Year :
2024
| Month :
July
| Volume :
18
| Issue :
7
| Page :
UC07 - UC11
Full Version
Effect of Intravenous Vitamin C and N-acetylcysteine on Postoperative Pain and Opioid Consumption after Laparoscopic Gynaecologic Oncosurgeries: A Randomised Controlled Study
Published: July 1, 2024 | DOI: https://doi.org/10.7860/JCDR/2024/69526.19623
ND Rachana, Namrata Ranganath, VR Pallavi, GS Shashidhar, BH Arathi, VB Gowda
1. Associate Professor, Department of Anaesthesiology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India.
2. Professor, Department of Anaesthesiology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India.
3. Professor, Department of Gynaeconcology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India.
4. Associate Professor, Department of Anaesthesiology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India.
5. Professor and Head, Department of Anaesthesiology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India.
6. Professor and Ex-Head, Department of Anaesthesiology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India.
Correspondence Address :
Dr. GS Shashidhar,
Kidwai Cancer Institute, Dr. MH Marigowda Road, Near Dairy Circle, Bengaluru-560029, Karnataka, India.
E-mail: rachanakiran84@gmail.com
Abstract 
Introduction: Postoperative pain is one of the common causes of increased postoperative morbidity and delayed recovery. Pain causes adverse effects such as hypertension, tachycardia, myocardial ischaemia, decreased alveolar ventilation, poor wound healing, and postoperative morbidity. Vitamin C and N-acetylcysteine (NAC), which is a novel co-analgesic, are being studied to reduce postoperative pain and opioid consumption.
Aim: To study the effect of intravenous Vitamin C and NAC on postoperative surgical pain and opioid consumption after laparoscopic gynaecologic oncosurgeries.
Materials and Methods: The present study was a randomised controlled study conducted at the Department of Anaesthesiology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India on 300 patients of American Society of Anaesthesiologists (ASA) physical status 1 and 2 scheduled for laparoscopic Gynaeconcology surgery after obtaining written informed consent. All the selected patients were randomly allocated into three groups. Group P was the control group in Group N patients received intravenous injections of NAC (50 mg/kg) and vitamin C infusion (50 mg/kg) in Group C. Patients were explained about the visual analogue pain scale preoperatively. In the postoperative period, VAS scores were recorded and noted along with the rescue analgesics received and side-effects.
Results: Haemodynamic variables were comparable among all three groups. The number of patients who had VAS scores of more than 4 was lower in group C (Vitamin C) at various time intervals when compared to the NAC and placebo groups. It was also statistically significant at 45 minutes, 60 minutes, 90 minutes, 150 minutes, 180 minutes, 300 minutes, and 10 hours (p-value=0.014, <0.001, <0.001, <0.001, 0.003, 0.005, 0.006, respectively). Postoperative opioid consumption was significantly reduced in group C (Vitamin C) compared to the other two groups (p-value <0.001).
Conclusion: Intraoperative Vitamin C usage reduced postoperative pain and fentanyl consumption in the postoperative period, and NAC can be used as a part of multimodal analgesia.
Keywords
Analgesia, Co-analgesics, Fentanyl, Pain scores
Introduction
Pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (1). Adequate pain control in cancer patients undergoing surgical procedures remains the primary goal of anaesthesiologists. Inadequate postoperative analgesia can lead to delayed recovery, mobility issues, delay in initiating chemotherapy, pneumonia, myocardial infarction, and depression. This can further increase morbidity and mortality in cancer patients, contributing to a diminished quality of life (2).
The goal of adequate postoperative pain control is best achieved through multimodal and preemptive analgesia. Postsurgery pain is mainly an inflammatory nociceptive kind of pain related to noxious stimuli, resulting in the perception of pain. It could also result from the release of chemical mediators due to tissue inflammation (3). In postoperative pain management, opioids are one of the most widely used classes of analgesics as part of multimodal analgesia. The use of opioids can be associated with Postoperative Nausea and Vomiting (PONV), sedation, respiratory depression, and delayed recovery in the postsurgical period. Additionally, some patients are known to develop an addiction to opioids with long-term use. Recently, non opioid analgesic modalities and alternatives have been introduced to enhance pain management and reduce the consumption of opioids and opioid-related side-effects in the postoperative period (3). Among the various available co-analgesics, Vitamin C and NAC have also been studied.
Vitamin C (ascorbic acid) is a water-soluble vitamin that has antioxidant, neuromodulating, and neuroprotective effects (4),(5). Additionally, vitamin C has been shown to modulate pain sensitisation through its action on the N-methyl-D-aspartate (NMDA) receptor. Recent studies have indicated that vitamin C supplementation can be useful as an adjunct to pain management by reducing opioid consumption and side-effects related to opioids (6),(7),(8).
Analgesic drugs currently under trial target group-II metabotropic glutamate receptor subtypes (mGlu2 and mGlu3 receptors) (9),(10). NAC is a novel co-analgesic under trial for its analgesic properties. It acts by activating the glutamate: cystine antiporter (Sxc) and thus reinforcing the endogenous activation of mGlu2/3 receptors (11). In animal models, it has been shown to have analgesic effects on neuropathic and inflammatory pain types, thereby reducing opioid consumption and related side-effects (12),(13). NAC is known to regulate oxidative stress, reduce reactive oxygen species release, and has been used in treating complex pain syndromes, as chronic pain states often have excessive levels of reactive oxygen species (14),(15). NAC has shown positive effects on chronic neuropathic pain, but no studies have been conducted on acute pain conditions (15). Due to its easy availability and cost-effectiveness, NAC can be used as an adjunct to opioids in an attempt to reduce opioid consumption.
Therefore, aim was to study the effects of high-dose vitamin C (50 mg/kg) and the novel co-analgesic NAC on postoperative opioid consumption in patients undergoing laparoscopic gynaecological oncosurgeries during the first 24 hours after surgery as the primary objective. The secondary objectives included studying pain scores in all three groups and postoperative side-effects. This was the first study of its kind to assess the safety and efficacy of perioperative administration of Vitamin C and NAC for postoperative surgical pain relief and opioid consumption in laparoscopic gynaeco-onco surgeries.
Material and Methods
This prospective non blinded randomised controlled study was conducted between January 2019 and December 2022. Approval for the study was obtained from the ethical committee of Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India Institutional Ethical Committee (IEC) number (KMIO/MEC/2018/02/C/AN/35). The study was registered under CTRI with the CTRI No – CTRI/2019/09/021332.
Inclusion criteria: All patients aged 18 to 75 years undergoing elective laparoscopic gynaecological oncology procedures under general anaesthesia were enrolled in the study.
Exclusion criteria: Patients with a history of allergy to systemic opioids, chronic opioid use, substance use disorder, sleep apnoea, coagulopathy, and analgesic use within 24 hours were excluded from the study.
A member of the research team contacted the patients to explain the study protocol and obtain written informed consent for participation. The day before surgery, all patients were provided with information on how to rate pain intensity on the Numeric Rating Scale (NRS), with 0 indicating no pain and 10 indicating the worst pain imaginable. Patients were randomly allocated to groups based on the randomisation table.
Sample size calculation: A sample size of 300 (100 cases in each group) was deemed adequate, considering 80% power and a 5% alpha level of significance.
Methodology: General anaesthesia was administered according to a standard protocol and monitored in accordance with the American Society of Anaesthesiologists guidelines (16). Anaesthesia was induced with intravenous midazolam 1 mg, fentanyl 1 μg/kg, propofol (1 to 2 mg/kg), and vecuronium (0.1 mg/kg) to facilitate intubation. After anaesthesia induction and creation of pneumoperitoneum at a flow rate of 12 to 14 mL per minute with intraperitoneal pressures ranging from 12 to 14 mm Hg, the prepared injection was administered by a team member based on group allocation. Patients in the Vitamin C group (group C) received vitamin C 50 mg/kg (17) (ascorbic acid 10 g/20 mL), those in the NAC group (group N) received NAC 50 mg/kg (18). Both drugs were administered as an infusion mixed with normal saline for a total injection volume of 50 mL, and normal saline 50 mL was infused to the placebo group (Group P) of patients. The prepared solution was infused over 30 minutes using an infusion pump once the pneumoperitoneum was created. Doses of Vitamin C and NAC were adjusted from the doses mentioned in CTRI accordingly after the pilot study. Anaesthesia was maintained using 1-1.5% isoflurane in a mixture of 50% oxygen in air. Vecuronium was utilised to maintain adequate muscle relaxation, i.v. injection of fentanyl 25 μg bolus was used as intraoperative analgesia, and intravenous lactated Ringer’s solution was administered at a rate of 4 to 5 mL/kg/h during surgery as maintenance fluid. Ondansetron 4 mg intravenously was administered to prevent PONV unless contraindicated. All surgeries were performed with a mini-laparotomy incision below the umbilicus at the camera port using a 4-port technique with patients in the Trendelenburg position.
After completion of surgery and meeting extubation criteria, neuromuscular blockade was reversed using Neostigmine and Glycopyrrolate. Extubated patients were transferred to the postoperative care unit. Upon arrival at the postoperative care unit, patients were evaluated for pain using a Visual Analog Scale (VAS) score. If the pain intensity exceeded a VAS score of 4 for ≥30 minutes, rescue analgesia (Inj. fentanyl 25 μg) was administered.
A research assistant was assigned to monitor patients’ postoperative surgical pain scores, PONV, fentanyl consumption, side-effects, and the need for rescue analgesia every 15 minutes during their stay in the PACU for the first hour, and every 30 minutes until four hours postsurgery, and then at 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours after surgery. A total of 300 patients were enrolled in the study with written informed consent. Five patients were excluded from the study as laparoscopy was converted to open laparotomy intraoperatively (Table/Fig 1).
Statistical Analysis
The collected data was entered into the Microsoft Excel program. Univariate and multivariate frequency tables were generated using Statistical Package for the Social Sciences (SPSS) statistical software. A comparison of parameters between cases and controls, measured on a continuous scale, was conducted using the Independent Student’s t-test. For categorical variables, an association study was performed using the Mantel-Haenszel Chi-square test. A p-value of <0.05 was considered statistically significant.
Results
Demographic details were similar among all three study groups and was not significant statistically (Table/Fig 2).
Haemodynamic variables noted at the baseline (B) at the beginning of infusion (IN) and at the End of Infusion (EIN) showed no difference between all three groups (Table/Fig 3).
Postoperative pain scores in the three groups at various time intervals are presented in (Table/Fig 4). Mean pain scores, when compared between the three groups, demonstrated that group C (Vitamin C group) had more consistent and lower pain scores compared to the other two groups.
The VAS score was assessed for 24 hours postsurgery. In this study, the number of patients with VAS scores exceeding four was lower in group C (Vitamin C) at various time intervals compared to the NAC and placebo groups. The differences were statistically significant at 45 minutes, 60 minutes, 90 minutes, 150 minutes, 180 minutes, 300 minutes, and 10 hours (p-value=0.014, <0.001, <0.001, <0.001, 0.003, 0.005, 0.006 respectively) (Table/Fig 5).
Postoperative opioid consumption was significantly reduced in group C (vitamin C) as compared to the other two groups with a p-value of <0.001 (Table/Fig 6).
A total of 31 patients in group C, 49 in group N, and 58 patients in group P received rescue analgesics. A significantly lower number of patients in the Vitamin C group received rescue analgesics (p-value=0.0013) (Table/Fig 7).
In this study, minimal side-effects were observed in group C compared to the other two groups. In the control group, 10% of patients experienced vomiting, and 10% experienced drowsiness compared to the other groups. None of the patients in any group experienced respiratory depression (Table/Fig 8).
Discussion
In this study, a significant reduction in opioid consumption and postoperative pain was observed in the Vitamin C group. Jeon Y et al., conducted a randomised controlled trial on the effect of using intravenous high-dose vitamin C on postoperative pain and morphine consumption after laparoscopic colectomy. Their study showed that postoperative pain at rest during the first 24 hours and morphine consumption during the first two hours were reduced after laparoscopic colectomy. However, no difference was noted in the consumption of morphine between the treatment and control groups at six hours and 24 hours. High-dose vitamin C infusion also decreased the frequency of demand for rescue analgesics (17). Similarly, in this study, there were decreased postoperative pain scores and reduced cumulative opioid consumption in the group of patients who received Vitamin C.
Wilson SH et al., conducted a randomised pilot trial on the impact of intraoperative NAC on opioid consumption following spine surgery. They used NAC in doses of 50, 100, and 150 mg/kg, and recorded opioid consumption, pain scores, and time to opioid rescue. The study found that patients who received NAC had lower consumption of postoperative opioids and pain scores. These results were comparable to the present study, showing a slight reduction in opioid consumption and pain scores, though not statistically significant (18).
Hung KC et al., conducted a meta-analysis of randomised controlled trials on the effect of perioperative Vitamin C on postoperative analgesic consumption. Their results demonstrated significant postoperative reductions in the requirement for opioids and a decrease in pain severity in patients receiving perioperative vitamin C. This suggests that vitamin C may be beneficial as part of a multimodal approach to postoperative analgesia in surgical patients (19). These findings were consistent with the results of the current study.
Mulkens CE et al., conducted a randomised controlled clinical trial on postoperative pain reduction by pre-emptive NAC. They concluded that there were no differences in pain scores postoperatively between the placebo group and the NAC group. However, the percentage of bothersome side-effects in the NAC group was high, leading them to not recommend the preemptive intravenous use of NAC to reduce postoperative pain in patients undergoing laparoscopic inguinal hernia repair (20). In the present study, the NAC group of patients had slightly lower pain scores compared to the control group, but the difference was not statistically significant. The incidence of side-effects related to NAC in present study was also not significant.
Gorpynchenko I et al., conducted an observational comparative cohort study on the patients with chronic prostatitis and chronic pelvic pain syndrome, oral NAC (600 mg) daily over one month resulted in a 25% decrease in pain scores. This study suggests that NAC has anti-inflammatory effects and helps in reducing pain (21).
Seyfi S et al., conducted a randomised controlled study on NAC’s effect on postoperative pain after laparoscopic cholecystectomy. The study concluded that NAC can inhibit the function of lipoproteins and prostaglandins due to its anti-inflammatory properties. It was found that reduced glutathione peroxidase and dismutase were restored, indicating that NAC can be used to treat pain or reduce analgesic doses (15). However, in this study, there was no significant decrease in pain scores in the NAC group compared to the other two groups. Li J et al., suggested that NAC attenuates neuropathic pain by suppressing matrix metalloproteinases (22).
Suter M et al., conducted a study on Vitamin C perioperatively in patients undergoing non cardiac surgery. A systematic review and meta-analysis of randomised trials revealed a small reduction in postoperative pain in patients who received Vitamin C. This finding was similar to the reduction in postoperative pain observed in patients receiving Vitamin C in the current study (23).
Limitation(s)
There was no consensus on the dosing of NAC.
Conclusion
There was a significant reduction in opioid consumption and pain scores in the postoperative period in the Vitamin C group compared to the NAC and control groups of patients. The NAC group of patients also experienced reduced opioid consumption and pain scores, but this was not statistically significant. Therefore, Vitamin C can be used as part of multimodal analgesia for acute postoperative pain, with the additional benefit of reducing opioid consumption and its associated side-effects. NAC as a co-analgesic for pain needs further evaluation regarding dosing and efficacy.
Reference
|
| | 1. | International association for the study of pain [Internet]. International Association for the Study of Pain (IASP). International Association for the Study of Pain; 2022 [cited 2024 May 13]. Available from: http://www.iasp-pain.org/.
| | 2. | Breivik H. Postoperative pain management: Why is it difficult to show that it improves outcome? Eur J Anaesthesiol. 1998;15(6):748-51. Available from: http://dx.doi.org/10.1097/00003643-199811000-00022.
[ CrossRef] [ PubMed] | | 3. | Kehlet H, Dahl JB. Anaesthesia, surgery, and challenges in postoperative recovery. Lancet. 2003;362(9399):1921-28. Available from: http://dx.doi.org/10.1016/S0140-6736(03)14966-5.
[ CrossRef] [ PubMed] | | 4. | Majewska MD, Bell JA. Ascorbic acid protects neurons from injury induced by glutamate and NMDA. Neuroreport. 1990;1(3):194-96. Available from: http://dx.doi.org/10.1097/00001756-199011000-00004.
[ CrossRef] [ PubMed] | | 5. | Majewska MD, Bell JA, London ED. Regulation of the NMDA receptor by redox phenomena: Inhibitory role of ascorbate. Brain Res. 1990;537(1–2):328-32. Available from: http://dx.doi.org/10.1016/0006-8993(90)90379-p.
[ CrossRef] [ PubMed] | | 6. | Besse JL, Gadeyne S, Galand-Desmé S, Lerat JL, Moyen B. Effect of vitamin C on prevention of complex regional pain syndrome type I in foot and ankle surgery. Foot Ankle Surg. 2009;15(4):179-82. Available from: http://dx.doi.org/10.1016/j.fas.2009.02.002.
[ CrossRef] [ PubMed] | | 7. | Chen JY, Chang CY, Feng PH, Chu CC, So EC, Hu ML. Plasma vitamin C is lower in postherpetic neuralgia patients and administration of vitamin C reduces spontaneous pain but not brush-evoked pain. Clin J Pain. 2009;25(7):562-69. Available from: http://dx.doi.org/10.1097/AJP.0b013e318193cf32.
[ CrossRef] [ PubMed] | | 8. | Hasanzadeh KF, Soleimani A, Habibi MR, Emami A. Can vitamin C be used as an adjuvant for managing post-operative pain? A short literature review. Korean J Pain. 2013;26:209-10.
[ CrossRef] [ PubMed] | | 9. | Chiechio S, Copani A, De Petris L, Morales ME, Nicoletti F. Gereau 4th RW. Transcriptional regulation of metabotropic glutamate receptor 2/3 expression by the NF-kappaB pathway in primary dorsal root ganglia neurons: A possible mechanism for the analgesic effect of L-acetylcarnitine. Mol Pain. 2006;2:20.
[ CrossRef] [ PubMed] | | 10. | Montana MC, Gereau RW. Metabotropic glutamate receptors as targets for analgesia: Antagonism, activation, and allosteric modulation. Curr Pharm Biotechnol. 2011;12(10):1681-88. Available from: http://dx.doi.org/10.2174/138920111798357438.
[ CrossRef] [ PubMed] | | 11. | Bridges R, Lutgen V, Lobner D, Baker DA. Thinking outside the cleft to understand synaptic activity: Contribution of the cystine-glutamate antiporter (System xc-) to normal and pathological glutamatergic signaling. Pharmacol Rev. 2012;64(3):780-802. Available from: http://dx.doi.org/10.1124/pr.110.003889.
[ CrossRef] [ PubMed] | | 12. | Bernabucci M, Notartomaso S, Zappulla C, Fazio F, Cannella M, Motolese M, et al. N-Acetyl-cysteine causes analgesia by reinforcing the endogenous activation of type-2 metabotropic glutamate receptors. Mol Pain. 2012;8:77. Available from: http://dx.doi.org/10.1186/1744-8069-8-77.
[ CrossRef] [ PubMed] | | 13. | Truini A, Piroso S, Pasquale E, Notartomaso S, Stefano GD, Lattanzi R, et al. N-acetyl-cysteine, a drug that enhances the endogenous activation of group-II metabotropic glutamate receptors, inhibits nociceptive transmission in humans. Mol Pain. 2015;11:s12990-015–0009. Available from: http://dx.doi.org/10.1186/s12990-015-0009-2.
[ CrossRef] [ PubMed] | | 14. | Naik AK, Tandan SK, Dudhgaonkar SP, Jadhav SH, Kataria M, Prakash VR, et al. Role of oxidative stress in pathophysiology of peripheral neuropathy and modulation by N-acetyl-l-cysteine in rats. Eur J Pain. 2006;10(7):573-73. Available from: http://dx.doi.org/10.1016/j.ejpain.2005.08.006.
[ CrossRef] [ PubMed] | | 15. | Seyfi S, Zahedian A, Kiabi FH. The effect of N-acetylcysteine on postoperative pain after laparoscopic cholecystectomy: A randomized clinical trial. Tehran Univ Med J. 2017;75(2):96-102.
| | 16. | Standards for Basic Anaesthetic Monitoring Developed By: Committee on Standards and Practice Parameters (CSPP) Last Affirmed: December 13, 2020 (last amended October). 1986;20. Available from: https://www.asahq.org.
| | 17. | Jeon Y, Park JS, Moon S, Yeo J. Effect of intravenous high dose vitamin C on postoperative pain and morphine use after laparoscopic colectomy: A randomized controlled trial. Pain Res Manag. 2016;2016:9147279. Available from: http://dx.doi.org/10.1155/2016/9147279.
[ CrossRef] [ PubMed] | | 18. | Wilson SH, Sirianni JM, Bridges KH, Wolf BJ, Valente IE, Scofield MD. The impact of intraoperative N-acetylcysteine on opioid consumption following spine surgery: A randomized pilot trial. Pain Manag. 2023; Available from: http://dx.doi.org/10.2217/pmt-2023-0061.
[ CrossRef] [ PubMed] | | 19. | Hung KC, Lin YT, Chen KH, Wang LK, Chen JY, Chang YJ, et al. The effect of perioperative vitamin C on postoperative analgesic consumption: A meta-analysis of randomized controlled trials. Nutrients. 2020;12(10):3109. Available from: http://dx.doi.org/10.3390/nu12103109.
[ CrossRef] [ PubMed] | | 20. | Mulkens CE, Staatsen M, van Genugten L, Snoeker BAM, Vissers KCP, Bruhn J, et al. Postoperative pain reduction by pre-emptive N-acetylcysteine: An exploratory randomized controlled clinical trial. Reg Anaesth Pain Med. 2021;46(11):960-64. Available from: http://dx.doi.org/10.1136/rapm-2021-102884.
[ CrossRef] [ PubMed] | | 21. | Gorpynchenko I, Nurimanov K, Poroshina T, Savchenko V, Drannik G, Dubuske L. The clinical and immunologic effects of acetylcysteine in the treatment of chronic abacterial Prostatitis. J Allergy and Clin Immunol 2020;145(2):AB30.
[ CrossRef] | | 22. | Li J, Xu L, Deng X, Jiang C, Pan C, Chen L, et al. N-acetyl-cysteine attenuates neuropathic pain by suppressing matrix metalloproteinases. Pain. 2016;157(8):1711-23. Available from: http://dx.doi.org/10.1097/j.pain.0000000 000000575.
[ CrossRef] [ PubMed] | | 23. | Suter M, Bollen Pinto B, Belletti A, Putzu A. Efficacy and safety of perioperative vitamin C in patients undergoing noncardiac surgery: A systematic review and meta-analysis of randomised trials. Br J Anaesth. 2022;128(4):664-78. Available from: http://dx.doi.org/10.1016/j.bja.2021.11.039. [ CrossRef] [ PubMed] |
DOI: 10.7860/JCDR/2024/69526.19623
Date of Submission: Jan 13, 2024
Date of Peer Review: Feb 03, 2024
Date of Acceptance: Jun 11, 2024
Date of Publishing: Jul 01, 2024
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. NA
PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Jan 13, 2024
• Manual Googling: Feb 08, 2024
• iThenticate Software: Jun 10, 2024 (15%)
ETYMOLOGY: Author Origin
EMENDATIONS: 9
|