PK PD of the Enantiomers of Tramadol and O-desmethyltramadol in Elderly and Young Subjects

Comparative, Randomized, Double-Blind, Single-Dose, 2-way Crossover Study to Evaluate the Pharmacokinetics and Analgesic Effect of Labopharm Tramadol Contramid® OAD 200 mg Tablets or Placebo in Healthy Young and Elderly Adult Volunteers

This study evaluates the pharmacokinetics and pharmacodynamics of the enantiomers of tramadol and O-desmethyltramadol (ODM) in generally healthy young and elderly adults. Using a randomised, double-blind, crossover design, participants were administered a single 200mg tramadol extended-release tablet and placebo.

The pharmacokinetics of the enantiomers of tramadol and O-desmethyltramadol (ODM) have not been extensively studied in elderly patients. Given the importance of hepatic function in the metabolism of tramadol into the more potent ODM metabolite and the fact that tramadol is primarily renally excreted, age-related changes in hepatic and renal function may affect the pharmacokinetics and pharmacodynamics of tramadol. Data on the pharmacokinetics of tramadol, the ODM metabolite and their enantiomers will provide important information as to the source of any differences in the metabolism or elimination of Tramadol Contramid® OAD in the elderly as compared to younger subjects. Differences in the PK of tramadol and O-desmethyltramadol could result in differences in Pharmacodynamics of tramadol, specifically in analgesic effect. An Electrically Stimulated Pain Model was used to evaluate any differences in current perception and pain tolerance between the age groups.

Inclusion Criteria:

• Healthy adult male or female volunteers, 18-40 years of age.
• Adult male or female volunteers aged 75 years or more
• Subjects with a BMI less than 35 kg/m2.
• Generally healthy, elderly subjects with mild renal impairment (creatinine clearance 50-80 mL/min or glomerular filtration rate ≥ 50 mL/min/1.73 m2) or mild hepatic impairment (Child-Pugh Class A)
• Medically stable healthy subjects with non-clinically significant laboratory profiles, vital signs and ECGs.
• Subjects will be non-smokers for at least 3 months prior to the first dose or consistent moderate smokers (fewer than 10 cigarettes per day) for at least 3 months prior to the first dose.
• Females of childbearing potential must be using medically acceptable birth control methods
• Voluntary written informed consent

Exclusion Criteria:

• History or presence of significant unstable or untreated cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or psychiatric disease.
• alcoholism or drug abuse within the past year;
• previous or current opioid dependency or other substance abuse or dependence, other than nicotine;
• hypersensitivity or idiosyncratic reaction to tramadol hydrochloride, codeine, opioids or other synthetic opioids of the aminocyclohexanol group;
• seizures (other than infantile febrile seizures);
• significant head trauma.
• Subjects who tested positive at screening for HIV, HBsAg or HCV.
• Subjects whose sitting blood pressure is less than 110/60 mmHg at screening or prior to dosing.
• Subjects whose pulse is lower than 55 b.p.m. at screening or prior to dosing for young subjects or less than 60 b.p.m at screening or prior to dosing for the elderly subjects.
• Subjects who have used any drugs or substances known to be strong inhibitors of CYP enzymes (formerly known as cytochrome P450 enzymes) within 10 days prior to the first dose.
• Subjects who have used any drugs or substances known to be strong inducers of CYP enzymes (formerly known as cytochrome P450 enzymes) within 28 days prior to the first dose.
• Subjects who are revealed upon genotyping to be CYP2D6 poor metabolisers.
• Subjects who have received monoamine oxidase inhibitors (MAOI) or antidepressants (tricyclic or SSRIs), within 28 days prior to the first dose.
• Subjects who have received drugs belonging to the opioids/analgesic class, within 5 elimination half-lives prior to the first dose.
• Subjects who have received coumarin derivatives (e.g warfarin) or digoxin, within 28 days prior to the first dose.
• Subjects who have received CNS depressant drugs (such as benzodiazepines, barbiturates, sedative H1 antihistamines, neuroleptics, some beta-blockers, anxiolytics other than benzodiazepines), tricyclic compounds (such as cyclobenzaprine, promethazine), drugs increasing serotonin levels or thalidomide within 5 elimination half-lives prior to the first dose.
• Subjects with significant liver disease (Child-Pugh Score greater than or equal to 7).
• Significant renal disease as determined by the Cockcroft-Gault formula
• Bowel disease affecting absorption.
• Major illness requiring hospitalization during the last 3 months prior to the first dose.
• Previous failure of treatment with tramadol or discontinuation of treatment with tramadol due to adverse events.
• Subjects who have been on a special diet (for whatever reason) during the 28 days prior to the first dose and throughout the study.
• Subjects who have any condition that, in the opinion of the Investigator, makes the subject unsuitable for the study.
• Subjects who donated significant amounts of blood in the last year
• Subjects who have participated in another clinical trial within 28 days prior to the first dose.
• Subjects who are unable to tolerate the training for the ESEPM.