<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02246712</url>
  </required_header>
  <id_info>
    <org_study_id>DIABETRA</org_study_id>
    <nct_id>NCT02246712</nct_id>
  </id_info>
  <brief_title>Influence of Diabetes on Tramadol Pharmacokinetics</brief_title>
  <official_title>Influence of Uncontrolled Diabetes on the Kinetic Disposition, Metabolism and Pharmacokinetics-pharmacodynamics of Tramadol Enantiomers in Patients With Neuropathic Pain</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Universidade Estadual Paulista Júlio de Mesquita Filho</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Sao Paulo</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Universidade Estadual Paulista Júlio de Mesquita Filho</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study aimed to investigate the influence of uncontrolled type 1 and type 2 diabetes&#xD;
      mellitus (DM) on the kinetic disposition, metabolism and pharmacokinetics-pharmacodynamics of&#xD;
      tramadol enantiomers in patients with neuropathic pain. Thus, nondiabetic patients (control&#xD;
      group, n = 12), patients with type 1 DM (n = 9), and patients with type 2 DM (n = 9), all&#xD;
      with neuropathic pain and phenotyped as extensive metabolizers of cytochrome P450 2D6&#xD;
      (CYP2D6) who were treated with a single oral dose of 100 mg racemic tramadol were&#xD;
      investigated.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Tramadol is a centrally acting analgesic that effectively relieves acute and chronic pain,&#xD;
      including neuropathic pain in diabetic patients. The drug is available in clinical practice&#xD;
      as a mixture of the (+)-tramadol and (-)-tramadol enantiomers. Tramadol is metabolized by&#xD;
      CYP2D6 to O-desmethyltramadol (M1) and by cytochrome P450 3A (CYP3A4) and cytochrome P450 2B6&#xD;
      (CYP2B6) to N-desmethyltramadol (M2). Both tramadol enantiomers and (+)-M1 contribute to the&#xD;
      analgesic activity of the drug: (+)-tramadol and the (+)-M1 metabolite act as -opioid&#xD;
      receptor agonists; (+)-tramadol inhibits serotonin reuptake; and (-)-tramadol inhibits the&#xD;
      reuptake of norepinephrine. This study investigated the influence of uncontrolled type 1 and&#xD;
      type 2 diabetes mellitus (DM) on the kinetic disposition, metabolism and&#xD;
      pharmacokinetics-pharmacodynamics of tramadol enantiomers in patients with neuropathic pain.&#xD;
      Nondiabetic patients (control group, n = 12), patients with type 1 DM (n = 9), and patients&#xD;
      with type 2 DM (n = 9), all with neuropathic pain and phenotyped as extensive metabolizers of&#xD;
      CYP2D6, received a single oral dose of 100 mg racemic tramadol. Serial blood samples were&#xD;
      collected up to 24 h after administration of the drug for pharmacokinetic study and for the&#xD;
      analysis of noradrenaline in plasma. Pain was rated on a visual analog pain scale at the same&#xD;
      time as blood sampling. The patients were evaluated for in vivo CYP3A activity using&#xD;
      midazolam as a probe drug and genotyped for CYP2B6. Total and unbound plasma concentrations&#xD;
      of the tramadol, M1 and M2 enantiomers were analyzed by liquid chromatography coupled to&#xD;
      tandem mass spectrometry (LC-MS/MS).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>June 2008</start_date>
  <completion_date type="Actual">December 2011</completion_date>
  <primary_completion_date type="Actual">May 2010</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Kinetic parameters (AUC, Cmax, Tmax, apparent total clearance, and apparent volume of distribution) of tramadol enantiomers were estimated.</measure>
    <time_frame>Up to 24h after a single oral dose of tramadol (100 mg)</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Urinary concentration ratio (metoprolol/alfa-hydroxymetoprolol) as an in vivo measure of CYP2D6 activity</measure>
    <time_frame>Up to 8h after metoprolol administration</time_frame>
    <description>The CYP2D6 phenotype was determined by urinary concentration ratio metoprolol/alfa-hydroxymetoprolol</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clearance of midazolam as a measure of CYP3A in vivo activity</measure>
    <time_frame>Up to 6h after midazolam administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain scores on the visual analog scale</measure>
    <time_frame>Up to 24h after a single oral dose of tramadol (100 mg)</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Neuropathic Pain</condition>
  <condition>Type 1 Diabetes Mellitus</condition>
  <condition>Type 2 Diabetes Mellitus</condition>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <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&gt;T in CYP2B6 gene (CYP2B6 genotype).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>T2DM group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <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&gt;T in CYP2B6 gene (CYP2B6 genotype).&#xD;
The diagnosis of type 2 DM was performed according to the American Diabetes Association (2010).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>T1DM group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <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&gt;T in CYP2B6 gene (CYP2B6 genotype).&#xD;
The diagnosis of type 1 DM was performed according to the American Diabetes Association (2010).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Single oral dose of 100 mg racemic tramadol</intervention_name>
    <description>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</description>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_label>T1DM group</arm_group_label>
    <arm_group_label>T2DM group</arm_group_label>
    <other_name>Tramadol treament</other_name>
    <other_name>Blood sampling</other_name>
    <other_name>Tramadol pharmacokinetics</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>CYP2D6 phenotype</intervention_name>
    <description>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.&#xD;
CYP2D6 phenotyped was determined by alfa-hydroxymetoprolol/metoprolol urinary rato</description>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_label>T1DM group</arm_group_label>
    <arm_group_label>T2DM group</arm_group_label>
    <other_name>CYP2D6 phenotyping</other_name>
    <other_name>CYP2D6 in vivo activity</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>CYP3A phenotype</intervention_name>
    <description>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.&#xD;
The concentration of midazolam was determined in plasma in order to calculate midazolam clearance.&#xD;
The in vivo activity of CYP3A was evaluated by midazolam oral clearance.</description>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_label>T1DM group</arm_group_label>
    <arm_group_label>T2DM group</arm_group_label>
    <other_name>CYP3A phenotyping</other_name>
    <other_name>CYP3A in vivo activity</other_name>
  </intervention>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>CYP2B6 genotype</intervention_name>
    <description>The single nucleotide polymorphism 516G&gt;T in CYP2B6 gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).</description>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_label>T1DM group</arm_group_label>
    <arm_group_label>T2DM group</arm_group_label>
    <other_name>Genotype of SNP 516G&gt;T in CYP2B6</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult patients, both gender&#xD;
&#xD;
          -  Patients with self-reported neuropathic pain (score &gt;4 in a 0-10 visual analog scale)&#xD;
&#xD;
          -  Patients with normal renal function (creatinine clearance &gt;60 mL/min)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with nociceptive somatic pain, visceral or autonomic associated during the&#xD;
             study period;&#xD;
&#xD;
          -  Patients with morbid obesity (BMI&gt; 40), congestive heart failure, severe hypertension&#xD;
&#xD;
          -  Patients who have had acute myocardial infarction or accident stroke less than 6&#xD;
             months of the period of investigation.&#xD;
&#xD;
          -  Patients with chronic obstructive pulmonary disease&#xD;
&#xD;
          -  Patients who were in use of analgesics, CYP2D6 inhibitors or CYP3A4 inducers or&#xD;
             inhibitors were excluded.&#xD;
&#xD;
          -  Pregnant and lactating patients were excluded.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>59 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Natalia V de Moraes, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Universidade Estadual Paulista Julio de Mesquita Filho</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Universidade Estadual Paulista Julio de Mesquita Filho</name>
      <address>
        <city>Araraquara</city>
        <state>SP</state>
        <zip>14801902</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <results_reference>
    <citation>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.</citation>
    <PMID>24717054</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>22173007</PMID>
  </results_reference>
  <verification_date>September 2014</verification_date>
  <study_first_submitted>September 16, 2014</study_first_submitted>
  <study_first_submitted_qc>September 18, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 23, 2014</study_first_posted>
  <last_update_submitted>September 18, 2014</last_update_submitted>
  <last_update_submitted_qc>September 18, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 23, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Universidade Estadual Paulista Júlio de Mesquita Filho</investigator_affiliation>
    <investigator_full_name>Natalia Valadares de Moraes</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>tramadol</keyword>
  <keyword>pharmacokinetics</keyword>
  <keyword>enantiomers</keyword>
  <keyword>metabolism</keyword>
  <keyword>diabetes</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuralgia</mesh_term>
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 1</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tramadol</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02246712
org study id: DIABETRA
nct id: NCT02246712
lead sponsor: 
collaborator: 
has dmc: No
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.
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).
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: 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)
measure: Urinary concentration ratio (metoprolol/alfa-hydroxymetoprolol) as an in vivo measure of CYP2D6 activity
time frame: Up to 8h after metoprolol administration
description: The CYP2D6 phenotype was determined by urinary concentration ratio metoprolol/alfa-hydroxymetoprolol
measure: Clearance of midazolam as a measure of CYP3A in vivo activity
time frame: Up to 6h after midazolam administration
measure: Pain scores on the visual analog scale
time frame: Up to 24h after a single oral dose of tramadol (100 mg)
arm group label: Control group
arm group type: Active Comparator
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).
arm group label: T2DM group
arm group type: Experimental
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).
arm group label: T1DM group
arm group type: Experimental
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).
intervention type: Drug
intervention name: Single oral dose of 100 mg racemic tramadol
description: 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
arm group label: Control group
arm group label: T1DM group
arm group label: T2DM group
other name: Tramadol treament
other name: Blood sampling
other name: Tramadol pharmacokinetics
intervention type: Other
intervention name: CYP2D6 phenotype
description: 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
arm group label: Control group
arm group label: T1DM group
arm group label: T2DM group
other name: CYP2D6 phenotyping
other name: CYP2D6 in vivo activity
intervention type: Other
intervention name: CYP3A phenotype
description: 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.
arm group label: Control group
arm group label: T1DM group
arm group label: T2DM group
other name: CYP3A phenotyping
other name: CYP3A in vivo activity
intervention type: Genetic
intervention name: CYP2B6 genotype
description: The single nucleotide polymorphism 516G>T in CYP2B6 gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
arm group label: Control group
arm group label: T1DM group
arm group label: T2DM group
other name: Genotype of SNP 516G>T in CYP2B6
criteria: 
gender: All
minimum age: 18 Years
maximum age: 59 Years
healthy volunteers: No
last name: Natalia V de Moraes, PhD
role: Principal Investigator
affiliation: Universidade Estadual Paulista Julio de Mesquita Filho
facility: 
country: Brazil
citation: 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.
PMID: 24717054
citation: 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.
PMID: 22173007
responsible party type: Principal Investigator
investigator affiliation: Universidade Estadual Paulista Júlio de Mesquita Filho
investigator full name: Natalia Valadares de Moraes
investigator title: Assistant Professor
mesh term: Neuralgia
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
mesh term: Diabetes Mellitus, Type 2
mesh term: Tramadol