Influence of Diabetes on Tramadol Pharmacokinetics

Universidade Estadual Paulista Júlio de Mesquita Filho30 enrolled

Overview

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.

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).

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

Interventions

Single oral dose of 100 mg racemic tramadolDRUG

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

CYP2D6 phenotypeOTHER

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

CYP3A phenotypeOTHER

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.

CYP2B6 genotypeGENETIC

The single nucleotide polymorphism 516G\>T in CYP2B6 gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

Eligibility

Sex: ALLMin age: 18 YearsMax age: 59 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Kinetic parameters (AUC, Cmax, Tmax, apparent total clearance, and apparent volume of distribution) of tramadol enantiomers were estimated.

Time frame: Up to 24h after a single oral dose of tramadol (100 mg)

Secondary Outcomes

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

Time frame: Up to 8h after metoprolol administration

Clearance of midazolam as a measure of CYP3A in vivo activity

Time frame: Up to 6h after midazolam administration

Pain scores on the visual analog scale