Influence of Diabetes on Tramadol Pharmacokinetics

Universidade Estadual Paulista Júlio de Mesquita Filho

Status and phase: Completed; Phase 4

Conditions: Type 1 Diabetes Mellitus; Type 2 Diabetes Mellitus; Neuropathic Pain

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

Study type: Interventional

Funder types: Other

Identifiers

NCT02246712

DIABETRA

Details and patient eligibility

About

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.

Full 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).

Enrollment: 30 patients

Sex: All

Ages: 18 to 59 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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30 participants in 3 patient groups

Control group

Active Comparator group

Description:

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).

Treatment:

Genetic: CYP2B6 genotype

Other: CYP2D6 phenotype

Drug: Single oral dose of 100 mg racemic tramadol

Other: CYP3A phenotype

T2DM group

Experimental group

Description:

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).

Treatment:

Genetic: CYP2B6 genotype

Other: CYP2D6 phenotype

Drug: Single oral dose of 100 mg racemic tramadol

Other: CYP3A phenotype

T1DM group

Experimental group

Description:

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).

Treatment:

Genetic: CYP2B6 genotype

Other: CYP2D6 phenotype

Drug: Single oral dose of 100 mg racemic tramadol

Other: CYP3A phenotype