Pharmacokinetics of Oxycodone and Paracetamol in the Elderly. Clinical Pharmacokinetic Study on Orthopaedic Surgical Patients and Healthy Volunteers

The proportion of elderly people over 65 years of age in Finland is expected to grow to over 25% by the 2025. It has been estimated that elderly people today consume nearly 40% of all drugs. Age brings about number of physiological changes that may affect the disposition, metabolism and excretion of drugs. The function of heart, lungs, liver and kidneys decreases even in healthy people, as they get older. The proportion of total body water decreases and the relative fat percentage increases. Also several other factors such as concurrent diseases, concomitant medication and nutritional factors have an effect on drug therapy in elderly. Age increases the risk of adverse drug reactions, which most often are dose-dependent. Despite all this there are not enough studies involving the elderly people and the elderly are most often excluded from clinical trials. Oxycodone is a strong opioid analgesic, which is used to treat moderate or severe pain. Paracetamol is a widely used nonopioid analgesic, which has become popular in the treatment of pain in many patient groups. In this series of studies the pharmacokinetics of oral and intravenous oxicodone as well as intravenous paracetamol in the elderly and young adult patients were investigated. Also a study investigating the interaction of oral antibiotic clarityhromycin, a known cytochrome P450 (CYP) 3A4 inhibitor, with oxycodone pharmacokinetics and pharmacodynamics in elderly and young healthy volunteers was carried out. The pharmacokinetics of oxycodone showed a clear age depency. Patients over 70 years had 50-80% higher mean exposure to oral oxycodone and a twofold greater plasma concentration than young adults 12 h after ingestion of the drug. Elderly patients had 40-80% greater exposure to intravenous oxycodone and patients over 80 years had over twofold greater plasma concentrations 8 h post dose than the young adults. The elderly patients had also greater exposure to intra venous paracetamol compared to young adults. Clarithromycin increased the exposure to oral oxycodone in both young and elderly volunteers. The elderly had marked interindividual variation in the pharmacokinetics and pharmacodynamics when clarithromycin was given concomitantly with oxycodone. Because the pharmacokinetics of oxycodone and intravenous paracetamol depend on the age of the subject, it is important to titrate the analgesic dose individually in the elderly.Oksikodonin ja parasetamolin farmakokinetiikka vanhuksilla. Kliininen farmkokineettinen tutkimus ortopedisilla leikkauspotilailla ja terveillä vapaaehtoisilla koehenkilöillä Yli 65-vuotiaiden vanhusten osuus Suomessa on arvioitu kasvavan yli 25%:in vuoteen 2025 mennessä. Nykypäivänä vanhukset kuluttavat 40% kaikista lääkkeistä. Ikääntyessä elimistön fysiologia muuttuu, mikä saattaa vaikuttaa lääkeaineiden imeytymiseen, jakautumiseen, aineenvaihduntaan ja eritykseen elimistöstä. Sydämen, keuhkojen, maksan ja munuaisten toiminta heikkenee iän myötä myös terveilläkin ihmisillä. Veden määrä elimistössä laskee ja rasvan suhteellinen osuus lisääntyy. Myös muut tekijät kuten sairaudet, mahdollinen muu lääkitys ja ravitsemukselliset tekijät vaikuttavat ikäihmisten lääkehoitoon. Suurin osa lääkkeiden aiheuttamista haittavaikutuksista on lääkkeen annostuksesta riippuvaisia. Korkea ikä nostaa lääkkeiden haittavaikutusten riskiä. Tästä huolimatta vanhuksia ei ole riittävästi tutkittu ja usein ikäihmiset suljetaan pois kliinisistä tutkimuksista. Oksikodoni on vahva opiaatti-kipulääke, jota käytetään keskivaikean ja kovan kivun hoitoon. Parasetamoli on yleisesti käytetty kipulääke kaikissa ikäryhmissä. Tässä tutkimuksessa selvitettiin sekä suun kautta annetun että suonensisäisesti annetun oksikodonin ja suonensisäisesti annetun parasetamolin farmakokinetiikkaa nuorilla aikuisilla ja vanhuksilla. Lisäksi selvitettiin sytokromi P450 (CYP) 3A:ta estävän antibiootin, suun kautta annostellun klaritromysiinin vaikutusta oksikodonin farmakokinetiikkaan ja farmakodynamiikkaan sekä iäkkäillä, että nuorilla vapaaehtoisilla. Tutkimuksessa ikä vaikutti selvästi oksikodonin farmakokinetiikkaan. Yli 70-vuotiailla altistuminen suun kautta annetulle oksikodonille oli 50-80% suurempaa ja heillä oli yli kaksinkertainen oksikodonin plasmapitoisuus nuoriin aikuisiin verrattuna 12 tuntia lääkkeen ottamisesta. Iäkkäillä altistuminen suonensisäisesti annostellulle oksikodonille oli 40- 80%suurempaa ja oksikodonin plasmapitoisuus oli yli kaksinketainen 8 tuntia lääkkeen antamisesta nuoriin aikuisiin verrattuna. Myös suonensisäisesti annostellulle parasetamolille altistuminen oli suurempaa iäkkäillä potilailla. Klaritromysiini lisäsi altistumista oksikodonille sekä nuorilla että iäkkäillä vapaaehtoisilla. Iäkkäillä yksilöiden väliset erot olivat suuria oksikodonin farmakokinetiikassa ja farmakodynamiikassa samanaikaisen klaritromysiinikuurin yhteydessä. Koska potilaan ikä vaikuttaa oksikodonin ja suonensisäisesti annostellun parasetamolin farmakokinetiikkaan ja farmakodynamiikkaan, tulee näidnen lääkkeiden annos arvioida aina yksilöllisesti iäkkäillä potilailla.Siirretty Doriast

Cementing does not increase the immediate postoperative risk of death after total hip arthroplasty or hemiarthroplasty: a hospital-based study of 10,677 patients

Background and purpose: It has been suggested that cemented arthroplasty is associated with increased peri- and postoperative mortality due to bone cement implanting syndrome, especially in fracture surgery. We investigated such an association in elective total hip arthroplasty (THA) patients and hemiarthroplasty (HA) patients treated for femoral neck fracture.Patients and methods: All 10,677 patients receiving elective THA or HA for fracture in our hospital between 2004 and 2015 were identified. Mortality rates for cemented and uncemented THA and HA were compared at different times postoperatively using logistic regression analysis. Analysis was adjusted for age, sex, ASA class, and year of surgery.Results: Adjusted 10- and 30-day mortality after cemented THA was comparable to that of the uncemented THA (OR 1.7; 95% CI 0.3–8.7 and OR 1.6; CI 0.7–3.6, respectively). There was no statistically significant difference in the adjusted 2-day mortality in the cemented HA group when compared with the uncemented group. However, in a subgroup analyses of ASA-class IV HA patients there was a difference, statistically not significant, during the first 2 days postoperatively in the cemented HA group compared with the uncemented HA group (OR 2.1; CI 0.9–4.7).Interpretation: Cementing may still be a safe option in both elective and hip fracture arthroplasty. Excess mortality of cemented THA and HA in the longer term is comorbidity related, not due to bone cement implantation syndrome. However, in the most fragile HA patient group caution is needed at the moment of cementing.</p

Poor 10-year survivorship of hip resurfacing arthroplasty : 5,098 replacements from the Finnish Arthroplasty Register

Background and purpose In a previous registry report, short-term implant survival of hip resurfacing arthroplasty (HRA) in Finland was found to be comparable to that of total hip arthroplasty (THA). Since then, it has become evident that adverse reactions to metal debris (ARMDs) may also be associated with HRA, not only with large-diameter head metal-on-metal THA. The aim of the study was to assess medium- to long-term survivorship of HRA based on the Finnish Arthroplasty Register (FAR).Patients and methods 5,068 HRAs performed during the period 2001-2013 in Finland were included. Kaplan-Meier survival analysis was used to calculate survival probabilities and their 95% confidence intervals (CIs). Cox multiple regression, with adjustment for age, sex, diagnosis, femoral head size, and hospital volume was used to analyze implant survival of HRA devices with revision for any reason as endpoint. The reference group consisted of 6,485 uncemented Vision/Bimetric and ABG II THAs performed in Finland over the same time period.Results The 8-year survival, with any revision as an endpoint, was 93% (CI: 92-94) for Birmingham Hip Resurfacing (BHR), 86% (CI: 78-94) for Corin, 91% (CI: 89-94) for ReCap, 92% (CI: 89-96) for Durom, and was 72% (CI: 69-76) for the Articular Surface Replacement (ASR). The 10-year survival, with any revision as an endpoint, for reference THAs was 92% (CI: 91-92) and for all HRAs it was 86% (CI: 84-87%). Female HRA patients had about twice the revision risk of male patients. ASR had an inferior outcome: the revision risk was 4-fold higher than for BHR, the reference implant.Interpretation The 10-year implant survival of HRAs is 86% in Finland. According to new recommendations from NICE (The National Institute for Health and Care Excellence), an HRA/THA should have a revision rate of 5% or less at 10 years. None of the HRAs studied achieved this goal.Peer reviewe

S-ketamine in patient-controlled analgesia reduces opioid consumption in a dose-dependent manner after major lumbar fusion surgery: A randomized, double-blind, placebo-controlled clinical trial

Background Spinal fusion surgery causes severe pain. Strong opioids, commonly used as postoperative analgesics, may have unwanted side effects. S-ketamine may be an effective analgesic adjuvant in opioid patient-controlled analgesia (PCA). However, the optimal adjunct S-ketamine dose to reduce postoperative opioid consumption is still unknown.Methods We randomized 107 patients at two tertiary hospitals in a double-blinded, placebo-controlled clinical trial of adults undergoing major lumbar spinal fusion surgery. Patients were randomly allocated to four groups in order to compare the effects of three different doses of adjunct S-ketamine (0.25, 0.5, and 0.75 mg ml-1) or placebo on postoperative analgesia in oxycodone PCA. Study drugs were administered for 24 hours postoperative after which oxycodone-PCA was continued for further 48 hours. Our primary outcome was cumulative oxycodone consumption at 24 hours after surgery.Results Of the 100 patients analyzed, patients receiving 0.75 mg ml(-1) S-ketamine in oxycodone PCA needed 25% less oxycodone at 24 h postoperatively (61.2 mg) compared with patients receiving 0.5 mg ml(-1) (74.7 mg) or 0.25 mg ml(-1) (74.1 mg) S-ketamine in oxycodone or oxycodone alone (81.9 mg) (mean difference: -20.6 mg; 95% confidence interval [CI]: -41 to -0.20; P = 0.048). A beneficial effect in mean change of pain intensity at rest was seen in the group receiving 0.75 mg ml(-1) S-ketamine in oxycodone PCA compared with patients receiving lower ketamine doses or oxycodone alone (standardized effect size: 0.17, 95% CI: 0.013-0.32, P = 0.033). The occurrence of adverse events was similar among the groups.Conclusions Oxycodone PCA containing S-ketamine as an adjunct at a ratio of 1: 0.75 decreased cumulative oxycodone consumption at 24 h after major lumbar spinal fusion surgery without additional adverse effects

Cementing does not increase the immediate postoperative risk of death after total hip arthroplasty or hemiarthroplasty: a hospital-based study of 10,677 patients

Background and purpose — It has been suggested that cemented arthroplasty is associated with increased peri- and postoperative mortality due to bone cement implanting syndrome, especially in fracture surgery. We investigated such an association in elective total hip arthroplasty (THA) patients and hemiarthroplasty (HA) patients treated for femoral neck fracture. Patients and methods — All 10,677 patients receiving elective THA or HA for fracture in our hospital between 2004 and 2015 were identified. Mortality rates for cemented and uncemented THA and HA were compared at different times postoperatively using logistic regression analysis. Analysis was adjusted for age, sex, ASA class, and year of surgery. Results — Adjusted 10- and 30-day mortality after cemented THA was comparable to that of the uncemented THA (OR 1.7; 95% CI 0.3–8.7 and OR 1.6; CI 0.7–3.6, respectively). There was no statistically significant difference in the adjusted 2-day mortality in the cemented HA group when compared with the uncemented group. However, in a subgroup analyses of ASA-class IV HA patients there was a difference, statistically not significant, during the first 2 days postoperatively in the cemented HA group compared with the uncemented HA group (OR 2.1; CI 0.9–4.7). Interpretation — Cementing may still be a safe option in both elective and hip fracture arthroplasty. Excess mortality of cemented THA and HA in the longer term is comorbidity related, not due to bone cement implantation syndrome. However, in the most fragile HA patient group caution is needed at the moment of cementing

S-ketamine in patient-controlled analgesia reduces opioid consumption in a dose-dependent manner after major lumbar fusion surgery : A randomized, double-blind, placebo-controlled clinical trial

Background Spinal fusion surgery causes severe pain. Strong opioids, commonly used as postoperative analgesics, may have unwanted side effects. S-ketamine may be an effective analgesic adjuvant in opioid patient-controlled analgesia (PCA). However, the optimal adjunct S-ketamine dose to reduce postoperative opioid consumption is still unknown. Methods We randomized 107 patients at two tertiary hospitals in a double-blinded, placebo-controlled clinical trial of adults undergoing major lumbar spinal fusion surgery. Patients were randomly allocated to four groups in order to compare the effects of three different doses of adjunct S-ketamine (0.25, 0.5, and 0.75 mg ml-1) or placebo on postoperative analgesia in oxycodone PCA. Study drugs were administered for 24 hours postoperative after which oxycodone-PCA was continued for further 48 hours. Our primary outcome was cumulative oxycodone consumption at 24 hours after surgery. Results Of the 100 patients analyzed, patients receiving 0.75 mg ml(-1) S-ketamine in oxycodone PCA needed 25% less oxycodone at 24 h postoperatively (61.2 mg) compared with patients receiving 0.5 mg ml(-1) (74.7 mg) or 0.25 mg ml(-1) (74.1 mg) S-ketamine in oxycodone or oxycodone alone (81.9 mg) (mean difference: -20.6 mg; 95% confidence interval [CI]: -41 to -0.20; P = 0.048). A beneficial effect in mean change of pain intensity at rest was seen in the group receiving 0.75 mg ml(-1) S-ketamine in oxycodone PCA compared with patients receiving lower ketamine doses or oxycodone alone (standardized effect size: 0.17, 95% CI: 0.013-0.32, P = 0.033). The occurrence of adverse events was similar among the groups. Conclusions Oxycodone PCA containing S-ketamine as an adjunct at a ratio of 1: 0.75 decreased cumulative oxycodone consumption at 24 h after major lumbar spinal fusion surgery without additional adverse effects.Peer reviewe

Functional results of total-knee arthroplasty versus medial unicompartmental arthroplasty:two-year results of a randomised, assessor-blinded multicentre trial

Abstract Objective:The primary objective of the trial was to assess the clinical effectiveness of medial unicompartmental knee arthroplasty versus total knee arthroplasty in patients with isolated medial osteoarthritis of the knee. Design: Prospective, randomised, 2 years, assessor-blind, multicentre, superiority trial. Setting: The patients were enrolled between December 2015 and May 2018 from the outpatient clinics of three public high-volume arthroplasty hospitals (Finland). Participants: We recruited 143 patients with symptomatic-isolated medial osteoarthritis of the knee needing an arthroplasty procedure. All the patients were suitable for both unicompartmental and total knee arthroplasties. Population was selected as the end-stage-isolated medial osteoarthritis. Interventions: All patients, randomized 1:1, received a medial unicompartmental arthroplasty or a total knee arthroplasty through a similar midline skin incision. Patients were blinded to the type of arthroplasty for the whole 2 years of follow-up. Main outcome measures: Primary outcome measure was between-group differences in the Oxford Knee Score (OKS) and secondary outcome Knee injury and Osteoarthritis Score (KOOS) at 2 years postoperatively. The changes within and between the groups were analysed with analysis of variance for repeated measurements. Results: The primary outcome was comparable for medial unicompartmental arthroplasty and total knee arthroplasty at 2 years. The mean difference in the OKS between the groups was 1.6 points (95% CI −0.7 to 3.9). In the KOOS subscales, the mean difference between the groups was 0.1 points (95% CI −4.8 to 5.0) for pain, 7.8 points (95% CI 1.5 to 14.0) for symptoms, 4.3 points (95% CI −0.6 to 9.2) for function in daily living, 4.3 points (95% CI −3.0 to 11.6) for function in sports, and 2.1 points (95% CI −4.8 to 9.1) for knee-related quality of life. Conclusions: The recovery after unicompartmental knee arthroplasty was faster compared with total knee arthroplasty, but unicompartmental arthroplasty did not provide a better patient-reported outcome at 2 years. Trial registration number: NCT02481427