Comparison of the analgesic effects of transdermal fentanyl and intravenous patient controlled fentanyl after laparotomy

Abstract

AimIn our study, we aimed to show whether TDF patch application is effective and acceptable in the management of postoperative pain management.MethodsIn this prospective randomized study, 60 patients, aged between 18-65 years, who had undergone laparotomy, were included in the American Society of Anesthesiologists (ASA) I-II-III, after Gaziantep University local ethics committee approval. No patient was given premedication. The patients were randomly divided into two groups. TDF patch (50µg/hour) was applied to group TDF (n = 30) 12 hours before the operation and removed 24 hours after the operation. Group patient-controlled intravenous fentanyl analgesia (PCA) (n = 30) was administered postoperatively in the PACU with patient-controlled analgesia with Intravenous fentanyl. When group TDF had pain (VAS 4≥), 100 mg of tramadol was administered as an additional analgesic. Group TDF and Group PCA were clinically observed in the perioperative period.ResultsResting VAS was statistically significantly better in Group PCA than Group TDF at the 2nd, 4th, 6th, 12th, and 24th hours except the postoperative 1st hour (P < .05). Additional analgesic requirement was statistically higher in group TDF than group PCA at 1st, 2nd, 6th, 12th, and 24th hours except postoperative 4th hour (P < .05).ConclusionIt has been concluded that IV fentanyl and PCA are more effective than TDF in the evaluation of patients in the postoperative period in terms of VAS scores, but TDF can be used as an alternative to patient-controlled analgesia for postoperative analgesia with tramadol support if necessary.

Keywords

Introduction

One of the important causes of post-surgical anxiety is postoperative pain. Postoperative pain, which starts with surgical trauma and gradually decreases with wound healing, should be relieved quickly and effectively due to undesirable effects such as sympathetic, endocrinological and metabolic changes caused in the postoperative process and the anxiety it causes. A well-provided analgesia will increase the postoperative comfort of the patient, as well as reduce the cost and the development of complications that will lead to a longer stay in the hospital.¹
Various pain management guidelines have been developed for postoperative analgesia in the last 20 years. Patient-controlled analgesia method used in postoperative analgesia is a contemporary method that allows the patient to provide self-analgesia. However, the cost of the device and the sets, the need for patient cooperation, the need for the patient and staff to be trained in this regard, limiting mobility and incorrect dose applications may be in question.^2-3
Transdermal fentanyl administration is an easy and non-invasive procedure. It was studied for postoperative analgesia in the 1990s and was not preferred due to its disadvantages such as inability to titrate patient-specific doses and insufficient effect in early postoperative analgesia.^4-5 It is understood that the pharmacokinetic properties of transdermal fentanyl were not taken into account in these studies. In the study conducted by Minville et al.⁶ transdermal fentanyl was applied a few hours before the operation, whereas other studies revealed that its effectiveness reached a plateau level in 14 hours and lasted up to 72 hours.^7-8
In our study, we aimed to compare the analgesic effects of transdermal fentanyl and intravenous patient-controlled fentanyl after laparotomy.

Materials and Methods

None of the patients included in the study wanted to quit the study or were included and then excluded from the study. Sixty patients, aged between 18 and 65, who were evaluated as I-II-III according to the American Society of Anesthesiologists classification in the pre-anesthesia evaluation, were included in the study. Patients with kidney and liver failure, patients with cardiac problems, patients with a history of allergy to opioids and the drugs to be administered, pregnant women, patients with opioid dependence, patients with chronic lung disease, patients with dermatological disorders, those with a weight below 50 kg, patients over 100 kg and patients with psychiatric disorders were excluded from the study. The patients were randomly divided into two groups: Group TDF (n = 30): patients treated with transdermal fentanyl patch, and Group PCA (n = 30): patients undergoing intravenous patient-controlled fentanyl analgesia. After that, the patients were evaluated preoperatively one day before the operation, and written and verbal consent forms were obtained. In Group TDF, systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, heart rate, visual analog scale, Ramsey sedation score, peripheral oxygen saturation and respiratory rate values were recorded. To patients in the transdermal fentanyl group, 50 µg/h to the anterior chest wall or arm 12 hours before the operation was applied. A tape giving fentanyl (Durogesic 50 µg/h 5TTS Flaster, Johnson & Johnson, Istanbul, Turkey) was used. The symptoms and signs of nausea, vomiting, bradycardia, dyspnea and itching were recorded in the patients who underwent transdermal fentanyl until the operation. No treatment was given to Group PCA until the operation. Neither group was given any medication or premedication in the preoperative preparation room.
Hemodynamic measurements, sedation scores and visual analog scale values of both groups were recorded in the operating room before induction. Sedation scores of the patients were evaluated with Ramsey sedation score. 2 mg/kg propofol (Propofol 1% Fresenius Kabi, Istanbul, Turkey), 1 µ/kg fentanyl (Adilat, 0.5 mg, 10 ml, Vem İlaç, Istanbul, Turkey) for anesthesia induction after preoxygenation (from 10 L/min for 1 min) in the operating room, and 0.6 mg/kg intravenous rocuronium bromide (Myocron 10 mg, 5 ml vial, Vem İlaç, Istanbul, Turkey) were administered. Hemodynamic measurements were recorded before and after extubation. In the recovery unit, the duration of the modified Aldrete recovery score ≥9 and the sedation scale were evaluated and recorded. After the patients were compiled, they were sent to the relevant service. Side effects such as hemodynamic parameters, Ramsey sedation score, visual analog scale level, nausea, vomiting and pruritus were recorded at postoperative 1, 2, 4, 6, 12 and 24 hours.
In the patient-controlled analgesia group, patient-controlled analgesia was started with a device (Cadd Legacy 6300 ambulatory infusion pump) with a loading dose of 40 µg, a basal infusion of 20 µg/h, a bolus dose of 40 µg, and a lock-in time of 10 minutes with fentanyl. Amounts of fentanyl consumed were recorded.Ethical ApprovalThis study was approved by the Ethics Committee of Gaziantep University, Faculty of Medicine (Date: 18.12.2012, Decision No: 460). Informed written consent was obtained from the patients for this prospective randomized study. It was carried out in Gaziantep University Şahinbey Training Research and Application Hospital Operating Room.Statistical AnalysisSPSS for Windows v13 package program was used for statistical analysis, and P < .05 was considered statistically significant. Kolmogorov-Smirnov test was used to check the conformity of continuous variables with normal distribution. Student’s t-test was used for the comparison of normally distributed variables in two independent groups, and Mann-Whitney U test was used for non-normally distributed variables. The single-sample Z test was used in order to compare the population value versus the sample. Analysis of variance with repeated measures was used in the analysis of data with more than two repeated measures. The relationship between categorical variables was tested with chi-square analysis. Frequency, percentage and mean ± SD values are given as descriptive statistics.

Results

60 randomized clinical trials patients were included in and completed the study. Demographic data are shown in Table 1. When these data were analyzed statistically, no significant difference was found between the groups (P > .05). There was no significant difference between the groups in pre-induction and intraoperative measurements in terms of hemodynamic parameters such as SAP, DAP, MAP, CAD, and SPO2 (P > .05).
When MAP and CAD, which are among the postoperative hemodynamic parameters of the patients, were examined, no significant difference was found between the groups (P > .05).
When the postoperative peripheral oxygen saturations of the patients were evaluated, no significant difference was observed between the groups (P > .05).
When the postoperative respiratory rates of the patients were evaluated, no significant difference was observed between the groups (P > .05).
In terms of postoperative VAS values of the patients, there was statistically significant differences between groups at 2nd hour (P = .001), 4th hour (P = .001), 6th hour (P = .001), 12th hour (P = .001), and 24th hour (P = .001). It was lower in Group PCA (Table II). It was lower in Group PCA (Table 2).
The time for the Aldret recovery score (ARS) to be 9 was statistically higher in Group TDF (P = .001) (Table 3). There was no statistically significant difference between the two groups in terms of postoperative RSS, nausea, vomiting and pruritus data (P > .05). There was a statistically significant difference in the postoperative additional analgesic consumption at the 1st, 2nd, 6th, 12th, and 24th hours, excluding the postoperative 4th hour (P = .001).
Postoperative total fentanyl consumption of the patients was statistically higher in group PCA at 1st-2nd-4th-6th hours compared to group TDF (P = .001). At the 12th and 24th hours postoperatively, group TDF was higher than group PCA (P = .001).

Discussion

In our study in which we compared the postoperative analgesic efficacy of transdermal fentanyl and intravenous patient-controlled fentanyl in elective laparotomy, there was no statistically significant difference between the groups in terms of demographic findings, preoperative and postoperative hemodynamic parameters, and Ramsey sedation score. Postoperative visual analog scale values were significantly lower in the patient-controlled analgesia group compared to the transdermal fentanyl group at all times except the first hour. Postoperative analgesia consumption was significantly lower in the patient-controlled analgesia group than in the transdermal fentanyl group at all times except the fourth hour. Total fentanyl consumption was significantly higher in the patient-controlled analgesia group than in the transdermal fentanyl group in the first six hours.
The transdermal fentanyl method is suggested to be an alternative option for patients who cannot use patient-controlled analgesia, who are not oriented, who are unable to use their hands, and who have difficulty in providing a venous route.⁹ However, in studies conducted, it was observed that respiratory depression was seen in patients who were given additional opioids in cases where the transdermal fentanyl patch was insufficient in terms of analgesia.¹⁰ In this study, we preferred to use tramadol as an analgesic drug as a support in cases where analgesia was insufficient due to the risk of respiratory depression.
Transdermal fentanyl and placebo groups were applied eight hours before the operation and removed 24 hours after the operation.¹¹ Additional analgesia needs of both groups were met with intravenous patient-controlled fentanyl. Compared to the placebo group, the transdermal fentanyl group had less pain and less need for additional analgesia.¹¹ In our study, we aimed to compare the effects of transdermal and intravenous application of fentanyl on postoperative analgesia and to show the feasibility of postoperative use of transdermal fentanyl as an alternative method to patient-controlled intravenous fentanyl. Minville et al. applied patient-controlled analgesia to all groups after the operation and thus compared transdermal fentanyl plus patient-controlled analgesia with placebo patch plus patient-controlled analgesia. This study leads to an investigation of the effect of transdermal fentanyl on opioid consumption in addition to patient-controlled analgesia, rather than investigating the efficacy of transdermal fentanyl alone in the treatment of postoperative pain. That is, these studies investigated the safety and effectiveness of transdermal fentanyl compared to placebo.⁶ In our study, we applied transdermal fentanyl to the patient approximately 12 hours before the induction of anesthesia, based on its pharmacokinetic properties. Thus, we designed to evaluate the effect of fentanyl in serum on visual analog scale and sedation scores more healthily and reliably by providing the time required for it to reach its minimum effective concentration.
Since Varvel et al. showed that serum fentanyl level starts to increase in 4-8 hours in transdermal application, it is seen that application of transdermal fentanyl 1-2 hours before or just before surgery will not have a significant effect on hemodynamic and clinical parameters in operations lasting 2-3 hours.¹² In the studies, it is seen that 25 µg, 50 µg and 75 µg hourly doses are used for postoperative analgesia of transdermal fentanyl.^13-14 In these studies, transdermal fentanyl above 50 µg/h was not preferred because it may cause respiratory depression. Generally, intravenous morphine was used in addition to patient-controlled transdermal fentanyl in these studies. In our study, we did not combine transdermal fentanyl and patient-controlled analgesia, but used it for postoperative analgesic purposes separately for each group, aiming not to overestimate respiratory depression and other side effects, and to see the effects of using a single drug with two different methods on postoperative analgesia.
Ketene et al. used tramadol as an additional analgesic in their study with 25 µg/h, 50 µg/h and placebo patch, looked at total analgesic consumption and found that the analgesic requirement was significantly lower in the 50 µg/h transdermal fentanyl group.¹⁵ In our study, the postoperative analgesic requirement was at the 1st, 2nd, 6th, 12th and 24th hours in the transdermal fentanyl group. There was no significant difference at the postoperative 4th hour. There was no need for additional postoperative analgesics in the patient-controlled analgesia group. In the transdermal fentanyl group, it was observed that additional analgesics were needed at all times except the postoperative 4th hour. In addition, among the studies, there is no standard in terms of removing transdermal fentanyl in the postoperative period. It is usually removed at 24 or 72 hours.^4,15-16
A study examining the variation of postoperative visual analog scale values over time proved that pain intensity decreased over time.¹⁷ Another study showed that most patients who underwent surgery experienced severe pain in the first 24 hours.¹⁸ In our study, the fact that the hourly fentanyl consumption in the patient-controlled analgesia group in the first six hours, which is the acute period, was much higher than in the transdermal fentanyl group and the patients in the transdermal fentanyl group required additional analgesics supports these findings. As a result of the studies, both resting and movement visual analog scale values were found to be lower in the transdermal fentanyl group.^6,15,19 Contrary to these studies, Minville et al.⁶ who compared transdermal fentanyl with placebo, showed that the visual analog scale values were lower in the transdermal fentanyl group and therefore more effective.
The opioids we used in the study generally have a sedative effect. Fentanyl, which is stronger than morphine, has a mild sedative effect at low doses (1-2 µg/kg), while it causes deep sedation at high doses (50-150 µg/kg). Although different sedation scoring systems were used, no difference was observed between the groups.^15,19-20 In our study, we concluded that the sedation values measured in the postoperative period between the transdermal fentanyl group and the patient-controlled analgesia group were not statistically different. In our study, when the Aldrete recovery score and recovery times were compared, we found that the patient-controlled analgesia group was statistically significantly lower than the transdermal fentanyl group. This may be due to the delay in the onset of patient-controlled analgesia and the increased plasma fentanyl concentration in the transdermal fentanyl group. There are studies that did not find a statistically significant difference in terms of side effects in the postoperative period.^11,20-21-22 Siafaka et al.²³ argued that local erythema, Ketene et al.¹⁵ nausea, and Miguel et al.²¹ respiratory depression were more common in the transdermal fentanyl group. According to our results, typical opioid-related side effects were observed in both groups. However, there was no statistically and clinically significant difference between the groups in terms of side effects.

Limitations

The limitations of the study are that it was performed in a single center, and the number of patients is small. However, the study has many strengths such as its prospective nature, low cost, ease of use, and the use of many parameters and scoring scales.

Conclusion

In conclusion, it was concluded that there was no significant difference between TDF and PCA in terms of intraoperative and postoperative hemodynamic monitoring, but patient-controlled analgesia with IV fentanyl was more effective than TDF in the evaluation of VAS in the postoperative period. However, we believe that effective postoperative analgesia will be provided with an additional analgesic such as tramadol when TDF is required as an alternative to patient-controlled analgesia due to its ease of use in postoperative analgesia.

References

1. Chen YK, Boden KA, Schreiber KL. The role of regional anaesthesia and multimodal analgesia in the prevention of chronic postoperative pain: a narrative review. Anaesthesia. 2021;76(Suppl 1):8-17. doi:10.1111/anae.15256
   Article · PubMed · Google Scholar
2. Macintyre PE, Quinlan J, Levy N, Lobo DN. Current issues in the use of opioids for the management of postoperative pain: a review. JAMA Surg. 2022;157(2):158-166. doi:10.1001/jamasurg.2021.6210
   Article · PubMed · Google Scholar
3. Schneider A, Hirth M. Pain management in chronic pancreatitis: summary of clinical practice, current challenges, and potential contribution of the M-ANNHEIM classification. Drugs. 2021;81(5):533-546. doi:10.1007/s40265-021-01472-7
   Article · PubMed · Google Scholar
4. Rawal N. Current issues in postoperative pain management. Eur J Anaesthesiol. 2016;33(3):160-171. doi:10.1097/eja.0000000000000366
   Article · PubMed · Google Scholar
5. Marchand G, Ware K, Govindan M, et al. A systematic review and meta-analysis of intraperitoneal bupivacaine in laparoscopic gynecologic surgery. J Pain Res. 2021;14:2699-2707. doi:10.2147/jpr.s326145
   Article · PubMed · Google Scholar
6. Minville V, Lubrano V, Bounes V, et al. Postoperative analgesia after total hip arthroplasty: patient-controlled analgesia versus transdermal fentanyl patch. J Clin Anesth. 2008;20(4):280-283. doi:10.1016/j.jclinane.2007.12.013
   Article · PubMed · Google Scholar
7. Mitra S, Carlyle D, Kodumudi G, Kodumudi V, Vadivelu N. New advances in acute postoperative pain management. Curr Pain Headache Rep. 2018;22(5):1-11.
   PubMed · Google Scholar
8. Glaun GD, Caram AM, Patel N, Sandler HM. Comparison of pain scores in postoperative patients: intravenous morphine patient-controlled analgesia vs iontophoretic transdermal fentanyl. Cureus. 2016;8(8):1-5. doi:10.7759/cureus.752
   Article · PubMed · Google Scholar
9. Romualdi P, Santi P, Candeletti S. Alghedon fentanyl transdermal system. Minerva Med. 2017;108(2):169-175. doi:10.23736/s0026-4806.16.04930-2
   Article · PubMed · Google Scholar
10. Ishii H, Kokubun H, Tabata KI, Kanai A. Case reports of transdermal fentanyl patch administration difficulties in cancer patients with excess sweating. J Pain Palliat Care Pharmacother. 2023;37(1):72-77. doi:10.1080/15360288.2022.2141413
    Article · PubMed · Google Scholar
11. Lehmann KA, Einnolf C, Eberlein HJ, Nagel R. Transdermal fentanyl for the treatment of pain after major urological operations: a randomized double-blind comparison with placebo using intravenous patient-controlled analgesia. Eur J Clin Pharmacol. 1991;41(1):17-21. doi:10.1007/bf00280100
    Article · PubMed · Google Scholar
12. Varvel JR, Shafer SL, Hwang SS, Coen PA, Stanski DR. Absorption characteristics of transdermally administered fentanyl. Anesthesiology. 1989;70(6):928-934. doi:10.1097/00000542-198906000-00008
    Article · PubMed · Google Scholar
13. Montanari S, Davani L, Terenzi C, et al. Fentanyl pharmacokinetics in blood of cancer patients by gas chromatography-mass spectrometry. J Pharm Biomed Anal. 2022;219(9):1-4. doi:10.1016/j.jpba.2022.114913
    Article · PubMed · Google Scholar
14. Zhou J, Curd L, Lohmer LRL, et al. A population pharmacodynamic Markov mixed-effects model for determining remimazolam-induced sedation when co-administered with fentanyl in procedural sedation. Clin Transl Sci. 2021;14(4):1554-1565. doi:10.1111/cts.13023
    Article · PubMed · Google Scholar
15. Ketene A. Postoperatif ağrıda transdermal fentanil kullanımı. Ankara Sağlık Hizmetleri Dergisi. 2004;6(2):9-16. doi:10.1501/ashd_0000000051
    Article · PubMed · Google Scholar
16. Kaye AD, Menard BL, Ehrhardt KP, et al. Consensus perioperative management best practices for patients on transdermal fentanyl patches undergoing surgery. Curr Pain Headache Rep. 2019;23(7):50-55. doi:10.1007/s11916-019-0780-2
    Article · PubMed · Google Scholar
17. Arshad Z, Prakash R, Gautam S, Kumar S. Comparison between transdermal buprenorphine and transdermal fentanyl for postoperative pain relief after major abdominal surgeries. J Clin Diagn Res. 2015;9(12):1-4. doi:10.7860/jcdr/2015/16327.6917
    Article · PubMed · Google Scholar
18. Yoshino K, Nishiumi N, Masuda R, et al. A case of pain management using transdermal fentanyl patches for peritoneal carcinomatosis in a patient with small intestine stoma. Gan To Kagaku Ryoho. 2011;38(2):325-327.
    PubMed · Google Scholar
19. Sevarino FB, Sinatra RS, Paige D, Silverman DG. Intravenous ketorolac as an adjunct to patient-controlled analgesia for management of postgynecologic surgical pain. J Clin Anesth. 1994;6(1):23-27. doi:10.1016/0952-8180(94)90113-9
    Article · PubMed · Google Scholar
20. Sevarino FB, Paige D, Sinatra RS, Silverman DG. Postoperative analgesia with parenteral opioids: does continuous delivery utilizing a transdermal opioid preparation affect analgesic efficacy or patient safety? J Clin Anesth. 1997;9(3):173-178. doi:10.1016/s0952-8180(97)00043-3
    Article · PubMed · Google Scholar
21. Miguel R, Kreitzer JM, Reinhart D, et al. Postoperative pain control with a new transdermal fentanyl delivery system: a multicenter trial. Anesthesiology. 1995;83(3):470-477. doi:10.1097/00000542-199509000-00005
    Article · PubMed · Google Scholar
22. Sandler AN, Baxter AD, Katz J, et al. A double-blind, placebo-controlled trial of transdermal fentanyl after abdominal hysterectomy: analgesic, respiratory, and pharmacokinetic effects. Anesthesiology. 1994;81(5):1169-1180.
    PubMed · Google Scholar
23. Siafaka I, Rellia P, Argyra E, Iakovidou N, Sykiotis C, Vadalouka A. Pharmacokinetic profile and efficacy of a fentanyl transdermal delivery system for acute postoperative pain after intra-abdominal gynecologic surgery for cancer. Pain Pract. 2004;4(2):98-104. doi:10.1111/j.1533-2500.2004.04206.x
    Article · PubMed · Google Scholar

Tables

Additional Information

Publisher’s Note
Bayrakol MP remains neutral with regard to jurisdictional and institutional claims.

Rights and Permissions

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). To view a copy of the license, visit https://creativecommons.org/licenses/by-nc/4.0/

View full license details →