Influence of Diabetes on Tramadol Pharmacokinetics

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

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus; Type 1 Diabetes Mellitus; Neuropathic Pain
• Intervention / Treatment: Drug: Single oral dose of 100 mg racemic tramadol; Other: CYP2D6 phenotype; Other: CYP3A phenotype; Genetic: CYP2B6 genotype

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).

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 4

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 59 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control group; 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; 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; Other Names: Blood sampling; Tramadol treament; Tramadol pharmacokinetics; Other: CYP2D6 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; Other Names: CYP2D6 phenotyping; CYP2D6 in vivo activity; Other: CYP3A 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.; Other Names: CYP3A phenotyping; CYP3A in vivo activity; Genetic: CYP2B6 genotype; The single nucleotide polymorphism 516G>T in CYP2B6 gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).; Other Names: Genotype of SNP 516G>T in CYP2B6
Experimental: T2DM group; 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; 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; Other Names: Blood sampling; Tramadol treament; Tramadol pharmacokinetics; Other: CYP2D6 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; Other Names: CYP2D6 phenotyping; CYP2D6 in vivo activity; Other: CYP3A 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.; Other Names: CYP3A phenotyping; CYP3A in vivo activity; Genetic: CYP2B6 genotype; The single nucleotide polymorphism 516G>T in CYP2B6 gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).; Other Names: Genotype of SNP 516G>T in CYP2B6
Experimental: T1DM group; 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; 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; Other Names: Blood sampling; Tramadol treament; Tramadol pharmacokinetics; Other: CYP2D6 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; Other Names: CYP2D6 phenotyping; CYP2D6 in vivo activity; Other: CYP3A 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.; Other Names: CYP3A phenotyping; CYP3A in vivo activity; Genetic: CYP2B6 genotype; The single nucleotide polymorphism 516G>T in CYP2B6 gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).; Other Names: Genotype of SNP 516G>T in CYP2B6

What is the study measuring?

Primary Outcome Measures

Outcome 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 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)

Collaborators and Investigators

• Sponsor: Universidade Estadual Paulista Júlio de Mesquita Filho
• Collaborators: University of Sao Paulo
• Investigators: Principal Investigator: Natalia V de Moraes, PhD, Universidade Estadual Paulista Julio de Mesquita Filho

Publications and helpful links

General Publications

• de Moraes NV, Lauretti GR, Lanchote VL. Effects of type 1 and type 2 diabetes on the pharmacokinetics of tramadol enantiomers in patients with neuropathic pain phenotyped as cytochrome P450 2D6 extensive metabolizers. J Pharm Pharmacol. 2014 Sep;66(9):1222-30. doi: 10.1111/jphp.12255. Epub 2014 Apr 10.
• de Moraes NV, Lauretti GR, Napolitano MN, Santos NR, Godoy AL, Lanchote VL. Enantioselective analysis of unbound tramadol, O-desmethyltramadol and N-desmethyltramadol in plasma by ultrafiltration and LC-MS/MS: application to clinical pharmacokinetics. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Jan 1;880(1):140-7. doi: 10.1016/j.jchromb.2011.11.033. Epub 2011 Nov 28.

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: September 16, 2014
• First Submitted That Met QC Criteria: September 18, 2014
• First Posted (Estimate): September 23, 2014

Study Record Updates

• Last Update Posted (Estimate): September 23, 2014
• Last Update Submitted That Met QC Criteria: September 18, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: diabetes; pharmacokinetics; metabolism; tramadol; enantiomers
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Nervous System Diseases; Immune System Diseases; Autoimmune Diseases; Pain; Neurologic Manifestations; Endocrine System Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1; Neuralgia; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Tramadol
• Other Study ID Numbers: DIABETRA