Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 2D6 activity

BACKGROUND: Tramadol is potentially a very useful pain relief medication in neonates and infants. It is primarily metabolized into O-demethyl tramadol (M1) by CYP2D6. Data concerning tramadol disposition and CYP2D6 activity in young infants are not available. METHODS: A population pharmacokinetic analysis of tramadol and M1 time-concentration profiles was undertaken using non-linear mixed-effects models (NONMEM), based on newly collected data on tramadol and M1 time-concentration profiles in neonates and young infants (n=20) and published studies on intravenous tramadol in children and adults. M1 formation served as a surrogate for CYP2D6 activity. RESULTS: Tramadol clearance was described using a two-compartment linear model with zero-order input and first-order elimination. Clearance increased from 25 weeks post-conception age (PCA) (5.52 litre h(-1) [70 kg](-1)) to reach 84% of the mature value by 44 weeks PCA (standardized to a 70 kg adult using allometric 1/4 power models). The central volume of distribution decreased from 25 weeks PCA (256 litre [70 kg](-1)) to reach 120% of its mature value by 87 weeks PCA. Formation clearance to M1 contributed 43% of tramadol clearance, but had no relationship with PCA. There was a weak non-linear relationship between PCA and M1 metabolite clearance. CONCLUSIONS: Maturational clearance of tramadol is almost complete by 44 weeks PCA. A target concentration of 300 microg litre(-1) is achieved after a bolus of tramadol hydrochloride 1 mg kg(-1) and can be maintained by infusion of tramadol hydrochloride 0.09 mg kg(-1) h(-1) at 25 weeks PCA, 0.14 mg kg(-1) h(-1) at 30 weeks PCA, 0.17 mg kg(-1) h(-1) at 35 weeks PCA, 0.18 mg kg(-1) h(-1) at 40 weeks, 0.19 mg kg(-1) h(-1) at 50 weeks PCA to 1 yr, 0.18 mg kg(-1) h(-1) at 3 yr and 0.12 mg kg(-1) h(-1) in adulthood. CYP2D6 activity was observed as early as 25 weeks PCA, but the impact of CYP2D6 polymorphism on the variability in pharmacokinetics, metabolism and pharmacodynamics of tramadol remains to be established. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15951326&query_hl=1

Rheumatologic illnesses: treatment strategies for older adults

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15948663&query_hl=1 Basic objectives of arthritis therapy are to reduce musculoskeletal pain, slow progression of disease, maintain and improve function and quality of life, and avoid adverse drug reactions. Both nonpharmacologic and pharmacologic approaches may be taken. The former include patient education, cognitive therapy, high-intensity progressive-resistance or strength training, weight control, cold therapy, heat, massage, relaxation and distraction techniques. Guiding principles for the pharmacologic management of musculoskeletal disease in geriatric patients are to start low and go slow, and to provide adequate pain relief. The latter may include the use of topicals, such as 5% lidocaine patches or capsaicin, or orally administered analgesics, such as acetaminophen, tramadol, nonsteroidal anti-inflammatory drugs (NSAIDs), and opiates. Although attractive because of the reduced incidence of serious gastrointestinal adverse reactions, selective COX-2 inhibitors may have significant renal and cardiovascular toxicities, and thus should be used with caution in the older patient with co-morbid diseases affecting these organs. Intraarticular therapies with corticosteroids, or as viscosupplementation, may have a role in the management of osteoarthritis. For patients with inflammatory arthropathies, low-dose systemic steroids or disease-modifying agents are therapeutic. When therapy fails and pain remains intolerable or disabling, surgical options may be considered.