MISCELLANEOUS Intra-operative Oxycodone Reduced Postoperative Catheter-Related Bladder Discomfort Undergoing Transurethral Resection Prostate: A Prospective, Double Blind Randomized Study Juncheng Xiong 1, Xiang Chen 1, Chengwei Weng 1, Shuqun Liu 1, Jian Li2* Purpose: To observe the efficacy of intravenously injected oxycodone intraoperative on postoperative urinary catheter-related bladder discomfort (CRBD). Materials and Methods: Patients with ASA I-III who received trans-urethral resection of prostate under general anesthesia were observed. Patients who were randomized to the control group(C) (n = 45) received placebo and the group oxycodone(Q) received oxycodone (n =46 ) 0.03mg/kg of oxycodone before the end of operative 10min. The incidence and severity (mild, moderate, severe) of CRBD were assessed at 0, 1/2 h, 2 h and 6 h postoperatively. VAS scores were used to assess pain intensity during the same period. Postoperative PCA analgesic sufentanil dose and the incidences of nausea, vomiting, dizziness, over sedation were recorded in these patients. Result: Compared with the control group, the incidence of CRBD was significantly lower in the oxycodone group at 0 [22 (49 %) vs. 10 (22%); P = .007], 1/2h [18 (40%) vs. 9 (20%); P = .033], 2h [11 (24%) vs. 4 (9%); P = .001]. The severity of CRBD at 0 [mild, 9 (38%) ; moderate 9 (20%), severe 4 (9%)] was lower in the group Q than the controlled group [mild, 4 (38%) P = .023; moderate 5 (11%), P = .034, severe 1 (2%), P = .012]. 1/2 h [mild, 11 (24%) Vs 5(11%), P = .020]. Compared with the group C, VAS scores were lower in group Q at 0, 1/2h (P = .001) and significantly decreased sufentanil dosage within 6h ( P = .001). There were no significant differences in the incidence of postoperative adverse effects between two groups. Conclusion: Oxycodone can effectively prevent patients with CRBD after TURP without incurring serious ad- verse effects. Keywords: oxycodone; catheter-related bladder discomfort; postoperative, complication; trans-urethral resection prostate; visual analgesic score INTRODUCTION Patients with urinary bladder catheterization fre-quently complain of catheter-related bladder dis- comfort (CRBD) postoperatively.(1) CRBD is a com- mon and distressing complication that often occurs in post-anesthesia care unit(PACU). CRBD causes irri- tability and delirium, aggravates pain, and reduces the quality of recovery.(2) Many risk factors for CRBD have been indentified in previous studies such as male sex, diameter of the Foley catheter, and types of operations. (3,4) In our previous study, we have observed a high oc- currences of CRBD in female patients underwent lapa- roscopic hysterectomy.(5) Unlike postoperative pain, CRBD may be resistant to conventional analgesic therapy such as opioids, because a different underlying mechanism is involved. Many agents, including the muscarinic receptor blockers such as Oxybutynin, tolterodine, tramadol and butylscopol- amine(6-9) and central nerves system inhibitors such as ketamine and gabapentin(10,11), have been investigated as approaches in the prevention or treatment of CRBD. 1Department of anesthesiology, Wenzhou people’s hospital. No.57 canghou street, Lucheng District of Wenzhou City, Zhejiang prov- ince, People Republic of China, 325000. 2 Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Ouhai District of Wen- zhou, Zhejiang, P. R. China, 325000. *Correspondence: Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, NanbaixiangOuhai District of Wenzhou, Zhejiang,P.R.China, 325000. Tel: +8613758431800. E-mail: 313591073@qq.com. Received November 2017 & Accepted February 2018 But various side-effects of these agents limited their use. Oxybutynin, tolterodine, are oral agents with vari- ous anticholinergic side-effects.(6,7) Tramadol and keta- mine were effective for the prevention and treatment of CRBD, but these agents can cause sedation after oper- ation.(8,10,11) Oxycodone is a semi-synthetic opioids prepared from opium alkaloidthebaine plant derivative.(12) Its μ and κ dual-receptor agonism has a unique effect in the treat- ment of visceral pain.(13-15) We have reported that oxy- codone was effective for the treatment of CRBD after laparoscopic hysterectomy in our previous study.(5) But the effects for CRBD during TURP has no investigated. We conducted a prospective, double-blind randomized, single-center study to investigate whether oxycodone has preventive effects on early postoperative CRBD after TURP. MATERIALS AND METHODS Study Population This prospective, randomized, double-blind and place- bo controlled study was performed after approval from Urology Journal/Vol 16 No. 4/ July-August 2019/ pp. 392-396. [DOI: http://dx.doi.org/10.22037/uj.v0i0.4267] ethic committee of Wenzhou people’s hospital, number: 2016003. The protocol for this clinical trial was regis- tered at CHICTR.ORG.CN (ChiCTR-IPR-16008814). During preoperative visit, all patients provided in- formed consents and were educated about the symp- toms of CRBD (characterized as a burning sensation with an urge to void or as discomfort in the suprapubic area). Inclusion and exclusion criteria Patients with an ASA physical status I to III, who were scheduled to transurethral resection prostate, were in- cluded. Patients were excluded if they had a history of severity heart disease, lung disease, psychiatric disease, chronic pain or long-term administration of analgesics. Procedures Patients were randomly assigned to one of two groups (control(C) or oxycodone(Q)) with the help of a com- puter generated random number table. The assignments were concealed in opaque envelopes and opened imme- diately before induction by a nurse who was blinded to this study and was responsible for preparing the study drugs. All medications were administered in identical 2 mL syringes. All patients had no premedication, standard monitor- ing consisted of ECG, non-invasive arterial pressure (NIBP), and pulse oximetry (SpO2). Anesthesia was induced with 0.05 mgkg midazolam, 4μg/kg fentanyl, 1.5 mg/kg propofol and 0.6mgkg-1rocuronium. Intra- operative maintenance anesthesia relied on intravenous anesthesia; remifentanil infusion were maintained 0.2 μg/kg/min; intraoperative propofol infusion rate was adjusted to maintain BIS value within 40-60; rocuroni- um was intermittently injected. 10min before the end of operative, the group controlled received same volume normal saline, whereas the oxycodone group received intravenous inject oxycodone 0.03mgkg-1(product batch number: AW259, Mundipharma, Britain). 22/24 Foley urinary catheter was inserted and 5 mL sterile normal saline was injected into the balloon at the end of operation. After the surgery, 0.5 mg atropine and 1 mg neostigmine were administered to antagonize resid- ual muscle relaxation. These patients were transferred to PACU after the endotracheal catheter was removed. PCIA analgesia was postoperatively applied. The an- algesic was 100 μg sufentanil added to 100ml normal saline, the background infusion was 1 mL per hour, the predetermined time was 8 min and the volume of each press was 2 mL. Oxycodone reduce CRBD in TURP-Xiong et al. Figure1. Patient flow diagram Table1. Characteristics of patients, anesthesia and surgery. A Con group Oxy group P value Age (yr) 71 ± 8 74 ± 9 .577 BMI (kg/m2) 24 ± 6 26 ± 5 .087 ASA class (Ⅰ~Ⅱ/Ⅲ) 32/14 34/11 .522 Urinary catheter size (F22/F24) 26/20 28/17 .580 Duration of anesthesia (min) 118 ± 25 123 ± 32 .409 Duration of surgery (min) 101 ± 24 105 ± 18 .372 Time to extubation (min) 7.1 ± 1.6 7.7 ± 2.2 .140 Intraoperative remifentanil resumption (mg) 1.84 ± 0.25 1.79 ± 0.32 .409 Intraoperative propofol resumption (mg) 697 ± 185 731 ± 223 .431 a Data are presented as mean ± SD or number (percent) Abbreviations: BMI, Body Mass Index；ASA, American society of anesthetists Miscellaneus 393 Evaluations The primary outcome was defined as the reduction in the severity of CRBD.(7) Occurrences and severity of bladder discomfort was recorded as: none, when pa- tients did not complain of any CRBD on questioning; mild discomfort, patients were reported CRBD on questioning only; moderate, urge to pass urine reported by the patient without questioning; severe discomfort, urge to pass urine accompanied by behavioral respons- es, such as flailing limbs, strong vocal responses or at- tempts to pull the catheter out. Secondary outcomes were time to extubation, sufentanil consumption, heart rates (HRs), mean arterial pressure (MAP) in PACU, and adverse effects included PONV, over sedation, dry mouth and facial flushing. All these outcomes were assessed at 0, 1/2 h, 2, and 6 h after ad- ministration of the study drug by blinded assessors. VAS scores were used to assess pain in these patients: 0 point, no pain; 10 points, unbearable pain. The Ramsay Sedation Scale was measured postoperatively at 0, 1/2 h, 2, 6 hand recorded as follows: 1 (anxious, agitated or restless); 2 (cooperative, oriented and tranquil); 3 (responds to commands, asleep); 4 (brisk response to light glabellar tap or loud noise); 5 (sluggish response to light glabellar taps or loud noise); or 6 (no response). Patients with a sedation scale score of at least 4 were considered over sedation. The patients with severe vomiting received intrave- nous injection of 4 mg ondansetron. Analgesic doses received by the two groups of patients within 6 hours after the operation were recorded. Statistical analysis According to a previous study, 53% of patients com- plain of CRBD postoperatively.(7) Assuming that this incidence would decrease to 15% after intervention, we calculated that 36 patients would be needed in each group to achieve statistical significance (α = .05 and β = .20). Considering a 20% dropout rate, 91 patients per group were included. All data were analyzed with SPSS16.0 software pack- age(SPSS, Inc., Chicago, IL,USA). The severity of CRBD were analyzed by Mann-Whitney U test, HR and MAP over time between the groups were analyzed by repeated measures analysis of variance (ANOVA) and then t-test was used to compare values at each time point. Rescue analgesics was analysed by t-test. Anal- yses of categorical variables (incidence of side effects) were performed by χ2 or Fisher’s exact-tests. Data were analyzed according to the intention-to-treat principle. P < 0.05 indicated statistically significant differences. RESULTS 110 patients from August 2016 to December 2016were screened for inclusion in the study. Nineteen patients were excluded [not meeting inclusion criteria (n = 11), declined to participate (n = 6), cancelled operation (n = 2)]. The remaining 91 patients comprised the study group (Figure 1). No differences in the demographic characteristics of the groups were observed (Table 1). Compared with the control group, the incidence of CRBD was significantly lower in the group Q at 0 [22(49%) vs. 10 (22%); P = .007], 1/2h [18 (40%) vs. 9(20%); P = .033], 2 h [11 (24%) vs. 4(9%); P = .001], respective. The severity of CRBD at 0 [mild, 9 (38%) ; moderate 9 (20%), severe 4 (9%)] was lower in the group Q than the controlled group [mild, 4 (38%) P = .023; moderate 5 (11%), P = .034, severe1 (2%), P = .012]. 1/2 h [mild, 11 (24%) Vs 5(11%), P = .020]. (Table 2) The difference in VAS scores in 0 and 1/2h in group Q was significance lower compared with group C (P = .001). Sufentanil dosage within 6 hours after the op- eration was lower in observation group than in control group (P = .001). There were no statistical significant differences in MAP, HR and SPO2 in any period be- Table 2. Incidence and severity of postoperative CRBD, VAS scores and sufentanil consumptions 6 h after operation A Group Group Oxycodone Group control Time (h) 0 1/2 2 6 0 1/2 2 6 CRBD 10 9 9 5 22 18 16 12 CRBD severity Mild 4 5 3 2 9 11 7 4 Moderate 5 3 1 1 9 5 3 1 Severe 1 1 0 0 4 2 1 0 Postoperative VAS value 3.05 ± 0.14 2.61 ± 0.66 1.79 ± 0.67 1.75 ± 0.17 6.72 ± 0.21 4.89 ± 0.14 3.52 ± 0.33 3.06 ± 0.41 Sufentanil consumption(ug) 8.2 ± 0.85 12.1 ± 1.16 a Data are presented as mean ± SD or number (percent) Abbreviation: CRBD, catheter related bladder discomfort A Group T0 T1 T2 T3 T4 MAP (mmHg) Group C 88 ± 22 82 ± 19 85 ± 18 74 ± 16 72 ± 22 Group Q 92 ± 18 75 ± 7 76 ± 12 77 ± 18 74 ± 18 HR (bpm) Group C 78 ± 12 65 ± 8 71 ± 7 73 ± 8 72 ± 8 Group Q 82 ± 10 63 ± 9 75 ± 7 68 ± 8 65 ± 8 SpO2 (%) Group C 97 ± 2 98 ± 1 98 ± 2 96 ± 2 99 ± 1 Group Q 98 ± 1 96 ± 2 97 ± 2 98 ± 2 98 ± 1 a Data are presented as mean±SD Table 3. Patients' vital signs of preoperative and postoperative Oxycodone reduce CRBD in TURP-Xiong et al. Vol 16 No 04 July-August 2019 394 tween two groups (Table 3). During this study, 3 cases (7%) in trial group and 1 case (2%) in control group experienced over-sedation (P = .317); There were no significant differences nausea [3(7%) vs. 1 (2%); P = .317], and vomiting [2 (4%) vs. 1 (2%); P = .570] between group Q and group C. The difference in dizziness between twogroups had no significance [5 (11%) vs. 3 (7%); P = .479] (Table 4). DISCUSSION We have demonstrated that intraoperative oxycodone reduces the incidence and severity of postoperative CRBD and postoperative opioid requirements in pa- tients undergoing TURP. CRBD is one of the most important factors causing postoperative irritability. The incidence of CRBD in previous studies was reported with various ranges of 64 to 90% after general anesthesia in varies operations. In this study, 28 (60%) of 46 patients in the control group complained of CRBD at 6 h postoperatively undergo- ing TURP, which is lower than the incidence of CRBD after urological operations, and according to the previ- ous study. The causes for CRBD include urethral mu- cosa injury due to urethral catheterization, the central nervous system is in the inhibitory state and the patients psychologically reject catheter-related discomfort. Gynecological endoscopic procedures and retraction the uterus through the vagina may irritate the neck of bladder, constituting one of the causes for occurrence of CRBD. The peripheral nerves of lower urinary tract consist of sacral parasympathetic nerve, thoracolumbar sympathetic nerve and sacral-pudendal nerve.(16) Previ- ous studies had shown that application of muscarinic subtype 3 receptor inhibitors Oxybutynin, tolterodine, can substantially reduce the risk or severity of CRBD. But these drugs have many adverse effects, such as dry mouth, dizziness and facial flushing, that cannot be ful- ly avoided.(6-8,10) CNS acting drugs and opiods receptors agonists ketamine, pentazocine, tramadol, were effec- tive for the prevention and treatment of CRBD, but these agents can cause sedation and PONV after oper- ation.(11) Oxycodone is μ and κ opioid receptor dual agonist. It can be used intraoperatively and postoperatively to re- lieve pain, especially with unique analgesic effect on visceral pain.(17,18) The onset of iv. oxycodone is 2-3 min, with a peak effect at 5min, and a elimination halt effects ranged from 4-6 h. In our study, we adminis- tered oxycodone 0.03mg/kg, which is used to treatment of acute pain postoperative single injection, reduced the postoperative incidence of CRBD at 0, 1, 2, and 6h re- spectively. The mechanism of oxycodone action in the treatment of CRBD may include: Firstly, oxycodone activates κ receptor to effectively relieve pain induced by spasms of vesical neck and urethra mucosal injury in patients. Secondly, oxycodone acts on central nervous system to regulate and control the central excitability of vesical afferent reflex and sacral reflex, leading to reduced sensitivity to CRBD in patients. Thirdly, the in- hibitory effect of oxycodone on M1 and M3 muscarin- ic receptors is not yet confirmed, but previous studies showed that tramadol, a drug similar to oxycodone, was able to inhibit M1 and M3 muscarinic receptors to ef- fectively prevent the occurrence of CRBD in addition to its opioid receptor agonism.(8) I.V. oxycodone was clinically effective for the treatment of CRBD as an an- timuscarinic agent, but an inhibitory action of oxyco- done on the activity of the detrusor muscle has not been reported in animal or human studies. Further experi- ments in these areas are warranted. This study showed that oxycodone could reduce VAS scores and PCA dosage in all postoperatively periods, suggesting that oxycodone was able to relieve postoperative pain and reduce postoperative analgesic dosage in addition to its efficacy on CRBD. There was no significant difference of extubation time. 3 cases in the observed group and 1 case in the control group had finger pulse oxygen satu- ration less than 90%, the condition returned to normal after oxygen inhalation through the mask. Compared with the controlled group, the incidence of nausea and vomiting was not higher in the oxycodone group. There were no significant differences in other adverse reac- tions such as dizziness and sedation between the two groups. Several limitations of the current study should be considered. First, a single dose of 0.03 mg/kg ox- ycodone was used in this study. We did not evaluate the dose–response effect of oxycodone for the preven- tion of CRBD. In our previous study, however, it was shown that increase dose of oxycodone could result in adverse effects of vomiting and dizziness.(19) Secondly, various agents are routinely used to decrease CRBD. In this study, however, a direct comparison between the effect of oxycodone and others agents on the incidence of CRBD was not performed. CONCLUSIONS Intravenous injection of 0.03mg/kg oxycodone 10 min- utes before the end of operation can effectively prevent the occurrence and severity of CRBD, decrease PCA dosage, and reduce VAS scores without causing severe adverse reactions in these patients after the operation. ACKNOWLEDGEMENT We thank Wu YQ, Li H, who is anesthetists in the de- partment of Anesthesiology, Wenzhou people’s hospi- tal for invaluable assistance in collecting the data in this study. CONFLICT OF INTEREST No other competing interests declared. REFERENCES 1. 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