Influence of Diabetes on Tramadol Pharmacokinetics
Condition: Neuropathic Pain; Type 1 Diabetes Mellitus; Type 2 Diabetes Mellitus
MeSH terms: Neuralgia; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

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).
    

Intervention name(s): Single oral dose of 100 mg racemic tramadol; CYP2D6 phenotype; CYP3A phenotype; CYP2B6 genotype
Intervention type(s): Drug; Other; Other; Genetic
Intervention description(s): 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; 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; 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.; The single nucleotide polymorphism 516G>T in CYP2B6 gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
Other intervention name(s): Tramadol treament; Blood sampling; Tramadol pharmacokinetics; CYP2D6 phenotyping; CYP2D6 in vivo activity; CYP3A phenotyping; CYP3A in vivo activity; Genotype of SNP 516G>T in CYP2B6
Intervention MeSH terms: Tramadol
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: tramadol; pharmacokinetics; enantiomers; metabolism; diabetes