Comparing the pain relief effectiveness of intravenous magnesium sulfate and ketorolac versus intravenous morphine and ketorolac for kidney stones

Abstract

BACKGROUND:

Pain is one of the most common symptoms in various diseases. While morphine is widely used for pain relief, its adverse effects and potential for misuse have led to the exploration of safer alternatives. This study aimed to compare the analgesic effectiveness of intravenous magnesium sulfate versus morphine, both in combination with ketorolac, in patients with renal colic.

MATERIALS AND METHODS:

In this double-blind randomized controlled trial, 174 patients with renal colic referred to the emergency department of Shahid Ganjiyan Hospital in Dezful were enrolled. Patients were randomly allocated into two equal groups (n = 87). The intervention group received intravenous magnesium sulfate (50 mg/kg diluted in 100 mL normal saline over 15 minutes) plus ketorolac (30 mg), while the control group received intravenous morphine (0.1 mg/kg) plus ketorolac (30 mg). Pain intensity was measured using the Visual Analog Scale (VAS) at baseline (admission), and 20, 40, and 60 minutes after drug administration. Demographic data were also collected.

RESULT:

Among the 174 participants included in the study, 65% were male and aged between 40 and 60 years. Statistical tests indicated no significant differences between the two groups concerning demographic characteristics. Thus, the groups are comparable in terms of demographic variables. Comparison of pain reduction between the two groups at different time points revealed no statistically significant difference. The mean pain scores decreased over time in both groups; however, the differences between the groups were not significant at 20 minutes (P = 0.45), 40 minutes (P = 0.74), or 60 minutes post-intervention (P = 0.65). These findings indicate that both treatment protocols (morphine plus ketorolac and magnesium sulfate plus ketorolac) had similar effects on pain reduction at all measured intervals.

CONCLUSION:

The findings of this study demonstrate that intravenous magnesium sulfate, in combination with ketorolac, is as effective as morphine-based regimens in managing acute renal colic pain. Given the current global health policies emphasizing opioid stewardship and the reduction of opioid-related adverse effects, magnesium sulfate emerges as a valuable, low-risk alternative. Its incorporation into emergency pain management protocols may not only reduce opioid dependency and misuse but also align with broader public health goals aimed at promoting safer and more sustainable pain relief strategies. Health policymakers should consider including non-opioid analgesics like magnesium sulfate in national and institutional guidelines for acute pain management, especially in settings where opioid overuse presents a clinical and social challenge.

Introduction

Urinary system stones are a common urological problem and are considered the second most common chronic kidney disease.[1] These stones typically form in the kidneys, ureters, bladder, or urinary tract.[2] According to NHANES data collected from 2017 to 2020, approximately 9.9 % of U.S. adults reported a lifetime history of kidney stones.[3] A recent analysis of U.S. healthcare data from 2011 to 2018 estimated the total economic burden of upper urinary tract stone disease at approximately $10 billion, with a median annual expenditure of $1.4 billion.[4] In Iran, based on clinical symptoms, for every 100,000 individuals, an additional 87 patients are added to the kidney stone population annually.[5] Urinary stones can cause severe obstruction of the urinary tract, infection, bleeding, and acute pain.[6,7] These stones can lead to obstructive pain (renal colic) or cause intermittent, periodic pain without obstruction.[8] Renal colic is characterized by sudden, severe pain, nausea, and vomiting, necessitating timely and accurate diagnosis and treatment.[9,10] Patients experiencing colicky pain perceive it in the flank or back as deep and vague, with variable intensity.[11] Severe pain caused by stones can prevent patients from engaging in daily activities, leading to prolonged absences from work.

Pain relief is the first therapeutic step for these patients, and appropriate analgesics with minimal side effects can somewhat alleviate pain from stone movement. Medications used for acute renal colic are primarily non-steroidal analgesics and narcotics.[12] Narcotics, particularly morphine (given its easier access in hospital settings), are commonly used medications for pain reduction.[2] Morphine reduces patient discomfort by acting on central nervous system receptors, but does not address the underlying cause of the pain and requires repeated dosing.[13] Additionally, issues such as dependency, nausea, vomiting, constipation, sedation, and respiratory depression at higher doses have prompted physicians to seek alternative medications.[14,15]

The analgesic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are due to the inhibition of prostaglandins, which subsequently reduce vasodilation, increase their permeability, exhibit diuretic effects on the kidneys, and decrease pressure in the renal pelvis and urinary collecting system.[16,17] Injectable NSAIDs such as ketorolac are preferred in acute care due to their rapid action and relatively low risk of gastrointestinal or systemic side effects.[18] Nevertheless, even NSAIDs may not always provide adequate pain control when used alone, leading to the exploration of multimodal approaches.[19]

In addition to the aforementioned drug categories (narcotics and non-steroidal analgesics), another group of medications has come into focus, including magnesium sulfate. Magnesium is a physiological blocker of calcium channels and a non-competitive antagonist of NMDA receptors, theoretically playing a role in the molecular sensitization process and modulating pain through NMDA receptor blockade.[20,21] A study demonstrated the efficacy of magnesium sulfate as an adjunct treatment in patients with renal colic.[22] Furthermore, the muscle-relaxant effect of magnesium sulfate on the smooth muscles of the urinary tract could reduce pain intensity by alleviating stone-induced obstruction, unlike morphine, which can cause spasms of smooth muscles.[23]

Given the current focus on reducing opioid use and promoting safer analgesic options, the combination of magnesium sulfate with ketorolac may offer a viable alternative. Prior studies, such as those by Basmah Safdar in the United States, have shown that combining ketorolac with morphine is more effective in reducing pain and decreasing the need for additional analgesia than either drug alone.[24] Similarly, Pourafzali et al.[2] found that the ketorolac-morphine combination is superior to each agent individually. However, there is a lack of comparative studies evaluating the efficacy of ketorolac-magnesium sulfate versus ketorolac-morphine in the management of acute renal colic. Therefore, controlling acute pain in patients with renal colic is important from various perspectives. To help guide optimal therapeutic and pain management decisions for these patients, a comprehensive drug treatment protocol is needed that effectively manages pain in this patient population with minimal medication-related side effects. This study aims to address this research gap by comparing the analgesic effects and safety profiles of intravenous ketorolac-morphine versus ketorolac-magnesium sulfate in patients with renal colic. The findings may contribute to the development of more effective and safer pain management strategies aligned with opioid stewardship and evidence-based health policy initiatives.

Materials and Methods

Study design and setting

This double-blind randomized controlled trial (RCT) was conducted in accordance with the CONSORT guidelines [Figure 1]. The study took place in the emergency department of Ganjavian Hospital, a tertiary care teaching hospital located in Dezful, Iran (with research ID: IR.DUMS.REC.1401.071). The research was carried out over a six-month period from March 2022 to August 2023. Both patients and healthcare personnel assessing pain intensity were blinded to group assignments. All study medications were prepared in identical coded syringes (labeled A and B) to ensure allocation concealment.

Figure 1.

CONSORT of Study Groups

Study participants and sampling

A total of 174 patients experiencing renal colic presented to the emergency department of Ganjavian Hospital in Dezful, Iran. Inclusion criteria included patients over the age of 16 presenting with unilateral or upper abdominal pain diagnosed as acute renal colic confirmed by ultrasonography (patients were required to undergo ultrasound upon admission). Ultrasound examinations were performed by emergency medicine physicians as part of the standard diagnostic procedure upon admission. These physicians were not involved in treatment allocation and were blinded to the group assignments to minimize diagnostic bias. Exclusion criteria included any history of opioid abuse, heart failure, or renal failure, a respiratory rate of less than 12 breaths per minute, systolic blood pressure lower than 100 mmHg, unwillingness to participate in the study, known allergy to ketorolac, morphine, or magnesium sulfate, inability to comprehend the Visual Analog Scale (VAS), and pregnancy or breastfeeding.

After selecting patients based on the inclusion and exclusion criteria, participants were randomly assigned to one of two groups (intervention or control) using a computer-generated randomization sequence. A simple randomization method with equal allocation (1:1 ratio) was applied. The randomization list was prepared by a researcher not involved in patient enrollment or outcome assessment to ensure allocation concealment. Each participant received a unique code corresponding to a pre-prepared syringe labeled either A or B, which was indistinguishable in appearance and content volume. This process ensured that both the patients and the researcher responsible for assessing pain intensity were blinded to group allocation throughout the study.

Data collection tool and technique

In this study, all data collected were fully anonymized and de-identified prior to analysis to ensure the protection of patient privacy. To maintain data security, advanced encryption methods were employed for data storage and transfer. Data were stored on secure servers, with access strictly limited to authorized members of the research team. Additionally, specific protocols were implemented for data collection and analysis to prevent any unauthorized access. These measures were taken to ensure compliance with ethical standards and to promote transparency in the research process.

Intervention protocol

This study was conceptually informed by the NMDA receptor modulation theory, which posits that magnesium sulfate acts as a non-competitive NMDA receptor antagonist, thereby reducing central sensitization and opioid demand in acute pain management [Figure 2].

Figure 2.

Theoretical and Conceptual Framework based on NMDA Receptor Modulation Theory

After participants were assigned to groups, the demographic information and baseline characteristics of patients, as well as data collected during the study, were recorded by the researcher (FR) on pre-designed checklists.

In group A, referred to as the intervention group, after the study’s objective was explained and written informed consent obtained, the researcher (FR) recorded the vital signs of the patients and measured their pain levels using the Visual Analog Scale (VAS). The choice of VAS for pain measurement in this study was based on its demonstrated reliability and validity in assessing pain intensity across varying populations and clinical settings, particularly in patients experiencing acute pain, such as renal colic.[25,26] Numerous studies have confirmed its effectiveness in capturing subjective pain experiences in similar patient populations, making it a suitable tool for this study.[25,26,27] The nurse (who was unaware of the research process) then administered an intravenous infusion of 50 mg/kg (maximum 2 grams) magnesium sulfate and 30 mg of ketorolac (in 100 cc normal saline over 15 minutes) while closely monitoring vital signs. Heart rate and O2 saturation were monitored using a pulse oximeter, and blood pressure was assessed with a digital sphygmomanometer. Pain scores were measured at 20, 40, and 60 minutes post-medication administration. A reduction of three points or more on the VAS was considered a positive response to the medications. If the pain reduction after 20 minutes was less than three points, a negative response was recorded, and an additional intravenous injection of 30 mg of ketorolac was administered for supplemental pain relief. Notably, both the patients and the personnel assessing pain intensity remained blinded to the group assignments throughout the study. Medications for both the intervention and control groups were prepared prior to the intervention and placed in identical syringes labeled with codes A (medication prepared for the intervention group) and B (medication prepared for the control group).

Group B (control group) received intravenous morphine sulfate at a dose of 0.1 mg/kg, along with 30 mg of ketorolac, prepared in an identical volume and format to Group A. To ensure blinding, the medications for both groups were prepared prior to administration in identical syringes labeled only with codes “A” and “B.” Both patients and the personnel assessing pain remained blinded to the group allocation throughout the study.

The primary outcome of this study was the change in pain intensity measured by the Visual Analog Scale (VAS) at 20, 40, and 60 minutes after the intervention. The secondary outcomes included the need for rescue analgesia (additional ketorolac administration), hemodynamic changes (heart rate, blood pressure, and oxygen saturation), and any reported adverse effects following the intervention.

Statistical analysis method

Statistical analyses were performed using SPSS version 22. The normality of data distribution was assessed using the Kolmogorov–Smirnov test. Descriptive statistics, including mean and standard deviation (SD) for continuous variables and frequency (percentage) for categorical variables, were used to summarize the demographic and clinical characteristics of participants.

For comparisons between the two groups (morphine-ketorolac vs. magnesium sulfate-ketorolac), we used an independent t-test for normally distributed continuous variables (e.g. pain intensity scores) and the Mann–Whitney U test for non-normally distributed variables. A Chi-square test was used to compare categorical variables, such as gender distribution and side effects. Pain intensity changes over time (at baseline, 20, 40, and 60 minutes post-intervention) were analyzed using repeated measures ANOVA. Post-hoc analyses with Bonferroni correction were applied where necessary to control for type I error. Effect sizes (Cohen’s d and partial eta squared) were calculated using SPSS version 22 to assess the clinical relevance of differences between groups. A P value < 0.05 was considered statistically significant. Effect sizes were calculated to determine the clinical relevance of differences between groups.

Ethical considerations

This study was approved by the Ethics Committee of Dezful University of Medical Sciences with the ethical approval code IR.DUMS.REC.1401.071. Additionally, the study was registered in the Iranian Registry of Clinical Trials (IRCT) with the registration number IRCT20221219056870N1. All procedures were conducted in accordance with the ethical standards of the Declaration of Helsinki.

Result

Demographic characteristics

Table 1 displays the distribution of demographic variables such as age, gender, education, marital status, and body mass index in both the intervention and control groups. Among the 174 participants included in the study, 65% were male and aged between 40 to 60 years. Statistical tests indicated no significant differences between the two groups concerning demographic characteristics. Thus, the groups are comparable in terms of demographic variables.

Table 1.

Socio-demographic characteristics of participants at baseline

Baseline Characteristic		Intervention Group (Ketorolac-Magnesium) n		%		Control Group (Morphine-Ketorolac) n		%		Chi-square Test (χ2, df)		P
Gender										χ2=0.22, df=1		0.85
Female		31		35		35		40
Male		56		65		52		60
Age (year)										χ2=1.54, df=3		0.22
<20		8		9.19		5		5.7
20–40		27		31.03		29		33.3
41–60		42		48.27		39		44.8
60 and more		10		11.49		14		16.2
Marital status										χ2=0.66,s df=1		0.40
Single		31		37.5		25		28.8
Married		56		64.3		62		71.2
Educational Level										χ2=0.03, df=1		0.82
Middle school		0		0		0		0
High school/some college		68		78		66		75.7
University or postgraduate degree		19		22		21		24.3
Body Mass Index (BMI)*										χ2=12.7, df=3		0.52
<18.5		0		0		10		11.49
18.5–24.9		28		32.1		28		32.18
25–29. 9		31		35.8		32		36.78
30 and More		28		32.1		17		19.54

*BMIs were analyzed based on WHO classification criteria

Pain management results

Findings presented in Table 2 reveal that after the intervention, the mean pain levels reported in the intervention group (receiving ketorolac and magnesium sulfate) at 20, 40, and 60 minutes post-administration did not show a significant difference compared to the control group (receiving morphine and ketorolac) (P > 0.05). Moreover, participants in both the intervention and control groups exhibited significant differences were observed regarding changes in heart rate, systolic and diastolic blood pressure, body temperature, respiratory rate, and blood oxygen saturation at 20, 40, and then 60 minutes post-drug administration (P < 0.05)

Table 2.

Changes in the intensity of pain scores in intervention and control groups

Characteristic findings of patients		Control Group (morphine + ketorolac) (Mean)		Intervention Group (magnesium sulfate + ketorolac) (Mean)		P*
Pre-Intervention - Temperature		36.9		37.1		0.07
Pre-Intervention - O2 Saturation		99.1		98.8		0.31
Pre-Intervention - Respiratory Rate		17.4		16.9		0.32
Pre-Intervention - Heart Rate		89.6		88.6		0.09
Pre-Intervention - Systolic Blood Pressure		130.25		132.45		0.12
Pre-Intervention - Diastolic Blood Pressure		78.56		80.45		0.57
Post-Intervention - O2 Saturation		98.8		98.6		0.63
Post-Intervention - Respiratory Rate		14.3		15.5		0.52
Post-Intervention - Heart Rate		87.6		86.5		0.68
Post-Intervention - Systolic Blood Pressure		110.25		112.6		0.08
Post-Intervention - Diastolic Blood Pressure		75.6		77.5		0.78

*P values were obtained using repeated measures ANOVA for within-group comparisons over time

As shown in Table 3, the comparison of pain reduction between the two groups at different time points revealed no statistically significant difference. The mean pain scores decreased over time in both groups; however, the differences between the groups were not significant at 20 minutes (P = 0.45), 40 minutes (P = 0.74), or 60 minutes post-intervention (P = 0.65). These findings indicate that both treatment protocols (morphine plus ketorolac and magnesium sulfate plus ketorolac) had similar effects on pain reduction at all measured intervals.

Table 3.

Comparison of pain intensity in intervention and control groups

Before Receiving the Drug		Control group		Intervention group		P*
Before Receiving the Drug		7.41±1.82		7.52±1.54		0.25
After 20 minutes		3.15±2.10		3.32±2.57		0.45
After 40 minutes		2.16±0.24		2.10±0.54		0.74
After 60 minutes		1.84±0.56		1.32±0.71		0.65

Data are presented as Mean+SE. *P values were obtained from paired t-test

Discussion

The baseline pain scores were similar between the intervention and control groups (7.52 vs. 7.41), and both groups experienced a statistically significant reduction in pain over time. However, there were no significant differences between the two groups at 20 minutes (P = 0.45), 40 minutes (P = 0.74), or 60 minutes (P = 0.65) post-intervention. These results suggest that both treatment protocols (magnesium sulfate plus ketorolac and morphine plus ketorolac) were similarly effective in managing acute renal colic pain.

These findings are consistent with recent clinical trials. Majidi and Derakhshani[28] conducted a double-blind RCT comparing IV magnesium sulfate to morphine in renal colic patients and found no significant difference in pain reduction at 20, 30, 60, or 120 minutes (P values > 0.05). Moreover, a randomized trial by Verki et al.[29] evaluating magnesium sulfate with ketorolac versus ketorolac alone reported similar outcomes at 15 and 30 minutes with no significant difference between groups. A meta-analysis analyzing four RCTs (total N = 373) concluded that IV magnesium sulfate did not significantly reduce pain severity compared to controls at 15, 30, or 60 minutes, but may serve as a rescue analgesic option in non-responders.[22]

These findings are consistent with previous research evaluating the role of magnesium sulfate as an analgesic. For instance, Joker et al. conducted a randomized clinical trial assessing pain relief in patients receiving morphine and ketorolac with or without magnesium sulfate. Unlike our findings, they reported significantly lower pain scores in the group receiving magnesium sulfate. This discrepancy may be due to differences in study design and medication combinations. In our study, both groups received ketorolac, and the comparison was between morphine and magnesium sulfate, while in the Joker et al. study, morphine was administered in both arms.[30]

Demographic characteristics such as age, gender, marital status, education, and body mass index were comparable between the groups: age (P = 0.22), gender (P = 0.85), BMI (P = 0.52), marital status (P = 0.40), and education level (P = 0.82). The most common site of pain was the groin region, with no significant difference in pain location between the two groups.

One possible interpretation of our findings is that magnesium sulfate, through NMDA receptor antagonism, offers comparable analgesic efficacy to morphine without the opioid-related adverse effects. This supports its consideration as an alternative analgesic agent, particularly in clinical settings where opioid use is limited due to risk of side effects or dependence.

The primary aim of this study was to compare the analgesic effectiveness of intravenous magnesium sulfate versus morphine when combined with ketorolac in patients with renal colic. The findings demonstrated no statistically significant differences in pain scores between the groups at any measured time point, suggesting that the null hypothesis (indicating no difference in efficacy) was not rejected. Therefore, our results support the potential of magnesium sulfate as an effective alternative to morphine in acute renal colic management, aligning with the study’s hypothesis that NMDA receptor antagonism could provide comparable analgesia.

Despite the promising results observed in our study, several potential confounding factors should be acknowledged that could have influenced the outcomes. First, although we randomized patients into control and intervention groups, inherent variability in patient demographics, such as age, gender, and pre-existing psychological conditions, may affect pain perception and reporting. For instance, studies have shown that both age and psychological factors like anxiety can significantly alter individuals’ experiences of pain.[31,32,33] Secondly, the concurrent use of different medications prior to the initiation of our study may have introduced variability in baseline pain levels, potentially impacting the effectiveness of the interventions administered. Furthermore, the use of self-reported measures such as the VAS can lead to assessment bias, as individuals may interpret and utilize the scale differently based on personal thresholds and experiences. Lastly, environmental factors, including the clinical environment and observer presence during assessments, may influence patients’ pain reporting, leading to variability in the results. Recognizing these confounding factors is crucial for accurately interpreting our findings and underscores the need for further studies that control for these variables in future research endeavors.

Limitations and recommendations

This study has several strengths. It employed a randomized double-blind design, reducing the risk of selection and assessment bias. The use of a standardized protocol for drug administration and pain measurement (VAS) increased the internal validity and comparability of outcomes between groups. Additionally, the relatively large sample size (n = 174) enhances the statistical power of the findings. However, some limitations should be acknowledged. The study was conducted at a single center, which may limit the generalizability of the findings to other settings or populations. Although randomization was applied, unmeasured confounding variables such as prior medication use or psychological status may have influenced pain perception. Moreover, pain assessment was based on self-reported VAS scores, which are inherently subjective and prone to individual variability. Finally, the short follow-up duration limited the assessment of sustained analgesic effects or delayed adverse outcomes.

Study suggestions for further research

Future studies are recommended to explore the long-term analgesic effects and safety profile of magnesium sulfate in different clinical settings. Comparative trials with larger sample sizes and diverse populations could help confirm its efficacy as a non-opioid alternative in renal colic pain. Additionally, further research should focus on identifying optimal dosing strategies and evaluating its use alongside other non-opioid analgesics.

Conclusion

Opioid analgesics are widely used for acute pain relief but are associated with significant side effects and dependency risks. Although ketorolac is commonly used in emergency settings, it may lead to complications such as gastrointestinal bleeding, renal impairment, and bronchospasm, which limit its use in some patients. Moreover, its short duration of action may necessitate repeated interventions.

This study found that magnesium sulfate provided analgesic effects comparable to morphine, without statistically significant differences in pain reduction. Given morphine’s adverse effects and dependency potential, magnesium sulfate may be considered a viable non-opioid alternative for managing acute renal colic pain. Further large-scale randomized clinical trials are recommended to confirm these findings and assess long-term safety and efficacy.

Abbreviations

BMI: Body Mass Index; CONSORT: Consolidated Standards of Reporting Trials; IV: Intravenous; NMDA: N-methyl-D-aspartate; RCT: Randomized Controlled Trial; VAS: Visual Analog Scale; SD: Standard Deviation; SPSS: Statistical Package for the Social Sciences

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.