Out-of-hospital opioid prescriptions after knee and hip arthroplasty: prescribers and the first prescribed opioid.

BACKGROUND: We determined the first prescribed opioid and the prescribers of opioids after knee and hip arthroplasty (KA/HA) between 2013 and 2018 in the Netherlands. We also evaluated whether the first prescribed opioid dose was associated with the total dispensed dose and long-term opioid use in the first postoperative year. METHODS: The Dutch Foundation for Pharmaceutical Statistics was linked to the Dutch Arthroplasty Register. Stratified for KA/HA, the first out-of-hospital opioid within 30 days of operation was quantified as median morphine milligram equivalent (MME). Opioid prescribers were orthopaedic surgeons, general practitioners, rheumatologists, anaesthesiologists, and other physicians. Long-term use was defined as ≥1 opioid prescription for >90 postoperative days. We used linear and logistic regression analyses adjusted for confounders. RESULTS: Seventy percent of 46 106 KAs and 51% of the 42 893 HAs were prescribed ≥1 opioid. Oxycodone increased as first prescribed opioid (from 44% to 85%) whereas tramadol decreased (64-11%), but their dosage remained stable (stronger opioids were preferred by prescribers). An increase in the first prescription of 1% MME resulted in a 0.43%/0.37% increase in total MME (KA/HA, respectively). A 100 MME increase in dose of the first dispensed opioid had a small effect on long-term use (prevalence: 25% KA, 20% HA) (odds ratio=1.02/1.01 for KA/HA, respectively). Orthopaedic surgeons increasingly prescribed the first prescription between 2013 and 2018 (44-69%). General practitioners mostly prescribed consecutive prescriptions (>50%). CONCLUSION: Oxycodone increased as first out-of-hospital prescription between 2013 and 2018. The dose of the first prescribed opioid was associated with the total dose and a small increased risk of prolonged use. First prescriptions were mostly written by orthopaedic surgeons and consecutive prescriptions by general practitioners.

What Changes Have Occurred in Opioid Prescriptions and the Prescribers of Opioids Before TKA and THA? A Large National Registry Study.

BACKGROUND: Opioid use before TKA or THA is linked to a higher risk of revision surgery and less functional improvement. In Western countries, the frequency of preoperative opioid use has varied, and robust information on temporal changes in opioid prescriptions over time (in the months before surgery as well as annual changes) and among prescribers is necessary to pinpoint opportunities to improve on low-value care patterns, and when they are recognized, to target physician populations for intervention strategies. QUESTIONS/PURPOSES: (1) What proportion of patients undergoing arthroplasties receive an opioid prescription in the year before TKA or THA, and what were the preoperative opioid prescription rates over time between 2013 and 2018? (2) Does the preoperative prescription rate vary between 12 and 10 months and between 3 and 1 months in the year before TKA or THA, and did it change between 2013 and 2018? (3) Which medical professionals were the main prescribers of preoperative opioids 1 year before TKA or THA? METHODS: This was a large-database study drawn from longitudinally maintained national registry sources in the Netherlands. The Dutch Foundation for Pharmaceutical Statistics was linked to the Dutch Arthroplasty Register from 2013 to 2018. TKAs and THAs performed because of osteoarthritis in patients older than 18 years, which were also uniquely linked by age, gender, patient postcode, and low-molecular weight heparin use, were eligible. Between 2013 and 2018, 146,052 TKAs were performed: 96% (139,998) of the TKAs were performed for osteoarthritis in patients older than 18 years; of them, 56% (78,282) were excluded because of our linkage criteria. Some of the linked arthroplasties could not be linked to a community pharmacy, which was necessary to follow patients over time, leaving 28% (40,989) of the initial TKAs as our study population. Between 2013 and 2018, 174,116 THAs were performed: 86% (150,574) were performed for osteoarthritis in patients older than 18 years, one arthroplasty was excluded because of an outlier opioid dose, and a further 57% (85,724 of 150,574) were excluded because of our linkage criteria. Some of the linked arthroplasties could not be linked to a community pharmacy, leaving 28% (42,689 of 150,574) of THAs, which were performed between 2013 and 2018. For both TKA and THA, the mean age before surgery was 68 years, and roughly 60% of the population were women. We calculated the proportion of patients undergoing arthroplasties who had at least one opioid prescription in the year before arthroplasty and compared data from 2013 to 2018. Opioid prescription rates are given as defined daily dosages and morphine milligram equivalents (MMEs) per arthroplasty. Opioid prescriptions were assessed by preoperative quarter and by operation year. Possible changes over time in opioid exposure were investigated using linear regression, adjusted for age and gender, in which the month of operation since January 2013 was used as the determinant and MME as the outcome. This was done for all opioids combined and per opioid type. Possible changes in opioid prescription rates in the year before arthroplasty were assessed by comparing the time period of 1 to 3 months before surgery with the other quarters. Additionally, preoperative prescriptions per operation year were assessed per prescriber category: general practitioners, orthopaedic surgeons, rheumatologists, and others. All analyses were stratified by TKA or THA. RESULTS: The proportion of patients undergoing arthroplasties who had an opioid prescription before TKA increased from 25% (1079 of 4298) in 2013 to 28% (2097 of 7460) in 2018 (difference 3% [95% CI 1.35% to 4.65%]; p < 0.001), and before THA increased from 25% (1111 to 4451) to 30% (2323 to 7625) (difference 5% [95% CI 3.8% to 7.2%]; p < 0.001). The mean preoperative opioid prescription rate increased over time between 2013 and 2018 for both TKA and THA. For TKA, an adjusted monthly increase of 3.96 MME was observed (95% CI 1.8 to 6.1 MME; p < 0.001). For THA, the monthly increase was 3.8 MME (95% CI 1.5 to 6.0; p = 0.001. For both TKA and THA, there was a monthly increase in the preoperative oxycodone rate (3.8 MME [95% CI 2.5 to 5.1]; p < 0.001 and 3.6 [95% CI 2.6 to 4.7]; p < 0.001, respectively). For TKA, but not for THA, there was a monthly decrease in tramadol prescriptions (-0.6 MME [95% CI -1.0 to -0.2]; p = 0.006). Regarding the opioids prescribed in the year before surgery, there was a mean increase of 48 MME (95% CI 39.3 to 56.7 MME; p < 0.001) for TKA between 10 and 12 months and the last 3 months before surgery. For THA, this increase was 121 MME (95% CI 110 to 131 MME; p < 0.001). Regarding possible differences between 2013 and 2018, we only found differences in the period 10 to 12 months before TKA (mean difference 61 MME [95% CI 19.2 to 103.3]; p = 0.004) and the period 7 to 9 months before TKA (mean difference 66 MME [95% CI 22.0 to 110.9]; p = 0.003). For THA, there was an increase in the MMEs prescribed between 2013 and 2018 for all four quarters, with mean differences ranging from 43.9 to 55.4 MME (p < 0.05). The average proportion of preoperative opioid prescriptions prescribed by general practitioners ranged between 82% and 86% (41,037 of 49,855 for TKA and 49,137 of 57,289 for THA), between 4% and 6% (2924 of 49,855 for TKA and 2461 of 57,289 for THA), by orthopaedic surgeons, 1% by rheumatologists (409 of 49,855 for TKA and 370 of 57,289 for THA), and between 9% and 11% by other physicians (5485 of 49,855 for TKA and 5321 of 57,289 for THA). Prescriptions by orthopaedic surgeons increased over time, from 3% to 7% for THA (difference 4% [95% CI 3.6 to 4.9]) and 4% to 10% for TKA (difference 6% [95% CI 5% to 7%]; p < 0.001). CONCLUSION: Between 2013 and 2018, preoperative opioid prescriptions increased in the Netherlands, mainly because of a shift to more oxycodone prescriptions. We also observed an increase in opioid prescriptions in the year before surgery. Although general practitioners were the main prescribers of preoperative oxycodone, prescriptions by orthopaedic surgeons also increased during the study period. Orthopaedic surgeons should address opioid use and its associated negative effects in preoperative consultations. More intradisciplinary collaboration seems important to limit the prescribing of preoperative opioids. Additionally, research is necessary to assess whether opioid cessation before surgery reduces the risk of adverse outcomes. LEVEL OF EVIDENCE: Level III, therapeutic study.

Association between prescription opioid use and unplanned intensive care unit admission and mortality in the adult population of the Netherlands: a registry study.

BACKGROUND: Opioid overdoses are increasing in the Netherlands, and there may be other harms associated with prescription opioid use. We investigated the relationship between prescription opioid use and unplanned ICU admission and death. METHODS: This is an analysis of linked government registries of the adult Dutch population (age ≥18 years) alive on January 1, 2018. The co-primary outcomes were ICU admission and death up to 1 year. Crude event rates and event-specific adjusted hazard rates (aHRs) with 95% confidence intervals (CIs) were calculated using multivariable analysis for people with and without exposure to an opioid prescription. RESULTS: We included 13 813 173 individuals, of whom 32 831 were admitted to the ICU and 152 259 died during the 1 year follow-up. Rates of ICU admission and death amongst people who reimbursed an opioid prescription were 5.87 and 62.2 per 1000 person-years, and rates of ICU admission and death in those without a prescription were 2.03 and 6.34, respectively. Exposed individuals had a higher rate of both ICU admission (aHR 2.53; 95% CI: 2.45-2.60) and death (aHR 7.11; 95% CI: 7.02-7.19) compared with unexposed individuals. Both outcomes were more frequent amongst prescription opioid users across a range of subgroups. CONCLUSIONS: The rate of ICU admission and death was higher amongst prescription opioid users than non-users in the full cohort and in subgroups. These findings represent an important public health concern.

Opioid prescribing patterns after arthroplasty of the knee and hip: a Dutch nationwide cohort study from 2013 to 2018.

BACKGROUND AND PURPOSE: Numbers on opioid prescriptions over time in arthroplasty patients are currently lacking. Therefore we determined the annual opioid prescribing rate in patients who received a hip/knee arthroplasty (HA/KA) between 2013 and 2018. PATIENTS AND METHODS: The Dutch Foundation for Pharmaceutical Statistics, which provides national coverage of medication prescriptions, was linked to the Dutch Arthroplasty Register, which provides arthroplasty procedures. The opioid prescription rates were expressed as the number of defined daily dosages (DDD) and morphine milligram equivalent (MME) per person year (PY) and stratified for primary and revision arthroplasty. Amongst subgroups for age (< 75; ≥ 75 years) and sex for primary osteoarthritis arthroplasties, prescription rates stratified for opioid type (weak/strong) and prevalent preoperative opioid prescriptions (yes/no) were assessed. RESULTS: 48,051 primary KAs and 53,964 HAs were included, and 3,540 revision KAs and 4,118 HAs. In 2013, after primary KA 58% were dispensed ≥ 1 opioid within the first year; this increased to 89% in 2018. For primary HA these numbers increased from 38% to 75%. In KAs the prescription rates increased from 13.1 DDD/PY to 14.4 DDD/PY, mainly due to oxycodone prescriptions (2.9 DDD/PY to 7.3 DDD/PY), while tramadol decreased (7.3 DDD/PY to 4.6 DDD/PY). The number of MME/PY also increased (888 MME/PY to 1224 MME/PY). Similar changes were observed for HA and revision arthroplasties. Irrespective of joint, prescription of opioid medication increased over time, with highest levels in groups with preoperative opioid prescriptions while weak opioid prescriptions decreased. INTERPRETATION: In the Netherlands, between 2013 and 2018 postoperative opioid prescriptions after KA and HA increased, mainly due to increased oxycodone prescriptions with highest levels after surgeries with preoperative prescriptions.

Does nociception monitor-guided anesthesia affect opioid consumption? A systematic review of randomized controlled trials.

Monitors that estimate nociception during anesthesia may be used to guide opioid and other analgesics administration to optimize anesthesia care and possibly outcome. We reviewed the literature to evaluate current evidence of the effect of nociception-guided management over standard anesthesia practice during surgery. A systematic review of the literature on the effect of nociception monitoring on anesthesia practice was conducted. Reports were eligible if they compared nociception-guided anesthesia to standard practice during surgery. Primary endpoint of this review is intraoperative opioid consumption. Secondary endpoints included hemodynamic control, postoperative pain and pain treatment. We identified 12 randomized controlled trials that compared one of five different nociception monitoring techniques to standard anesthesia care. Most studies were single center studies of small sample size. Six studies reported intraoperative opioid consumption as primary outcome. There was considerable variability with respect to surgical procedure and anesthesia technique. For nociception monitors that were investigated by more than one study, analysis of the pooled data was performed. The surgical plethysmographic index was the only monitor for which an intra operative opioid sparing effect was found. For the other monitors, either no effect was detected, or pooled analysis could not be performed due to paucity of study data. On secondary outcomes, no consistent effect of nociception-guided anesthesia could be established. Although some nociception monitors show promising results, no definitive conclusions regarding the effect of nociception monitoring on intraoperative opioid consumption or other anesthesia related outcome can be drawn.Clinical trial number PROSPERO ID 102913.

Thoracic Epidural Anesthesia Reduces Right Ventricular Systolic Function With Maintained Ventricular-Pulmonary Coupling.

BACKGROUND: Blockade of cardiac sympathetic fibers by thoracic epidural anesthesia may affect right ventricular function and interfere with the coupling between right ventricular function and right ventricular afterload. Our main objectives were to study the effects of thoracic epidural anesthesia on right ventricular function and ventricular-pulmonary coupling. METHODS: In 10 patients scheduled for lung resection, right ventricular function and its response to increased afterload, induced by temporary, unilateral clamping of the pulmonary artery, was tested before and after induction of thoracic epidural anesthesia using combined pressure-conductance catheters. RESULTS: Thoracic epidural anesthesia resulted in a significant decrease in right ventricular contractility (ΔESV25: +25.5 mL, P=0.0003; ΔEes: -0.025 mm Hg/mL, P=0.04). Stroke work, dP/dtMAX, and ejection fraction showed a similar decrease in systolic function (all P<0.05). A concomitant decrease in effective arterial elastance (ΔEa: -0.094 mm Hg/mL, P=0.004) yielded unchanged ventricular-pulmonary coupling. Cardiac output, systemic vascular resistance, and mean arterial blood pressure were unchanged. Clamping of the pulmonary artery significantly increased afterload (ΔEa: +0.226 mm Hg/mL, P<0.001). In response, right ventricular contractility increased (ΔESV25: -26.6 mL, P=0.0002; ΔEes: +0.034 mm Hg/mL, P=0.008), but ventricular-pulmonary coupling decreased (Δ(Ees/Ea) = -0.153, P<0.0001). None of the measured indices showed significant interactive effects, indicating that the effects of increased afterload were the same before and after thoracic epidural anesthesia. CONCLUSIONS: Thoracic epidural anesthesia impairs right ventricular contractility but does not inhibit the native positive inotropic response of the right ventricle to increased afterload. Right ventricular-pulmonary arterial coupling was decreased with increased afterload but not affected by the induction of thoracic epidural anesthesia. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2844. Unique identifier: NTR2844.

Does a Platelet Transfusion Independently Affect Bleeding and Adverse Outcomes in Cardiac Surgery?

BACKGROUND: Conflicting results have been reported concerning the effect of platelet transfusion on several outcomes. The aim of this study was to assess the independent effect of a single early intraoperative platelet transfusion on bleeding and adverse outcomes in cardiac surgery patients. METHODS: For this observational study, 23,860 cardiac surgery patients were analyzed. Patients who received one early (shortly after cardiopulmonary bypass while still in the operating room) platelet transfusion, and no other transfusions, were defined as the intervention group. By matching the intervention group 1:3 to patients who received no early transfusion with most comparable propensity scores, the reference group was identified. RESULTS: The intervention group comprised 169 patients and the reference group 507. No difference between the groups was observed concerning reinterventions, thromboembolic complications, infections, organ failure, and mortality. However, patients in the intervention group experienced less blood loss and required vasoactive medication 139 of 169 (82%) versus 370 of 507 (74%; odds ratio, 1.65; 95% CI, 1.05 to 2.58), prolonged mechanical ventilation 92 of 169 (54%) versus 226 of 507 (45%; odds ratio, 1.47; 94% CI, 1.03 to 2.11), prolonged intensive care 95 of 169 (56%) versus 240 of 507 (46%; odds ratio, 1.49; 95% CI, 1.04 to 2.12), erythrocytes 75 of 169 (44%) versus 145 of 507 (34%; odds ratio, 1.55; 95% CI, 1.08 to 2.23), plasma 29 of 169 (17%) versus 23 of 507 (7.3%; odds ratio, 2.63; 95% CI, 1.50-4.63), and platelets 72 of 169 (43%) versus 25 of 507 (4.3%; odds ratio, 16.4; 95% CI, 9.3-28.9) more often compared to the reference group. CONCLUSIONS: In this retrospective analysis, cardiac surgery patients receiving platelet transfusion in the operating room experienced less blood loss and more often required vasoactive medication, prolonged ventilation, prolonged intensive care, and blood products postoperatively. However, early platelet transfusion was not associated with reinterventions, thromboembolic complications, infections, organ failure, or mortality.

Erythropoietin does not have effects on the ventilatory and pulmonary vascular response to acute hypoxia in men and women.

NEW FINDINGS: What is the central question of this study? Does a clinically relevant intravenous dose of erythropoeitin affect the hypoxic ventilatory response and/or hypoxic pulmonary vasoconstriction in healthy humans? What is the main finding and its importance? Erythropoeitin does not influence the ventilatory and pulmonary vascular responses to acute hypoxia in men or women. Sustained and chronic hypoxia lead to an increase in pulmonary ventilation (hypoxic ventilatory response, HVR) and to an increase in pulmonary vascular resistance (hypoxic pulmonary vasoconstriction, HPV). In this study, we examined the effect of a clinical i.v. dose of recombinant human erythropoietin (50 IU kg-1 ) on the isocapnic HVR and HPV in seven male and seven female subjects by exposing them to hypoxia for 20 min (end-tidal PO2  âˆ¼50 mmHg) while measuring their ventilation and estimating pulmonary arterial pressure from the maximal velocity of the regurgitant jet over the tricuspid valve during systole (ΔPmax ) with echocardiography. In the placebo session, after 5 and 20 min men responded with an increase in ventilation by 0.0056 and 0.0023 l min-1  kg-1   %SpO2-1 , respectively, indicating the presence of hypoxic ventilatory depression. In women, the increase in ventilation was 0.0067 and 0.0047 l min-1  kg-1   %SpO2-1 , respectively. In both sexes, erythropoietin did not alter these responses significantly. In the placebo session, mean ΔPmax increased by 6.1 ± 0.7 mmHg in men (P = 0.035) and by 8.4 ± 1.4 mmHg in women (P = 0.020) during the hypoxic exposure, whereby women had a âˆ¼5 mmHg lower end-tidal PCO2 . Erythropoietin did not alter these responses; in men, ΔPmax increased by 7.5 ± 1.1 mmHg (n.s. versus placebo) and in women by 9.7 ± 2.2 mmHg (n.s. versus placebo). We conclude that women tended to have a greater HPV in placebo conditions and that a clinical dose of erythropoietin has no effect on the HVR and HPV in either sex.

Risk of drug-related upper gastrointestinal bleeding in the total population of the Netherlands: a time-trend analysis.

OBJECTIVE: Many prescribed and over-the-counter medications, for example, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with upper gastrointestinal bleeding (UGIB). Recently, a decrease in prescribing of NSAIDs was observed in the Netherlands, but whether a similar decreasing trend could be observed in the incidence of severe UGIB (either fatal or requiring hospitalisation), contingent on medication prescription, is unknown. DESIGN: We conducted a cohort study using Dutch national statistics on pharmacy claims, hospitalisation and mortality between 2013 and 2018. We explored the incidence of sex-specific and age-specific severe UGIB in four (sub)populations: (A) total population, (B) without a filled prescrption for NSAIDs, (C) without filled prescriptions for NSAIDs and antithrombotic agents, (D) without any risk factors for UGIB. RESULTS: The cumulative incidence of severe UGIB did not decrease throughout the study period, regardless of the subgroup analysis. In the total population, it was 199 per 100 000 inhabitants (95% CI 197 to 201) in 2013-2014 and 260 (95% CI 258 to 263) in 2017-2018. The absolute risk of severe UGIB was 50% lower in the subgroup B than in the full cohort. It decreased further by 50% in the subgroup D when compared with subgroup B. The risk of severe UGIB was 1.5-1.9 fold higher in young women than in young men; an indication of over-the-counter NSAIDs use being more prevalent in women than men in this age group. CONCLUSION: We found no evidence to support a relationship between reduced prescribing of NSAIDs and the incidence of severe UGIB in the Netherlands since 2013. The relationship was also not observed when we removed the effect of risk factors.

Opioid epidemic: lessons learned and updated recommendations for misuse involving prescription versus non-prescription opioids.

INTRODUCTION: In the past decades, the opioid crisis has heavily impacted parts of the US society and has been followed by an increase in the use of opioids worldwide. It is of paramount importance that we explore the origins of the US opioid epidemic to develop best practices to tackle the rising tide of opioid overdoses. AREAS COVERED: In this expert review, we discuss opioid (over)prescription, change in perception of pain, and false advertisement of opioid safety as the leading causes of the US opioid epidemic. Then, we review the evidence about opioid dependence and addiction potential and provide current knowledge about predictors of aberrant opioid-related behavior. Lastly, we discuss different approaches that were considered or undertaken to combat the rising tide of opioid-related deaths by regulatory bodies, pharmaceutical companies, and health-care professionals. For this expert review, we considered published articles relevant to the topic under investigation that we retrieved from Medline or Google scholar electronic database. EXPERT OPINION: The opioid epidemic is a dynamic process with many underlying mechanisms. Therefore, no single approach may be best suited to combat it. In our opinion, the best way forward is to employ multiple strategies to tackle different underlying mechanisms.

Efficacy of ketamine in relieving neuropathic pain: a systematic review and meta-analysis of animal studies.

ABSTRACT: In humans, proof of long-term efficacy of ketamine treatment in neuropathic pain is lacking. To improve our understanding of ketamine behavior under various administration conditions, we performed a systematic review and meta-analyses of controlled studies on the efficacy of ketamine in mice and rats with a disease model of nerve injury on relief of allodynia. Searches in PubMed and EMBASE identified 31 unique studies. Four meta-analyses were conducted. The first analysis included 19 comparisons on a single ketamine dose and measurement of effect within 3 hours of dosing and showed an appreciable effect (standardized mean difference 1.6, 95% confidence interval 1.1-2.1). Subgroup analyses showed no effect of species, administration route, or dose. A single administration was insufficient to sustain relief of allodynia at 24 or 72 hours after dosing, as observed in our second analysis (7 comparisons) with similar effects in ketamine-treated and control animals. Chronic ketamine administration (9 comparisons) caused profound relief of allodynia when tested during ketamine exposure (effect size 5.1, 3.7-6.5). The final analysis (6 comparisons) showed that chronic administration caused a slow loss of relief of allodynia with 70% loss of effect 24 days after end of treatment. No subgroups analyses were possible in the last 3 meta-analyses due to small group sizes. These results indicate long-term ketamine anti-allodynic effects after chronic exposure (>3 days) but not after a single administration. Given several limitations, extrapolation of the animal data to the human condition is tenuous.

Comparison of Two Different Analgesic Prescription Strategies and Healthcare Systems: Slovenia vs. the Netherlands.

Background: Prescribing practice of pain medication is changing in the Netherlands; opioids are used more often instead of nonsteroidal anti-inflammatory drugs (NSAIDs), therefore we aimed to compare the use of pain medication with Slovenia which has stringent prescribing rules for strong opioids. Methods: We conducted a cohort study into national prescription databases of the Netherlands and Slovenia covering pharmacy claims between January 1, 2013 and December 31, 2019. In the analysis about 17 million Dutch and 2 million Slovenian residents were included. Findings: The use of opioids and NSAIDs was higher in Slovenia than in the Netherlands. More frequent use of opioids in Slovenia could be almost entirely explained by weak opioids (about 6% of the population), whereas they were prescribed 50% less frequently in the Netherlands. The opioid use has increased by about 20% in the Netherlands (4.85 and 6.00% of the population in 2013 and 2018, respectively), and the majority of this increase could be explained by strong opioids (4.05% in 2018), specifically, by oxycodone whose use increased by more than 2-fold between 2013 and 2019. In comparison, oxycodone was seldomly used in Slovenia (about 0.3% of the population received a prescription in a year). Interpretation: When medication use is controlled by stringent prescribing rules, like for strong opioids in Slovenia, the use is lower as compared to when such rules do not exist.

Arterial [H+] and the ventilatory response to hypoxia in humans: influence of acetazolamide-induced metabolic acidosis.

In this study, we investigated possible separate effects of H+ ions and CO2 on hypoxic sensitivity in humans. We also examined whether hypoxic sensitivity, conventionally defined as the ratio of (hypoxic - normoxic) ventilation over (hypoxic - normoxic) Hb oxygen saturation can also be estimated by taking the ratio (hypoxic - normoxic) ventilation over (logPa(O2) hypoxia - logPa(O2) normoxia), enabling one to measure the hypoxic response independently from potential confounding influences of changes in position of the Hb oxygen saturation curve. We used acetazolamide to induce a metabolic acidosis. To determine the acute hypoxic response (AHR), we performed step decreases in end-tidal Po2 to approximately 50 Torr lasting 5 min each at three different constant end-tidal Pco2 levels. Nine subjects ingested 250 mg of acetazolamide or placebo every 8 h for 3 days in a randomized double-blind crossover design. The metabolic acidosis was accompanied by a rise in ventilation, a substantial fall in Pa(CO2), and a parallel leftward shift of the ventilatory CO2 response curve. In placebo, CO2 induced equal relative increases in hypoxic sensitivity (O2-CO2 interaction) regardless of the way it was defined. Acetazolamide shifted the response line representing the relationship between hypoxic sensitivity and arterial [H+] ([H+](a)) to higher values of [H+](a) without altering its slope, indicating that it did not affect the O2-CO2 interaction. So, in contrast to an earlier belief, CO2 and H+ have separate effects on hypoxic sensitivity. This was also supported by the finding that infusion of bicarbonate caused a leftward shift of the hypoxic sensitivity-[H+](a) response lines in placebo and acetazolamide. A specific inhibitory effect of acetazolamide on hypoxic sensitivity was not demonstrated.

Causes and consequences of the opioid epidemic in the Netherlands: a population-based cohort study.

Over the past decade opioid use has risen globally. The causes and consequences of this increase, especially in Europe, are poorly understood. We conducted a population-based cohort study using national statistics on analgesics prescriptions, opioid poisoning hospital admissions and deaths in the Netherlands from 2013 to 2017. Pain prevalence and severity was determined by using results of 2014-2017 Health Interview Surveys. Between 2013 and 2017 the proportion of residents receiving opioid prescription rose from 4.9% to 6.0%, and the proportion of those receiving NSAIDs decreased from 15.5% to 13.7%. Self-reported pain prevalence and severity remained constant, as 44.7% of 5,119 respondents reported no pain-impeded activities-of-daily-living in 2014 (aRR, 1.00 [95% CI, 0.95-1.06] in 2017 vs 2014). Over the observation period, the incidence of opioid poisoning hospitalization and death increased from 8.6 to 12.9 per 100,000 inhabitants. The incidence of severe outcomes related to opioid use increased, as 3.9% of 1,343 hospitalized for opioid poisoning died in 2013 and 4.6% of 2,055 in 2017. We demonstrated that NSAIDs prescription decreased and opioid prescription increased in the Netherlands since 2013, without an increase in pain prevalence and severity. Consequently, the incidence of severe outcomes related to opioids increased.

Morphine-6beta-glucuronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans.

BACKGROUND: Previous data indicate that morphine-6beta-glucuronide (M6G), a morphine metabolite with analgesic properties, can paradoxically increase pain sensitivity in mice and humans. The authors tested mice and humans for M6G hyperalgesia and assessed the contribution of N-methyl-D-aspartate receptor activity in mice. METHODS: Nociception after acute injection (10 mg/kg) and chronic infusion (1.6 mg/kg per 24 h) of M6G or saline was assayed using the tail-withdrawal test in CD-1 mice implanted with pellets containing the opioid antagonist naltrexone or placebo and in knockout mice lacking mu-, kappa-, and delta-opioid receptors and their B6129F(1) controls. In volunteers, responses to heat pain were tested after a M6G (0.4 mg/kg) injection in the presence of a continuous high naloxone (0.04-mg/kg bolus followed by 0.04 mg/kg per hour) or saline background infusion. RESULTS: Acute M6G injection evoked analgesia in CD-1 mice implanted with placebo pellets and B6129F(1) control mice, whereas it caused hyperalgesia in CD-1 mice treated concurrently with naltrexone and in knockout mice. Continuous M6G infusion produced hyperalgesia within 24 h, lasting for a minimum of 6 days, in both placebo- and naltrexone-pelleted mice. The N-methyl-D-aspartate receptor antagonist MK-801 (0.05 mg/kg) blocked and reversed hyperalgesia after the acute injection and continuous infusion of M6G, respectively. In humans, M6G increased heat pain sensitivity for at least 6 h independently of simultaneous naloxone infusion. CONCLUSIONS: These data indicate that M6G causes hyperalgesia independent of previous or concurrent opioid receptor activity or analgesia. In mice, a causal role for the N-methyl-D-aspartate receptor is also indicated.

Opioid Prescription Patterns and Risk Factors Associated With Opioid Use in the Netherlands.

Importance: An increase in opioid prescription has been observed in the Netherlands. It is vital to understand this increase and to identify risk factors for opioid prescription to ensure that health interventions remain appropriately targeted. Objectives: To determine the prevalence of opioid prescriptions and adverse events associated with opioids, and to identify risk factors associated with opioid prescription in the Dutch population. Design, Setting, and Participants: This cohort study used national statistics from the Netherlands from January 1, 2013, to December 31, 2017, including the full Dutch population of 16 779 575 people in 2013 and 17 081 507 people in 2017. Data from the Dutch Health Monitor surveys of 2012 and 2016 were also included. Databases were anonymized prior to analysis. All analyses were performed between December 2018 and February 2019. Exposure: Opioid prescription. Main Outcomes and Measures: The main outcomes were the dynamics of opioid prescriptions, hospital admissions for opioid overdose, and opioid overdose mortalities. The secondary outcome was risk factors associated with opioid prescription. Results: In 2013, 814 211 individuals (4.9% of the total population) received an opioid prescription. In 2017, 1 027 019 individuals (6.0% of the total population) received at least 1 opioid prescription (mean [SD] age, 59.3 [18.5] years; 613 203 [59.7%] women). The rate of hospital admissions for opioid overdose was 9.2 per 100 000 inhabitants in 2013 and 13.1 per 100 000 inhabitants in 2017 (relative risk, 1.43 [95% CI, 1.34-1.52]). Similarly, an increased risk of opioid overdose death was observed, from 0.83 per 100 000 inhabitants in 2013 to 1.2 per 100 000 inhabitants in 2017 (relative risk, 1.49 [95% CI, 1.20-1.85]). Based on data from the 2012 Dutch Health Monitor survey, risk factors associated with opioid prescription included being older than 65 years (odds ratio [OR], 4.20 [95% CI, 3.98-4.43]), having only a primary school education (OR, 3.62 [95% CI, 3.46-3.77]), being widowed (OR, 3.30 [95% CI, 3.13-3.49]), reporting always feeling symptoms of depression (OR, 3.77 [95% CI, 3.41-4.18]), and reporting poor or very poor physical health (OR, 10.40 [95% CI, 10.01-10.81]). Self-reported back pain (OR, 4.34 [95% CI, 4.23-4.46]) and rheumatoid arthritis or fibromyalgia (OR, 3.77 [95% CI, 3.65-3.90]) were also associated with opioid prescription. However, unemployment (OR, 1.05 [95% CI, 0.96-1.13]) was not associated with opioid prescription, and alcohol use disorder (OR, 0.76 [95% CI, 0.73-0.80]) was negatively associated with opioid prescription. Conclusions and Relevance: This study found that opioid prescriptions have increased in the Netherlands. Although the risk of adverse events is still relatively low, there is an urgent need to review pain management to prevent a further increase in opioid prescription.

Morphine-6-glucuronide: morphine's successor for postoperative pain relief?

In searching for an analgesic with fewer side effects than morphine, examination of morphine's active metabolite, morphine-6-glucuronide (M6G), suggests that M6G is possibly such a drug. In contrast to morphine, M6G is not metabolized but excreted via the kidneys and exhibits enterohepatic cycling, as it is a substrate for multidrug resistance transporter proteins in the liver and intestines. M6G exhibits a delay in its analgesic effect (blood-effect site equilibration half-life 4-8 h), which is partly related to slow passage through the blood-brain barrier and distribution within the brain compartment. In humans, M6G's potency is just half of that of morphine. In clinical studies, M6G is well tolerated and produces adequate and long lasting postoperative analgesia. At analgesic doses, M6G causes similar reduction of the ventilatory response to CO2 as an equianalgesic dose of morphine but significantly less depression of the hypoxic ventilatory response. Preliminary data indicate that M6G is associated less than morphine with nausea and vomiting, causing 50% and 75% less nausea in postoperative and experimental settings, respectively. Although the data from the literature are very promising, we believe that more studies are necessary before we may conclude that M6G is superior to morphine for postoperative analgesia.

A retrospective study on persistent pain after childbirth in the Netherlands.

Reported prevalence rates of persistent postpartum pain (PPP) range from less than 1% to almost 20%. The aim of this study was to examine the prevalence of PPP in a Dutch cohort and to evaluate a possible causal role for specific risk factors on the development of chronic pain after childbirth. A questionnaire was sent to 960 postpartum women approximately 2 years after delivery. Primary outcome was pain that arose from childbirth at follow-up, and secondary outcomes included quality of life (QoL) and Hospital Anxiety and Depression Scale scores. Tested risk factors included mode of labor analgesia, history of negative effect, history of chronic pain, delivery route, parity, and ethnicity. A total of 495 (51.6%) women participated. At a mean time of 2.3 postpartum years, 7.3% of women reported any pain and 6.1% reported significant pain related to the delivery. Compared to spontaneous delivery, cesarean delivery provided protection against persistent pain (odds ratio, 0.12; 95% CI, 0.01-0.63, P<0.05). None of the other risk factors, including remifentanil use for labor pain, were of influence on the prevalence of persistent pain. Women with PPP experienced greater negative effects and had lower QoL scores compared to women without pain. In this cohort of Dutch patients, PPP is a serious problem with a great impact on the physical and mental health of women.

Morphine-6-glucuronide: potency and safety compared with morphine.

BACKGROUND: In contemporary medicine, morphine remains the drug of choice in the treatment of severe postoperative pain. Nevertheless, morphine has several side effects, which can seriously compromise its analgesic effectiveness and the patient safety/compliance. The search for opioid analgesics with a better side-effect profile than morphine has led to a morphine metabolites, morphine-6-glucuronide (M6G). OBJECTIVE: The objectives of the current paper are to give an overview of the analgesic properties of M6G, assess the dose range at which it produces equianalgesia to morphine and explore its side-effect profile. METHODS: A review of published clinical studies (Phase II - III) on M6G in the treatment of experimental and clinical pain is given. RESULTS/CONCLUSIONS: M6G > 0.2 mg/kg is an effective analgesic with a slower onset but longer duration of action (> 12 h) compared with morphine. Side effects, most importantly postoperative nausea and vomiting, occur less frequent after M6G treatment. M6G is an attractive alternative to morphine in the treatment of severe postoperative pain.