Nalmefene effectively relieves thoracic epidural opioid-induced pruritus without affecting analgesia: a randomized controlled clinical trial

Introduction

Thoracic epidural analgesia is strongly recommended in Enhanced Recovery After Surgery (ERAS) guidelines as an effective approach for postoperative analgesia, especially for thoracic-abdominal procedures, such as esophagectomy and gastrointestinal surgery (1). Besides superior analgesia, it also reduces cardiovascular and respiratory complications, accelerates the recovery of gastrointestinal function, and decreases insulin resistance (2). Epidural opioids combined with epidural local anesthetics are used to achieve additive or synergistic analgesia and prolong the duration of analgesia while reducing the dose-related adverse effects of either drug alone (3,4). However, neuraxial opioids have side effects such as pruritus, nausea, sedation, and urinary retention. Among those side effects, pruritus is the most common, ranging from 30% to 80% (5).

Pruritus is an unpleasant sensation that leads to scratching and discomfort. Severe pruritus not only directly aggravates anxiety or interferes with sleep quality but also causes skin damage and infection due to repeated scratching. Treatments for opioid-induced pruritus include histamine receptor antagonist, µ-antagonist, mixed µ-antagonist and κ-agonist, 5-hydroxytryptamine receptor 3A antagonist, dopamine receptor antagonist, and γ-aminobutyric acid (GABA) receptor agonists. Among the above agents, the most effective pharmacologic treatment for opioid-induced pruritus is µ-antagonists (6). However, concerns exist about their potential to reverse analgesia (7). The dynorphin/κ-opioid receptor system is strongly associated with itching. Both mice and nonhuman primate models showed that κ-opioid receptor agonists reduce morphine-induced itching without affecting analgesia (8), while human clinical trials remain controversial (9). Therefore, mixed opioid receptor agonists are preferred. A mixed antagonist of the µ-opioid receptor and agonist of the κ-opioid receptor, such as nalbuphine, has been shown to be effective for treating neuraxial opioid-induced pruritus but causing sedations with high doses (10,11).

Nalmefene, an opioid antagonist, was formerly considered a pure µ-opioid receptor antagonist. Compared to naloxone, it has a longer duration of action. Moreover, it has been recently reported as a partial agonist of the κ-opioid receptor (12). Nalmefene has been used successfully to relieve opioid overdose and reverse postoperative opioid actions. Unlike other mixed µ-antagonist and κ-agonist, nalmefene’s most common side effect is light-headedness instead of sedation, even at high doses (13).

Therefore, we conducted a randomized, double-blinded, placebo-controlled clinical trial to study nalmefene’s efficacy for treating epidural opioid-induced pruritus and its effect on postoperative patient-controlled epidural analgesia (PCEA). Our research might provide another option for the treatment of epidural opioid-induced pruritus. We present this article in accordance with the CONSORT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1455/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Zhong Shan Hospital Affiliated of Fudan University (No. B2020-217R). Written informed consent was obtained from all patients before enrollment. The study was retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR2000039596) on November 2, 2020.

Patients

From November 3, 2020, to March 20, 2021, patients between 18 and 80 years old, the American Society of Anesthesiologists classification of physical status (ASA PS) was I and II, normal coagulation tests, who were scheduled for surgery under general and epidural anesthesia, and developed postoperative pruritus due to epidural analgesia, were screened for enrollment. The exclusion criteria included: (I) patients with severe vital organ dysfunctions, mainly liver dysfunction or renal dysfunction; (II) patients unable to use PCEA device, unable to understand the severity of pruritus and Visual Analog Scale (VAS) pain score; (III) history of any disease associated with pruritus, complaint of pruritus before surgery; (IV) history of allergy to nalmefene; (V) dislodgement or occlusion of the epidural catheter; (VI) patients with severe perioperative surgery-related complications.

Sample size, randomization, blinding and allocation concealment

The sample size calculation was conducted according to the primary outcome using Power Analysis and Sample Size version.15 software. According to a previous study (14), the expected complete relief rate of pruritus in the nalmefene group was about 60%, and that in the control group was about 35%; a total of 158 patients were required to achieve 90% power with an α of 0.05. Assuming a 5% dropout rate, the final sample size was 166 patients.

This study enrolled 166 patients who developed pruritus under patient-controlled epidural analgesia postoperatively at Zhongshan Hospital, Fudan University. According to the random number table, patients were randomly assigned to the nalmefene or control group in a 1:1 ratio. The random number table was generated by an independent study investigator who was not involved in the trial using the RAND function of EXCEL. Group allocations were stored in opaque, sealed envelopes and opened by researchers after enrolment. All patients, members of the Acute Pain Service (APS), and statisticians were blinded to the group allocation.

Intervention

All patients received general anesthesia combined with epidural anesthesia. The members of the APS group educated both groups on the use of a patient-controlled analgesia pump, potential anesthesia/analgesia-related adverse events, VAS pain score, and pruritus severity score preoperatively.

After arrival in the operating room, patients received epidural catheterization at T6–7, T7–8, T8–9, or T9–10 level with an epidural kit according to the surgery sites before the induction of anesthesia. Successful epidural catheterization was confirmed by a test dose of lidocaine (1%, 5 mL). Anesthesia was induced with propofol and remifentanil via target-controlled infusion using a Target Control Infusion (TCI) pump (8913030, B.Braun Melungeon AG, Germany). Sufentanil 0.2 µg/kg was also used during induction. After loss of consciousness, 0.6 mg/kg rocuronium was administered. Once intubation was completed, propofol and remifentanil were stopped. Anesthesia was maintained intraoperatively with inhaled halogenated gas (sevoflurane or desflurane) with minimal alveolar concentration (MAC) between 0.8 and 1.2. Sufentanil and additional rocuronium were given if necessary. Epidural injection of 10 mL of 0.25% ropivacaine was given every hour intraoperatively. In addition, a dose of opioids (10–15 µg sufentanil or 0.4–0.5 mg hydromorphone) in 8 mL saline was given through the epidural catheter half an hour before the end of the operation. Vasoactive medicines were used to maintain the hemodynamic parameters within 20% of preoperative levels as needed. Parecoxib sodium 40 mg and tropisetron 5 mg were given before the end of the operation.

After extubation and transfer to the post-anesthesia care unit (PACU), all patients received postoperative epidural analgesia with a mixed solution of 0.12% ropivacaine and opioid (0.4–0.6 µg/mL sufentanil or 8–16 µg/mL hydromorphone). The infusion rate was 3 mL/h with 4 mL patient-controlled bolus administration. The lockout interval was 8 minutes.

All patients with postoperative epidural analgesia were followed up postoperatively by APS. When patients experienced hypotension, dizziness, nausea, vomiting, respiratory depression, and pruritus, which are adverse events associated with epidural analgesia, they would be recorded. Hypotension was defined as systolic blood pressure below 90 mmHg, diastolic blood pressure below 50 mmHg, or a 20% decrease in systolic blood pressure from baseline; dizziness was defined as the subjective sensation of relling. Nausea was defined as discomfort in the upper abdomen and a feeling of urgency to vomit; vomiting was defined as the phenomenon of ejecting the contents of the stomach due to the strong contraction of the stomach; respiratory depression was defined as SpO₂ <90% under inhalation of air; the ward nurse paged APS members once patients complained of pruritus, and the APS members assessed these patients subsequently. Patients who met the inclusion criteria would be informed of the study protocol by APS members. Once the written informed consent form was obtained, patients were randomly allocated to receive either IV nalmefene (in a total volume of 20 mL) (nalmefene group) or an equivalent volume of saline (control group). Based on the previous studies (15,16), the dose of nalmefene was set at 0.5 µg/kg. The drugs were prepared by a nurse who was blinded to the allocation. Then, study solutions were administered by an anesthesiologist who did not know the allocation. After administration, this anesthesiologist monitored the patients for at least 1 hour. This anesthesiologist assessed the severity of pruritus by a verbal rating scale (17), and the relief of pruritus at 24 hours after administration. Trained APS members assessed postoperative analgesia at 24 hours postoperatively and 48 hours postoperatively, the assessments included pain scores at rest (static) and during movement (dynamic), the onset time of itching, the severity of itching, whether the itching was completely relieved, the time of itching relief, and the epidural analgesia related adverse events. We also extracted the pain scores from the PACU nursing records before the PACU discharge. Pain at rest and during movement at postoperative days 1 and 2 were assessed with VAS score. Pain scores were recorded by using a 10 cm, 11-point VAS where zero represented no pain, and ten indicated the worst imaginable pain. The pain scores were categorized into three levels in the PACU (VAS pain scores 0–3 were defined as “mild pain”, VAS pain scores of 4–6 as “moderate pain”, and VAS pain score 7–10 as “severe pain”). The onset time of itching was defined as the time from the start of PCEA to the first report of itching postoperatively by patients. The time of itching relief was defined as the time from the administration of study drugs to the maximum relief of pruritus symptoms. Complete relief of pruritus was defined as complete disappearance of itching symptoms with pruritus severity score of 0. Pruritus severity was assessed using a verbal rating scale: 0= no itch, 1= mild itch (no need to scratch), 2= moderate itch (need to scratch), and 3= severe itch (need to scratch and requiring treatment) (17). Patients in both groups received parecoxib (40 mg, intravenously, q12h), and no patient received intravenous or oral opioids in the postoperative period. In addition, no antihistamine, dexamethasone, or other drugs for pruritus were administered to the enrolled patients.

Outcomes

The primary outcome of this study was the complete relief rate of pruritus within 24 hours after the treatment. The secondary outcomes were VAS pain scores at rest and during movement on postoperative days 1 and 2, other PCEA-related adverse events (hypotension, dizziness, nausea, vomiting and respiratory depression), the itch scores, the time of itching relief.

Statistical analysis

Statistical analysis was performed following the per-protocol approach. Normally distributed continuous data were expressed as the mean and standard deviation (SD) and compared using the Student’s t-test. Non-normally distributed continuous data were described as median [interquartile range (IQR)] and compared using the Mann-whiney U test, whereas nominal variables were expressed as frequency (percentage, %), and the Chi-squared test or Fisher’s exact test was used to determine significance. The time of itching relief was analyzed using time-to-event analysis by the Kaplan-Meier method and log-rank test. Factors associated with the time of itching relief were studied by univariate analysis of the Cox regression model with seven variables: (I) the administration of nalmefene; (II) sex; (III) history of allergy; (IV) severity of pruritus; (V) types of opioids in epidural analgesic pump (hydromorphone or sufentanil); (VI) age; and (VII) body mass index, and all statistically significant variables were subsequently entered into a multivariable Cox regression model. Subsequently, univariate and multivariate logistic regression models were used to analyze the risk factors for the complete relief of pruritus. Both unadjusted and adjusted logistic regression models were performed. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were presented. All statistical analyses were conducted using SPSS 25.0 (SPSS, Inc., Chicago, IL, USA). Statistical significance was accepted at P values smaller than 0.05.

Results

Patient characteristics

One hundred and sixty-six patients were enrolled in the study and randomized to either the nalmefene group or the control group. One patient in the control group was excluded from the study due to a dislodged epidural catheter, and one patient in the control group required reoperation due to postoperative bleeding. One patient in the control group and three patients in the nalmefene group withdrew from the study voluntarily. Finally, 160 patients were included in the final analysis. The study design and process are described in Figure 1. The baseline characteristics of the two groups were shown in Table 1. Postoperatively, the time of itching onset did not differ significantly between the two groups (Table 2).

Figure 1 Flow diagram of the study.

Primary outcome

The complete pruritus relief rate in the nalmefene group was significantly higher than that in the control group within 24 hours after the treatment (68 of 80; 85% vs. 51 of 80; 63.7%, P=0.002, Table 3).

Secondary outcomes

Acute postoperative pain

Median VAS pain scores at rest and during movement were similar between the two groups on either postoperative day 1 or 2 (Table 2). No patients in the nalmefene group experienced a significant increase in pain intensity after the injection of nalmefene.

PCEA-related adverse events

No respiratory depression was observed in this study. No difference was observed between groups on the other PCEA-related adverse events (Table 2).

Itch score and the time of itching relief

There was no significant difference in the highest itch scores between the two groups of patients within 48 hours postoperatively (Table 2). The Kaplan-Meier curves comparing the time of itching relief showed that intravenous nalmefene reduced the median (IQR) time of itching relief from 15.62 (7.59–23.65) to 1.5 (0.84–2.16) hours (P<0.001, Figure 2).

Figure 2 Time to event analysis showed that intravenous nalmefene reduced the median time of itching relief significantly. Group C, the control group; group N, the nalmefene group.

Exploratory analyses

The multivariate Cox regression analysis indicated that nalmefene administration (adjusted hazard ratio: 2.29; 95% CI: 1.58 to 3.31; P<0.001) and no allergies history (adjusted hazard ratio: 1.87; 95% CI: 1.05 to 3.34; P=0.03) were significantly associated with reduced time of itching relief (Table 4). This indicated that the use of 0.5 µg/kg nalmefene injection was effective in the relief of postoperative epidural opioid-induced pruritus.

Univariate logistic analysis on the occurrence of complete relief of pruritus (Table 5) showed the administration of nalmefene, sex, allergy history, height, and types of opioids in epidural analgesic solutions were correlated with complete relief of pruritus. A multivariable logistic regression analysis with these five variables was included in the final model. Table 4 shows that female patients with no allergic history were more likely to have complete pruritus relief. Excluding other confounding factors, there was still a significant difference between the nalmefene group and the control group on complete relief of pruritus (adjusted OR: 4.14; 95% CI: 1.73 to 9.91; P=0.001).

Discussion

In this randomized, double-blinded, single-center clinical trial, we investigated the effect of intravenous nalmefene on the relief of epidural opioid-induced pruritus after surgery. This study showed that a single 0.5 µg/kg dose of nalmefene significantly relieved pruritus with a complete relief rate of 85% without affecting postoperative analgesia. The median onset time of pruritus relief with intravenous nalmefene was only 1.5 hours.

Epidural opioids are frequently used in acute postoperative pain management, especially in upper abdominal and thoracic surgeries, as a part of the ERAS bundles. Pruritus is one of the prominent side effects reported by patients receiving epidural opioid analgesia (18,19). The incidence of pruritus ranges from 30% to 80% in a dose-response manner. Epidural combination of local anesthetics with opioids decreases the incidence of pruritus due to less opioid use (20).

Multiple pharmacological treatments are used to relieve the pruritus, including histamine receptor antagonists, µ-antagonist, mixed µ-antagonist and κ-agonist, 5-hydroxytryptamine receptor 3A antagonists, dopamine receptor antagonists, and GABA analogs (6). Histamine receptor antagonists for the treatment of neuraxial opioid-induced pruritus are less than ideal because of their sedative effects (21). 5-hydroxytryptamine receptor antagonists are currently not considered as front-line therapies for opioid-induced pruritus due to conflicting results from human clinical trials (6). Gabapentin delays onset and reduces severity of intrathecal morphine-induced pruritus in high doses, which also hinder its use clinically (6).

Since spinal neurons mediate neuraxial opioid-induced pruritus (5,8), the most effective treatment for epidural opioid-induced pruritus could include agents which antagonize the µ-opioid receptor. Naloxone and naltrexone are used to reduce the frequency as well as the severity of pruritus from neuraxial opioid analgesia (6). However, concern exists about the potential reduction of the analgesic effects of opioids by those antagonists. Considering this, mixed opioid receptor agonists such as butorphanol are used in clinical situations. Butorphanol is effective in the treatment of pruritus from epidural opioids, but the potential limitations of butorphanol are its side effects, such as somnolence and dizziness (22).

In this study, nalmefene, a µ-opioid receptor antagonist recently reported as a partial agonist of a κ-opioid receptor, is used to treat epidural opioid-induced pruritus. It is equipotent to naloxone while the mean terminal elimination half-life is much longer than naloxone.

In previous clinical studies (16,23), the conclusions on whether prophylactic nalmefene reduces the incidence of intrathecal opioid-induced pruritus are inconsistent. While previous studies focused on the preventive effects of nalmefene, this study aims to evaluate whether nalmefene was effective in treating pruritus. This study showed that nalmefene effectively relieved pruritus from epidural opioids. There were significant individual differences in the incidence of epidural opioid-induced pruritus. Female patients are more prone to experience pruritus compared with males (24). This might partly explain the difference between preventive administration and treatment.

Compared to the previous studies (11,25), the higher pruritus relief in the control group (placebo, 63.7%) within 24 hours after treatment in this study could be explained by: (I) the majority of the patients in the control group (77.5%) suffered mild itch, and mild itch tends to relieve spontaneously (26); (II) placebo effects (27). Although the actual pruritus relief rate between the two groups (21.3%) was lower than expected (25%) based on the research from Cook et al. (28), there was still a statistically and clinically significant difference between nalmefene and controls.

Nalmefene did not affect the analgesic quality at resting and during movement states. Local anesthetics combined with opioids were used in this study. Local anesthetics might contribute to the unchanged analgesia when nalmefene, µ-opioid receptor antagonist, was administered to treat pruritus.

There were limitations of this study. Firstly, we did not study the dose-response effect of nalmefene or the optimal strategy. After a single dose of nalmefene, the recurrence of pruritus still existed for some patients after complete relief of pruritus. Additional studies are needed to optimize the dosage and strategy of nalmefene administration. Secondly, different types of opioids were used in our study; further studies are required in order to focus on individual opioids. Thirdly, as this was a single-center study, the generalizability of our results may be limited. Fourthly, the administration timing of nalmefene was not standardized, and there might be a difference when administered at various times.

Conclusions

A single 0.5 µg/kg dose of intravenous nalmefene could relieve patients’ pruritus from epidural opioids without affecting analgesia. In addition, a single dose of nalmefene did not increase PCEA-related adverse events postoperatively.

Acknowledgments

We appreciate for the statistical review from Fei Liang (Department of Statistics, Zhongshan Hospital, Fudan University, Shanghai, China), and thank Dr. Mengping Wei (Department of Anesthesiology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China) and Dr. Rui Hao (Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China) for assistance with data collection.

Footnote

Reporting Checklist: The authors have completed the CONSORT reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1455/rc

Trial Protocol: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1455/tp

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1455/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1455/prf

Funding: This work was supported by Shanghai Municipal Key Clinical Specialty from Shanghai Municipal Health Commission (No. shslczdzk03603) to J.C.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1455/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Zhong Shan Hospital Affiliated of Fudan University (No. B2020-217R). Written informed consent was obtained from all patients before enrollment.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. van Samkar G, Ru Tan Y, Hermanns H, et al. Comparison of Patient-Controlled versus Continuous Epidural Analgesia in Adult Surgical Patients: A Systematic Review. J Clin Med 2023;12:3164. [Crossref] [PubMed]
2. Parks L, Routt M, De Villiers A. Enhanced Recovery After Surgery. J Adv Pract Oncol 2018;9:511-9. [PubMed]
3. Ruzzon A, Nassif PAN, Prigol L, et al. Roux-in-Y gastrojejunal bypass: which anesthetic technique has best results? Arq Bras Cir Dig 2021;34:e1530. [Crossref] [PubMed]
4. Jouybar R, Saravi ZF, Dehghani N, et al. Comparative Efficacy of 3 Adjuvant Medications Used in Combination with Intrathecal Bupivacaine for Caesarian Section Anesthesia: A Randomized, Double-Blind Clinical Trial. Curr Ther Res Clin Exp 2022;97:100688. [Crossref] [PubMed]
5. Wang Z, Jiang C, Yao H, et al. Central opioid receptors mediate morphine-induced itch and chronic itch via disinhibition. Brain 2021;144:665-81. [Crossref] [PubMed]
6. Okutani H, Lo Vecchio S, Arendt-Nielsen L. Mechanisms and treatment of opioid-induced pruritus: Peripheral and central pathways. Eur J Pain 2024;28:214-30. [Crossref] [PubMed]
7. Evangelista MC, Steagall P, Garofalo NA, et al. Morphine-induced pruritus after epidural administration followed by treatment with naloxone in a cat. JFMS Open Rep 2016;2:2055116916634105. [Crossref] [PubMed]
8. Nguyen E, Lim G, Ding H, et al. Morphine acts on spinal dynorphin neurons to cause itch through disinhibition. Sci Transl Med 2021;13:eabc3774. [Crossref] [PubMed]
9. Kozono H, Yoshitani H, Nakano R. Post-marketing surveillance study of the safety and efficacy of nalfurafine hydrochloride (Remitch(®) capsules 2.5 µg) in 3,762 hemodialysis patients with intractable pruritus. Int J Nephrol Renovasc Dis 2018;11:9-24. [Crossref] [PubMed]
10. Zeng Z, Lu J, Shu C, et al. A comparision of nalbuphine with morphine for analgesic effects and safety : meta-analysis of randomized controlled trials. Sci Rep 2015;5:10927. [Crossref] [PubMed]
11. Jannuzzi RG. Nalbuphine for Treatment of Opioid-induced Pruritus: A Systematic Review of Literature. Clin J Pain 2016;32:87-93. [Crossref] [PubMed]
12. Stokłosa I, Więckiewicz G, Stokłosa M, et al. Medications for the Treatment of Alcohol Dependence-Current State of Knowledge and Future Perspectives from a Public Health Perspective. Int J Environ Res Public Health 2023;20:1870. [Crossref] [PubMed]
13. Jia Z, Chen Y, Gao T, et al. Nalmefene vs. dexmedetomidine for prevention of postoperative hyperalgesia in patients undergoing laparoscopic gynecological surgery with remifentanil infusion: A randomized double-blind controlled trial. Front Pharmacol 2023;14:1131812. [Crossref] [PubMed]
14. Borgeat A, Stirnemann HR. Ondansetron is effective to treat spinal or epidural morphine-induced pruritus. Anesthesiology 1999;90:432-6. [Crossref] [PubMed]
15. Dougherty TB, Porche VH, Thall PF. Maximum tolerated dose of nalmefene in patients receiving epidural fentanyl and dilute bupivacaine for postoperative analgesia. Anesthesiology 2000;92:1010-6. [Crossref] [PubMed]
16. Pellegrini JE, Bailey SL, Graves J, et al. The impact of nalmefene on side effects due to intrathecal morphine at cesarean section. AANA J 2001;69:199-205. [PubMed]
17. Hirabayashi M, Doi K, Imamachi N, et al. Prophylactic Pentazocine Reduces the Incidence of Pruritus After Cesarean Delivery Under Spinal Anesthesia With Opioids: A Prospective Randomized Clinical Trial. Anesth Analg 2017;124:1930-4. [Crossref] [PubMed]
18. Tian X, Niu K, Cao H, et al. Pruritus after continuous administration of epidural morphine for post-cesarean delivery analgesia: a case control study. BMC Pregnancy Childbirth 2021;21:60. [Crossref] [PubMed]
19. Li N, Wang C, Zhao Y, et al. STING controls opioid-induced itch and chronic itch via spinal tank-binding kinase 1-dependent type I interferon response in mice. J Neuroinflammation 2023;20:101. [Crossref] [PubMed]
20. Xie K, Wang YL, Teng WB, et al. The Median Effective Concentration (EC50) of Epidural Ropivacaine With Different Doses of Oxycodone During Limb Surgery in Elderly Patients. Front Med (Lausanne) 2022;8:808850. [Crossref] [PubMed]
21. Gyimesi G, Hediger MA. Transporter-Mediated Drug Delivery. Molecules 2023;28:1151. [Crossref] [PubMed]
22. Fang B, Wang L, Gu J, et al. Physicochemical stability of ternary admixtures of butorphanol, ketamine, and droperidol in polyolefin bags for patient-controlled analgesia use. Drug Des Devel Ther 2016;10:3873-8. [Crossref] [PubMed]
23. Yan H, Chen J, Luo J, et al. Prophylatic use of IV nalmefene to prevent epidural opioid-induced pruritus: A multicenter, randomized clinical trial. J Clin Anesth 2024;92:111301. [Crossref] [PubMed]
24. Elsayed MM, Elgohary IE, Abdelhamid HHS, et al. The effectiveness of sertraline in alleviating uremic pruritus in hemodialysis patients: a randomized clinical trial. BMC Nephrol 2023;24:155. [Crossref] [PubMed]
25. Becker LM, Teunissen AJW, Koopman JSHA. Prevention and Treatment of Neuraxial Morphine-Induced Pruritus: A Scoping Review. J Pain Res 2022;15:1633-45. [Crossref] [PubMed]
26. Gammaitoni AR, Davis MW. Comparison of the pharmacokinetics of oxycodone administered in three Percocet formulations. J Clin Pharmacol 2002;42:192-7. [Crossref] [PubMed]
27. Nakatsuka N, Minogue SC, Lim Masc J, et al. Intravenous nalbuphine 50 µg·kg(-1) is ineffective for opioid-induced pruritus in pediatrics. Can J Anaesth 2006;53:1103-10. [Crossref] [PubMed]
28. Cook JA, Julious SA, Sones W, et al. DELTA(2) guidance on choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial. BMJ 2018;363:k3750. [Crossref] [PubMed]