Tramadol in the elderly : pharmacokinetic and pharmacodynamic modelling in healthy young and elderly subjects

Although pain is highly prevalent among the elderly and they are amongst the highest users of analgesics, research to support evidence based treatment decisions is limited. Recently a systematic review of clinical trials in low back pain found that elderly adults older than 65 were systematically excluded from randomised clinical trials despite calls to include elderly subjects in such studies. Pharmacokinetic (PK) and Pharmacodynamic (PD) data on analgesics in elderly patients, especially those older than 75 years, is sparse. Understanding the pharmacokinetic/pharmacodynamic relationship (PK/PD) of medicines used to treat conditions that commonly affect elderly people is key to treating them effectively, allowing them to live with quality of life and dignity and minimising the side effects that can interfere with this. Tramadol is a weak opioid commonly used in elderly patients for pain relief. Yet there is little data on its PK/PD in the elderly.  Many later phase clinical trials, especially in analgesics produce inconclusive or negative results; experimental pain models offer the opportunity to understand the PD of analgesics on a smaller scale and minimise confounding environmental circumstances.  Population PK/PD analyses of early research data permit the optimisation of dosing regimens  and of the design of phase III clinical trials by taking  into account what is learned. The pain model utilised in this research program gives us a way to look at the differences in pain tolerance between young and elderly in a quantitative fashion. The objective of this thesis is to contribute to the knowledge about age-related differences in the PK/PD of tramadol and its active metabolite O-desmethyltramadol (ODM) in subjects 75 years and older in order to examine whether there are age-related differences.  We conducted a double-blind randomised, placebo-controlled, two-period crossover study including 13 elderly subjects (≥75 years) with mild renal insufficiency and 16 young (18-40 years) subjects. Blood samples and urine were collected for 48 hours post-dose. An electrically stimulated pain model (ESPM) was used to test pain tolerance threshold (PTT), the maximum intensity a subject is willing to tolerate, using a painful but non-injuring electrical stimulus applied to the non-dominant middle finger. PTT was tested at both 250 and 5 Hz at each of 17 time-points over 30 hours after a 200 mg dose of extended release tramadol .  An in depth noncompartmental analysis of the PK of  (+)- and (-)-tramadol and (+)- and (-)-ODM plasma and urine concentrations as well as a population PK analysis of tramadol were performed. Maximum plasma concentrations of (+)-ODM, the active metabolite, occurred later and plasma concentrations declined more slowly in the elderly than in young subjects. These analyses showed that overall exposure to tramadol in elderly subjects is comparable to that in young subjects. No differences in absorption processes were observed. However, there was a significant difference in tramadol elimination half-life, most probably due to increased distribution in elderly subjects. The most remarkable differences were in the PK of (+)-ODM, the metabolite with opioid activity. Exposure to ODM was significantly greater in elderly subjects and both renal and overall clearance from the body were slower. The population PK analysis supported our findings and identified that a higher distribution and a 50% longer mean elimination half-life was associated with age of 75 or older. A key observation was that in our study population renal insufficiency was more prevalent in the elderly subjects than hepatic insufficiency.  Subsequently, in preparation for a population analysis of the PK and pain tolerance effect of tramadol’s active metabolite, (+)-ODM, we analysed pain tolerance data under placebo and tramadol administration to validate the exploratory experimental pain model that we used. We wanted to select the electrical stimulus (5 Hz or 250 Hz) that was most sensitive to detect changes in pain tolerance. Young and elderly subjects showed similar baseline pain tolerance at both 5 Hz and 250 Hz before administration of active and placebo, suggesting that pain tolerance is similar in either frequency. In the elderly, the peak pain tolerance was 30% greater for both 5 and 250 Hz after administration of tramadol as compared to placebo, but the response was noisier for the last frequency. The net pain tolerance over the 24 hours, as measured by area under the effect-time curve (AUEC) during active treatment was significantly higher (over 160%) compared to placebo for both 5 and 250 Hz stimulations in the elderly but no significant difference was observed in the young. We hypothesised that this difference might be due to the higher exposure of elderly subjects to ODM. And therefore, a PK/PD analysis was required to determine whether these age-related changes were due to altered sensitivity in elderly subjects to PTT or to a greater exposure to the active (+)-ODM metabolite.  Finally utilising plasma concentrations of (+)-ODM and the PTT data from the 5 Hz stimulus, we conducted an exploratory population analysis to determine any age-related effects on the relationship between (+)-ODM concentrations and pain tolerance threshold. Although pain tolerance was similar between young and elderly subjects at baseline, there was a 15% higher maximum possible treatment-related effect that may be associated with the higher systemic exposure to ODM., the active metabolite, thereby confirming its opioid mechanism of action. The concentration at which 50% of effect was achieved was not reduced between the young and elderly, indicating that age was not associated with greater sensitivity to (+)-ODM.  In conclusion, this is the first research program to extensively report the PK and PD of tramadol in subjects 75 and older. The value of this research program goes beyond that of a better understanding of the PK of tramadol, by delineating the relative contribution of renal clearance versus overall clearance to age-related alterations in the PK of tramadol and ODM in generally healthy elderly people. This research program also contributes to the development of population models to support further research in the elderly being the first population PK/PD model developed for (+)-ODM in subjects 75 and older. Our findings show that age-related changes in renal clearance versus overall clearance can result in a proportional increase in ODM exposure, and may explain the observation of some clinicians and literature that there is increased side effects at equivalent doses in the elderly. This is potentially of clinical significance since opioid-related efficacy and side effects of tramadol, among them sedation, are primarily linked to (+)-ODM and the risk of side effects would likely be greater in frail elderly subjects with greater renal impairment than those studied in our research.

Keyphrases: Tramadol, O-desmethyltramadol, non-compartmental analysis, population pharmacokinetics, population pharmacodynamics, PK/PD, pain tolerance threshold, elderly, geriatric, pain