COMPARISON OF FENTANYL AND MORPHINE IN INTRAVENOUS PATIENT-CONTROLLED ANALGESIA AFTER OPEN GASTRECTOMY SURGERY

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1 COMPARISON OF FENTANYL AND MORPHINE IN INTRAVENOUS PATIENT-CONTROLLED ANALGESIA AFTER OPEN GASTRECTOMY SURGERY Nguyen Toan Thang, Nguyen Huu Tu Department of Anesthesia Critical Care, Hanoi Medical University A prospective romized study was conducted to assess the efficacy adverse effects of a fentanyl intravenous patient - controlled analgesia (IV - PCA) compared with a morphine IV-PCA after open gastrectomy surgery. Ninety patients were romly allocated into two groups: Group F with a fentanyl concentration of 25 μg/ml, a bolus of 25 μg a lockout time of 10 minutes Group M with a morphine concentration of 1 mg/ml, a bolus of 1 mg a lockout time of 10 minutes. No background infusion was included in either group. Pain severity was assessed by Visual Analogue Scale (VAS) at rest on coughing, the incidence of adverse effects was assessed postoperatively during the first 24 hours. Group F showed significantly lower mean VAS scores at rest on coughing compared to Group M. The incidence of postoperative nausea vomiting (PONV) in group M was 31.1% in group F was 15.5%, p < The incidence of pruritus in group M was 17.8% in group F was 8.9%, p < The incidence of patients reporting that they were very satisfied with their pain relief in Group F was higher than that in Group M (71.1% of patients in group F versus 51.1% of patients in group M, p < 0.05). No respiratory or cardiovascular complications were observed in either group. The fentanyl IV - PCA is a more effective postoperative analgesia than the morphine IV - PCA, providing greater patient satisfaction lower incidences of PONV pruritus after open gastrectomy surgery. Keywords: intravenous PCA, fentanyl, morphine, gastric surgery I. INTRODUCTION Postoperative pain has substantial, physical psychosocial effects on patients. Insuf- stard method of pain relief that allows patients to self - administer small preset ficient analgesia can thereby delay patient boluses recovery. Although there has been increased conventional methods, IV - PCA provides understing of the pathophysiology of pain of opioids. In comparison with slightly better pain control higher patient in recent years, as well as the recent develop- satisfaction. In the United States, there are ment of improved pharmacology analge- approximately 13 millions patients per year sic techniques, acute pain treatment after using this method to control acute pain [3; 4]. surgery remains insufficient, even in devel- In Vietnam, IV - PCA with opioids has also oped countries [1; 2]. Intravenous Patient- been widely adopted for postoperative pain Controlled Analgesia (IV - PCA) is a popular management. Traditionally, morphine is the most commonly utilized opioid in this setting, yet studies providing evidence that morphine Corresponding author: Nguyen Toan Thang, Department of Anesthesia Critical Care, Hanoi Medical University thanggmhs@gmail.com Received: 20 October 2016 Accepted: 10 December is the preferred opioid for IV - PCAs are lacking. In spite of having strong analgesic effects being low - cost, morphine can cause respiratory depression other

2 adverse effects such as deep sedation, who were scheduled for open gastrectomy nausea vomiting, pruritus, urinary surgery under general anesthesia were en- retention [1; 2]. rolled in this study. Patients were excluded if Fentanyl is a 4 - amilidopiperidien com- they were younger than 18 years or older than pound with high lipid solubility, which greatly 80 years old, had a history of allergy to reduces the onset time of the analgesic effect. opioids, had daily intake of opioids or other It takes 30 seconds for fentanyl to begin to analgesics, had known or suspected drug take effect, with its maximum effect reached addiction, or were unable to underst or use five minutes after administration. Fentanyl is a visual analogue scale (VAS) a patient- also a potent ideal drug for IV - PCA, as controlled analgesia (PCA) device. Patients its redistribution is rapid wide with a short with severe renal hepatic diseases were duration, it does not produce the active also excluded. metabolites that cause respiratory depression 2. Study design [5, 6]. Fentanyl is a µ opioid receptor agonist with several advantageous pharmacological characteristics, including strong analgesic effects (approximately times more potent than morphine) as mentioned above, a more rapid onset of action compared to morphine [7]. Studies by Hutchison Stavropoulou suggested that fentanyl, with its effective ability to relieve pain its low A prospective romized study was carried out in the Anesthesia Critical Care Department of Bach Mai University Hospital in Hanoi, Vietnam from October 2014 to November In this study, patients were blinded to their group assignment, which was undertaken using a sealed envelope technique (Group F, n = 45; Group M, n = 45). frequency of adverse effects such as postop- In the operating room, all patients were erative nausea vomiting (PONV), pruritus monitored using electrocardiography (ECG), or urinary retention, might be more preferable noninvasive arterial blood pressure devices, than morphine for IV - PCA [8; 9]. However, oxygen saturation end-tidal carbon little information in the literature has been re- dioxide measuring equipment. Patients were ported regarding the analgesic efficacy induced with 2 mg/kg of intravenous (IV) adverse effects of the fentanyl IV - PCA [10]. propofol. After muscle relaxation had been This study was carried out to prospectively achieved by IV administration of 0.6 mg/kg compare the postoperative analgesic efficacy rocuronium adverse effects of IV - PCAs using intubated fentanyl morphine in patients who just started. recently underwent open gastrectomy. propofol infusion at a rate of 6-8 mg/kg/hour II. SUBJECTS AND METHODS 1. Subjects bromide, the controlled Anesthesia was trachea was ventilation was maintained by intermittent IV injection of fentanyl rocuronium. At the end of surgery, all patients received one gram of paracetamol. Ninety patients with American Society of Intensities of postoperative pain at rest Anesthesiologists (ASA) physical status I - II on active coughing were evaluated using a 89

3 VAS, from 0 ( no pain ) to 10 ( the worst pain a respiratory rate of less than 8 breaths per imaginable ). Adequate analgesia was defined minute was observed, the PCA pump was as VAS < 3 at rest. A Modified Ramsay stopped. VAS at rest on active coughing, Sedation Scale (from 1 to 6), where 1 is any incidence of PONV, the patient s anxious or restless or both 6 is no Ramsay scale were recorded at 2, 6, 12 response to stimulus, was used to determine 24 hours after the end of surgery. The degree the After of patient satisfaction was evaluated extubation, patients received 100 μg of fen- categorized into three levels at the 24th hour tanyl or 1 mg of morphine every 10 min when after surgery: very satisfied, satisfied, or they experienced pain at rest until they dissatisfied. For patients experiencing severe reached an adequate level of comfort before PONV, 10 mg of metoclopramide or 4 mg of starting the IV - PCA. ondansetron was given intravenously. Oxygen appropriate level of sedation. The PCA device used a mechanical pump (B Braun, Germany). In Group F, the PCA (2 liters per minute) was administration for 24 hours postoperatively in all cases. pump was programmed with the following set- Results were analysed using the Student's tings: bolus, 1 ml; lockout time, 10 min; t test, the Mann Whitney test chi-square maximum dose per 4 hours, 15 ml/h. The in- tests where appropriate values of p < 0.05 fusion solution containing 1.25 mg of fentanyl were considered statistically significant. was adjusted to 50 ml by dilution with 0.9% normal saline (the concentration of fentanyl 3. Research ethics was 25 μg/ml). In Group M, the PCA device All study procedures complied with the was programmed with the following settings: ethical principles of biomedical research. bolus, 1 ml; lockout time, 10 min; maxi- Written informed consent was obtained from mum dose per 4 hours, 15 ml/h. The infusion patients. All patient information was kept confi- solution containing 50 mg of morphine was dential secure. adjusted to 50 ml by dilution with 0.9% normal saline (the concentration of morphine was 1 mg/ml). The background infusion dose was not applied an both groups. III. RESULTS A total of 90 patients were involved in this study, with 45 patients receiving morphine During the first 24 hours postoperatively, (Group M) 45 patients receiving fentanyl non-invasive artery blood pressure, heart rate, (Group F). The demographic, surgical, oxygen saturation, respiratory rate occur- anesthetic characteristics of all patients by rence of untoward events were recorded at group are shown in Table 1. There were no two hour, three hour six hour intervals. statistically significant differences between Hypotension (20% reduction in systolic blood the two groups in terms of age, sex, weight, pressure compared with preoperative base- ASA physical classification, intraoperative an- line) was treated using a vasopressor /or esthetic sum, size of incision during surgery, IV fluid, at the anesthesiologist s discretion. If or surgical time (table 1). 90

4 Table 1. The demographic, surgical anesthetic characteristics of the participants in each group Groups Group M (n = 45) Group F (n = 45) Age (year)ª 54.2 ± ± 10.2 Weight (kg)ª 52.7 ± ± 10.7 Male gender (%) ASA I - II (%) ± ± ± ± 3.8 Intraoperative fentanyl (mcg)ª ± ± 59.2 Intraoperative propofol (mg)ª ± ± Characteristics Operating time (minutes)ª Size of incision (cm)ª ª Mean value ± SD 8 7 VAS at rest Group F 6 Group M 6 VAS at coughing 5 4 Group F 4 Group M Ext H0 H1 H2 H3 H6 H9 H12 H18 H24 Time (hour) p <0.05 Time (hour) 1 p <0.05 Ext H0 H1 H2 H3 H6 H9 H12 H18 H24 Figure 1. VAS score during IV-PCA use Participants postoperative pain scores at rest on active coughing are presented in Figure 1. Mean VAS scores at rest were significantly lower in Group F than in Group M at the twelfth, eighteenth, twenty-fourth hour after surgery. Mean VAS scores on active coughing were significantly lower in Group F than in Group M at all time points from the third hour to the twenty-fourth hour during IV - PCA use (p < 0.05). 91

5 100 Heart rate (bpm) Ext Ho H Time (hour) 70 H9 H12 H18 H24 Group F H2 H3 H6 Group M MAP (mmhg) Group F Group M Time (hour) Ext Ho H1 H2 H3 H6 H9 H12 H18 H24 Figure 2. Changes in mean heart rate mean arterial blood pressure (MAP) The average values of heart rate MAP at all time points evaluated in each group remained within normal limits. There were no statistically significant differences between the two groups in terms of heart rate or MAP (Figure 2). Table 2. Adverse events while using the IV-PCA patient satisfaction with the IV - PCA Group M (n = 45) Group F (n = 45) p Ramsay 4 (%) > 0.05 PONV (%) < 0.05 Pruritus (%) < 0.05 Degree of satisfaction (%) Very satisfied Satisfied Dissatisfied Groups Adverse Events < 0.05 PONV pruritus were the two most patients experienced vomiting (1 in group M, 1 common adverse effects during IV - PCA use. in group F), one patient in Group M had Group M experienced higher rate of PONV severe pain on nighttime awakening. pruritus than Group F (Table 2). The large Six patients from Group F five patients majority of patients (97.7%) from the two from Group M showed scores of 4 on the groups were satisfied with the PCA - based Ramsay scale on the first day after surgery. method of pain relief. There was a statistically No significant differences were found between significant higher incidence of patients in groups, no cases of Ramsay 5 (deep se- Group F reporting feeling very satisfied with dation) or 6 (coma) were seen. Respiratory their IV - PCA, as compared to the number of depression, as indicated by a decrease in a patients reporting that they were "very satis- patient's respiratory rate to less than 8 breaths fied" in Group M (p < 0.05). Three patients per minute, was not observed among any pa- were dissatisfied with analgesia. In which, two tients using the IV - PCA. Oxygen saturation 92

6 was maintained at more than 92% among all results are consistent with what Hutchison et. participants. No hypotension was observed al. (2006) found in orthopedic patients. In their among any participants in either group. study, they found that the median VAS on post -operative days one two were significantly IV. DISCUSSION lower in fentanyl IV - PCA group compared to Optimal pain management requires a the morphine IV - PCA group [8]. Stavropoulou reasonable balance of adequate analgesia et. al. (2008) compared fentanyl morphine minimal adverse effects. The selection of in patients who had just had major abdominal the opioid to use for acute postoperative pain surgery found that the patients in the fen- management has not always been based on tanyl group had significantly improved pain the evidence. relief [9]. However, of note, Howell et al found Moreover, morphine has become the drug of no differences in efficacy among the two anal- choice used for IV - PCAs because of its low gesics [11]. most cost. up-to-date Recently, scientific however, fentanyl has In the present study, fentanyl may have emerged as a potentially more appropriate provided opioid to use in IV - PCAs. This study was because of its pharmacological profile. The conducted to further clarify the role of fentanyl onset of analgesic effects is more rapid with in IV - PCA use [1; 4; 10]. fentanyl than with morphine. Since fentanyl Table 1 showed no statistically significant the superior analgesic effects shows fold greater liposolubility than differences in patients, anesthesia levels, or morphine, surgery-related characteristics among partici- elicitation of pain relief is much quicker. penetration into tissues pants in Group F Group M. These charac- Analgesic effects of bolus administration can teristics may affect the severity duration of thus be rapidly achieved for patients when postoperative pain, analgesic consumption, as they feel pain. In addition, the analgesic well as the ability of tolerance to opioid-related potency of fentanyl is times greater adverse effects. The homogeneity of the two than that of morphine [7]. groups in terms of these characteristics makes Group F using the fentanyl IV - PCA saw the comparison between these groups more significantly lower rates of PONV pruritus accurate objective. than Group M using the morphine IV - PCA. The present study indicates that an IV - Furthermore, the number of patients that were PCA for postoperative analgesia is more effec- very satisfied with their pain relief was higher tive with fentanyl than with morphine. Lower in Group F than in Group M (Table 2). The pain scores both at rest (at the twelfth, eight- incidence of patients with Ramsay 4 was eenth, twenty-fourth hours after surgery) comparable between Groups F M (13.3% on active coughing (at time points from 11.1 %, respectively, p > 0.05) at the time the third hour on) were observed in patients of the twenty-fourth hour of measurement. receiving the fentanyl IV - PCA when com- Hutchison et al (2006) found a higher rate of pared to patients receiving the morphine IV - sedation, nausea/vomiting, pruritus in the PCA after open gastrectomy (Figure 1). These group of patients using morphine as the IV- 93

7 PCA in their study, as compared with the College of Anaesthetists Faculty of Pain group using fentanyl as the IV - PCA [8]. Medicine. Melbourne: ANZCA & FPM. Stavropoulou et al found that the rates of 3. Macintyre, P.E (2001). Safety nausea pruritus were also significantly efficacy of patient-controlled analgesia. Br J lower than among patients using fentanyl as Anaesth, 87(1), compared to those using morphine [9]. Patients on fentanyl morphine IV- 4. Cashman, J.N., S. George (2006). Chapter 16 - Patient-Controlled Analgesia, in PCAs saw similar heart rates, blood pressure Postoperative readings, SpO2 measurements (figure 2). Saunders: Philadelphia, No cases of respiratory arrest were observed in either group. These results are consistent with the previous studies comparing fentanyl to morphine [3; 9; 12]. Pain Management, W.B. 5. Grass, J.A (2005). Patient-controlled analgesia. Anesth Analg, 101(5), S Momeni, M., M. Crucitti, M. De Kock (2006). Patient-controlled analgesia in the management of postoperative pain. Drugs, V. CONCLUSION In summary, we found that an IV - PCA using fentanyl had better analgesic efficacy, led to higher patient satisfaction, caused fewer incidences of PONV pruritus, compared with using a morphine IV - PCA. Patients on both fentanyl morphine IV - PCAs had normal pulmonary cardiovascular vital signs throughout the twenty four hours that their use was monitored. Acknowledgement 66(18), Peng, P.W. A.N. Sler (1999). A review of the use of fentanyl analgesia in the management of acute pain in adults. Anesthesiology, 90(2), Hutchison, R (2006). A comparison of a fentanyl, morphine, patient-controlled hydromorphone intravenous delivery for acute postoperative analgesia: a multicentered study of opioid induced adverse reactions Hospital Pharmacy, 41(7), Stavropoulou, E (2008). Opioid Induced Adverse Reactions of Intravenous We would like to express our sincere thanks to the doctors medical staff at the Anesthesia Critical Care Department in the Bach Mai Hospital for their support during this study. Patient Controlled Analgesia: Comparison of Morphine Fentanyl for Acute Postoperative Analgesia. Regional Anesthesia Pain Medicine, 33(5), e Schug SA, Palmer GM, Scott DA, REFERENCES Halliwell R, Trinca J (2015). APM:SE Working Group of the Australian New 1. Hurley, R.W., J.D. Murphy C. Zeal College of Anaesthetists Faculty Wu., Miller et al (2015). Acute Postoperative of Pain Medicine, Acute Pain Management: Pain, in Miller s anesthesia R.D Scientific Evidence (4th edition), ANZCA & 2. Macintyre, P.E (2010). Acute Pain Ma- FPM, Melbourne, 242. nagement: Scientific Evidence. 3rd ed. Wor- 11. Howell, P.R (1995). Patient-controlled king Group of the Australian New Zeal analgesia following caesarean section under 94

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