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Trial record 11 of 88 for:    "Neuromuscular Disease" | "Norepinephrine"

Influence of Diabetes on Tramadol Pharmacokinetics

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ClinicalTrials.gov Identifier: NCT02246712
Recruitment Status : Completed
First Posted : September 23, 2014
Last Update Posted : September 23, 2014
Sponsor:
Collaborator:
University of Sao Paulo
Information provided by (Responsible Party):
Natalia Valadares de Moraes, Universidade Estadual Paulista Júlio de Mesquita Filho

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.

Condition or disease Intervention/treatment Phase
Neuropathic Pain Type 1 Diabetes Mellitus Type 2 Diabetes Mellitus Drug: Single oral dose of 100 mg racemic tramadol Other: CYP2D6 phenotype Other: CYP3A phenotype Genetic: CYP2B6 genotype Phase 4

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Influence of Uncontrolled Diabetes on the Kinetic Disposition, Metabolism and Pharmacokinetics-pharmacodynamics of Tramadol Enantiomers in Patients With Neuropathic Pain
Study Start Date : June 2008
Actual Primary Completion Date : May 2010
Actual Study Completion Date : December 2011

Resource links provided by the National Library of Medicine

Drug Information available for: Tramadol

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:
  • Tramadol treament
  • Blood sampling
  • 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 Name: 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:
  • Tramadol treament
  • Blood sampling
  • 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 Name: 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:
  • Tramadol treament
  • Blood sampling
  • 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 Name: Genotype of SNP 516G>T in CYP2B6




Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. Urinary concentration ratio (metoprolol/alfa-hydroxymetoprolol) as an in vivo measure of CYP2D6 activity [ Time Frame: Up to 8h after metoprolol administration ]
    The CYP2D6 phenotype was determined by urinary concentration ratio metoprolol/alfa-hydroxymetoprolol

  2. Clearance of midazolam as a measure of CYP3A in vivo activity [ Time Frame: Up to 6h after midazolam administration ]
  3. Pain scores on the visual analog scale [ Time Frame: Up to 24h after a single oral dose of tramadol (100 mg) ]


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Ages Eligible for Study:   18 Years to 59 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02246712


Locations
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Brazil
Universidade Estadual Paulista Julio de Mesquita Filho
Araraquara, SP, Brazil, 14801902
Sponsors and Collaborators
Universidade Estadual Paulista Júlio de Mesquita Filho
University of Sao Paulo
Investigators
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Principal Investigator: Natalia V de Moraes, PhD Universidade Estadual Paulista Julio de Mesquita Filho

Publications of Results:
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Responsible Party: Natalia Valadares de Moraes, Assistant Professor, Universidade Estadual Paulista Júlio de Mesquita Filho
ClinicalTrials.gov Identifier: NCT02246712     History of Changes
Other Study ID Numbers: DIABETRA
First Posted: September 23, 2014    Key Record Dates
Last Update Posted: September 23, 2014
Last Verified: September 2014
Keywords provided by Natalia Valadares de Moraes, Universidade Estadual Paulista Júlio de Mesquita Filho:
tramadol
pharmacokinetics
enantiomers
metabolism
diabetes
Additional relevant MeSH terms:
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Neuromuscular Diseases
Neuralgia
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Peripheral Nervous System Diseases
Nervous System Diseases
Pain
Neurologic Manifestations
Signs and Symptoms
Metoprolol
Midazolam
Tramadol
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents