INTRODUCTION:

Hysterectomy is defined as the surgical procedure of removal of uterus and the cervix. It is performed for a wide variety of clinical symptoms some of which include heavy menstrual, fibroid, uterine prolapses, endometriosis and gynaecological cancers¹.

According to the estimates from CDC, hysterectomy is the most common type of surgical procedure performed in women amounting to about 600,000 procedures done each year². Approximately 11% of women above the age of 45 years underwent hysterectomy in India and it is also noted that the prevalence of hysterectomies among young women is significantly increasing due to various medical conditions like abdominal bleeding, fibroids and cancers^3,4. Post-operative pain after hysterectomy is noticed in majority of the patients which seen to affect patient’s quality of life and also patient recovery. High or severe intensity of pain in the first 20 hours post-surgery in the patient is strong predictor of the probability of persistent pain 6 months after the surgery and chronic pain syndrome⁵. Poor management of pain after hysterectomy results in increased length of stay, delayed recovery and risk of developing long term complications⁶. Therefore, it is essential to manage pain appropriately and effectively within the first 24-48hours post-surgery. A stepwise multi modal approach is utilized for the management of post-operative-hysterectomy pain to minimize opioid administration. The American college of obstetrics and gynaecology (ACOG) recommends the use of ketorolac and NSAIDs as the first line choice of drugs for the treatment or management of post-operative pain⁷. Use of opioid analgesics has been linked with respiratory distress, changes gastrointestinal function, post-operative nausea and vomiting⁸ and strong potential to develop drug addiction⁹. Therefore, NSAIDs are preferred over opioid analgesics¹⁰. Acetaminophen and Diclofenac are few of the most commonly utilized drug interventions for the treatment of post-operative hysterectomy pain management^11,12. Acetaminophen commonly termed as paracetamol¹³ provides pain relief through its metabolite N-acylphenolamine abbreviated as AM404 elicits analgesic action through TRPV1 and CB1 receptors along with COX pathways is administered as per oral tablet or as intravenous infusion^14,15. Diclofenac is generally administered as an intramuscular injection for pain management. The drug acts inhibiting the COX-1 and COX-2 in a similar fashion equally along with action thromboxane-B2 and it is regarded as strong inhibitor of PGE2 which is elevated during the inflammatory response¹⁶. Abdominal hysterectomies often cause moderate to severe pain and therefore it is very imperative to treat the post-operative pain in the patients. Various research studies have been conducted to assess and determine the efficacy of Acetaminophen compared with Diclofenac to effectively manage pain however the results and outcomes are very inconclusive and therefore we conducted this study to determine the more effective and cost-effective drug. This study also has a potential to aid in providing post-operative pain management strategies associated with utilization of non-opioid analgesics medications.

MATERIALS AND METHODS:

This prospective, open-label, parallel-arm, double-blinded randomized study was conducted from March to September 2022 at the Department of Obstetrics and Gynaecology, MVJ Medical College and Research Hospital, Bangalore, India. Female patients aged 18-65 who underwent surgical hysterectomy and received post-operative intravenous acetaminophen or intramuscular diclofenac were included, while those with allergies, known contraindications, or uncontrolled major systemic diseases were excluded. Using STATA 17.0 and data from Pal et al. 2014,¹⁷ a minimum sample size of 49 per arm was required, with a total of 110 participants (55 per arm) included to account for loss to follow-up. Patients were randomized (1:1) to receive either intravenous acetaminophen 1000mg or intramuscular diclofenac 75mg every 8hours, using simple randomization from www.randomiser.com. Pain intensity was measured using the visual analogue scale (VAS)¹⁸ at 2, 4, 8, 12, and 24 hours post-administration, with VAS scores categorized as 1-3 (mild pain), 4-6 (moderate pain), and 7-10 (severe pain). The primary outcome was the change in VAS score. Safety was assessed by monitoring adverse drug reactions, graded using Naranjo’s Algorithm and Hartwig-Siegel Severity scale¹⁹. The study followed the Declaration of Helsinki and local regulatory requirements, with ethical approval (Document No. MVJMC&RH/IEC-26/2022, dated 16th February 2022). Data were analyzed using SPSS 20.0, with descriptive statistics summarized into means, medians, standard deviations, or interquartile ranges. Paired samples T-tests assessed analgesic effects at different time points, independent samples T-tests compared mean differences between groups, and Levene's test evaluated variances in pain scores. Cost-effectiveness analysis was conducted using R Studio 4.3.2.

RESULTS:

Demographic Profile Analysis:

A total of 110 females were screened to be included in the study and after strict consideration with respect to protocol inclusion and exclusion criteria, a total of 100 female eligible candidates were included in the study. The participants ranged in age from 35 to 62 years old, with a mean age of 46.47±6.229 years. The median age of the patients were 46 years indicating a normal symmetrical distribution. The median onset of symptoms began at 4 weeks and the range of onset of symptoms varied from 1 week to 60 weeks suggesting variability in onset of the disease inter-individually. The average onset of symptoms began at 8.33±9.606 weeks. Majority of the patient undergoing hysterectomies were from urban areas 67%. Thirty-three percent of the patients came from rural areas, and sixty-seven percent lived in urban areas. Pelvic pain and heavy periods were the most common presenting symptoms (43%) and were followed by prolapse of the uterus (14%) and heavy periods (15%). A smaller proportion of patients reported a history of diabetes mellitus (5%), hypertension (7%), asthma (1%), or COPD (1%), whereas the majority (86%), had no significant past medical history. In a similar vein, 97% of patients said they had no notable past habits, compared to 1% who had smoked, 1% who had alcoholism, and 1% who had drug abuse. The different types of hysterectomy that were performed were laparoscopic (15%), supracervical (11%), radical (28%), total (36%), and hysterectomy with oophorectomy (10%). (Table-1)

Table 1: Demographic Profile Of The Patients

Characteristic	Mean and SD	Median
Age (years)	46.47±6.229	46
Onset of symptoms (weeks)	8.33±9.606 weeks	4
Characteristic	Frequency (n=100)	Percentage (%)
Patient Residential Area
Urban	67	67
Rural	33	33
Presenting Symptoms
Cancer of the womb, ovaries or cervix	1	1.0
Heavy periods	15	15.0
Heavy periods, Pelvic pain	2	2.0
Heavy periods, Pelvic pain, Prolapse of the uterus	43	43.0
Pelvic pain	15	15.0
Pelvic pain, Cancer of the womb, ovaries or cervix	7	7.0
Pelvic pain, Discharge from uterus	1	1.0
Pelvic pain, Irregular periods	1	1.0
Pelvic pain, Prolapse of the uterus	1	1.0
Prolapse of the uterus	14	14.0
Past Medical History
Asthma	1	1.0
COPD	1	1.0
Diabetes mellitus	5	5.0
Hypertension	7	7.0
None	86	8.0
Past History of Any Habits
Alcoholic	1	1.0
None	97	97.0
Smoking	1	1.0
Substance abuse	1	1.0
Type of Hysterectomy
Hysterectomy with oophorectomy	10	10.0
Laparoscopic Hysterectomy	15	15.0
Radical Hysterectomy	28	28.0
Supracervical Hysterectomy	11	11.0
Total Hysterectomy	36	36.0

Treatment Comparison Analysis:

The study employed paired samples t-tests to evaluate the efficaciousness of intramuscular (IM) administration of diclofenac and intravenous (IV) infusion of acetaminophen in pain mitigation over a 24-hour period. After treatment with both drugs, the results showed statistically significant reductions in pain scores at all observation intervals (1, 4, 8, 12, and 24 hours) (p< 0.05). Specifically, acetaminophen infusion by IV had a more robust and sustained analgesic effect in comparison to intravenous diclofenac, with the greatest reduction occurring 24 hours after therapy.Furthermore, Acetaminophen IV infusion showed significant positive associations with pain scores before and after treatment at all-time points, with the exception of the 1-hour post-treatment assessment (p<0.05). In contrast, IM diclofenac showed significant correlations at all-time points, with the exception of the 8 and 12-hour intervals (p<0.05). These results imply that, although both drugs successfully reduce pain, acetaminopheninfusion via IV may be a more trustworthy and consistent method of managing pain than IM Diclofenac. (Table-2) Paired samples t-tests were used to examine the paired differences in pain scores between pre- and post-treatment with IV inf. acetaminophen and IM diclofenac. After an hour of therapy, there was no significant difference in pain scores between the two drugs (p = 0.188 for IV infusion of acetaminophen and p = 0.116 for intramuscular diclofenac). However, at 4, 8, 12, and 24 hours later, there were substantial reductions in pain scores (p<0.001 for all). These findings demonstrate the effectiveness of IV acetaminophen and IM diclofenac in reducing pain, with the latter effects being most noticeable later in the course of treatment. (Table-3)The effectiveness of IV acetaminophen and IM diclofenac in lowering pain scores at different times after therapy was compared using independent samples t-tests. After 4 hours of treatment, the analysis showed a significant difference (t = 2.670, p = 0.009), suggesting that IV acetaminophen was considerably more effective than IM diclofenac at relieving pain at this point. Nevertheless, at 1, 8, 12, and 24hours after therapy, no discernible variations were found, indicating that IV acetaminophen and IM diclofenac both provide comparable levels of long-term pain relief efficacy. These results show the potential superiority of IV acetaminophen over IM diclofenac in pain management and emphasize the significance of taking the timing of pain evaluation into account when assessing the efficacy of various analgesic therapies in early management of pain. (Table-4)

Table 2: Comparison of Pain Score Changes Before and After Treatment with IV INF. Acetaminophen and Im Diclofenac at Different Time Points

Treatment	Time Point	Mean Before	Mean After	Std. Deviation Before	Std. Deviation After	Std. Error Mean Before	Std. Error Mean After	Correlation	p-value
IV Inf. Acetaminophen	1 hour	8.66	8.42	1.118	0.785	0.158	0.111	0.143	0.322
IV Inf. Acetaminophen	4 hours	8.66	7.12	1.118	0.872	0.158	0.123	0.378	0.007
IV Inf. Acetaminophen	8 hours	8.66	5.58	1.118	0.731	0.158	0.103	0.521	0.000
IV Inf. Acetaminophen	12 hours	8.66	4.44	1.118	0.760	0.158	0.108	0.516	0.000
IV Inf. Acetaminophen	24 hours	8.66	2.52	1.118	0.839	0.158	0.119	0.105	0.467
IM Diclofenac	1 hour	8.86	8.62	1.088	0.530	0.154	0.075	0.295	0.038
IM Diclofenac	4 hours	8.86	7.94	1.088	0.956	0.154	0.135	0.325	0.021
IM Diclofenac	8 hours	8.86	6.12	1.088	0.849	0.154	0.120	0.085	0.558
IM Diclofenac	12 hours	8.86	4.36	1.088	0.802	0.154	0.113	-0.152	0.294
IM Diclofenac	24 hours	8.86	2.46	1.088	0.676	0.154	0.096	0.200	0.163

Table 3: Paired Samples T-Test Results for IV Acetaminophen and IM Diclofenac At Various Time Points

Treatment	Time Point	Mean Difference	Std. Deviation	Std. Error Mean	t-value	Degrees of Freedom	p-value
IV Acetaminophen	1 hour	0.240	1.271	0.180	1.336	49	0.188
IV Acetaminophen	4 hours	1.540	1.129	0.160	9.648	49	<0.001
IV Acetaminophen	8 hours	3.080	0.966	0.137	22.556	49	<0.001
IV Acetaminophen	12 hours	4.220	0.975	0.138	30.605	49	<0.001
IV Acetaminophen	24 hours	6.140	1.325	0.187	32.768	49	<0.001
IM Diclofenac	1 hour	0.240	1.061	0.150	1.600	49	0.116
IM Diclofenac	4 hours	0.920	1.192	0.169	5.455	49	<0.001
IM Diclofenac	8 hours	2.740	1.322	0.187	14.657	49	<0.001
IM Diclofenac	12 hours	4.500	1.446	0.205	22.001	49	<0.001
IM Diclofenac	24 hours	6.400	1.161	0.164	38.993	49	<0.001

Table 4: Comparison of IV INF. Acetaminophen and IM Diclofenac: Group Statistics and Independent Samples Test Results At Different Time Points

Treatment	Time Point	N	Mean	Std. Deviation	Std. Error Mean	Levene's Test for Equality of Variances	t-test for Equality of Means
IV inf. Acetaminophen	1 hour	50	0.240	1.27071	0.17970	F = 0.017, p = 0.898	t = 0.000, df = 98, p = 1.000
IV inf. Acetaminophen	4 hours	50	1.540	1.12866	0.15962	F = 4.268, p = 0.041	t = 2.670, df = 98, p = 0.009
IV inf. Acetaminophen	8 hours	50	3.080	0.96553	0.13655	F = 17.839, p < 0.001	t = 1.469, df = 98, p = 0.145
IV inf. Acetaminophen	12 hours	50	4.220	0.97499	0.13788	F = 11.254, p = 0.001	t = -1.135, df = 98, p = 0.259
IV inf. Acetaminophen	24 hours	50	6.140	1.32496	0.18738	F = 0.340, p = 0.561	t = -1.044, df = 98, p = 0.299
IM Diclofenac	1 hour	50	0.240	1.06061	0.14999	F = 0.017, p = 0.898	t = 0.000, df = 98, p = 1.000
IM Diclofenac	4 hours	50	0.920	1.19249	0.16864	F = 4.268, p = 0.041	t = 2.670, df = 98, p = 0.009
IM Diclofenac	8 hours	50	2.740	1.32187	0.18694	F = 17.839, p < 0.001	t = 1.469, df = 98, p = 0.145
IM Diclofenac	12 hours	50	4.500	1.44632	0.20454	F = 11.254, p = 0.001	t = -1.135, df = 98, p = 0.259
IM Diclofenac	24 hours	50	6.400	1.16058	0.16413	F = 0.340, p = 0.561	t = -1.044, df = 98, p = 0.299

Table 5: Drug ADR Profile Chi-Square Analysis

Adverse Drug Reactions	Chi-Square Statistic	P-Value	IV Inf. Acetaminophen Proportions	IM Diclofenac Proportions
Itching	1.95	0.162	FALSE: 86%, TRUE: 14%	FALSE: 96%, TRUE: 4%
Rashes	0.00	1.000	FALSE: 96%, TRUE: 4%	FALSE: 98%, TRUE: 2%
Vomiting	2.34	0.126	FALSE: 92%, TRUE: 8%	FALSE: 100%, TRUE: 0%
Nausea	0.00	1.000	FALSE: 98%, TRUE: 2%	FALSE: 100%, TRUE: 0%
Constipation	1.37	0.241	FALSE: 94%, TRUE: 6%	FALSE: 100%, TRUE: 0%
Pain in site of injection	3.68	0.055	FALSE: 96%, TRUE: 4%	FALSE: 82%, TRUE: 18%
Diarrhea	0.18	0.674	FALSE: 96%, TRUE: 4%	FALSE: 92%, TRUE: 8%
NONE	0.69	0.407	FALSE: 42%, TRUE: 58%	FALSE: 32%, TRUE: 68%

Table 6: COST-Effectiveness Ratio Calculations

Time Point	IV-Inf. Acetaminophen	IM Diclofenac	Cost (Acetaminophen)	Cost (Diclofenac)	Effectiveness (Acetaminophen)	Effectiveness (Diclofenac)	CER
1 hour	0.24	0.24	0.05	0.133	4.8	1.80	-0.027777778
4 hours	1.54	0.92	0.05	0.133	30.8	6.90	-0.003486750
8 hours	3.08	2.74	0.05	0.133	61.6	20.55	-0.002030045
12 hours	4.22	4.50	0.05	0.133	84.4	33.75	-0.001645278
24 hours	6.14	6.40	0.05	0.133	122.8	48.00	-0.001114082

Drug safety profile Comparisons and Cost-Effectiveness Analysis:

When comparing the incidence of symptoms between IV Inf. Acetaminophen and IM Diclofenac treatments, the Chi-square analysis revealed variations in some symptoms, such as injection site pain and vomiting, but not in others, such as rashes and nausea. The therapeutic importance of these findings is critical in directing treatment options, taking individual patient variables and preferences into account, not withstanding statistical differences. Clinicians can choose the best course of action and improve patient outcomes by managing adverse responses effectively when they are aware of the unique side effect profiles of each medicine. (Table-5)

In this study, we evaluated the cost-effectiveness of intravenous acetaminophen and intramuscular diclofenac for the treatment of pain at different time intervals.Based on the cost and effectiveness analysis of intravenous acetaminophen (IV-Inf. Acetaminophen) and intramuscular diclofenac (IM Diclofenac) for pain management at different time intervals, IV-Inf. Acetaminophen emerges as the more cost-effective option despite its higher daily cost of 150 INR compared to IM Diclofenac, which costs 29.925 INR per day. The cost-effectiveness ratios (CERs) illustrate that IV-Inf. Acetaminophen consistently outperforms IM Diclofenac across all evaluated time points (1 hour, 4 hours, 8 hours, 12hours, and 24hours), with negative CER values indicating better cost-effectiveness. In contrast, IM Diclofenac shows positive CER values, signifying less favorable cost-effectiveness. Therefore, despite its higher daily expenditure, IV-Inf. Acetaminophen provides superior pain reduction per unit cost compared to IM Diclofenac, making it the recommended choice for pain management based on this study's findings. (Table-6)The cost-effectiveness plane plot contrasts the cost and efficacy of intravenous acetaminophen and intramuscular diclofenac for the treatment of pain at various time intervals. Each point denotes a distinct time point, and the y-coordinate shows effectiveness (pain reduction per unit cost), while the x-coordinate shows the cost of the medication per milligram (mg). More substantial and warmer-colored spots denote lower cost-effectiveness, whereas cooler-colored points show higher cost-effectiveness. Points in the lower-right quadrant denote the dominance of IM Diclofenac, while points in the upper-left quadrant indicate the greater cost-effectiveness of IV inf. Acetaminophen. IV infusion acetaminophen is consistently more cost-effective than other medications when trends over time are examined. All things considered, the storyline helps with making well-informed decisions about pain management treatments. (Figure-2)

Figure 1: Mean Pain Score over time for different treatmentsFigure -2: Cost-Effectiveness IV inf. Acetaminophen vs. IM Diclofenac

DISCUSSION:

Management of post-hysterectomy pain is of paramount importance in order to improve results after surgery and patient satisfaction. A wide variety of analgesics both opioid and non-opioid analgesics are available to treat and manage pain however use of opioids is significantly associated with increased potential for dependency and various side-effects²⁰. On the other hand, NSAIDs have been shown to lower postoperative opioid requirements, potentially decreasing opioid-related side effects, although also being connected to unfavourable gastrointestinal events²¹. To effectively customize pain management techniques, a full study of the demographic features of the patient population having this surgery is imperative. Furthermore, comparing the safety and effectiveness of various analgesic modalities can help guide evidence-based choices made in clinical settings. In order to offer a comprehensive understanding of these crucial facets of pain management for patients undergoing hysterectomy. Considerations for individualized pain management plans for hysterectomy patients must take a number of things into account. Many patients do not use postoperative opioid analgesia without having inadequate pain management, which highlights the necessity for individual assessment and optimization of non-opioid choices²². Age, socioeconomic level, and comorbidities are examples of demographic variables that can affect how someone perceives pain and reacts to analgesic treatments. Various studies, emphasize the importance of psychological components, emphasizing the importance of anxiety and pain-specific psychological predictors in pain perception and response^23–26. Significance of an all-encompassing pain service organization in the management of postoperative pain, implying that methods and medications alone may not be enough to effectively manage pain²⁷. Within the context of our findings, the results of other studies offer insightful information about the relative effectiveness of intramuscular (IM) diclofenac and intravenous (IV) acetaminophen in managing pain following a hysterectomy. In addressing post-hysterectomy pain, Faiz et al. (2014)²⁸ showed that IV acetaminophen was superior to ketamine, leading to reduced pain levels and a decreased need for breakthrough analgesics. This is consistent with the findings of our study, which showed that administering IV acetaminophen at different times after therapy resulted in statistically significant decreases in pain scores. According to Urman et al. (2018)²⁹, patients having hysterectomies and Caesarean sections benefit from IV acetaminophen since it shortens their length of stay and lowers their intake of opioids. Although they focused on C-sections, the results indicate that IV acetaminophen may be helpful in improving recovery and lowering the negative effects of opioids during the post-hysterectomy phase. Our research provides important information regarding the relative effectiveness of intravenous acetaminophen and intramuscular diclofenac, particularly in women having hysterectomy, in light of these studies. The statistically significant decreases in pain scores that were seen with the administration of IV acetaminophen at different intervals after therapy are consistent with earlier results, indicating that this medication may be a useful analgesic in this particular population.The study conducted a comparative examination of the effectiveness, safety, and cost-effectiveness of intravenous (IV) acetaminophen and intramuscular (IM) diclofenac for the management of pain following a hysterectomy. Our work supports earlier research on the effectiveness of both treatments in reducing postoperative pain by Shah et al (2019)³⁰ and Mulita et al (2021)³¹. However, as shown by the differences in adverse drug reactions (ADRs) between the two drugs, our analysis also emphasizes how crucial it is to take into account unique patient characteristics and preferences when choosing a course of therapy. Even though IM diclofenac and IV acetaminophen are both usually well tolerated, subtle differences in adverse drug reactions (ADRs), especially those involving injection site discomfort and vomiting, highlight the necessity of customized pain management strategies³². Additionally, our cost-effectiveness study consistently supported IV acetaminophen, which is similar with Shah et al (2019)³⁰ findings that IV acetaminophen is more cost-effective while being more expensive. The recommendations for IV acetaminophen as the recommended analgesic regimen for post-hysterectomy pain treatment are supported by these data collectively, highlighting the importance of an individualized approach that incorporates cost, safety, and efficacy factors. Although this study provides insightful information about the effectiveness, safety, and cost-effectiveness of intramuscular (IM) diclofenac and intravenous (IV) acetaminophen for the management of pain following a hysterectomy, there are a few limitations to take into account as well as future possibilities. The sample size and single-centre design of the study are potential limitations that could affect the robustness and generalizability of the results. To evaluate sustained efficacy and safety profiles, larger, multicentre prospective studies with longer follow-up periods could be conducted in the future to address these constraints. Our knowledge of the best pain treatment techniques might also be improved by looking into combination therapies, underlying mechanisms of action, and patient-reported outcomes. It is advised that in order to apply these findings to clinical practice, they be disseminated through training programs, evidence-based guidelines be developed, and clinical decision support systems be integrated.

CONCLUSIONS:

In conclusion, this study demonstrates that intravenous (IV) acetaminophen is more cost-effective and provides longer-lasting pain relief than intramuscular (IM) diclofenac following a hysterectomy. Despite its higher cost, IV acetaminophen shows superior analgesic effects, especially 24 hours post-treatment. These findings advocate for personalized pain management plans and support the widespread use of IV acetaminophen for post-hysterectomy pain relief. Future research should explore combination therapies and mechanisms to further optimize pain management.

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Received on 04.03.2024 Revised on 28.05.2024

Accepted on 09.07.2024 Published on 27.03.2025

Available online from March 27, 2025

Research J. Pharmacy and Technology. 2025;18(3):1040-1046.

DOI: 10.52711/0974-360X.2025.00149

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