmethyltramadol (M1) and by cytochrome P450 3A (CYP3A4) and cytochrome P450 2B6 (CYP2B6) to N-desmethyltramadol (M2). Both tramadol enantiomers and (+)-M1 contribute to the analgesic activity of the drug: (+)-tramadol and the (+)-M1 metabolite act as -opioid receptor agonists; (+)-tramadol inhibits serotonin reuptake; and (-)-tramadol inhibits the reuptake of norepinephrine. This study investigated the influence of uncontrolled type 1 and type 2 diabetes mellitus (DM) on the kinetic disposition, metabolism and pharmacokinetics-pharmacodynamics of tramadol enantiomers in patients with neuropathic pain. Nondiabetic patients (control group, n = 12), patients with type 1 DM (n = 9), and patients with type 2 DM (n = 9), all with neuropathic pain and phenotyped as extensive metabolizers of CYP2D6, received a single oral dose of 100 mg racemic tramadol. Serial blood samples were collected up to 24 h after administration of the drug for pharmacokinetic study and for the analysis of noradrenaline in plasma. Pain was rated on a visual analog pain scale at the same time as blood sampling. The patients were evaluated for in vivo CYP3A activity using midazolam as a probe drug and genotyped for CYP2B6. Total and unbound plasma concentrations of the tramadol, M1 and M2 enantiomers were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS).

Official Title
-----------------
Influence of Uncontrolled Diabetes on the Kinetic Disposition, Metabolism and Pharmacokinetics-pharmacodynamics of Tramadol Enantiomers in Patients With Neuropathic Pain

Conditions
-----------------
Neuropathic Pain, Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Single oral dose of 100 mg racemic tramadol
* Other: CYP2D6 phenotype
* Other: CYP3A phenotype
* Genetic: CYP2B6 genotype


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult patients, both gender Patients with self-reported neuropathic pain (score >4 in a 0-10 visual analog scale) Patients with normal renal function (creatinine clearance >60 mL/min) Exclusion Criteria: Patients with nociceptive somatic pain, visceral or autonomic associated during the study period; Patients with morbid obesity (BMI> 40), congestive heart failure, severe hypertension Patients who have had acute myocardial infarction or accident stroke less than 6 months of the period of investigation. Patients with chronic obstructive pulmonary disease Patients who were in use of analgesics, CYP2D6 inhibitors or CYP3A4 inducers or inhibitors were excluded. Pregnant and lactating patients were excluded.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 59 Years

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

Accepts Healthy Volunteers
-----------------
No

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

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control group<br>Patients received a single oral dose of 100 mg racemic tramadol. Serial blood samples were collected up to 24 h after administration of the drug for pharmacokinetic study and for the analysis of noradrenaline in plasma. Pain was rated on a visual analog pain scale at the same time as blood sampling. CYP2D6 phenotype was evaluated using metoprolol as probe drug. CYP3A phenotype was evaluated using midazolam. Patients were genotyped for the single nucleotide polymorphism (SNP) 516G>T in CYP2B6 gene (CYP2B6 genotype). | Drug: Single oral dose of 100 mg racemic tramadol<br>* Serial blood samples were collected up to 24 h after drug administration; Pain was evaluated at the same time of blood sampling using visual analog scale<br>* Other names: Tramadol pharmacokinetics;Other: CYP2D6 phenotype<br>* Patients were phenotyped using metoprolol (100 mg, single oral dose). Urine was collected up to 8 hours after metoprolol administration. Urinary concentrations of metoprolol and alfa-hydroxymetoprolol were determined by high performance liquid chromatography (HPLC), using fluorescence detector. CYP2D6 phenotyped was determined by alfa-hydroxymetoprolol/metoprolol urinary rato<br>* Other names: CYP2D6 in vivo activity;Other: CYP3A phenotype<br>* A single oral dose of midazolam (15 mg) was administered to all patients. Serial blood samples were collected up to 6 hours after the administration of midazolam. The concentration of midazolam was determined in plasma in order to calculate midazolam clearance. The in vivo activity of CYP3A was evaluated by midazolam oral clearance.<br>* Other names: CYP3A in vivo activity;Genetic: CYP2B6 genotype<br>* The single nucleotide polymorphism 516G>T in CYP2B6 gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).<br>* Other names: Genotype of SNP 516G>T in CYP2B6;|
| Experimental: T2DM group<br>Patients received a single oral dose of 100 mg racemic tramadol. Serial blood samples were collected up to 24 h after administration of the drug for pharmacokinetic study and for the analysis of noradrenaline in plasma. Pain was rated on a visual analog pain scale at the same time as blood sampling. CYP2D6 phenotype was evaluated using metoprolol as probe drug. CYP3A phenotype was evaluated using midazolam. Patients were genotyped for SNP 516G>T in CYP2B6 gene (CYP2B6 genotype). The diagnosis of type 2 DM was performed according to the American Diabetes Association (2010). | Drug: Single oral dose of 100 mg racemic tramadol<br>* Serial blood samples were collected up to 24 h after drug administration; Pain was evaluated at the same time of blood sampling using visual analog scale<br>* Other names: Tramadol pharmacokinetics;Other: CYP2D6 phenotype<br>* Patients were phenotyped using metoprolol (100 mg, single oral dose). Urine was collected up to 8 hours after metoprolol administration. Urinary concentrations of metoprolol and alfa-hydroxymetoprolol were determined by high performance liquid chromatography (HPLC), using fluorescence detector. CYP2D6 phenotyped was determined by alfa-hydroxymetoprolol/metoprolol urinary rato<br>* Other names: CYP2D6 in vivo activity;Other: CYP3A phenotype<br>* A single oral dose of midazolam (15 mg) was administered to all patients. Serial blood samples were collected up to 6 hours after the administration of midazolam. The concentration of midazolam was determined in plasma in order to calculate midazolam clearance. The in vivo activity of CYP3A was evaluated by midazolam oral clearance.<br>* Other names: CYP3A in vivo activity;Genetic: CYP2B6 genotype<br>* The single nucleotide polymorphism 516G>T in CYP2B6 gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).<br>* Other names: Genotype of SNP 516G>T in CYP2B6;|
| Experimental: T1DM group<br>Patients received a single oral dose of 100 mg racemic tramadol. Serial blood samples were collected up to 24 h after administration of the drug for pharmacokinetic study and for the analysis of noradrenaline in plasma. Pain was rated on a visual analog pain scale at the same time as blood sampling. CYP2D6 phenotype was evaluated using metoprolol as probe drug. CYP3A phenotype was evaluated using midazolam. Patients were genotyped for SNP 516G>T in CYP2B6 gene (CYP2B6 genotype). The diagnosis of type 1 DM was performed according to the American Diabetes Association (2010). | Drug: Single oral dose of 100 mg racemic tramadol<br>* Serial blood samples were collected up to 24 h after drug administration; Pain was evaluated at the same time of blood sampling using visual analog scale<br>* Other names: Tramadol pharmacokinetics;Other: CYP2D6 phenotype<br>* Patients were phenotyped using metoprolol (100 mg, single oral dose). Urine was collected up to 8 hours after metoprolol administration. Urinary concentrations of metoprolol and alfa-hydroxymetoprolol were determined by high performance liquid chromatography (HPLC), using fluorescence detector. CYP2D6 phenotyped was determined by alfa-hydroxymetoprolol/metoprolol urinary rato<br>* Other names: CYP2D6 in vivo activity;Other: CYP3A phenotype<br>* A single oral dose of midazolam (15 mg) was administered to all patients. Serial blood samples were collected up to 6 hours after the administration of midazolam. The concentration of midazolam was determined in plasma in order to calculate midazolam clearance. The in vivo activity of CYP3A was evaluated by midazolam oral clearance.<br>* Other names: CYP3A in vivo activity;Genetic: CYP2B6 genotype<br>* The single nucleotide polymorphism 516G>T in CYP2B6 gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).<br>* Other names: Genotype of SNP 516G>T in CYP2B6;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kinetic parameters (AUC, Cmax, Tmax, apparent total clearance, and apparent volume of distribution) of tramadol enantiomers were estimated. |  | Up to 24h after a single oral dose of tramadol (100 mg) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary concentration ratio (metoprolol/alfa-hydroxymetoprolol) as an in vivo measure of CYP2D6 activity | The CYP2D6 phenotype was determined by urinary concentration ratio metoprolol/alfa-hydroxymetoprolol | Up to 8h after metoprolol administration | 
| Clearance of midazolam as a measure of CYP3A in vivo activity |  | Up to 6h after midazolam administration | 
| Pain scores on the visual analog scale |  | Up to 24h after a single oral dose of tramadol (100 mg) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
tramadol, pharmacokinetics, enantiomers, metabolism, diabetes