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ORIGINAL ARTICLE
Year : 2023 | Volume
: 13
| Issue : 1 | Page : 65-70
Opioid-sparing post-cesarean analgesia using intravenous diclofenac-acetaminophen combination: A prospective, randomized clinical trial
Nidhi Bhatia, Kajal Jain, Kamlesh Kumari, Vighnesh Ashok, Ankita Dhir, Mandeep Kumar
Department of Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
Correspondence Address:
Dr. Kajal Jain
Department of Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/JOACC.JOACC_49_22
Background: Current research promotes opioid-sparing analgesia as an approach to enhanced recovery after cesarean (ERAC). In developing countries, non-opioid-based analgesia is routinely practiced in obstetric settings, as opioids are not freely accessible. There are no randomized trials evaluating intravenous diclofenac and acetaminophen for postoperative analgesia following elective cesarean section. Methods: Women scheduled for elective cesarean delivery under subarachnoid block were enrolled if they fulfilled the inclusion criteria. They were randomized to receive either intravenous diclofenac or intravenous diclofenac-acetaminophen combination at the end of surgery and at predefined time intervals during the 24-hour postoperative period. The primary outcome measure of our study was 24-hour rescue analgesic (tramadol) consumption. Secondary outcome measures included time to first request for rescue analgesia, postoperative pain at rest and on movement, episodes of nausea, retching, and vomiting during the 24-hour postoperative period and overall patient satisfaction. Results: The 24-hour rescue analgesic consumption was significantly lesser in the diclofenac-acetaminophen group compared to the diclofenac group (56.25 ± 47.73 mg vs. 92.86 ± 50.83 mg; P = 0.00). Time to first request for rescue analgesia was earlier in the diclofenac group compared to the diclofenac-acetaminophen group (3.96 ± 2.40 h vs. 5.64 ± 3.58 h, P = 0.01). Parturients given a combination of intravenous diclofenac and acetaminophen used 40% less tramadol in the first 24 hours following cesarean section and were more satisfied with their pain management when compared to those given intravenous diclofenac alone. Conclusion: Following cesarean section, intravenous diclofenac-acetaminophen combination provides superior analgesia with significantly lesser opioid consumption and higher patient satisfaction when compared to intravenous diclofenac alone. This combination is effective, easy to administer, opioid-sparing and is compatible with ERAC regimens.
Keywords: Cesarean section, intravenous acetaminophen, intravenous diclofenac, postoperative pain
Enhanced recovery after cesarean (ERAC) is a globally practiced and current standard of perioperative care program.[1] ERAC is known to result in a number of clinical benefits that include reduction in length of hospital stay, lesser complications, and fewer readmissions. In addition to this, enhanced recovery following surgery also reduces the cost of hospital stay, thereby benefitting the health system.[1] Although ERAC includes management of several perioperative parameters, one of the essential components of ERAC is providing good postoperative analgesia, as inadequate pain relief following surgery may be detrimental to recovery and delay discharge. Furthermore, pain after cesarean section can interfere with care of the newborn and prove to be very distressing for the mother.[1],[2]
Administering opioids, either orally or intravenously, in the form of patient-controlled analgesia (PCA) is a common strategy for managing postoperative pain after cesarean section. The systemic use of opioids is, however, not without adverse effects that range from nausea, vomiting, and itching to sedation and respiratory depression.[2] Additionally, opioids administered to the mother can be secreted into the breast milk, causing neuropsychiatric behavioral changes in the neonate as well.[3] All of these side-effects can significantly delay discharge after surgery. Thus, providing opioid-free analgesia, with the goal to reduce opioid use in the perioperative setting, can prove to be extremely beneficial for ERAC.
The use of non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen have been shown to have a significant opioid-sparing effect in providing good postoperative analgesia in a wide range of surgeries.[4],[5] While diclofenac is a NSAID that is a combined cyclo-oxygenase (COX)-1 and -2 inhibitor, acetaminophen is an inhibitor of central COX-3 in the brain. In this way, diclofenac and acetaminophen exert synergistic effects and can enhance postoperative pain control, particularly when used in combination. Studies that have evaluated the analgesic efficacy of diclofenac and acetaminophen for post-cesarean section pain have used these drugs as oral, intramuscular, or rectal suppository.[6–8] While intramuscular injections are painful and not acceptable to most patients, the oral and rectal bioavailability of diclofenac and acetaminophen is moderate, variable, and often inconsistent. With opioids continuing to be the key component of postoperative analgesia regimens, it is important to note that opioids, by delaying gastric emptying, may have a negative effect on the absorption and bioavailability of orally administered drugs, particularly diclofenac and acetaminophen.[9],[10] Thus, the route of administration of analgesics in multimodal regimens might be an important factor to consider.
As is well known, when compared to other routes of drug administration, the bioavailability of intravenously administered drugs is most consistent. Furthermore, in developing countries non-opioid-based analgesia is routinely practiced in obstetric settings, as opioids are not freely accessible. No study, till date has investigated the benefits and risks of intravenous diclofenac preparation either alone or in combination with intravenous acetaminophen as a part of the ERAC bundles, particularly in a low-resource setting like ours. We hypothesized that the combination of intravenous diclofenac and acetaminophen would provide better analgesia and lesser need for rescue tramadol than intravenous diclofenac alone in women who have undergone elective cesarean section under spinal anesthesia. The present study was, hence, conducted to compare the analgesic efficacy of intravenous diclofenac-acetaminophen combination with intravenous diclofenac alone in women undergoing lower segment cesarean section. The primary outcome measure of our study was 24-hour rescue analgesic (tramadol) consumption. Secondary outcome measures included time to first request for rescue analgesia, postoperative pain at rest and on movement, episodes of nausea, retching, and vomiting during the 24-hour postoperative period, and overall patient satisfaction.
MethodsIn this prospective and double-blinded randomized control trial (RCT), 112 primigravidae at >37 weeks of gestation and who were scheduled to undergo lower segment cesarean section under subarachnoid block were included. The patients were recruited after receiving institutional ethics committee approval (reference no. NK/1782/study) and registering the trial with the Clinical Trial Registry, India (http://ctri.nic.in; CTRI registry no: CTRI/2015/02/005516). Written and informed consent was taken from all the patients prior to recruitment. Exclusion criteria were history of significant maternal medical or obstetric illness (diabetes mellitus, renal and/or hepatic disease, congenital or acquired cardiac disease, preeclampsia), peptic ulcer disease, or gastrointestinal bleeding; patients on long-term analgesics; at-risk fetus; and known hypersensitivity to any of the study medications.
In the operating theater, intravenous access was achieved and the patients were positioned for subarachnoid block after initiating standard ASA non-invasive monitors. Subarachnoid puncture was performed at the L3-L4 level under full asepsis using a 25-gauge pencil-point spinal needle with the patient in sitting position. Two milliliters to 2.4 ml of hyperbaric bupivacaine 0.5% with 20 μg fentanyl was injected intrathecally and the patient was placed in the supine position with left uterine displacement to attain a block level of T4 to cold temperature before commencement of the surgery. Patients were then randomly allocated into either the intravenous diclofenac group (group D; N = 56) or the intravenous diclofenac-acetaminophen group (group DA; N = 56) using computer generated random numbers. At the end of the surgery, patients in group D received 75 mg of intravenous diclofenac sodium (Dynapar AQ, Troikaa pharmaceuticals, Gujarat, India) diluted in 5 ml of isotonic saline and 100 ml of intravenous isotonic saline over 15 minutes. Patients in group DA received 75 mg of intravenous diclofenac sodium diluted in 5 ml of isotonic saline and 100 ml of intravenous acetaminophen 1 g (Perfalgan, Bristol-Myers Squibb Pharmaceuticals, Rueil-Malmaison, France) over 15 minutes.
The patients were then transferred to the postoperative ward for monitoring of vital signs till discharge to the routine post-delivery ward. Postoperative data was collected by a single investigator who was blinded to the group allocation. Postoperatively in the first 24 hours, patients in group D received 75 mg of intravenous diclofenac sodium every 12 hours and 100 ml intravenous isotonic saline every 6 hours, while patients in group DA received intravenous 75 mg of diclofenac sodium every 12 hours and 100 ml of intravenous acetaminophen 1 g every 6 hours. The drug labels were concealed with an opaque adhesive to ensure blinding of the nursing staff to the patient group allocation. Patients were asked about the severity of pain at rest and on movement using a 0–10 numeric rating scale (NRS) at 0, 1, 2, 4, 8, 12, and 24 hours, in which 0 represented no pain and 10 worst pain imaginable, by ward nurses blinded to the study group allocation. Effective pain control was defined as NRS ≤4. Rescue analgesia in the form of intravenous tramadol 50 mg was administered in case the patient's NRS pain score was >4 and was repeated, if required (NRS >4), every 6th hourly up to a maximum of 200 mg in a 24-hour period. The time to first request for rescue analgesic and the total 24-hour tramadol consumption was recorded. All episodes of nausea, retching, and vomiting during the 24-hour postoperative period were recorded as well. Intravenous ondansetron at a dose of 0.1 mg/kg was used as the rescue drug for nausea, retching, or vomiting. At the end of 24 hours, all patients were asked about the quality of pain relief they had received using a simple 4-point scale (excellent, very good, good, and poor). The overall patient satisfaction was analyzed as either satisfied (quality of pain relief excellent or very good) or not satisfied (quality of pain relief good or poor).
A sample size of 108 patients (54 patients in each group) was calculated to be needed in order to detect a 30% reduction in 24-hour tramadol consumption with an α of 0.05 and a power of 0.8, based on prior clinical data from our hospital. A total of 112 patients were enrolled in the study to account for any possible drop-outs. Statistical analysis was carried out using the Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, version 15.0 for Windows). All quantitative variables were estimated using measures of central tendency and measures of distribution. Descriptive data were summarized as numbers with percentage, while continuous ordinal data were expressed as mean and standard deviation. Normality of data was checked by Shapiro-Wilk's test. Normally distributed data was compared using the unpaired t-test while Mann–Whitney U test was used for non-normal data. For normally distributed time-related data, means was compared using analysis of variance (ANOVA). Adjusted odd's ratio and the corresponding 95% confidence interval were reported, wherever applicable. Qualitative variables were described as frequencies and proportions and compared using the Chi-squared test or Fisher's exact test, whichever applicable. All statistical tests were two-sided and performed at a significance level of a = 0.05 and 95% confidence interval (CI).
ResultsThe flow of patients through the study is depicted in [Figure 1]. A total of 112 patients completed the study with both groups being well-matched with respect to their demographic characteristics [Table 1]. The median block height level in all the patients was T4 (IQR T3-T4), with none of the patients requiring any additional analgesic supplementation intraoperatively. None of the patients had any major intraoperative adverse events, with the mean arterial pressure being 116.0 ± 11.8 mmHg in group D and 104.0 ± 11.4 mmHg in group DA (P = 0.08).
The 24-hour rescue analgesic consumption was significantly lesser in group DA compared to group D (56.2 ± 47.7 mg vs. 92.9 ± 50.8 mg; P < 0.01) [Table 2]. Furthermore, time to first request for rescue analgesia was earlier in group D compared to group DA (4.0 ± 2.4 h vs 5.6 ± 3.6 h), with this difference being statistically significant (P = 0.01) [Table 2]. A significantly higher number of patients (χ2 = 6.6, P = 0.01) in group D (50, 89.2%) required rescue tramadol postoperatively when compared to group DA (39, 69.6%). Kaplan–Meier curves for the time of rescue analgesia is shown in [Figure 2]. Postoperative NRS scores on rest and on movement were lower Group DA patients compared to group D patients, and this difference was statistically significant at 2, 8, 12, and 24 hours postoperatively (P < 0.01) [Table 3]. A greater number of patients in group D complained of nausea, retching, and/or vomiting when compared to group DA (20 [35.7%] vs. 10 [17.9%], P = 0.03). However, on multivariate logistic regression analysis there was no significant association between group allocation and incidence of nausea, retching, and/or vomiting after controlling for total tramadol consumption in 24 hours (aOR = 1.05, 95% CI 0.35–3.21, P = 0.93). Overall patient satisfaction with regards to postoperative pain relief was significantly better in patients belonging to group DA (χ2 = 9.54, df = 1, P = 0.01) [Table 4].
Figure 2: Kaplan–Meier curve for time to first rescue analgesia administration Discussion Our study showed that parturients who were given a combination of intravenous diclofenac and acetaminophen used 40% less tramadol in the first 24 hours following cesarean section and were more satisfied with their pain management compared to those who were given intravenous diclofenac alone. Tramadol consumption over the first 24-hour period was used as a surrogate marker of postoperative pain and was the primary outcome of our study.
Following cesarean delivery, increased pain scores prevent early mobilization and rehabilitation, thus delaying discharge. Post-cesarean pain relief using intravenous opioids is associated with a number of side-effects including nausea, vomiting, sedation, ileus, constipation, and fatigue, which may prove to be detrimental to the entire concept of ERAC.[1],[2] Providing multimodal analgesia by using opioid-sparing drugs with different mechanisms of action can significantly decrease opioid requirements and greatly enhance recovery following surgery.[1] Hence there is the need to evaluate the analgesic efficacy of opioid sparing drugs that provide good post cesarean pain relief and do not delay recovery.
In a previous study, Siddik et al.[6] demonstrated that diclofenac improved postoperative analgesia and had a morphine-sparing effect after cesarean delivery. However, in their study the combination of diclofenac and acetaminophen was not found to be better than diclofenac alone in its opioid sparing effect. Likewise, Munishankar et al.[7] observed that women who received a combination of diclofenac and acetaminophen, after cesarean section, had similar morphine requirements to patients given diclofenac alone. However, these studies did not use standard intravenous preparations of diclofenac and acetaminophen. While the former study used diclofenac as a rectal suppository and acetaminophen was administered intravenously, the later study used diclofenac and acetaminophen as suppositories and oral tablets, respectively. The bioavailability of drugs administered as rectal suppositories is variable and often inconsistent, with a slower rate of absorption and delayed plasma peak concentrations compared to parenteral administration.[11] The stress of surgery and postoperative use of opioids can delay gastric emptying and prolong intestinal transit times, thereby having a significantly negative effect on the absorption and bioavailability of orally administered drugs.[9],[10],[12] Despite current ERAC recommendations regarding switching over to oral analgesics as early as possible in the postoperative period, in our study we used intravenous preparations of diclofenac and acetaminophen to ensure 100% bioavailability and a reliable onset of analgesic action.[13] This reflects the general practice in a low-resource setting like ours, where long-acting intra-thecal opioids and intravenous PCA pumps are not available. We administered intra-thecal fentanyl along with a local anesthetic for the spinal anesthetic in our study. However, due to its relatively short duration of action, intra-thecal fentanyl is known to provide little postoperative analgesic benefit.
Diclofenac, like other NSAIDs, is a potent inhibitor of COX-1 and COX-2, thereby blocking the production of prostaglandins in inflamed and injured tissues.[14] In contrast, acetaminophen has a more central effect as a selective COX-3 inhibitor in the brain, activating descending inhibitory pain pathways.[15],[16] Our study demonstrated that combining these two drugs, with different mechanisms and sites of action, is more effective than using diclofenac alone. Furthermore, patients receiving both of these drugs had significantly lower pain scores in the postoperative period, both during rest and movement. Decreased pain during movement can greatly aid the mother to adequately breastfeed her baby.
Tramadol, given intravenously, was used as a rescue analgesic in our study and as such reflects the general practice in our hospital. Tramadol is a centrally acting analgesic with a multimodal action and mild side effects at therapeutically used doses.[17] It is a serotonergic and noradrenergic reuptake inhibitor and an mu opioid receptor agonist. Due to its relatively wide therapeutic window and a ceiling effect and a lower risk of respiratory depression, it is widely used in moderate-to-moderately severe acute postoperative pain, including post-cesarean section pain.[18] The amount of tramadol excreted in the breast milk is very low, and at usual maternal doses, the amount secreted in breast milk has not shown to be associated with any adverse effects in breastfed newborns.[19] As mentioned earlier, ours is a low-to-moderate resource setting where the non-availability of PCA pumps and high patient–nursing staff ratio makes monitoring of patients receiving potent intravenous opioids like morphine or fentanyl difficult in the post-delivery ward. Side effects of tramadol are few and mild at therapeutic doses and include, amongst others, nausea and vomiting. In our study too, a greater number of patients in the diclofenac group had nausea and vomiting, requiring rescue antiemetic, compared to those in the diclofenac-acetaminophen group. This can be explained by the greater tramadol requirements amongst the patients in the diclofenac group as a result of inadequate pain control.
Our study is, however, not without limitations. Though not done as a routine globally,[20] it is standard clinical practice in the developed world to add a long-acting opioid like morphine or diamorphine as an adjunct to local anesthetic in the subarachnoid block to provide postoperative analgesia. We did not use long-acting intra-thecal preservative-free opioids as adjuvants during spinal anesthesia, as they were not available in our set-up. Moreover, the limitations in monitoring for respiratory depression in our post-delivery wards was another reason for us to omit the use of long-acting spinal opioids in our routine clinical practice and in this study. Additionally, the use of intravenous diclofenac and acetaminophen would entail a minor inconvenience of retaining a functional peripheral intravenous line for at least 24 hours postoperatively and the risk of venous thrombophlebitis.
With these limitations in mind and to ensure that our patients benefited the most from analgesic medications, as a hospital policy we used the intravenous route for acetaminophen, NSAIDs, and tramadol in our post-delivery wards for the first 24 hours. We observed that postoperative pain following cesarean section was maximum around six hours, postoperatively, which roughly correlates to the regression of the spinal anesthetic from the abdominal dermatomes, particularly in the absence of a long-acting intrathecal opioid. The intravenous route ensures 100% bioavailability and nearly instantaneous onset of analgesic action. The postoperative analgesia management described in our study manuscript, as such, reflects our usual hospital practice. We hope that the findings of our study would be useful in other low-to-moderate resource set-ups facing similar challenges as ours.
In conclusion, the intravenous administration of diclofenac-acetaminophen combination in parturients after cesarean section provides better analgesia with significantly lesser opioid consumption and higher patient satisfaction compared to parturients given intravenous diclofenac alone. This combination is effective, easy to administer, opioid-sparing, and is compatible with ERAC regimens.
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