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,... Show moreBackground 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. Show less
BackgroundBalancing between opioid analgesia and respiratory depression continues to challenge clinicians in perioperative, emergency department, and other acute care settings. Morphine and... Show moreBackgroundBalancing between opioid analgesia and respiratory depression continues to challenge clinicians in perioperative, emergency department, and other acute care settings. Morphine and hydromorphone are postoperative analgesic standards. Nevertheless, their comparative effects and side effects, timing, and respective variabilities remain poorly understood. This study tested the hypothesis that IV morphine and hydromorphone differ in onset, magnitude, duration, and variability of analgesic and ventilatory effects.MethodsThe authors conducted a randomized crossover study in healthy volunteers. Forty-two subjects received a 2-h IV infusion of hydromorphone (0.05 mg/kg) or morphine (0.2 mg/kg) 1 to 2 weeks apart. The authors measured arterial opioid concentrations, analgesia in response to heat pain (maximally tolerated temperature, and verbal analog pain scores at discrete preset temperatures to determine half-maximum temperature effect), dark-adapted pupil diameter and miosis, end-expired carbon dioxide, and respiratory rate for 12 h after dosing.ResultsFor morphine and hydromorphone, respectively, maximum miosis was less (3.9 [3.4 to 4.2] vs. 4.6 mm [4.0 to 5.0], P < 0.001; median and 25 to 75% quantiles) and occurred later (3.1 ± 0.9 vs. 2.3 ± 0.7 h after infusion start, P < 0.001; mean ± SD); maximum tolerated temperature was less (49 ± 2 vs. 50 ± 2°C, P < 0.001); verbal pain scores at end-infusion at the most informative stimulus (48.2°C) were 82 ± 4 and 59 ± 3 (P < 0.001); maximum end-expired CO2 was 47 (45 to 50) and 48 mmHg (46 to 51; P = 0.007) and occurred later (5.5 ± 2.8 vs. 3.0 ± 1.5 h after infusion start, P < 0.001); and respiratory nadir was 9 ± 1 and 11 ± 2 breaths/min (P < 0.001), and occurred at similar times. The area under the temperature tolerance-time curve was less for morphine (1.8 [0.0 to 4.4]) than hydromorphone (5.4°C-h [1.6 to 12.1] P < 0.001). Interindividual variability in clinical effects did not differ between opioids.ConclusionsFor morphine compared to hydromorphone, analgesia and analgesia relative to respiratory depression were less, onset of miosis and respiratory depression was later, and duration of respiratory depression was longer. For each opioid, timing of the various clinical effects was not coincident. Results may enable more rational opioid selection, and suggest hydromorphone may have a better clinical profile. Show less
BackgroundNociception-guided intraoperative opioid administration might help reduce postoperative pain. A commonly used and validated nociception monitor system is nociception level (NOL), which... Show moreBackgroundNociception-guided intraoperative opioid administration might help reduce postoperative pain. A commonly used and validated nociception monitor system is nociception level (NOL), which provides the nociception index, ranging from 0 to 100, with 0 representing no nociception and 100 representing extreme nociception. We tested the hypothesis that NOL responses are similar in men and women given remifentanil and fentanyl, across various types of anesthesia, as a function of American Society of Anesthesiologists physical status designations, and over a range of ages and body morphologies.MethodsWe conducted a retrospective cohort analysis of trial data from eight prospective NOL validation studies. Among 522 noncardiac surgical patients enrolled in these studies, 447 were included in our analysis. We assessed NOL responses to various noxious and non-noxious stimuli.ResultsThe average NOL in response to 315 noxious stimuli was 47 ± 15 (95% CI = 45–49). The average NOL in response to 361 non-noxious stimuli was 10 ± 12 (95% CI = 9–11). NOL responses were similar in men and women, in patients given remifentanil and fentanyl, across various types of anesthesia, as a function of American Society of Anesthesiologists physical status designations, and over a range of ages and body morphologies.ConclusionNociception level appears to provide accurate estimates of intraoperative nociception over a broad range of patients and anesthetic conditions. Show less
BackgroundThere is lack of data on opioid (over)use for migraine in Europe.MethodsWe performed a cross-sectional study in a large Dutch cohort using a web-based questionnaire to assess opioid use... Show moreBackgroundThere is lack of data on opioid (over)use for migraine in Europe.MethodsWe performed a cross-sectional study in a large Dutch cohort using a web-based questionnaire to assess opioid use in individuals with migraine. Primary outcome was to assess opioid use for the treatment of migraine attacks. As secondary outcomes we specified use of opioids (duration of use, type of opioids, prescriber) and compared between persons with episodic migraine versus chronic migraine. Descriptive statistics, unpaired T-tests, Chi-square and Mann-Whitney U tests were used.ResultsIn total n = 3712 patients participated, 13% ever used opioids for headache. In opioid users, 27% did this for >1 month, and 11% for >1 year, and 2% without prescription. The majority of prescribing physicians were general practitioners (46%), followed by neurologists (35%), other specialists (9%), or emergency room doctors (8%). Opioids were used as acute treatment in 63%, in 16% as preventive treatment, and in 21% for both indications. Chronic migraine patients reported more opioid use compared with episodic migraine (22% versus 12%, p < 0.001), with also more prolonged use (>1 month: 34% chronic migraine versus 24% episodic migraine, p < 0.003).ConclusionOpioid use is more frequent and prolonged in chronic migraine patients. Further education for both doctors and migraine subjects and providing multimodal pain management strategies are needed to reduce opioid use in persons with migraine. Show less
Hellinga, M.; Algera, M.H.; Schrier, R.V.; Sarton, E.; Velzen, M. van; Dahan, A.; ... ; Niesters, M. 2023
Opioids are commonly used painkillers and drugs of abuse and have serious toxic effects including potentially lethal respiratory depression. It remains unknown which respiratory parameter is the... Show moreOpioids are commonly used painkillers and drugs of abuse and have serious toxic effects including potentially lethal respiratory depression. It remains unknown which respiratory parameter is the most sensitive biomarker of opioid-induced respiratory depression (OIRD). To evaluate this issue, we studied 24 volunteers and measured resting ventilation, resting end-tidal PCO2 (PETCO2) and the hypercapnic ventilatory response (HCVR) before and at 1-h intervals following intake of the opioid tapentadol. Pharmacokinetic/pharmacodynamic analyses that included CO2 kinetics were applied to model the responses with focus on resting variables obtained without added CO2, HCVR slope and ventilation at an extrapolated PETCO2 of 55 mmHg (V˙E55). The HCVR, particularly V˙E55 followed by slope, was most sensitive in terms of potency; resting variables were least sensitive and responded slower to the opioid. Using V˙E55 as biomarker in quantitative studies on OIRD allows standardized comparison among opioids in the assessment of their safety. Show less
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... Show moreBackground: 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, anaesthesiol-ogists, 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 pre-scription 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. Show less
Dam, C.J. van; Schrier, R. van der; Velzen, M. van; Lemmen, M. van; Simons, P.; Kuijpers, K.W.K.; ... ; Niesters, M. 2023
BackgroundIn humans, the effect of cannabis on ventilatory control is poorly studied, and consequently, the effect of Δ9-tetrahydrocannabinol (THC) remains unknown, particularly when THC is... Show moreBackgroundIn humans, the effect of cannabis on ventilatory control is poorly studied, and consequently, the effect of Δ9-tetrahydrocannabinol (THC) remains unknown, particularly when THC is combined with an opioid. We studied the effect of THC on breathing without and with oxycodone pretreatment. We hypothesised that THC causes respiratory depression, which is amplified when THC and oxycodone are combined.MethodsIn this randomised controlled crossover trial, healthy volunteers were administered inhaled Bedrocan® 100 mg (Bedrocan International B.V., Veendam, The Netherlands), a pharmaceutical-grade high-THC cannabis variant (21.8% THC; 0.1% cannabidiol), after placebo or oral oxycodone 20 mg pretreatment; THC was inhaled 1.5 and 4.5 h after placebo or oxycodone intake. The primary endpoint was isohypercapnic ventilation at an end-tidal Pco2 of 55 mm Hg or 7.3 kPa (VE55), measured at 1-h intervals for 7 h after placebo/oxycodone intake.ResultsIn 18 volunteers (age 22 yr [3]; 9 [50%] female), oxycodone produced a 30% decrease in VE55, whereas placebo was without effect on VE55. The first cannabis inhalation resulted in VE55 changing from 20.3 (3.1) to 23.8 (2.4) L min−1 (P=0.06) after placebo, and from 11.8 (2.8) to 13.0 (3.9) L min−1 (P=0.83) after oxycodone. The second cannabis inhalation also had no effect on VE55, but slightly increased sedation.ConclusionsIn humans, THC has no effect on ventilatory control after placebo or oxycodone pretreatment. Show less
Simons, P.; Schrier, R. van der; Lemmen, M. van; Jansen, S.; Kuijpers, K.W.K.; Velzen, M. van; ... ; Dahan, A. 2023
Background: Oliceridine is a G protein–biased μ-opioid, a drug class thatis associated with less respiratory depression than nonbiased opioids, suchas morphine. The authors quantified the... Show moreBackground: Oliceridine is a G protein–biased μ-opioid, a drug class thatis associated with less respiratory depression than nonbiased opioids, suchas morphine. The authors quantified the respiratory effects of oliceridine andmorphine in elderly volunteers. The authors hypothesized that these opioidsdiffer in their pharmacodynamic behavior, measured as effect on ventilation atan extrapolated end-tidal Pco2 at 55 mmHg, V̇E55.Methods: This four-arm double-blind, randomized, crossover study examinedthe respiratory effects of intravenous 0.5 or 2 mg oliceridine and 2 or8 mg morphine in 18 healthy male and female volunteers, aged 55 to 89 yr, onfour separate occasions. Participants’ CYP2D6 genotypes were determined,hypercapnic ventilatory responses were obtained, and arterial blood sampleswere collected before and for 6 h after treatment. A population pharmacokinetic–pharmacodynamic analysis was performed on V̇E55, the primary endpoint;values reported are median ± standard error of the estimate.Results: Oliceridine at low dose was devoid of significant respiratory effects.High-dose oliceridine and both morphine doses caused a rapid onset of respiratorydepression with peak effects occurring at 0.5 to 1 h after opioid dosing.After peak effect, compared with morphine, respiratory depression inducedby oliceridine returned faster to baseline. The effect-site concentrationscausing a 50% depression of V̇E55 were 29.9 ± 3.5 ng/ml (oliceridine) and21.5 ± 4.6 ng/ml (morphine), the blood effect-site equilibration half-lives differedby a factor of 5: oliceridine 44.3 ± 6.1 min and morphine 214 ± 27 min.Three poor CYP2D6 oliceridine metabolizers exhibited a significant differencein oliceridine clearance by about 50%, causing higher oliceridine plasma concentrationsafter both low- and high-dose oliceridine, compared with the otherparticipants.Conclusions: Oliceridine and morphine differ in their respiratory pharmacodynamicswith a more rapid onset and offset of respiratory depression foroliceridine and a smaller magnitude of respiratory depression over time. Show less
Hoydonckx, Y.; Singh, M.; Gilron, I.; Khan, J.; Narouze, S.; Dahan, A.; ... ; Bhatia, A. 2023
BackgroundChronic daily headaches (CDH) are common and associated with significant morbidity, poor quality of life, and substantial burden on the healthcare system. CDH tends to be refractory to... Show moreBackgroundChronic daily headaches (CDH) are common and associated with significant morbidity, poor quality of life, and substantial burden on the healthcare system. CDH tends to be refractory to conventional medical management and/or patients cannot afford expensive treatments. It is stipulated that CDH share a mechanism of central sensitization in the trigeminocervical complex, mediated by activation of the N-methyl-d-aspartate (NMDA) receptors. Ketamine, a non-competitive NMDA antagonist, has been used in the treatment of chronic pain, but its role in CDH has not been completely established. This trial aims to evaluate the effect of high-dose IV ketamine infusions (compared to placebo) on the number of headache days at 28 days post-infusion.MethodsA multicenter, placebo-controlled, randomized controlled trial will be conducted with two parallel groups and blinding of participants and outcome assessors. The study will include 56 adults with a CDH diagnosis as per ICHD-3 criteria. Participants will be randomized (1:1) to either ketamine (1 mg. kg−1 bolus followed by infusion of 1 mg. kg−1. h−1 for 6 h) or placebo (0.9% saline in the same volume and infusion rate as the trial medication) bolus and infusion for 6 h. The impact on the number of monthly headache days, headache intensity, physical activity, mood, sleep, quality of life, analgesic consumption, and adverse effects will be recorded at baseline, immediately post-infusion, and from 1 to 28 days, 29 to 56 days, and 57 to 84 days after the infusionDiscussionDespite advancements in treatment, many patients continue to suffer from CDH. This trial investigates whether high-dose IV ketamine infusions can effectively and safely improve the CDH burden as compared to a placebo infusion. This treatment could become a safe, affordable, and widely available option for patients living with refractory headache. Show less
Hellinga, M.; Algera, M.H.; Olofsen, E.; Schrier, R. van der; Sarton, E.; Velzen, M. van; ... ; Niesters, M. 2023
The widely prescribed opioid oxycodone may cause lethal respiratory depression. We compared the effects of oxycodone on breathing and antinociception in healthy young volunteers. After... Show moreThe widely prescribed opioid oxycodone may cause lethal respiratory depression. We compared the effects of oxycodone on breathing and antinociception in healthy young volunteers. After pharmacokinetic/pharmacodynamic (PK/PD) modeling, we constructed utility functions to combine the wanted and unwanted end points into a single function. We hypothesized that the function would be predominantly negative over the tested oxycodone concentration range. Twenty-four male and female volunteers received 20 (n = 12) or 40 (n = 12) mg oral oxycodone immediate-release tablets. Hypercapnic ventilatory responses (visit 1) or responses to 3 nociceptive assays (pain pressure, electrical, and thermal tests; visit 2) were measured at regular intervals for 7 hours. the PK/PD analyses, that included carbon dioxide kinetics, stood at the basis of the utility function: probability of antinociception minus probability of respiratory depression. Oxycodone had rapid onset/offset times (30–40 minutes) with potency values (effect-site concentration causing 50% of effect) ranging from 0.05 to 0.13 ng/mL for respiratory variables obtained at hypercapnia and antinociceptive responses. Ventilation at an extrapolated end-tidal carbon dioxide partial pressure of 55 mmHg, was used for creation of 3 utility functions, one for each of the nociceptive tests. Contrary to expectation, the utility functions were close to zero or positive over the clinical oxycodone concentration range. The similar or better likelihood for antinociception relative to respiratory depression may be related to oxycodone's receptor activation profile or to is high likeability that possibly alters the modulation of nociceptive input. Oxycodone differs from other μ-opioids, such as fentanyl, that have a consistent negative utility. Show less
Dam, C.J. van; Velzen, M. van; Kramers, C.; Schellekens, A.; Olofsen, E.; Niesters, M.; Dahan, A. 2023
Background Opioids continue to be widely prescribed for chronic noncancer pain, despite the awareness that opioids provide only short-time pain relief, lead to dose accumulation, have numerous... Show moreBackground Opioids continue to be widely prescribed for chronic noncancer pain, despite the awareness that opioids provide only short-time pain relief, lead to dose accumulation, have numerous adverse effects, and are difficult to wean. As an alternative, we previously showed advantages of using pharmaceutical-grade cannabis in a population of chronic pain patients with fibromyalgia. It remains unknown whether combining an opioid with pharmaceutical-grade cannabis has advantages, such as fewer side effects from lesser opioid consumption in chronic pain.Methods Trial design: a single-center, randomized, three-arm, open-label, exploratory trial.Trial population: 60 patients with fibromyalgia according to the 2010 definition of the American College of Rheumatologists.Intervention: Patients will be randomized to receive up to 4 daily 5 mg oral oxycodone sustained release (SR) tablet, up to 5 times 150 mg inhaled cannabis (Bediol (R), containing 6.3% delta(9)-tetrahydrocannabinol and 8% cannabidiol), or the combination of both treatments. Treatment is aimed at self-titration with the daily maximum doses given. Treatment will continue for 6 weeks, after which there is a 6-week follow-up period.Main trial endpoint: The number of side effects observed during the course of treatment using a composite adverse effect score that includes the following 10 symptoms: dizziness (when getting up), sleepiness, insomnia, headache, nausea, vomiting, constipation, drug high, hallucinations, and paranoia.Secondary and tertiary endpoints include pain relief and number of oxycodone doses and cannabis inhalations.Discussion The trial is designed to determine whether self-titration of oxycodone and cannabis will reduce side effects in chronic pain patients with fibromyalgia. Show less
Wal, I. van der; Meijer, F.; Fuica, R.; Silman, Z.; Boon, M.; Martini, C.; ... ; Gozal, Y. 2023
In this pooled analysis of two randomized clinical trials, intraoperative opioid dosing based on the nociception level-index produced less pain compared to standard care with a difference in pain... Show moreIn this pooled analysis of two randomized clinical trials, intraoperative opioid dosing based on the nociception level-index produced less pain compared to standard care with a difference in pain scores in the post-anesthesia care unit of 1.5 (95% CI 0.8-2.2) points on an 11-point scale. The proportion of patients with severe pain was lower by 70%. Severe postoperative pain remains a significant problem and associates with several adverse outcomes. Here, we determined whether the application of a monitor that detects intraoperative nociceptive events, based on machine learning technology, and treatment of such events reduces pain scores in the post-anesthesia care unit (PACU). To that end, we performed a pooled analysis of two trials in adult patients, undergoing elective major abdominal surgery, on the effect of intraoperative nociception level monitor (NOL)-guided fentanyl dosing on PACU pain was performed. Patients received NOL-guided fentanyl dosing or standard care (fentanyl dosing based on hemodynamic parameters). Goal of the intervention was to keep NOL at values that indicated absence of nociception. The primary endpoint of the study was the median pain score obtained in the first 90 min in the PACU. Pain scores were collected at 15 min intervals on an 11-point Likert scale. Data from 125 patients (55 men, 70 women, age range 21-86 years) were analyzed. Sixty-one patients received NOL-guided fentanyl dosing and 64 standard care. Median PACU pain score was 1.5 points (0.8-2.2) lower in the NOL group compared to the standard care; the proportion of patients with severe pain was 70% lower in the NOL group (p = 0.045). The only significant factor associated with increased odds for severe pain was the standard of care compared to NOL treatment (OR 6.0, 95% CI 1.4 -25.9, p = 0.017). The use of a machine learning-based technology to guide opioid dosing during major abdominal surgery resulted in reduced PACU pain scores with less patients in severe pain. Show less
Torensma, B.; Hany, M.; Bakker, M.J.S.; Velzen, M. van; In't Veld, B.; Dahan, A.; Swank, D.J. 2022
Background: Spinal anesthesia causes short-term deafferentation and alters the crosstalk among brain regions involved in pain perception and pain modulation. In the current study, we examined the... Show moreBackground: Spinal anesthesia causes short-term deafferentation and alters the crosstalk among brain regions involved in pain perception and pain modulation. In the current study, we examined the effect of spinal anesthesia on pain response to noxious thermal stimuli in non-deafferented skin areas using a functional magnetic resonance imaging (fMRI) paradigm. Methods: Twenty-two healthy subjects participated in the study. We performed a task-based fMRI study using a randomized crossover design. Subjects were scanned under two conditions (spinal anesthesia or control) at two-time points: before and after spinal anesthesia. Spinal anesthesia resulted in sensory loss up to dermatome Th6. Calibrated heat-pain stimuli were administered to the right forearm (C8-Th1) using a box-car design (blocks of 10s on/25s off) during MRI scanning. Pain perception was measured using a visual analogue scale (1–100) at the beginning and the end of each session. Generalized estimating equations were used to examine the effect of intervention by time by order on pain scores. Similarly, higher level effects were tested with appropriate general linear models (accounting for within-subject variations in session and time) to examine: (1) Differences in BOLD response to pain stimulus under spinal anesthesia versus control; and (2) Effects of spinal anesthesia on pain-related modulation of the cerebral activation. Results: Complete fMRI data was available for eighteen participants. Spinal anesthesia was associated with moderate pain score increase. Significant differences in brain response to noxious thermal stimuli were present in comparison of spinal versus control condition (post—pre). Spinal condition was associated with higher BOLD signal in the bilateral inferior parietal lobule and lower BOLD signal in bilateral postcentral and precentral gyrus. Within the angular regions, we observed a positive correlation between pain scores and BOLD signal. These observations were independent from order effect (whether the spinal anesthesia was administered in the first or the second visit). However, we did observe order effect on brain regions including medial prefrontal regions, possibly related to anticipation of the experience of spinal anesthesia. Conclusions: The loss of sensory and motor activity caused by spinal anesthesia has a significant impact on brain regions involved in the sensorimotor and cognitive processing of noxious heat pain stimuli. Our results indicate that the anticipation or experience of a strong somatosensory response to the spinal intervention might confound and contribute to increased sensitivity to cognitive pain processing. Future studies must account for individual differences in subjective experience of pain sensation within the experimental context Show less
Torensma, B.; Hany, M.; Bakker, M.J.S.; Velzen, M. van; Veld, B.A.I. 't; Dahan, A.; Swank, D.J. 2022
Background: To assess the prevalence, incidence, location, and behavior of chronic pre- and postoperative pain in bariatric surgery, and the use of analgesics.Methods: A cross-sectional e-survey... Show moreBackground: To assess the prevalence, incidence, location, and behavior of chronic pre- and postoperative pain in bariatric surgery, and the use of analgesics.Methods: A cross-sectional e-survey was conducted on 3928 post-bariatric patients and four-time points for pain assessment were evaluated: preoperative, on the ward, day 1 at home postoperatively, and present time (at the time of the e-survey). A numerical rating scale (NRS) was used to assess the level of pain (0 to 10). The general incidence of chronic pain was calculated, as also, subgroups were defined as group A (pre and postoperative chronic pain), B (preoperative pain, and no longer postoperative), and C (preoperative painless, postoperative chronic pain). Besides the pain intensity, location of pain, and the use of analgesics were investigated. Results: A total of 3279 patients (83.9%) responded to the survey. Preoperative and postoperative chronic pain was found in 343 (10.5%) and 264 (8.1%) patients, respectively. In group A, chronic pain was present in 4.8% of the patients; in group B, it was present in 5.7%; and in group C in 3.3% of the patients. Furthermore, in 4.5% of patients pain was located in the abdomen, which was higher as compared to before surgery (+ 2.3%, p < 0.001). The ORs for present postoperative chronic pain were OR 1.45, 1.7, and 1.71 (p = 0.002, 0.003, 0.003) compared to respectively preoperative chronic pain, pain at the ward, and pain at day 1 after surgery. Among all participants, 4.6% consumed chronic analgesics. Of these, paracetamol was used most frequently (3.8%), followed by tramadol (1.3%) and oxycodone (0.5%). Conclusions: In this e-survey, chronic postoperative abdominal pain was prominent in patients after bariatric surgery. Of patients, 3.3% that were without preoperative chronic pain developed chronic pain after surgery. Opioid consumption in the queried population was relatively low. Show less
Schrier, R. van der; Velzen, M. van; Roozekrans, M.; Sarton, E.; Olofsen, E.; Niesters, M.; ... ; Dahan, A. 2022
Background: Due the increasing need for storage of carbon dioxide (CO2) more individuals are prone to be exposed to high concentrations of CO2 accidentally released into atmosphere, with... Show moreBackground: Due the increasing need for storage of carbon dioxide (CO2) more individuals are prone to be exposed to high concentrations of CO2 accidentally released into atmosphere, with deleterious consequences. Methods: We tested the effect of increasing CO2 concentrations in humans (6–12%) and rats (10–50%) at varying inhalation times (10–60 min). In humans, a continuous positive airway pressure helmet was used to deliver the gas mixture to the participants. Unrestrained rats were exposed to CO2 in a transparent chamber. In both species regular arterial blood gas samples were obtained. After the studies, the lungs of the animals were examined for macroscopic and microscopic abnormalities. Results: In humans, CO2 concentrations of 9% inhaled for >10 min, and higher concentrations inhaled for <10 min were poorly or not tolerated due to exhaustion, anxiety, dissociation or acidosis (pH < 7.2), despite intact oxygenation. In rats, concentrations of 30% and higher were associated with CO2 narcosis, epilepsy, poor oxygenation and, at 50% CO2, spontaneous death. Lung hemorrhage and edema were observed in the rats at inhaled concentrations of 30% and higher. Conclusion: This study provides essential insight into the occurrence of physiological changes in humans and fatalities in rats after acute exposure to high levels of CO2. Humans tolerate 9% CO2 and retain their ability to function coherently for up to 10 min. These data support reconsideration of the current CO2 levels (<7.5%) that pose a risk to exposed individuals (<7.5%) as determined by governmental agencies to ≤9%. Show less
Florian, J.; Schrier, R. van der; Gershuny, V.; Davis, M.C.; Wang, C.; Han, X.M.; ... ; Strauss, D.G. 2022
Importance: Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to... Show moreImportance: Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to benzodiazepine and opioid products about increased respiratory depression risk with simultaneous use, the US Food and Drug Administration evaluated whether other drugs that might be used in place of benzodiazepines may cause similar effects. Objective: To study whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia. Design, Setting, and Participants: Randomized, double-blind, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) with 25 healthy participants from January 2021 through May 25, 2021. Interventions: Oxycodone 10 mg on days 1 and 5 and the following in a randomized order for 5 days: paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo. Main Outcomes and Measures: Ventilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) using rebreathing methodology assessed for paroxetine or quetiapine with oxycodone, compared with placebo and oxycodone, on days 1 and 5 (primary) and for paroxetine or quetiapine alone compared with placebo on day 4 (secondary). Results: Among 25 participants (median age, 35 years [IQR, 30-40 years]; 11 female [44%]), 19 (76%) completed the trial. The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs placebo plus oxycodone on day 1 (29.2 vs 34.1 L/min; mean difference [MD], -4.9 L/min [1-sided 97.5% CI, -infinity to -0.6]; P = .01) and day 5 (25.1 vs 35.3 L/min; MD, -10.2 L/min [1-sided 97.5% CI, -infinity to -6.3]; P < .001) but was not significantly decreased with quetiapine plus oxycodone vs placebo plus oxycodone on day 1 (33.0 vs 34.1 L/min; MD, -1.2 L/min [1-sided 97.5% CI, -infinity to 2.8]; P = .28) or on day 5 (34.7 vs 35.3 L/min; MD, -0.6 L/min [1-sided 97.5% CI, -infinity to 3.2]; P = .37). As a secondary outcome, mean hypercapnic ventilation was significantly decreased on day 4 with paroxetine alone vs placebo (32.4 vs 41.7 L/min; MD, -9.3 L/min [1-sided 97.5% CI, -infinity to -3.9]; P < .001), but not with quetiapine alone vs placebo (42.8 vs 41.7 L/min; MD, 1.1 L/min [1-sided 97.5% CI, -infinity to 6.4]; P = .67). No drug-related serious adverse events were reported. Conclusions and Relevance: In this preliminary study involving healthy participants, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia on days 1 and 5, whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings. Show less
Algera, H.; Schrier, R. van der; Cavalla, D.; Velzen, M. van; Roozekrans, M.; McMorn, A.; ... ; Dahan, A. 2022
Background: Animal data suggest that the antidepressant and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor modulator tianeptine is able to prevent opioid-induced respiratory... Show moreBackground: Animal data suggest that the antidepressant and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor modulator tianeptine is able to prevent opioid-induced respiratory depression. The hypothesis was that oral or intravenous tianeptine can effectively prevent or counteract opioid-induced respiratory depression in humans. Methods: Healthy male and female volunteers participated in two studies that had a randomized, double blind, placebo-controlled, crossover design. First, oral tianeptine (37.5-, 50-, and 100-mg doses with 8 subjects) pretreatment followed by induction of alfentanil-induced respiratory depression (alfentanil target concentration, 100 ng/ml) was tested. Primary endpoint was ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg (V?(E)55). Next, the ability of four subsequent and increasing infusions of intravenous tianeptine (target tianeptine plasma concentrations 400, 1,000, 1,500, and 2,000 ng/ml, each given over 15 min) to counteract remifentanil-induced respiratory depression was determined in 15 volunteers. Ventilation was measured at isohypercpania (baseline ventilation 20 +/- 2 l/min). The primary endpoint was minute ventilation during the 60 min of tianeptine versus placebo infusion. Results: Alfentanil reduced V?(E)55 to 13.7 (95% CI, 8.6 to 18.8) l/min after placebo pretreatment and to 17.9 (10.2 to 25.7) l/min after 50-mg tianeptine pretreatment (mean difference between treatments 4.2 (-11.5 to 3.0) l/min, P = 0.070). Intravenous tianeptine in the measured concentration range of 500 to 2,000 ng/ml did not stimulate ventilation but instead worsened remifentanil-induced respiratory depression: tianeptine, 9.6 +/- 0.8 l/min versus placebo 15.0 +/- 0.9 l/min; mean difference, 5.3 l/min; 95% CI, 2.5 to 8.2 l/min; P = 0.001, after 1 h of treatment. Conclusions: Neither oral nor intravenous tianeptine were respiratory stimulants. Intravenous tianeptine over the concentration range of 500 to 2000 ng/ml worsened respiratory depression induced by remifentanil. Show less
Bedene, A.; Dahan, A.; Rosendaal, F.R.; Dorp, E.L.A. van 2022
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... Show moreIntroduction: 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. Show less
