Neuropathic Pain, Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus
Conditions
Keywords
tramadol, pharmacokinetics, enantiomers, metabolism, diabetes
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).
Interventions
DRUGSingle oral dose of 100 mg racemic tramadol
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
OTHERCYP2D6 phenotype
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
OTHERCYP3A phenotype
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.
GENETICCYP2B6 genotype
The single nucleotide polymorphism 516G\>T in CYP2B6 gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
Sponsors
University of Sao Paulo
Universidade Estadual Paulista Júlio de Mesquita Filho
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 59 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | 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
| Measure | Time frame | Description |
|---|---|---|
| Urinary concentration ratio (metoprolol/alfa-hydroxymetoprolol) as an in vivo measure of CYP2D6 activity | Up to 8h after metoprolol administration | The CYP2D6 phenotype was determined by urinary concentration ratio metoprolol/alfa-hydroxymetoprolol |
| 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) | — |
Countries
Brazil
Outcome results
None listed