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Influence of Diabetes on Tramadol Pharmacokinetics

Information source: Universidade Estadual Paulista Júlio de Mesquita Filho
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Neuropathic Pain; Type 1 Diabetes Mellitus; Type 2 Diabetes Mellitus

Intervention: Single oral dose of 100 mg racemic tramadol (Drug); CYP2D6 phenotype (Other); CYP3A phenotype (Other); CYP2B6 genotype (Genetic)

Phase: Phase 4

Status: Completed

Sponsored by: Universidade Estadual Paulista Júlio de Mesquita Filho

Official(s) and/or principal investigator(s):
Natalia V de Moraes, PhD, Principal Investigator, Affiliation: Universidade Estadual Paulista Julio de Mesquita Filho

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.

Clinical Details

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

Study design: Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

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

Secondary outcome:

Urinary concentration ratio (metoprolol/alfa-hydroxymetoprolol) as an in vivo measure of CYP2D6 activity

Clearance of midazolam as a measure of CYP3A in vivo activity

Pain scores on the visual analog scale

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).

Eligibility

Minimum age: 18 Years. Maximum age: 59 Years. Gender(s): Both.

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.

Locations and Contacts

Universidade Estadual Paulista Julio de Mesquita Filho, Araraquara, SP 14801902, Brazil
Additional Information

Starting date: June 2008
Last updated: September 18, 2014

Page last updated: August 23, 2015

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