Intravenous oxycodone compared to morphine for post-operative opioid-related adverse events in opioid naïve patients: a prospective randomized controlled trial

Intravenous oxycodone compared to morphine for post-operative opioid-related adverse events in opioid naïve patients: a prospective randomized controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Intravenous oxycodone compared to morphine for post-operative opioid-related adverse events in opioid naïve patients: a prospective randomized controlled trial philippe cuvillon, Sandrine Alonso, Joel Lhermite, Vanessa Reubrecht, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.22154/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Bacground: Intravenous oxycodone compared to morphine for postoperative pain relief is controversial. The purpose of this study was to assess opioid-related adverse events of oxycodone versus morphine in opioid-naive patients after orthopaedic surgery. Methods: Patients scheduled for total hip arthroplasty under general anesthesia combined with a multimodal analgesia (acetamnophen, nonsteroidal anti-inflammatory) were randomized in a triple-blinded trial to postopertaive pain treatment with either intravenous oxycodone or morphine (potency ratio 1:1). After surgery, patients received similar drug regimen for titration in the postoperative care unit (bolus 2-3 mg, 5 min period, when pain score was >3/10) followed by an intravenous patient controlled analgesia (bolus 1 mg, lockout time 7 min) postoperatively. The primary outcome was number of patients with ≥1 opioid-related adverse events within the first 24 hours (at least one of the following complications: nausea, vomiting, respiratory depression, pruritus, urinary retention requiring evacuation, allergy, hallucination). Secondary outcomes included pain scores, opioid consumption. Patients were followed up to 4 months. Results: The intention-to-treat analysis included 241 patients with similar characteristics. There were 55 patients with at least one opioid-related adverse events in oxycodone group versus 46 in morphine group (48% vs 40%, p=0.19; relative risk= 1.22 [0.91; 1.63]). Oxycodone versus morphine requirements were respectively: 6 [0-11] versus 8 [0-12] mg (p=0.06) for titration, 15 [8-26] versus 8 [5-16] mg (p=0.001) for PCA dose, and 22 [12-37] mg versus 19 [11-28] mg for the titration and PCA accumulated consumption (p=0.048). During the first 24 hours, there were no other differences in secondary outcomes between both drugs for (respectively oxycodone versus morphine in %): nausea (15 versus 13), vomiting (5 versus 5 ), urinary retention (20 versus 12 ) and pain scores. Conclusion: This study demonstrated that oxycodone required lower doses for titration in postoperative care unit, but did not significantly reduce opioid-related adverse events within the first 24 hours compared to morphine. Anesthesiology & Pain Medicine oxycodone morphine opioid surgery adverse event Figures Figure 1 Figure 2 Background Multimodal analgesic approach (including anti-inflammatory drugs, regional analgesia and local infiltration) have been recently developed to enhance post-operative rehabilitation and pain relief. This approach may lead to decreased narcotic consumption [ 1 – 4 ]. Despite the increase in clinical research on non-opioid analgesics, many patients still complain of severe postoperative pain and require opioid initiation (intravenous or oral) in the postoperative care unit (PACU) or in the first few days postoperatively [ 5 – 7 ]. In these situations of severe postoperative pain, the use of intravenous morphine for titration in PACU followed by an i.v. Patient-Controlled Analgesia (PCA) remains the gold standard as it provides rapid and effective pain relief [ 5 – 7 ]. Since the 1990s, oxycodone has been proposed as an alternative to morphine, because by acting on the µ1-receptors and on the κ-2-opioid agonist, it leads to a better anti nociceptive effect for post-operative pain relief or cancer-related pain [ 8 – 14 ]. Several studies have shown that per os oxycodone was associated with better pain control, less serious opioid-related adverse events (ORAEs) and a faster onset of action due to a better pharmacokinetic profile: higher oral bioavailability and lower plasma variability [ 15 – 19 ]. However, controversies have arisen as a result of recent clinical studies and meta-analysis that have shown that per os oxycodone did not reduce adverse events and pain relief. Not to mention that appetite for oxycodone itself is decreasing, due to concerns about addiction and the bad reputation that this drug has acquired in opiate-related crises [ 11 , 13 , 14 , 19 – 23 ]. As with the oral route, the intravenous use of oxycodone remains debated because the number of studies on the subject is limited and the potency ratio of oxycodone to morphine (1:1 or 1:2) unresolved [ 16 , 24 ]. Moreover, no large clinical studies have clearly demonstrated the benefit/risk (ORAEs) of i.v. oxycodone versus morphine. The hypothesis of this study was that i.v. oxycodone (versus i.v. morphine) would reduce ORAEs, assessed 24 hours post-operatively. At the same time, pain levels were as well evaluated (secondary outcome). Methods Institutional Human Committee, consent and setting In accordance with the French legislation, the present study was approved by the institutional human investigation committee (Comité de Protection des Personnes, CPP, Nîmes, France, EudraCT : 2011-004140-22, Chaiperson Prof T. Lavabre-Bertrand) on 7 January 2012 and was registered prior to enrolment on ClinicalTrials.gov (NCT 01536301) [ 25 ]. Study was conducted in two French University centres (APHP, La Pitié-Salpêtrière Paris, France; Hôpital Carémeau, Nîmes, France). The CONSORT (Consolidated Standards of Reporting Trials) recommendations for reporting randomized trial were followed. The analysis occurred after patient enrolment was completed. Written informed consent was obtained from all participants before inclusion. Study design and Patients This was a prospective, randomized, triple blinded (Participant, Investigator, Outcomes Assessor), 1:1 ratio, double center control trial. Patients > 18 yrs scheduled for unilateral elective total hip arthroplasty (posterolateral surgical approach) under general anesthesia and opioid naïve were eligible and approached by the surgeon or the investigators. Exclusion criteria were: refusal to participate, age > 80 yrs, weight 100 kg, emergency or bilateral surgery including hip fracture, any regional anesthesia or analgesia (including: wound infiltration, peripheral nerve block, epidural or spinal injection), cognitive disorders (delirium, dementia…), pregnancy, patients with alcohol or drugs abuse, uncontrolled epilepsy, patients unlikely to be fully cooperative during the study, participation in another study within the previous 30 days. Patients with chronic pain and/or reporting any allergy or contraindication to study drug (creatinine clearance 3 times of upper normal value, and/or prothrombin time < 70% of control), acute or chronic respiratory insufficiency (Spo2 < 94% in ambiant air), porphyria, intracranial hypertension, or ileus were not included. Finally, patient already taking narcotics or opioid, opiate agonist (codeine, dextromoramide, dihydrocodeine, oxycodone per os, tramadol, morphine-like antitussive…) or agonist-antagonists (buprenorphine, nalbuphine, pentazocine) were not included. Study Drug, randomization and blinding Patients were randomly assigned to the oxycodone group or morphine group using computer-generated random numbers created by the study statistician using a 1:1 randomization ratio. Group allocations were concealed in sequentially numbered opaque envelopes, which were opened by the research nurse just after the start of surgery. Randomization for the two centers were performed using blocks of randomization (8 patients per block). Pharmacy personnel not involved in clinical care of the patient prepared drug solutions. The morphine and oxycodone vials were similar, allowing a double-blinded design. In the case of a serious adverse event, the double–blind could be removed. Patients, surgeons, attending anesthetists, nurses and investigators were blinded to group assignment until data analysis. Drug solutions were prepared using: 95 mL of saline solution 5 mL solution of study drug (20 mg mL -1 ): 100 mg of oxycodone or morphine From the 100 mL drug solutions (1 mg: 1 mL), 20 mL of the solution were transferred in 20 mL syringe and used for titration in PACU. The remaining 80 mL were used for the patient-controlled analgesia (Gemstar, Abbott Laboratories, Abbott Park, IL, USA) for a 48-h period. The settings for PCA were boluses of 1 mL with a lockout interval of 7 min without infusion limit. No basal infusion was used. Study drug administration and background analgesic protocol Thirty minutes before the end of the surgery, all patients received i.v. 1 g paracetamol over 15 minutes, 100 mg ketoprofene and 20 mg nefopam. First two were continued for 48 hours (at 6-h intervals for paracetamol and 12-h for ketoprofene). In the PACU, patients experiencing pain with a numeric pain rating scale (NRS, 0–10) > 3 were given an i.v. manual titration of 3 mL of study drug (2 mL when body weight < 60 kg) at 5-min intervals until a NRS score ≤ 3 was obtained according to a protocol already used routinely in our PACU. All nurses in the PACU had been trained to assess pain using unidimensional scales and to perform opioid titration. At this time, the i.v. PCA with study drug (80 mL) was connected to the patient for 48 h. Drug titration was stopped if the patient had a respiratory rate lower than 12 breaths min − 1 and/or an SpO2 lower than 94% and/or experienced a serious adverse event related to opioid administration (allergy with cutaneous rash, vomiting, severe pruritus) and also if the patient was asleep. In case of severe ventilatory depression (respiratory rate, RR < 10 breaths min − 1 ) an intravenous bolus of 0.04 mg naloxone was administered until RR was greater than 12 breaths min − 1 , and this was defined as a severe ORAEs. General anesthesia and perioperative management In both groups, oral premedication was given 1 h before surgery (hydroxyzine 1 mg kg − 1 ). General anesthesia was induced with propofol (2–3 mg kg − 1 ), sufentanil (0.3 µg kg − 1 ), and cisatracrium (0.3–0.5 mg kg − 1 ). Airway was maintained with tracheal tube and the lungs were ventilated with a mix of oxygen–air (50/50). Tidal volume and respiratory rate were set to maintain end tidal volume CO 2 between 35 and 40 mmHg. A 5-cm H 2 0 positive end expiratory pressure was set. Anesthesia was maintained with sevoflurane 1–2% and additional intravenous sufentanil (5–10 µg) upon request i.v. fluid administration was ringer lactate < 10 mL kg − 1 h − 1 . Urinary intra-operative catheter was not placed. At the end of surgery, patients were extubated and transferred to the PACU. Prevention of nausea or vomiting was based on Apfel score (female sex, non smoker, history of motion sickness or postoperative nausea and vomiting, postoperative opioid treatment: 0 to 4 points). For patients with score 1 or 2, i.v. dexamethasone 0.1 mg.kg − 1 was injected after the induction of anesthesia, followed with i.v. 4–8 mg ondansetron for score > 2. The Aldrete’s scoring system was used for determining when the patient can be discharged (score: 0–10: a score ≥9 was required for discharge). Over the first 48 hours post-operative period, patients in both groups were managed similarly and standardized: early oral intake and post-operative rehabilitation, i.v. ondansetron (4 mg) was injected in case of nausea or vomiting. At the end of the PCA perfusion (48 h), oral acetaminophen, ketoprofen and tramadol (as rescue medication) were given to the patient for pain relief. Patients were discharged from the surgical ward at the discretion of the surgeon. Clinical assessment Preoperative evaluation was performed the day before surgery, including: NRS pain score at rest and at on movement (0–10), DN4 score (0–10), walking ability (m), medical diseases, physiological parameters (blood pressure, heart and respiratory rate, pulse oxymetry), biological variables (Hemoglobin, creatinine clearance). Pain intensity and adverse events were assessed in PACU and every 6 h over the study period (48 h). The nurse staff evaluated patient pain intensity using a NRS at rest and on movement (hip mobilization). When the patient was asleep, no attempt was made to wake him up, and the patient was considered as having analgesia and a score of 0 mm was assigned to the patient. Total drug administration in PACU and over the 24 hours were recorded. ORAEs. arising from the analgesic protocol were systematically assessed in PACU and surgical ward by nurses in charge of the patient (blinded to group assignment): nausea, vomiting, drowsiness, dizziness, headache, sweating, itching, confusion/hallucination, pruritus, sedation, arterial hypotension (mean arterial pressure < 80 mmHg), respiratory depression. Theses outcomes were viewed as binary (Yes/No), every 6 h after PACU. Arterial oxygen saturation (pulse oximetry), heart and respiratory rates and blood pressure was recorded every 6 h. Desaturation was considered pulse oxygen saturation < 94%. A respiratory rate 120 bpm and 2. After 4 months, all patients were called and questioned for pain, DN4 score (0–10 points), satisfaction about pain after surgery (using a NRS: 0–100) and other adverse events medical or surgical complications [ 26 ]. Endpoints The primary outpoint was the rate of opioid-related adverse effects from start of titration to 24 h. As previously described, the following ORAEs were the presence/absence of at least one of the following complications: nausea, vomiting, respiratory depression, pruritus (itch), urinary retention requiring evacuation (spontaneous voiding impossible despite bladder volume > 400 ml measured by ultrasound), allergy (skin reaction), hallucination (perception without object). Ventilator depression was defined as RR below 10 min − 1 or need for naloxone administration. Sedation was defined as a Ramsay score above 2 but was not considered as an ORAEs The secondary end-points were: the time to achieve pain relief in the PACU, the number of patients with post-operative severe pain, the number of patients who required titration, the duration of stay in the PACU period, the consumption of opioid during the PACU and PCA periods, the number of demands for opioid and the number of boluses received during the PCA period, the total dose administered over 24 h, pains scores during the PACU and the PCA periods, and the patient satisfaction assessment. Sample Size Calculation The sample size was calculated based on the ability to detect a significant difference in adverse events between oxycodone versus morphine groups with a difference in the ORAEs occurrence of 50% (32% vs 16%) with 80% power, based on previous study with morphine. 1−10 The level of significance was set at two-sided α = 0.05 to support the hypothesis that ORAEs oxycodone group were different than that in the morphine group. Using these assumptions, we calculated a sample size of 222 patients (111 patients per group). We increased the number to 246 patients (123 per group) to account for 10% loss to follow-up. Statistical analysis Statistical analysis was conducted using SAS (9.4; SAS Inc., Cary NC). An intention-to-treat analysis was performed without any interim analysis. Statistical results were expressed with mean (SD) or median [25–75 IQ] according to the distribution. The numbers and associated percentages were given for categorical variables. Comparisons of continuous variables between the groups were performed using a student’s t test or Wilcoxon-Mann-Whitney test according to the distribution. Categorical variables were compared between groups by X 2 or Fisher’s exact test. All statistical tests were conducted as 0.05 two-sided tests. Results Population of the study From June 2012 to July 2016, 623 patients scheduled for primary unilateral total hip arthrosplasty were screened and 246 patients were randomized (Fig. 1 ). After randomization, 5 patients withdrew from the study: 4 for protocol violation, one for a cancelled surgery. These patients were not included in the final analysis (n = 241). Three patients discontinued the treatment. At 4 months, 102 and 106 patients in oxycodone and morphine group completed their end-of-study visit, respectively. Baseline characteristics, preoperative pain, physiological and biological parameters, type of surgery and anesthesia were similar in both groups (Table 1 ). Premedication (64 versus 70 patients), intra operative sufentanil administration (40 [30–45] versus 35[30–45] ∝g), median perioperative i.v. fluid (1225 vs 1000 mL) and number of patients requiring red blood transfusion (1 vs 2) were well balanced between groups. Moreover, the number of patients receiving iv ondansetron (6 vs 3) or i.v. dexamethasone (72 vs 65) during general anesthesia was similar. Primary outcome (Table 2 ) The number of patients with at least one ORAEs was similar in both group: 55 (48%) in oxycodone group versus 46 (40%) in morphine group (p = 0.19) with a relative risk = 1.22 [0.91; 1.63]. Nausea and vomiting were the main ORAEs in 23% patients in both groups in PACU (Table 2 ). Respiratory depression was the first ORAEs in PACU (all patients: 21%), without any respiratory complication after PACU. Urinary retention was the first ORAEs in both groups after PACU discharge within the first 24 hours (all patients: 15%) (Table 2 ). Secondary outcomes The initial NRS pain at rest in PACU was similar in both groups: 4 [0–6] for oxycodone group vs 4[0–7] for morphine group (p = 0.7). The number of patients requiring titration (NRS pain > 3/10) was comparable for both groups. For these patinets, the number of boluses to obtain a NRS pain < 3/10 was reduced in oxycodone group as compared with morphine group (p = 0.03), but no difference was observed for the time of titration and the PACU time discharge (Table 3 ). Time < 45 min to get a NRS pain < 3/10 was recorded for 76 (95%) patients in oxycodone group versus 75 (85%) in morphine group (p = 0.036) with a relative risk oxycodone versus morphine = 0.34 [0.12; 0.99]. The number of ORAEs (Table 2 ), the number of sedated patients (1 versus 1), and the number of patients requiring termination of morphine titration (2 versus 3) were similar between groups. Morphine or oxycodone requirements during the PCA period were less in morphine group, but the total dose of both drugs administered within the first 24 h were significantly different between groups (Table 3 ). Over the study period, similar NRS pain at rest or movement were recorded for both groups, with a median score < 3/10 at each time (H6, 12, 18, 24, 30, 36, 42, 48) (Fig. 2 A and 2 B). Patient satisfaction at the end of PCA period was not different in both groups (77±26 in morphine group versus 73±27 in oxycodone group, p = 0.42). At the end of the follow up period (4 month), the number of patients included in this analysis was 51 in oxycodone group and 53 in morphine group. No difference was observed regarding DN4 scores (p = 0.78), median NRS pain score at movement (p = 0.67) and satisfaction (p = 0.47) (Table 3 ). Discussion This prospective triple blinded study demonstrated that intravenous oxycodone did not lead to less opioid-related ORAEs within the first 24 hours after major orthopedic surgery as compared with morphine. Post-operative pain relief and patient satisfaction were similar between the two drugs. In this prospective, randomized, large-scale study of patients, we hypothesized that oxycodone would reduce opioid-induced adverse effects, assuming that significantly less oxycodone would be administered compared to morphine. Finally, equivalent doses were administered in the first 24 hours. Also, this is the first study showing that choosing i.v. oxycodone for pain relief without a dose reduction strategy does not appear to be beneficial compared to morphine. This result is ultimately in line with previous studies which have shown that the occurrence of opioid-related side effects is primarily related to the total dose administered. Using morphine doses of 45 µg kg − 1 or oxycodone 30 µg kg − 1 as i.v. bolus, Silvasti et al. found no difference within the first 24 hours after breast surgery on a weak collective (50 patients) [ 19 ]. Performing plasma assays, these authors demonstrated that morphine and oxycodone appeared to be equipotent as described in our study. With less dose of oxycodone compared to morphine (respectively, 13±10 mg vs 22±10 mg, p < 0.001) after hysterectomy under general anesthesia, Lenz et al demonstrate a lower total rate of adverse events in favour of oxycodone, but there were no significant differences in the incidence of nausea, vomiting, or itching [ 22 ]. For theses authors, their results support the findings in experimental studies in humans, demonstrating that oxycodone is more potent than morphine in the treatment of visceral pain [ 22 ]. After laparoscopic supracervical hysterectomy, Kim et al. compared i.v. oxycodone to fentanyl (ratio1:75) and found that the amount of PCA during the first 48 hours after surgery was significantly less in group oxycodone than in group fentanyl group. However, rate of nausea (48% vs 14% in fentanyl group), vomiting, dizziness and drowsiness occurred significantly more often in group oxycodone within the first postoperative 48 hours [ 29 ]. Conversely, no significant difference between the 2 groups were noted for ORAEs in a similar study [ 28 ]. Finally, in our study including hip arthroplasty, both groups ultimately received equivalent doses and similar incidence ORAES occurred (Table 2 , 3 ). These results corroborate the latest meta-analyze performed in oncology [ 11 – 13 ]. Oxycodone Adverse Events And Pain Relief The incidence of nausea, vomiting or sedation were similar between the two groups, < 10% (Table 3 ). For NVPO, the rate appeared to be low but probably related to the systematic prevention of nausea used in this study. With oxycodone, the incidence of PONV in the literature vary according to dose-related studies and route of administration (p.o., i.v., s.c…) [ 15 – 19 , 23 ]. In fact, no study appears to ultimately demonstrate superiority to oxycodone versus morphine. Urinary retention was the most frequent ORAEs reported in PACU. This event may vary depending on the type of surgery and is largely linked to the duration of general anesthesia and intraoperative fluid administration. With similar characteristics in both groups (duration of surgery, intraopertaive sufentanyl), the main reason for this lack of difference between groups was probabaly linked to the similarity of the adjustment dosing regimen between the two groups with close final doses in PACU. With regard to acute postoperative pain during the first 48 hours postoperatively, oxycodone and morphine demonstrated similar NRS pain trajectory and satisfaction (Fig. 2 ) and no further conclusions can be drawn. Titration Studies conducted in major orthopedic surgery or comparing young patients with elderly patients have shown that i.v. morphine administration every 5 min with an unlimited number of 2- or 3-mg boluses provided the best and fastest analgesia [ 5 , 6 ]. In the present study, we demonstrated that with a similar administration regimen, the morphine group tended to experience more pain in the PACU and required more adjustments (p = 0.03) (Table 3 , Fig. 2 ). In fact, the difference between the groups for pain relief is summarized by the administration of a single additional dose of morphine. This small difference translates into a gain of only 5 minutes in favour of oxycodone in PACU. Moreover, the number of patients who had the full dose of maximal i.v. titration was similar between the two group. Is this really an argument in favour of its preferred use, given that the incidence of side effects remains the same? This question remains unanswered. Limite Of The Study The present study also had several limitations. First, this study included only arthroplasty surgery (intermediate pain). Also, different results could be noted with other surgeries and different selected populations (bias related to individual variations in psychological disorders or pain sensitivity). The incidence of pain and adjustment doses vary according to gender, age and type of surgery (anterior, posterolateral...). Our results are only valid for a relatively healthy patient population (not too old, not too fat, no kidney failure, no use of preoperative opioids) and for this procedure only. Second, this study was performed at two different centers, which may weaken the power of the data as many subtle issues (surgeons, anesthesiologists, everyday practice, patient recruitment), but intra and post-operative care were standardized. Third, the ratio chosen 1/1 is always a source of discussion and disagreement between the experts due to peak effect (1/1, 1 / 1.5, 1/2) [ 30 ]. To reduce external bias, we decided to use a similarity of all volumes and doses with an extending evaluation within the first 24 hours. Composites (results) are often used to reduce sample size, but can cause particular problems when the components are of different importance to patients, occur with different frequencies and are affected to a different degree by the intervention. The high and similar frequency of ORAEs in our study corresponds to this ideal of choice. Finally, the fact that this study excluded opioid patients prior to surgery is an important nuance that has a substantial impact on the generalizability of the study, as many patients who underwent surgery for painful reasons are already receiving opioid treatment. Moreover, this study did not assess oxycodone upon discharge that should be evaluated. Conclusion In conclusion, for orthopaedic pain relief, i.v. oxycodone, administered at a morphine dose conversion ratio of 1:1, did not reduce ORAEs for the first 24 hours post-operatively and provided similar pain scores and satisfaction. This appears to demonstrate that oxycodone is not more potent than morphine in this indication. Abbreviations i.v. intravenous NRS Numeric Rating Scale ORAEs Opioid-Related Adverse Events PACU Postoperative Care Unit PCA Patient Controlled Analgesia RR Respiratory Rate Declarations - Ethics approval and consent to participate: the present study was approved by the institutional human investigation committee (Comité de Protection des Personnes, CPP, Nîmes, France, EudraCT: 2011-004140-22, Chaiperson Prof T. Lavabre-Bertrand) on 7 January 2012 and was registered before started on ClinicalTrials.gov (NCT 01536301). A written informed consent was obtained from all participants before inclusion. - Consent for publication: not applicable - Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. - Competing interests: The authors declare that they have no competing interests - Funding: this work was only supported by our institutional sources (Carémau Hospital, Nîmes, France) and funding were only used for the payment of IRB and to purchase study drugs. - Authors' contributions: all authors have read, revised and approved the final manuscript. PC, MR and OL were responsible for the conception and design of the study, for the coordination of the centres and data analysis. PC and JYL wrote the manuscript. SA was responsible for data and statistical analysis. LZ, VR, CB, NV and JLH were responsible for the patient recruitment and for anesthetizing the patients. - Acknowledgements: Ariane Lannelongue for technical help (English spelling and Figure) References [1] Cuvillon P, Zoric L, Demattei C et al. Opioid-sparing effect of nefopam in combination with paracetamol after major abdominal surgery: a randomized double-blind study. Minerva Anestesiol 2017; 83: 914-920. [2] Kehlet H. Accelerated Recovery after Surgery: a continuous multidisciplinary challenge. Anesthesiology 2015; 123: 1219-20. [3] Richebé P, Capdevila X, Rivat C et al. Persistent postsurgical pain. Pathophysiology and preventive pharmacologic considerations. Anesthesiology 2018; 129: 590-607. [4] Zoric L, Cuvillon P, Alonso S et al. Single-shot intraoperative local anaesthetic infiltration does not reduce morphine consumption after total hip arthroplasty: a double-blinded placebo-controlled randomized study. Br J Anaesth 2014; 112: 722-8. [5] Aubrun F, Monsel S, Langeron O et al. Postoperative titration of intravenous morphine in the elderly patient. Anesthesiology 2002; 96: 17-23. [6] Aubrun F, Langeron O, Quesnel C et al. Relationships between measurement of pain using visual analog score and morphine requirements during postoperative intravenous morphine titration. Anesthesiology 2003; 98: 1415-21. [7] Pergolizzi JV Jr, Seow-Choen F, Wexner SD, et al. Perspectives on Intravenous Oxycodone for Control of Postoperative Pain. Pain Pract 2016; 16: 924-34. [8] Nozaki C, Kamei J. Involvement of mu1-opioid receptor on oxycodone-induced antinociception in diabetic mice. Eur J Pharmacol 2007; 560: 160-2 [9] Ross FB, Smith MT. The intrinsic antinociceptive effects of oxycodone appear to be kappa-opioid receptor mediated. Pain 1997; 73: 151-7. [10] Dieterich M, Müller-Jordan K, Stubert J et al. Pain management after cesarean: a randomized controlled trial of oxycodone versus intravenous piritramide. Arch Gynecol Obstet 2012; 286: 859-65. [11] Gaskell H, Derry S, Stannard C et al. Oxycodone for neuropathic pain in adults. Cochrane Database Syst Rev 2016; 7: CD010692. [12] Jiang Z, Zhou G, Song Q et al. Effect of Intravenous Oxycodone in combination with different doses of dexmedetomdine on sleep quality and visceral pain in patients after abdominal surgery: a randomized study. Clin J Pain 2018; 34: 1126-1132. [13] Lee KH, Kang JH, Oh HS et al. Intravenous Oxycodone versus Intravenous Morphine in Cancer Pain: A Randomized, Open-Label, Parallel-Group, Active-Control Study. Pain Res Manag 2017; 2017: 9741729. [14] Schmidt-Hansen M, Bennett MI, Arnold S et al. Oxycodone for cancer-related pain. Cochrane Database Syst Rev 2017; 8: CD003870. [15] Cheung CW, Ching Wong SS, Qiu Q et al. Oral Oxycodone for acute postoperative pain: A review of clinical trials. Pain Physician 2017; 20: SE33-SE52. [16] Liukas A, Kuusniemi K, Aantaa R et al. Elimination of intravenous oxycodone in the elderly: a pharmacokinetic study in postoperative orthopaedic patients of different age groups. Drugs Aging 2011; 28: 41-50. [17] Nie JJ, Sun S, Huang SQ et al. Effect of oxycodone patient controlled intravenous analgesia after cesarean section: a randomized controlled study. J Pain Res 2017; 10: 2649-2655. [18] Olczak B, Kowalski G, Leppert W et al. Analgesic efficacy, adverse effects, and safety of oxycodone administered as continuous intravenous infusion in patients after total hip arthroplasty. Pain Res 2017; 10: 1027-1032. [19] Silvasti M, Rosenberg P, Seppälä T et al. Comparison of analgesic efficacy of oxycodone and morphine in postoperative intravenous patient-controlled analgesia. Acta Anaesthesiol Scand 1998; 42: 576-580 [20] Abou hammoud A, Simon N, Urien S et al. Intravenous morphine titration in immediate postoperative pain management: population kinetic–pharmacodynamic and logistic regression analysis. Pain 2009; 144: 139-146. [21] Aubrun F, Mazoit JX, Riou B et al. Postoperative intravenous morphine titration. Br J Anaesth 2012; 108: 193-201. [22] Lenz H, Sandvik L, Qvigstad E et al. A Comparison of Intravenous Oxycodone and Intravenous Morphine in Patient-Controlled Postoperative Analgesia After Laparoscopic Hysterectomy. Anesth Analg 2009; 109:1279-83. [23] Rothwell MP, Pearson D, Hunter JD et al. Oral oxycodone offers equivalent analgesia to intravenous patient-controlled analgesia after total hip replacement: a randomized, single-centre, non-blinded, non-inferiority study. Br J Anaesth 2011; 106: 865-72. [24] Pereira J, Lawlor P, Vigano A et al. Equianalgesic dose ratios for opioids. a critical review and proposals for long-term dosing. J Pain Symptom Manage 2001; 22: 672-87. [25] Champigny V, Holmes-LeBlanc S, Pittet JF et al . New legal framework for human subject research in France: A step forward? Anaesth Crit Care Pain Med 2018; 37: 529-530. [26] Chatila N, Pereira B, Maarrawi J et al. Validation of a New Arabic Version of the Neuropathic Pain Diagnostic Questionnaire (DN4). Pain Pract 2017; 17: 78-87. [27] Biboulet P, Morau D, Aubas, Bringuier-Branchereau S, Capdevila X et al. Postoperative analgesia after total-hip arthroplasty: comparison of intravenous patient- controlled analgesia with morphine and single injection of femoral nerve or psoas compartment block. A prospective, randomized, double-blind study. Reg Anesth Pain Med 2004; 29: 102-9. [28] Ding Z, Wang K, Wang B et al . Efficacy and tolerability of oxycodone versus fentanyl for intravenous patient-controlled analgesia after gastrointestinal laparotomy. A prospective, randomized, double-blind study. Medicine (Baltimore) 2016 ;95: e4943. [29] Kim NS, Lee JS, Park SY et al. Oxycodone versus fentanyl for intravenous patient-controlled analgesia after laparoscopic supracervical hysterectomy: a prospective, randomized, double-blind study. Medicine (Baltimore) 2017; 96(10): e6286. [30] Levy M. Advancement of opioid analgesia with controlled-release oxycodone. European J Pain 2001; Suppl. A: 113-116. Tables Due to technical limitations, Tables 1-3 are provided in the Supplementary Files section. Supplementary Files Table3.docx Table2.docx CONSORTChecklist3.doc Table1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-12731","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":319127,"identity":"3fefca27-a385-4a80-872d-1eee6600b5a5","order_by":1,"name":"philippe cuvillon","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-4424-4280","institution":"Hopital Universitaire Caremeau","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"philippe","middleName":"","lastName":"cuvillon","suffix":""},{"id":319128,"identity":"2e35c961-84c6-42a7-965e-f58f95b23b68","order_by":2,"name":"Sandrine Alonso","email":"","orcid":"","institution":"Hopital Universitaire Caremeau","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sandrine","middleName":"","lastName":"Alonso","suffix":""},{"id":319129,"identity":"6c066fa2-af3a-43b2-bfaf-0bf950ac9f36","order_by":3,"name":"Joel Lhermite","email":"","orcid":"","institution":"Hopital Universitaire Caremeau","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Joel","middleName":"","lastName":"Lhermite","suffix":""},{"id":319130,"identity":"80b39ce3-8d7f-49a2-945e-23163a847711","order_by":4,"name":"Vanessa Reubrecht","email":"","orcid":"","institution":"Assistance Publique - Hopitaux de Paris","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Vanessa","middleName":"","lastName":"Reubrecht","suffix":""},{"id":319131,"identity":"325d747e-e899-4d00-a215-906bfc78fce8","order_by":5,"name":"Lana Zoric","email":"","orcid":"","institution":"Hopital Universitaire Caremeau","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lana","middleName":"","lastName":"Zoric","suffix":""},{"id":319132,"identity":"6eb935d9-3fd7-493f-b698-879f4b43fa43","order_by":6,"name":"Nathalie Vialees","email":"","orcid":"","institution":"Hopital Universitaire Caremeau","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nathalie","middleName":"","lastName":"Vialees","suffix":""},{"id":319133,"identity":"b28d7a56-79f0-4302-ae83-5578e324c674","order_by":7,"name":"jean-luc. faillie","email":"","orcid":"","institution":"Centre Hospitalier Regional Universitaire de Montpellier","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"jean-luc.","middleName":"","lastName":"faillie","suffix":""},{"id":319134,"identity":"bb803fbb-f047-4a20-b9b2-ca54e4476ec7","order_by":8,"name":"Pascal Kouyoumdjian","email":"","orcid":"","institution":"Hopital Universitaire Caremeau","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Pascal","middleName":"","lastName":"Kouyoumdjian","suffix":""},{"id":319135,"identity":"d083cc6c-4260-4983-8f7f-258bb00f298c","order_by":9,"name":"Christope Boisson","email":"","orcid":"","institution":"Hopital Universitaire Caremeau","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Christope","middleName":"","lastName":"Boisson","suffix":""},{"id":319136,"identity":"a9929ebf-c790-4162-a015-03d3085ea381","order_by":10,"name":"mathieu raux","email":"","orcid":"","institution":"Assistance Publique - Hopitaux de Paris","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"mathieu","middleName":"","lastName":"raux","suffix":""},{"id":319137,"identity":"1750c185-3fc3-4da1-8c18-3006f474fbe7","order_by":11,"name":"olivier langeron","email":"","orcid":"","institution":"Assistance Publique - Hopitaux de Paris","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"olivier","middleName":"","lastName":"langeron","suffix":""}],"badges":[],"createdAt":"2020-01-28 11:44:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.2.22154/v1","doiUrl":"https://doi.org/10.21203/rs.2.22154/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":440461,"identity":"40cd3a28-003f-4ac1-8a7e-cc69adb6b45f","added_by":"auto","created_at":"2020-02-03 17:05:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":81005,"visible":true,"origin":"","legend":"Flow diagram of the study","description":"","filename":"fig1.png","url":"https://assets-eu.researchsquare.com/files/895f0697-259a-4989-a6f4-c2bbeb0a27c8/v1/fig1.png"},{"id":440463,"identity":"51f9ea9d-fc53-49b7-a0bc-fb7874caba5e","added_by":"auto","created_at":"2020-02-03 17:05:18","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":51824,"visible":true,"origin":"","legend":"Box and wisker plots showing the median, interquartile range, and range of pain scores at rest (Fig2 A) and at movement (Fig2 B) across time for oxycodone and morphine group. Baseline was performed at inclusion (\u003e 24h and \u003c 6 weeks before surgery). PACUi: initial scores after extubation and before titration in Post Operative Care Unit. PACUd: scores at discharge. No difference was observed between groups at baseline.*\u003c 0.05 vs oxycodone","description":"","filename":"fig2.png","url":"https://assets-eu.researchsquare.com/files/895f0697-259a-4989-a6f4-c2bbeb0a27c8/v1/fig2.png"},{"id":13487659,"identity":"281d2320-b565-4a12-b39c-4c5ee10b4a00","added_by":"auto","created_at":"2021-09-16 22:11:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":491062,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-12731/v1/0e18a203-e218-4754-9a9a-a294e6f7fe3f.pdf"},{"id":440465,"identity":"3d644cb7-f951-4b6f-b138-c81cf92f6d4c","added_by":"auto","created_at":"2020-02-03 17:05:19","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":18409,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/895f0697-259a-4989-a6f4-c2bbeb0a27c8/v1/Table 3.docx"},{"id":440464,"identity":"804d444f-56ed-483d-ac0d-4791ac4a1588","added_by":"auto","created_at":"2020-02-03 17:05:18","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":17998,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/895f0697-259a-4989-a6f4-c2bbeb0a27c8/v1/Table 2.docx"},{"id":440460,"identity":"91db5fbf-1ca0-42ca-a7a0-9d5d2378b487","added_by":"auto","created_at":"2020-02-03 17:05:18","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":220672,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORTChecklist3.doc","url":"https://assets-eu.researchsquare.com/files/895f0697-259a-4989-a6f4-c2bbeb0a27c8/v1/CONSORT_Checklist-3.doc"},{"id":440462,"identity":"3f5f0a12-4841-4d23-8d48-ee41246599dc","added_by":"auto","created_at":"2020-02-03 17:05:18","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":18012,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/895f0697-259a-4989-a6f4-c2bbeb0a27c8/v1/Table 1.docx"}],"financialInterests":"","formattedTitle":"Intravenous oxycodone compared to morphine for post-operative opioid-related adverse events in opioid naïve patients: a prospective randomized controlled trial","fulltext":[{"header":"Background","content":" \u003cp\u003eMultimodal analgesic approach (including anti-inflammatory drugs, regional analgesia and local infiltration) have been recently developed to enhance post-operative rehabilitation and pain relief. This approach may lead to decreased narcotic consumption [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Despite the increase in clinical research on non-opioid analgesics, many patients still complain of severe postoperative pain and require opioid initiation (intravenous or oral) in the postoperative care unit (PACU) or in the first few days postoperatively [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In these situations of severe postoperative pain, the use of intravenous morphine for titration in PACU followed by an i.v. Patient-Controlled Analgesia (PCA) remains the gold standard as it provides rapid and effective pain relief [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSince the 1990s, oxycodone has been proposed as an alternative to morphine, because by acting on the \u0026micro;1-receptors and on the κ-2-opioid agonist, it leads to a better anti nociceptive effect for post-operative pain relief or cancer-related pain [\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral studies have shown that per os oxycodone was associated with better pain control, less serious opioid-related adverse events (ORAEs) and a faster onset of action due to a better pharmacokinetic profile: higher oral bioavailability and lower plasma variability [\u003cspan additionalcitationids=\"CR16 CR17 CR18\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, controversies have arisen as a result of recent clinical studies and meta-analysis that have shown that per os oxycodone did not reduce adverse events and pain relief. Not to mention that appetite for oxycodone itself is decreasing, due to concerns about addiction and the bad reputation that this drug has acquired in opiate-related crises [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20 CR21 CR22\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs with the oral route, the intravenous use of oxycodone remains debated because the number of studies on the subject is limited and the potency ratio of oxycodone to morphine (1:1 or 1:2) unresolved [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Moreover, no large clinical studies have clearly demonstrated the benefit/risk (ORAEs) of i.v. oxycodone versus morphine. The hypothesis of this study was that i.v. oxycodone (versus i.v. morphine) would reduce ORAEs, assessed 24 hours post-operatively. At the same time, pain levels were as well evaluated (secondary outcome).\u003c/p\u003e "},{"header":"Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eInstitutional Human Committee, consent and setting\u003c/h2\u003e \u003cp\u003eIn accordance with the French legislation, the present study was approved by the institutional human investigation committee (Comit\u0026eacute; de Protection des Personnes, CPP, N\u0026icirc;mes, France, \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eEudraCT\u003c/span\u003e: 2011-004140-22, Chaiperson Prof T. Lavabre-Bertrand) on 7 January 2012 and was registered prior to enrolment on ClinicalTrials.gov (NCT 01536301) [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Study was conducted in two French University centres (APHP, La Piti\u0026eacute;-Salp\u0026ecirc;tri\u0026egrave;re Paris, France; H\u0026ocirc;pital Car\u0026eacute;meau, N\u0026icirc;mes, France). The CONSORT (Consolidated Standards of Reporting Trials) recommendations for reporting randomized trial were followed. The analysis occurred after patient enrolment was completed.\u003c/p\u003e \u003cp\u003eWritten informed consent was obtained from all participants before inclusion.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and Patients\u003c/h2\u003e \u003cp\u003eThis was a prospective, randomized, triple blinded (Participant, Investigator, Outcomes Assessor), 1:1 ratio, double center control trial. Patients\u0026thinsp;\u0026gt;\u0026thinsp;18 yrs scheduled for unilateral elective total hip arthroplasty (posterolateral surgical approach) under general anesthesia and opioid na\u0026iuml;ve were eligible and approached by the surgeon or the investigators. Exclusion criteria were: refusal to participate, age\u0026thinsp;\u0026gt;\u0026thinsp;80 yrs, weight\u0026thinsp;\u0026lt;\u0026thinsp;50 or \u0026gt;\u0026thinsp;100\u0026nbsp;kg, emergency or bilateral surgery including hip fracture, any regional anesthesia or analgesia (including: wound infiltration, peripheral nerve block, epidural or spinal injection), cognitive disorders (delirium, dementia\u0026hellip;), pregnancy, patients with alcohol or drugs abuse, uncontrolled epilepsy, patients unlikely to be fully cooperative during the study, participation in another study within the previous 30 days. Patients with chronic pain and/or reporting any allergy or contraindication to study drug (creatinine clearance\u0026thinsp;\u0026lt;\u0026thinsp;50\u0026nbsp;mL min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, Cockroft formula), hepatic insufficiency (transaminases and/or alkaline phosphatases\u0026thinsp;\u0026gt;\u0026thinsp;3 times of upper normal value, and/or prothrombin time\u0026thinsp;\u0026lt;\u0026thinsp;70% of control), acute or chronic respiratory insufficiency (Spo2\u0026thinsp;\u0026lt;\u0026thinsp;94% in ambiant air), porphyria, intracranial hypertension, or ileus were not included. Finally, patient already taking narcotics or opioid, opiate agonist (codeine, dextromoramide, dihydrocodeine, oxycodone per os, tramadol, morphine-like antitussive\u0026hellip;) or agonist-antagonists (buprenorphine, nalbuphine, pentazocine) were not included.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy Drug, randomization and blinding\u003c/h2\u003e \u003cp\u003ePatients were randomly assigned to the oxycodone group or morphine group using computer-generated random numbers created by the study statistician using a 1:1 randomization ratio. Group allocations were concealed in sequentially numbered opaque envelopes, which were opened by the research nurse just after the start of surgery. Randomization for the two centers were performed using blocks of randomization (8 patients per block). Pharmacy personnel not involved in clinical care of the patient prepared drug solutions. The morphine and oxycodone vials were similar, allowing a double-blinded design. In the case of a serious adverse event, the double\u0026ndash;blind could be removed. Patients, surgeons, attending anesthetists, nurses and investigators were blinded to group assignment until data analysis.\u003c/p\u003e \u003cp\u003eDrug solutions were prepared using:\u003c/p\u003e \u003cul\u003e\n\u003cli\u003e95 mL of saline solution\u003c/li\u003e\n\u003cli\u003e5 mL solution of study drug (20 mg mL\u003csup\u003e-1\u003c/sup\u003e ): 100 mg of oxycodone or morphine\u003c/li\u003e\n\u003c/ul\u003e\u003cp\u003eFrom the 100\u0026nbsp;mL drug solutions (1\u0026nbsp;mg: 1\u0026nbsp;mL), 20\u0026nbsp;mL of the solution were transferred in 20\u0026nbsp;mL syringe and used for titration in PACU. The remaining 80\u0026nbsp;mL were used for the patient-controlled analgesia (Gemstar, Abbott Laboratories, Abbott Park, IL, USA) for a 48-h period. The settings for PCA were boluses of 1\u0026nbsp;mL with a lockout interval of 7\u0026nbsp;min without infusion limit. No basal infusion was used.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStudy drug administration and background analgesic protocol\u003c/h2\u003e \u003cp\u003eThirty minutes before the end of the surgery, all patients received i.v. 1\u0026nbsp;g paracetamol over 15 minutes, 100\u0026nbsp;mg ketoprofene and 20\u0026nbsp;mg nefopam. First two were continued for 48 hours (at 6-h intervals for paracetamol and 12-h for ketoprofene).\u003c/p\u003e \u003cp\u003eIn the PACU, patients experiencing pain with a numeric pain rating scale (NRS, 0\u0026ndash;10)\u0026thinsp;\u0026gt;\u0026thinsp;3 were given an i.v. manual titration of 3\u0026nbsp;mL of study drug (2\u0026nbsp;mL when body weight\u0026thinsp;\u0026lt;\u0026thinsp;60\u0026nbsp;kg) at 5-min intervals until a NRS score\u0026thinsp;\u0026le;\u0026thinsp;3 was obtained according to a protocol already used routinely in our PACU. All nurses in the PACU had been trained to assess pain using unidimensional scales and to perform opioid titration. At this time, the i.v. PCA with study drug (80\u0026nbsp;mL) was connected to the patient for 48\u0026nbsp;h.\u003c/p\u003e \u003cp\u003eDrug titration was stopped if the patient had a respiratory rate lower than 12 breaths min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and/or an SpO2 lower than 94% and/or experienced a serious adverse event related to opioid administration (allergy with cutaneous rash, vomiting, severe pruritus) and also if the patient was asleep. In case of severe ventilatory depression (respiratory rate, RR\u0026thinsp;\u0026lt;\u0026thinsp;10 breaths min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) an intravenous bolus of 0.04\u0026nbsp;mg naloxone was administered until RR was greater than 12 breaths min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, and this was defined as a severe ORAEs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eGeneral anesthesia and perioperative management\u003c/h2\u003e \u003cp\u003eIn both groups, oral premedication was given 1\u0026nbsp;h before surgery (hydroxyzine 1\u0026nbsp;mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e). General anesthesia was induced with propofol (2\u0026ndash;3\u0026nbsp;mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e), sufentanil (0.3\u0026nbsp;\u0026micro;g kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e), and cisatracrium (0.3\u0026ndash;0.5\u0026nbsp;mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e). Airway was maintained with tracheal tube and the lungs were ventilated with a mix of oxygen\u0026ndash;air (50/50). Tidal volume and respiratory rate were set to maintain end tidal volume CO\u003csub\u003e2\u003c/sub\u003e between 35 and 40\u0026nbsp;mmHg. A 5-cm H\u003csub\u003e2\u003c/sub\u003e0 positive end expiratory pressure was set. Anesthesia was maintained with sevoflurane 1\u0026ndash;2% and additional intravenous sufentanil (5\u0026ndash;10\u0026nbsp;\u0026micro;g) upon request i.v. fluid administration was ringer lactate\u0026thinsp;\u0026lt;\u0026thinsp;10\u0026nbsp;mL kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. Urinary intra-operative catheter was not placed.\u003c/p\u003e \u003cp\u003eAt the end of surgery, patients were extubated and transferred to the PACU. Prevention of nausea or vomiting was based on Apfel score (female sex, non smoker, history of motion sickness or postoperative nausea and vomiting, postoperative opioid treatment: 0 to 4 points). For patients with score 1 or 2, i.v. dexamethasone 0.1\u0026nbsp;mg.kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e was injected after the induction of anesthesia, followed with i.v. 4\u0026ndash;8\u0026nbsp;mg ondansetron for score\u0026thinsp;\u0026gt;\u0026thinsp;2. The Aldrete\u0026rsquo;s scoring system was used for determining when the patient can be discharged (score: 0\u0026ndash;10: a score \u0026ge;9 was required for discharge).\u003c/p\u003e \u003cp\u003eOver the first 48 hours post-operative period, patients in both groups were managed similarly and standardized: early oral intake and post-operative rehabilitation, i.v. ondansetron (4\u0026nbsp;mg) was injected in case of nausea or vomiting. At the end of the PCA perfusion (48\u0026nbsp;h), oral acetaminophen, ketoprofen and tramadol (as rescue medication) were given to the patient for pain relief. Patients were discharged from the surgical ward at the discretion of the surgeon.\u003c/p\u003e \u003ch2\u003eClinical assessment\u003c/h2\u003e \u003cp\u003ePreoperative evaluation was performed the day before surgery, including: NRS pain score at rest and at on movement (0\u0026ndash;10), DN4 score (0\u0026ndash;10), walking ability (m), medical diseases, physiological parameters (blood pressure, heart and respiratory rate, pulse oxymetry), biological variables (Hemoglobin, creatinine clearance). Pain intensity and adverse events were assessed in PACU and every 6\u0026nbsp;h over the study period (48\u0026nbsp;h). The nurse staff evaluated patient pain intensity using a NRS at rest and on movement (hip mobilization). When the patient was asleep, no attempt was made to wake him up, and the patient was considered as having analgesia and a score of 0\u0026nbsp;mm was assigned to the patient. Total drug administration in PACU and over the 24 hours were recorded.\u003c/p\u003e \u003cp\u003eORAEs. arising from the analgesic protocol were systematically assessed in PACU and surgical ward by nurses in charge of the patient (blinded to group assignment): nausea, vomiting, drowsiness, dizziness, headache, sweating, itching, confusion/hallucination, pruritus, sedation, arterial hypotension (mean arterial pressure\u0026thinsp;\u0026lt;\u0026thinsp;80\u0026nbsp;mmHg), respiratory depression. Theses outcomes were viewed as binary (Yes/No), every 6\u0026nbsp;h after PACU. Arterial oxygen saturation (pulse oximetry), heart and respiratory rates and blood pressure was recorded every 6\u0026nbsp;h. Desaturation was considered pulse oxygen saturation\u0026thinsp;\u0026lt;\u0026thinsp;94%. A respiratory rate\u0026thinsp;\u0026lt;\u0026thinsp;10 breaths/min was considered as respiratory depression. Heart rate\u0026thinsp;\u0026gt;\u0026thinsp;120\u0026nbsp;bpm and \u0026lt;\u0026thinsp;50\u0026nbsp;bpm defined tachycardia and bradycardia, respectively. Sedation was defined by a Ramsay scale\u0026thinsp;\u0026gt;\u0026thinsp;2.\u003c/p\u003e \u003cp\u003eAfter 4 months, all patients were called and questioned for pain, DN4 score (0\u0026ndash;10 points), satisfaction about pain after surgery (using a NRS: 0\u0026ndash;100) and other adverse events medical or surgical complications [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eEndpoints\u003c/h2\u003e \u003cp\u003eThe primary outpoint was the rate of opioid-related adverse effects from start of titration to 24\u0026nbsp;h. As previously described, the following ORAEs were the presence/absence of at least one of the following complications: nausea, vomiting, respiratory depression, pruritus (itch), urinary retention requiring evacuation (spontaneous voiding impossible despite bladder volume\u0026thinsp;\u0026gt;\u0026thinsp;400\u0026nbsp;ml measured by ultrasound), allergy (skin reaction), hallucination (perception without object). Ventilator depression was defined as RR below 10\u0026nbsp;min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e or need for naloxone administration. Sedation was defined as a Ramsay score above 2 but was not considered as an ORAEs\u003c/p\u003e \u003cp\u003eThe secondary end-points were: the time to achieve pain relief in the PACU, the number of patients with post-operative severe pain, the number of patients who required titration, the duration of stay in the PACU period, the consumption of opioid during the PACU and PCA periods, the number of demands for opioid and the number of boluses received during the PCA period, the total dose administered over 24\u0026nbsp;h, pains scores during the PACU and the PCA periods, and the patient satisfaction assessment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSample Size Calculation\u003c/h2\u003e \u003cp\u003eThe sample size was calculated based on the ability to detect a significant difference in adverse events between oxycodone \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eversus\u003c/span\u003e morphine groups with a difference in the ORAEs occurrence of 50% (32% vs 16%) with 80% power, based on previous study with morphine.\u003csup\u003e1\u0026minus;10\u003c/sup\u003e The level of significance was set at two-sided α\u0026thinsp;=\u0026thinsp;0.05 to support the hypothesis that ORAEs oxycodone group were different than that in the morphine group. Using these assumptions, we calculated a sample size of 222 patients (111 patients per group). We increased the number to 246 patients (123 per group) to account for 10% loss to follow-up.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was conducted using SAS (9.4; SAS Inc., Cary NC). An intention-to-treat analysis was performed without any interim analysis. Statistical results were expressed with mean (SD) or median [25\u0026ndash;75 IQ] according to the distribution. The numbers and associated percentages were given for categorical variables. Comparisons of continuous variables between the groups were performed using a student\u0026rsquo;s t test or Wilcoxon-Mann-Whitney test according to the distribution. Categorical variables were compared between groups by \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eX\u003c/span\u003e\u003csup\u003e2\u003c/sup\u003e or Fisher\u0026rsquo;s exact test.\u003c/p\u003e \u003cp\u003eAll statistical tests were conducted as 0.05 two-sided tests.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":" \u003ch2\u003ePopulation of the study\u003c/h2\u003e \u003cp\u003eFrom June 2012 to July 2016, 623 patients scheduled for primary unilateral total hip arthrosplasty were screened and 246 patients were randomized (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). After randomization, 5 patients withdrew from the study: 4 for protocol violation, one for a cancelled surgery. These patients were not included in the final analysis (n\u0026thinsp;=\u0026thinsp;241). Three patients discontinued the treatment. At 4 months, 102 and 106 patients in oxycodone and morphine group completed their end-of-study visit, respectively.\u003c/p\u003e \u003cp\u003eBaseline characteristics, preoperative pain, physiological and biological parameters, type of surgery and anesthesia were similar in both groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Premedication (64 \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eversus\u003c/span\u003e 70 patients), intra operative sufentanil administration (40 [\u0026lt;link rid=\"bib30\"\u0026gt;30\u0026lt;/link\u0026gt;\u0026ndash;45] \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eversus\u003c/span\u003e 35[\u0026lt;link rid=\"bib30\"\u0026gt;30\u0026lt;/link\u0026gt;\u0026ndash;45] \u0026prop;g), median perioperative i.v. fluid (1225 \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003evs\u003c/span\u003e 1000\u0026nbsp;mL) and number of patients requiring red blood transfusion (1 \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003evs\u003c/span\u003e 2) were well balanced between groups. Moreover, the number of patients receiving iv ondansetron (6 \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003evs\u003c/span\u003e 3) or i.v. dexamethasone (72 \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003evs\u003c/span\u003e 65) during general anesthesia was similar.\u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePrimary outcome (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/h2\u003e \u003cp\u003eThe number of patients with at least one ORAEs was similar in both group: 55 (48%) in oxycodone group versus 46 (40%) in morphine group (p\u0026thinsp;=\u0026thinsp;0.19) with a relative risk\u0026thinsp;=\u0026thinsp;1.22 [0.91; 1.63]. Nausea and vomiting were the main ORAEs in 23% patients in both groups in PACU (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Respiratory depression was the first ORAEs in PACU (all patients: 21%), without any respiratory complication after PACU. Urinary retention was the first ORAEs in both groups after PACU discharge within the first 24 hours (all patients: 15%) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSecondary outcomes\u003c/h2\u003e \u003cp\u003eThe initial NRS pain at rest in PACU was similar in both groups: 4 [0\u0026ndash;\u0026lt;link rid=\"bib6\"\u0026gt;6\u0026lt;/link\u0026gt;] for oxycodone group \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003evs\u003c/span\u003e 4[0\u0026ndash;\u0026lt;link rid=\"bib7\"\u0026gt;7\u0026lt;/link\u0026gt;] for morphine group (p\u0026thinsp;=\u0026thinsp;0.7). The number of patients requiring titration (NRS pain\u0026thinsp;\u0026gt;\u0026thinsp;3/10) was comparable for both groups. For these patinets, the number of boluses to obtain a NRS pain\u0026thinsp;\u0026lt;\u0026thinsp;3/10 was reduced in oxycodone group as compared with morphine group (p\u0026thinsp;=\u0026thinsp;0.03), but no difference was observed for the time of titration and the PACU time discharge (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Time\u0026thinsp;\u0026lt;\u0026thinsp;45\u0026nbsp;min to get a NRS pain\u0026thinsp;\u0026lt;\u0026thinsp;3/10 was recorded for 76 (95%) patients in oxycodone group \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eversus\u003c/span\u003e 75 (85%) in morphine group (p\u0026thinsp;=\u0026thinsp;0.036) with a relative risk oxycodone versus morphine\u0026thinsp;=\u0026thinsp;0.34 [0.12; 0.99].\u003c/p\u003e \u003cp\u003eThe number of ORAEs (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), the number of sedated patients (1 \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eversus\u003c/span\u003e 1), and the number of patients requiring termination of morphine titration (2 versus 3) were similar between groups. Morphine or oxycodone requirements during the PCA period were less in morphine group, but the total dose of both drugs administered within the first 24\u0026nbsp;h were significantly different between groups (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Over the study period, similar NRS pain at rest or movement were recorded for both groups, with a median score\u0026thinsp;\u0026lt;\u0026thinsp;3/10\u0026nbsp;at each time (H6, 12, 18, 24, 30, 36, 42, 48) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Patient satisfaction at the end of PCA period was not different in both groups (77\u0026plusmn;26 in morphine group versus 73\u0026plusmn;27 in oxycodone group, p\u0026thinsp;=\u0026thinsp;0.42).\u003c/p\u003e \u003cp\u003eAt the end of the follow up period (4 month), the number of patients included in this analysis was 51 in oxycodone group and 53 in morphine group. No difference was observed regarding DN4 scores (p\u0026thinsp;=\u0026thinsp;0.78), median NRS pain score at movement (p\u0026thinsp;=\u0026thinsp;0.67) and satisfaction (p\u0026thinsp;=\u0026thinsp;0.47) (Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e "},{"header":"Discussion","content":" \u003cp\u003eThis prospective triple blinded study demonstrated that intravenous oxycodone did not lead to less opioid-related ORAEs within the first 24 hours after major orthopedic surgery as compared with morphine. Post-operative pain relief and patient satisfaction were similar between the two drugs.\u003c/p\u003e \u003cp\u003eIn this prospective, randomized, large-scale study of patients, we hypothesized that oxycodone would reduce opioid-induced adverse effects, assuming that significantly less oxycodone would be administered compared to morphine. Finally, equivalent doses were administered in the first 24 hours. Also, this is the first study showing that choosing i.v. oxycodone for pain relief without a dose reduction strategy does not appear to be beneficial compared to morphine. This result is ultimately in line with previous studies which have shown that the occurrence of opioid-related side effects is primarily related to the total dose administered. Using morphine doses of 45\u0026nbsp;\u0026micro;g kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e or oxycodone 30\u0026nbsp;\u0026micro;g kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e as i.v. bolus, Silvasti et al. found no difference within the first 24 hours after breast surgery on a weak collective (50 patients) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Performing plasma assays, these authors demonstrated that morphine and oxycodone appeared to be equipotent as described in our study.\u003c/p\u003e \u003cp\u003eWith less dose of oxycodone compared to morphine (respectively, 13\u0026plusmn;10\u0026nbsp;mg vs 22\u0026plusmn;10\u0026nbsp;mg, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) after hysterectomy under general anesthesia, Lenz et al demonstrate a lower total rate of adverse events in favour of oxycodone, but there were no significant differences in the incidence of nausea, vomiting, or itching [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. For theses authors, their results support the findings in experimental studies in humans, demonstrating that oxycodone is more potent than morphine in the treatment of visceral pain [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. After laparoscopic supracervical hysterectomy, Kim et al. compared i.v. oxycodone to fentanyl (ratio1:75) and found that the amount of PCA during the first 48 hours after surgery was significantly less in group oxycodone than in group fentanyl group. However, rate of nausea (48% vs 14% in fentanyl group), vomiting, dizziness and drowsiness occurred significantly more often in group oxycodone within the first postoperative 48 hours [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Conversely, no significant difference between the 2 groups were noted for ORAEs in a similar study [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Finally, in our study including hip arthroplasty, both groups ultimately received equivalent doses and similar incidence ORAES occurred (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). These results corroborate the latest meta-analyze performed in oncology [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \n\u003ch2\u003eOxycodone Adverse Events And Pain Relief\u003c/h2\u003e\n \u003cp\u003eThe incidence of nausea, vomiting or sedation were similar between the two groups, \u0026lt;\u0026thinsp;10% (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). For NVPO, the rate appeared to be low but probably related to the systematic prevention of nausea used in this study. With oxycodone, the incidence of PONV in the literature vary according to dose-related studies and route of administration (p.o., i.v., s.c\u0026hellip;) [\u003cspan additionalcitationids=\"CR16 CR17 CR18\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In fact, no study appears to ultimately demonstrate superiority to oxycodone versus morphine. Urinary retention was the most frequent ORAEs reported in PACU. This event may vary depending on the type of surgery and is largely linked to the duration of general anesthesia and intraoperative fluid administration. With similar characteristics in both groups (duration of surgery, intraopertaive sufentanyl), the main reason for this lack of difference between groups was probabaly linked to the similarity of the adjustment dosing regimen between the two groups with close final doses in PACU.\u003c/p\u003e \u003cp\u003eWith regard to acute postoperative pain during the first 48 hours postoperatively, oxycodone and morphine demonstrated similar NRS pain trajectory and satisfaction (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) and no further conclusions can be drawn.\u003c/p\u003e \n\u003ch2\u003eTitration\u003c/h2\u003e\n \u003cp\u003eStudies conducted in major orthopedic surgery or comparing young patients with elderly patients have shown that i.v. morphine administration every 5\u0026nbsp;min with an unlimited number of 2- or 3-mg boluses provided the best and fastest analgesia [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In the present study, we demonstrated that with a similar administration regimen, the morphine group tended to experience more pain in the PACU and required more adjustments \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003e(p\u0026thinsp;=\u0026thinsp;0.03)\u003c/span\u003e (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In fact, the difference between the groups for pain relief is summarized by the administration of a single additional dose of morphine. This small difference translates into a gain of only 5 minutes in favour of oxycodone in PACU. Moreover, the number of patients who had the full dose of maximal i.v. titration was similar between the two group. Is this really an argument in favour of its preferred use, given that the incidence of side effects remains the same? This question remains unanswered.\u003c/p\u003e \n\u003ch2\u003eLimite Of The Study\u003c/h2\u003e\n \u003cp\u003eThe present study also had several limitations. First, this study included only arthroplasty surgery (intermediate pain). Also, different results could be noted with other surgeries and different selected populations (bias related to individual variations in psychological disorders or pain sensitivity). The incidence of pain and adjustment doses vary according to gender, age and type of surgery (anterior, posterolateral...). Our results are only valid for a relatively healthy patient population (not too old, not too fat, no kidney failure, no use of preoperative opioids) and for this procedure only. Second, this study was performed at two different centers, which may weaken the power of the data as many subtle issues (surgeons, anesthesiologists, everyday practice, patient recruitment), but intra and post-operative care were standardized. Third, the ratio chosen 1/1 is always a source of discussion and disagreement between the experts due to peak effect (1/1, 1 / 1.5, 1/2) [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. To reduce external bias, we decided to use a similarity of all volumes and doses with an extending evaluation within the first 24 hours. Composites (results) are often used to reduce sample size, but can cause particular problems when the components are of different importance to patients, occur with different frequencies and are affected to a different degree by the intervention. The high and similar frequency of ORAEs in our study corresponds to this ideal of choice. Finally, the fact that this study excluded opioid patients prior to surgery is an important nuance that has a substantial impact on the generalizability of the study, as many patients who underwent surgery for painful reasons are already receiving opioid treatment. Moreover, this study did not assess oxycodone upon discharge that should be evaluated.\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eIn conclusion, for orthopaedic pain relief, i.v. oxycodone, administered at a morphine dose conversion ratio of 1:1, did not reduce ORAEs for the first 24 hours post-operatively and provided similar pain scores and satisfaction. This appears to demonstrate that oxycodone is not more potent than morphine in this indication.\u003c/p\u003e "},{"header":"Abbreviations","content":" \u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ei.v.\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintravenous\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNRS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNumeric Rating Scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eORAEs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOpioid-Related Adverse Events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePACU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePostoperative Care Unit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePCA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePatient Controlled Analgesia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRespiratory Rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e "},{"header":"Declarations","content":"\u003cp\u003e- Ethics approval and consent to participate: the present study was approved by the institutional human investigation committee (Comit\u0026eacute; de Protection des Personnes, CPP, N\u0026icirc;mes, France, EudraCT: 2011-004140-22, Chaiperson Prof T. Lavabre-Bertrand) on 7 January 2012 and was registered before started on ClinicalTrials.gov (NCT 01536301). A written informed consent was obtained from all participants before inclusion.\u003c/p\u003e\n\u003cp\u003e- Consent for publication: not applicable\u003c/p\u003e\n\u003cp\u003e- Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e- Competing interests: \u0026nbsp;The authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e- Funding: this work was only supported by our institutional sources (Car\u0026eacute;mau Hospital, N\u0026icirc;mes, France) and funding were only used for the payment of IRB and to purchase study drugs.\u003c/p\u003e\n\u003cp\u003e- Authors' contributions: all authors have read, revised and approved the final manuscript. PC, MR and OL were responsible for the conception and design of the study, for the coordination of the centres and data analysis. PC and JYL wrote the manuscript. SA was responsible for data and statistical analysis. LZ, VR, CB, NV and JLH were responsible for the patient recruitment and for anesthetizing the patients.\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;Acknowledgements: \u0026nbsp;Ariane Lannelongue for technical help (English spelling and Figure)\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e[1] Cuvillon P, Zoric L, Demattei C et al. Opioid-sparing effect of nefopam in combination with paracetamol after major abdominal surgery: a randomized double-blind study. \u003cem\u003eMinerva Anestesiol\u003c/em\u003e 2017; 83: 914-920.\u003c/p\u003e\n\u003cp\u003e[2] Kehlet\u0026nbsp;H. Accelerated\u003cu\u003e\u0026nbsp;\u003c/u\u003eRecovery\u003cu\u003e\u0026nbsp;\u003c/u\u003eafter\u003cu\u003e\u0026nbsp;\u003c/u\u003eSurgery: a continuous multidisciplinary challenge. \u003cem\u003eAnesthesiology\u003c/em\u003e 2015; 123: 1219-20.\u003c/p\u003e\n\u003cp\u003e[3] Richeb\u0026eacute; P, Capdevila X, Rivat C et al. Persistent postsurgical pain. Pathophysiology and preventive pharmacologic considerations. \u003cem\u003eAnesthesiology\u003c/em\u003e 2018; 129: 590-607.\u003c/p\u003e\n\u003cp\u003e[4] Zoric L,\u0026nbsp;Cuvillon P, Alonso S et al. Single-shot intraoperative local anaesthetic infiltration does not reduce morphine consumption after total hip arthroplasty: a double-blinded placebo-controlled randomized study. \u003cem\u003eBr J Anaesth\u003c/em\u003e 2014; 112: 722-8.\u003c/p\u003e\n\u003cp\u003e[5] Aubrun\u0026nbsp;F, Monsel S, Langeron O et al. Postoperative titration of intravenous morphine in the elderly patient. \u003cem\u003eAnesthesiology\u003c/em\u003e 2002; 96: 17-23.\u003c/p\u003e\n\u003cp\u003e[6] Aubrun\u0026nbsp;F, Langeron O, Quesnel C et al. Relationships between measurement of pain using visual analog score and morphine requirements during postoperative intravenous morphine titration. \u003cem\u003eAnesthesiology\u003c/em\u003e 2003; 98: 1415-21.\u003c/p\u003e\n\u003cp\u003e[7] Pergolizzi JV Jr,\u0026nbsp;Seow-Choen F,\u0026nbsp;Wexner SD,\u0026nbsp;et al. Perspectives on\u0026nbsp;Intravenous\u0026nbsp;Oxycodone\u0026nbsp;for Control of Postoperative Pain. \u003cem\u003ePain Pract \u003c/em\u003e2016; 16: 924-34.\u003c/p\u003e\n\u003cp\u003e[8] Nozaki C, Kamei J. Involvement of mu1-opioid receptor on oxycodone-induced antinociception in diabetic mice.\u0026nbsp;\u003cem\u003eEur J Pharmacol\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e2007; 560: 160-2\u003c/p\u003e\n\u003cp\u003e[9] Ross FB, Smith MT. The intrinsic antinociceptive effects of oxycodone appear to be kappa-opioid receptor mediated.\u0026nbsp;\u003cem\u003ePain\u003c/em\u003e\u0026nbsp;1997; 73: 151-7.\u003c/p\u003e\n\u003cp\u003e[10] Dieterich M, M\u0026uuml;ller-Jordan K, Stubert J et al. Pain management after cesarean: a randomized controlled trial of oxycodone versus intravenous piritramide.\u003cem\u003e Arch Gynecol Obstet\u003c/em\u003e 2012; 286: 859-65.\u003c/p\u003e\n\u003cp\u003e[11] Gaskell H,\u0026nbsp;Derry S,\u0026nbsp;Stannard C et al. Oxycodone for neuropathic pain in adults. \u003cem\u003eCochrane Database Syst Rev \u0026nbsp;\u003c/em\u003e2016; 7: CD010692.\u003c/p\u003e\n\u003cp\u003e[12] Jiang Z, Zhou G, Song Q et al. Effect of\u0026nbsp;Intravenous\u0026nbsp;Oxycodone\u0026nbsp;in combination with different doses of dexmedetomdine on sleep quality and visceral pain in patients after abdominal\u0026nbsp;surgery: a randomized study. \u003cem\u003eClin J Pain\u003c/em\u003e 2018; 34: 1126-1132.\u003c/p\u003e\n\u003cp\u003e[13] Lee KH,\u0026nbsp;Kang JH,\u0026nbsp;Oh HS et al. Intravenous Oxycodone versus Intravenous Morphine in Cancer Pain: A Randomized, Open-Label, Parallel-Group, Active-Control Study. \u003cem\u003ePain Res Manag\u0026nbsp;\u003c/em\u003e2017; 2017: 9741729.\u003c/p\u003e\n\u003cp\u003e[14] Schmidt-Hansen M,\u0026nbsp;Bennett MI,\u0026nbsp;Arnold S\u0026nbsp;et al. Oxycodone for cancer-related pain. \u003cem\u003eCochrane Database Syst Rev\u0026nbsp;\u003c/em\u003e2017; 8: CD003870.\u003c/p\u003e\n\u003cp\u003e[15] Cheung CW, Ching Wong SS, Qiu Q et al. Oral Oxycodone\u0026nbsp;for acute postoperative pain: A review of clinical trials. \u003cem\u003ePain Physician\u003c/em\u003e 2017; 20: SE33-SE52.\u003c/p\u003e\n\u003cp\u003e[16] Liukas A, Kuusniemi K, Aantaa R et al. Elimination of\u003cu\u003e\u0026nbsp;\u003c/u\u003eintravenous\u003cu\u003e\u0026nbsp;\u003c/u\u003eoxycodone\u003cu\u003e\u0026nbsp;\u003c/u\u003ein the elderly: a pharmacokinetic study in postoperative orthopaedic patients of different age groups. \u003cem\u003eDrugs Aging\u003c/em\u003e 2011; 28: 41-50.\u003c/p\u003e\n\u003cp\u003e[17] Nie JJ, Sun S, Huang SQ et al. Effect of\u0026nbsp;oxycodone\u0026nbsp;patient controlled\u0026nbsp;intravenous\u0026nbsp;analgesia after cesarean section: a randomized controlled study. \u003cem\u003eJ Pain Res\u003c/em\u003e 2017; 10: 2649-2655.\u003c/p\u003e\n\u003cp\u003e[18] Olczak B,\u0026nbsp;Kowalski G,\u0026nbsp;Leppert W et al. Analgesic efficacy, adverse effects, and safety of\u0026nbsp;oxycodone\u0026nbsp;administered as continuous intravenous infusion in patients after total hip arthroplasty. \u003cem\u003ePain Res\u0026nbsp;\u003c/em\u003e2017; 10: 1027-1032.\u003c/p\u003e\n\u003cp\u003e[19] Silvasti M, Rosenberg P, Sepp\u0026auml;l\u0026auml; T et al. Comparison of analgesic efficacy of oxycodone and morphine in postoperative intravenous patient-controlled analgesia.\u0026nbsp;\u003cem\u003eActa Anaesthesiol Scand\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e1998; 42: 576-580\u003c/p\u003e\n\u003cp\u003e[20] Abou hammoud A, Simon N, Urien S et al. Intravenous morphine titration in immediate postoperative pain management: population kinetic\u0026ndash;pharmacodynamic and logistic regression analysis. \u003cem\u003ePain \u003c/em\u003e2009; 144: 139-146.\u003c/p\u003e\n\u003cp\u003e[21] Aubrun\u0026nbsp;F, Mazoit JX,\u0026nbsp;Riou\u0026nbsp;B et al. Postoperative intravenous morphine titration. \u003cem\u003eBr J Anaesth\u003c/em\u003e 2012; 108: 193-201.\u003c/p\u003e\n\u003cp\u003e[22] Lenz H, Sandvik L, Qvigstad E et al. A Comparison of Intravenous Oxycodone and Intravenous Morphine in Patient-Controlled Postoperative Analgesia After Laparoscopic Hysterectomy. \u003cem\u003eAnesth Analg\u003c/em\u003e 2009; 109:1279-83.\u003c/p\u003e\n\u003cp\u003e[23] Rothwell MP, Pearson D, Hunter JD et al. Oral\u0026nbsp;oxycodone offers equivalent analgesia to\u0026nbsp;intravenous patient-controlled analgesia after total hip replacement: a randomized, single-centre, non-blinded, non-inferiority study. \u003cem\u003eBr J Anaesth\u003c/em\u003e 2011; 106: 865-72.\u003c/p\u003e\n\u003cp\u003e[24] Pereira J, Lawlor P, Vigano A et al. Equianalgesic dose ratios for opioids. a critical review and proposals for long-term dosing. \u003cem\u003eJ Pain Symptom Manage \u003c/em\u003e2001; 22: 672-87.\u003c/p\u003e\n\u003cp\u003e[25] Champigny V, Holmes-LeBlanc S,\u0026nbsp;Pittet\u0026nbsp;JF et al . New\u0026nbsp;legal\u0026nbsp;framework for human subject research in France: A step forward? \u003cem\u003eAnaesth Crit Care Pain Med\u0026nbsp;\u003c/em\u003e2018; 37: 529-530.\u003c/p\u003e\n\u003cp\u003e[26] Chatila N,\u0026nbsp;Pereira B,\u0026nbsp;Maarrawi J et al. Validation of a New Arabic Version of the Neuropathic\u0026nbsp;Pain\u0026nbsp;Diagnostic Questionnaire (DN4). \u003cem\u003ePain\u0026nbsp;Pract\u003c/em\u003e 2017; 17: 78-87.\u003c/p\u003e\n\u003cp\u003e[27] Biboulet P, Morau D, Aubas, Bringuier-Branchereau S, Capdevila X et al. Postoperative analgesia after total-hip arthroplasty: comparison of intravenous patient- controlled analgesia with morphine and single injection of femoral nerve or psoas compartment block. A prospective, randomized, double-blind study. \u003cem\u003eReg Anesth Pain Med\u003c/em\u003e 2004; 29: 102-9.\u003c/p\u003e\n\u003cp\u003e[28] \u003cem\u003eDing Z, Wang K, Wang B\u003c/em\u003e et al\u003cem\u003e. \u003c/em\u003eEfficacy and tolerability of oxycodone versus fentanyl for intravenous patient-controlled analgesia after gastrointestinal laparotomy. A prospective, randomized, double-blind study. \u003cem\u003eMedicine\u003c/em\u003e (Baltimore) 2016 ;95: e4943.\u003c/p\u003e\n\u003cp\u003e[29] Kim NS, Lee JS, Park SY et al. Oxycodone versus fentanyl for intravenous patient-controlled analgesia after laparoscopic supracervical hysterectomy: a prospective, randomized, double-blind study. \u003cem\u003eMedicine\u003c/em\u003e (Baltimore) 2017; 96(10): e6286.\u003c/p\u003e\n\u003cp\u003e[30] Levy M. Advancement of opioid analgesia with controlled-release oxycodone. \u003cem\u003eEuropean J Pain \u003c/em\u003e2001; Suppl. A: 113-116.\u003c/p\u003e"},{"header":"Tables","content":"\u003cp\u003eDue to technical limitations, Tables 1-3 are provided in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"oxycodone, morphine, opioid, surgery, adverse event","lastPublishedDoi":"10.21203/rs.2.22154/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.22154/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBacground: Intravenous oxycodone compared to morphine for postoperative pain relief is controversial. The purpose of this study was to assess opioid-related adverse events of oxycodone versus morphine in opioid-naive patients after orthopaedic surgery. \u003c/p\u003e\u003cp\u003eMethods: Patients scheduled for total hip arthroplasty under general anesthesia combined with a multimodal analgesia (acetamnophen, nonsteroidal anti-inflammatory) were randomized in a triple-blinded trial to postopertaive pain treatment with either intravenous oxycodone or morphine (potency ratio 1:1). After surgery, patients received similar drug regimen for titration in the postoperative care unit (bolus 2-3 mg, 5 min period, when pain score was \u0026gt;3/10) followed by an intravenous patient controlled analgesia (bolus 1 mg, lockout time 7 min) postoperatively. The primary outcome was number of patients with ≥1 opioid-related adverse events within the first 24 hours (at least one of the following complications: nausea, vomiting, respiratory depression, pruritus, urinary retention requiring evacuation, allergy, hallucination). Secondary outcomes included pain scores, opioid consumption. Patients were followed up to 4 months. \u003c/p\u003e\u003cp\u003eResults: The intention-to-treat analysis included 241 patients with similar characteristics. There were 55 patients with at least one opioid-related adverse events in oxycodone group versus 46 in morphine group (48% vs 40%, p=0.19; relative risk= 1.22 [0.91; 1.63]). Oxycodone versus morphine requirements were respectively: 6 [0-11] versus 8 [0-12] mg (p=0.06) for titration, 15 [8-26] versus 8 [5-16] mg (p=0.001) for PCA dose, and 22 [12-37] mg versus 19 [11-28] mg for the titration and PCA accumulated consumption (p=0.048). During the first 24 hours, there were no other differences in secondary outcomes between both drugs for (respectively oxycodone versus morphine in %): nausea (15 versus 13), vomiting (5 versus 5 ), urinary retention (20 versus 12 ) and pain scores. \u003c/p\u003e\u003cp\u003eConclusion: This study demonstrated that oxycodone required lower doses for titration in postoperative care unit, but did not significantly reduce opioid-related adverse events within the first 24 hours compared to morphine.\u003c/p\u003e","manuscriptTitle":"Intravenous oxycodone compared to morphine for post-operative opioid-related adverse events in opioid naïve patients: a prospective randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-02-03 17:05:17","doi":"10.21203/rs.2.22154/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"69b40e1d-c03b-4e3f-b552-54ea68e2f972","owner":[],"postedDate":"February 3rd, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":54035,"name":"Anesthesiology \u0026 Pain Medicine"}],"tags":[],"updatedAt":"2020-03-30T08:41:30+00:00","versionOfRecord":[],"versionCreatedAt":"2020-02-03 17:05:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-12731","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-12731","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}