Clinical trial NCT02246712: Influence of Diabetes on Tramadol Pharmacokinetics
Official title: Influence of Uncontrolled Diabetes on the Kinetic Disposition, Metabolism and Pharmacokinetics-pharmacodynamics of Tramadol Enantiomers in Patients With Neuropathic Pain
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Neuropathic Pain
Type 1 Diabetes Mellitus
Type 2 Diabetes Mellitus
Keywords: tramadol
pharmacokinetics
enantiomers
metabolism
diabetes
Lead sponsor: Universidade Estadual Paulista Júlio de Mesquita Filho
Sponsor class: OTHER
Collaborators: name: University of Sao Paulo
First posted: 2014-09-23
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Eligibility 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.

Primary outcomes:
measure: Kinetic parameters (AUC, Cmax, Tmax, apparent total clearance, and apparent volume of distribution) of tramadol enantiomers were estimated.
timeFrame: Up to 24h after a single oral dose of tramadol (100 mg)
Secondary outcomes:
measure: Urinary concentration ratio (metoprolol/alfa-hydroxymetoprolol) as an in vivo measure of CYP2D6 activity
timeFrame: Up to 8h after metoprolol administration
measure: Clearance of midazolam as a measure of CYP3A in vivo activity
timeFrame: Up to 6h after midazolam administration
measure: Pain scores on the visual analog scale
timeFrame: Up to 24h after a single oral dose of tramadol (100 mg)
Other outcomes:
Locations:
city: Araraquara
country: Brazil
facility: Universidade Estadual Paulista Julio de Mesquita Filho
state: SP
Study officials:
affiliation: Universidade Estadual Paulista Julio de Mesquita Filho
name: Natalia V de Moraes, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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: 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.