a b s t r a c t

Introduction: The choice of Intravenous paracetamol or morphine for the pain control of renal colic remains con- troversial. We conduct a systematic review and meta-analysis to compare the Analgesic efficacy and safety of in- travenous paracetamol with morphine for renal colic pain.

Methods: We search PubMed, EMbase, Web of science, EBSCO, and Cochrane Library databases through Septem- ber 2019 for Randomized controlled trials assessing the analgesic efficacy and safety of intravenous para- cetamol versus morphine for renal colic pain. This meta-analysis is performed using the random-effect model. Results: Five RCTs are included in the meta-analysis. Intravenous paracetamol can lead to significantly lower pain scores at 30 min (standard mean difference (Std. MD) = -0.40; 95% confidence interval (CI) = -0.68 to -0.12; P = 0.005) and incidence of dizziness (risk ratio (RR) = 0.06; 95% CI = 0.01 to 0.48; P = 0.007) than morphine for renal colic pain. There is no statistical difference of pain scores at 15 min (Std. MD = -0.80; 95% CI = -1.84 to 0.24; P = 0.13), analgesic rescue (RR = 0.73; 95% CI = 0.45 to 1.19; P = 0.21), the incidence of adverse events (RR = 0.60; 95% CI = 0.35 to 1.03; P = 0.06), nausea or vomiting (RR = 0.61; 95% CI = 0.20 to 1.87; P = 0.38)

between two groups.

Conclusions: Intravenous paracetamol may result in lower pain scores at 30 min than morphine for renal colic pain, and more studies should be conducted to compare their analgesic efficacy.

(C) 2020

Introduction

Patients with renal colic pain are very common in the emergent department and have obviously reduced quality of life [1-5]. Oral drugs are always not effective to control the renal colic pain, and thus it is urgent to apply some intravenous analgesics [6,7]. Opioids such as morphine are widely used for the relief of renal colic pain because of its good analgesic effect, but may result in serious adverse events such as hypotension, respiratory depression, apnea and even intolerance [8-12]. The addiction is also documented while taking opioids [13-15].

Nonsteroidal anti-inflammatory drugs have effective analgesic effect in acute renal colic, but may be associated with potential adverse effects such as platelet dysfunction, nephropathy, and increasing cardiovascular mortality in ischemic heart disease

* Corresponding author at: NO.57 Canghou Street, Wenzhou, Zhejiang Province, P.R. China 325000.

E-mail address: [email protected] (Y. Baohua).

[16-18]. In addition, NSAIDs and opioids are unavailable in some emergency departments, and the alternative drugs with adequate analgesic property and few side effects are crucial for the patients with acute renal colic. Intravenous paracetamol is broadly used as an effective pain reliever in emergency department with few side effects [19-21]. Several studies demonstrated that intravenous paracetamol might be effective and safe for the relief of renal colic [22,23]. In one RCT involving 54 patients in each group, intravenous acetaminophen was associated with substantially reduced pain scores at 30 min after drug administration than that in the mor- phine group (P = 0.0001) [24]. In contrast, another study compar- ing intravenous morphine with acetaminophen for renal colic pain revealed that morphine led to greater pain relief than acetamino- phen [6].

Several studies have compared intravenous paracetamol with morphine for the pain control of renal colic, but there are some conflicting results [6,24-26]. This systematic review and meta- analysis of RCTs aims to compare the analgesic efficacy and safety of intravenous paracetamol versus morphine for the relief of renal colic pain.

https://doi.org/10.1016/j.ajem.2020.03.061 0735-6757/(C) 2020

Fig. 1. Flow diagram of study searching and Selection process.

Materials and methods

This systematic review and meta-analysis are performed based on the guidance of the Preferred Reporting Items for Systematic Reviews

and Meta-analysis statement and Cochrane Handbook for Systematic Reviews of Interventions [27,28]. Because only previously published data are used for this analysis, ethical approval and patient consent are not required.

Table 1

Characteristics of included studies

NO. Author Paracetamol group Morphine group Jada

		Number	Age	Female (n)	Hematuria (n)	Baseline pain intensity	Methods		Number	Age	Female (n)	Hematuria (n)	Baseline pain intensity	Methods	scores
1	Yazdani	50	33.51	17	26	76.1	A single dose of		50	33.51	11	32	79.9	A single dose of	4
	2018		+- 10.12			+- 13.9	1 g intravenous paracetamol in 100 mL normal			+- 10.12			+- 15.3	10 mg intravenous morphine sulfate
2	Masoumi	54	36.07	11	-	8.84	saline during 15 min One gram of		54	34.96	15	-	9.14	in 100 mL normal saline during 15 min 0.1 mg/kg	4
	2014		+- 9.7			+- 1.37	intravenous acetaminophen in 100 mL normal saline			+- 8.94			+- 1.13	morphine in 100 mL normal saline
3	Azizkhani	62	38.40	20	-	-	1 g intravenous		62	39.73	20	-	-	10 mg	3
4	2013 Serinken	38	+- 11.60 29.1	10	33	-	acetaminophen Intravenous		35	+- 11.62 31.3	12	32	-	intravenous morphine Intravenous	5
5	2012 Bektas	46	+- 8.2 35	15	33	73	paracetamol (1 g) Intravenous		49	+- 9.0 39	22	36	78	0.1 mg/kg morphine Intravenous doses	4
	2009		+- 10			(55-87), median (IQR)	doses of paracetamol (1 g)			+- 11			(64-98)	of 0.1 mg/kg morphine

IQR, interquartile range.

Fig. 2. Forest plot for the meta-analysis of pain scores at 15 min.

Literature search and selection criteria

We have systematically searched several databases including PubMed, EMbase, Web of science, EBSCO, and the Cochrane library from inception to September 2019 with the following keywords: “para- cetamol” or “acetaminophen”, and “morphine”, and “renal colic”. The reference lists of retrieved studies and relevant reviews are also hand- searched and the process above is performed repeatedly in order to in- clude additional eligible studies.

The inclusion criteria are presented as follows: (1) study design is RCT, (2) patients are diagnosed with renal colic pain, and (3) interven- tion treatments are intravenous paracetamol versus morphine.

Data extraction and outcome measures

Some baseline information is extracted from the original studies, and they include first author, number of patients, age, female, weight, hematuria, baseline pain intensity and detail methods in two groups. Data are extracted independently by two investigators, and discrepan- cies are resolved by consensus. We have contacted the corresponding author to obtain the data when necessary.

The primary outcomes are pain scores at 15 min and 30 min. Second- ary outcomes include analgesic rescue, adverse events, nausea, vomiting, and dizziness.

Quality assessment in individual studies

The methodological quality of each RCT is assessed by the Jadad Scale which consists of three evaluation elements: randomization (0-2 points), blinding (0-2 points), dropouts and withdrawals (0-1 points) [29]. One point would be allocated to each element if they have been conducted and mentioned appropriately in the original arti- cle. The score of Jadad Scale varies from 0 to 5 points. An article with Jadad score <= 2 is considered to have low quality. The study is thought to have high quality if Jadad score >= 3 [30,31].

Statistical analysis

We assess standard mean difference (Std. MD) with 95% confidence interval (CI) for continuous outcomes (pain scores at 15 min and 30 min) and risk ratio (RR) with 95% CIs for dichotomous outcomes (analgesic rescue, adverse events, nausea and vomiting, dizziness).

Heterogeneity is evaluated using the I² statistic, and I² N 50% indicates significant heterogeneity [31,32]. The random-effects model is used for all meta-analysis. We search for potential sources of heterogene- ity when encountering significant heterogeneity. Sensitivity analysis is performed to detect the influence of a single study on the overall estimate via omitting one study in turn or performing the subgroup analysis. Owing to the limited number (b10) of included studies, publication bias is not assessed. Results are considered as statisti- cally significant for P b 0.05. All statistical analyses are performed using Review Manager Version 5.3 (The Cochrane Collaboration, Software Update, Oxford, UK).

Results

Literature search, study characteristics and quality assessment

Fig. 1 shows the detail flowchart of the search and selection results. 264 potentially relevant articles are identified initially and five RCTs are finally included in the meta-analysis [6,22,24-26].

The baseline characteristics of five included RCTs are shown in Table 1. These studies are published between 2009 and 2018, and the total sample size is 500. Among the included RCTs, 1 g intravenous para- cetamol is compared to 10 mg intravenous morphine [6,25] or

0.1 mg/kg morphine [22,24,26].

Among the five included RCTs, three studies report pain scores at 15 min [22,24,26], four studies report 30 min [22,24-26], two studies re- port analgesic rescue [22,24], three studies report adverse events [22,24,26], four studies report nausea and vomiting [6,22,24,26], and two studies report dizziness [24,26]. Jadad scores of the five included studies vary from 3 to 5, and all five studies have high-quality.

Primary outcomes: pain scores at 15 min and 30 min

The random-effect model is used for the analysis of primary out- comes. The results find that compared to morphine group for renal colic pain, paracetamol shows no obvious impact on pain scores at 15 min (Std. MD = -0.80; 95% CI = -1.84 to 0.24; P = 0.13). There

is significant heterogeneity among the studies (I² = 94%, heterogeneity P b 0.00001, Fig. 2). However, paracetamol can result in significantly lower pain scores at 30 min than morphine (Std. MD = -0.40; 95% CI = -0.68 to -0.12; P = 0.005) with low heterogeneity among the studies (I² = 46%, heterogeneity P = 0.14, Fig. 3).

Fig. 3. Forest plot for the meta-analysis of pain scores at 30 min.

Fig. 4. Forest plot for the meta-analysis of analgesic rescue.

Fig. 5. Forest plot for the meta-analysis of analgesic rescue.

Sensitivity analysis

There is significant heterogeneity for pain scores at 15 min, while low heterogeneity remains for pain scores at 30 min. Thus, we perform the sensitivity analysis to detect the heterogeneity for pain scores at 15 min by omitting one study in turn, but there is still significant heterogeneity.

Secondary outcomes

In patients with renal colic pain, intravenous paracetamol and mor- phine show similar analgesic rescue (RR = 0.73; 95% CI = 0.45 to 1.19; P = 0.21; Fig. 4), the incidence of adverse events (RR = 0.60; 95% CI = 0.35 to 1.03; P = 0.06; Fig. 5), nausea and vomiting (RR = 0.61; 95% CI = 0.20 to 1.87; P = 0.38; Fig. 6). In addition, intravenous paracetamol is associated with significantly reduced incidence of dizziness (RR = 0.06; 95% CI = 0.01 to 0.48; P = 0.007; Fig. 7).

Discussion

Paracetamol and morphine have been commonly used for pain relief [33-37]. Craig et al. compared intravenous paracetamol (1 g) with mor- phine (10 mg) during 15 min in 55 patients with isolated limb trauma. The pain score was recorded at 0, 5, 15, 30 and 60 min, and the results found that the analgesic efficacy of intravenous morphine was compa- rable to intravenous paracetamol at any time interval. The number of Rescue analgesia showed no statistically significance between two groups, but morphine had higher incidence of complications than para- cetamol [38]. These results were consistent with those when comparing intravenous morphine (0.1 mg/kg) with paracetamol (1 g) for renal colic pain [26].

However, Masosumi et al. found that intravenous acetaminophen was significantly superior to morphine in terms of analgesic efficacy for renal colic [24]. Our meta-analysis finds that intravenous paraceta- mol is associated with significantly reduced pain scores at 30 min than morphine for renal colic pain, but there is no statistical difference of pain scores at 15 min and analgesic rescue between paracetamol and morphine.

Several studies have reported morphine has higher incidence of ad- verse events than acetaminophen when used for pain control, and these adverse events include dizziness, hypotension, dry mouth, nausea and vomiting [6,22,26]. In this meta-analysis, paracetamol has lower inci- dence of dizziness than morphine for renal colic pain, but adverse events including nausea and vomiting between two groups are compa- rable. Regarding the sensitivity analysis, there is significant difference for pain scores at 15 min. One gram intravenous paracetamol is com- pared to 10 mg intravenous morphine or 0.1 mg/kg morphine among included RCTs. Different methods of drugs may lead to the bias for the pooling results.

Several limitations exist in this meta-analysis. Firstly, our analysis is based on only five RCTs, and more RCTs with large sample size should be conducted to explore this issue. Next, there is significant heterogeneity, which may be derived from different methods of drugs and baseline pain intensity. Finally, it is not feasible to perform the subgroup analysis based on pain scores at long follow-up based on current studies.

Conclusion

Intravenous paracetamol may be superior to morphine in the control of pain at 30 min for renal colic pain, and more studies should be con- ducted to compare their analgesic efficacy and safety.

Fig. 6. Forest plot for the meta-analysis of nausea and vomiting.

Fig. 7. Forest plot for the meta-analysis of dizziness.

Compliance with ethical standards

Disclosure of potential conflicts of interest

The authors declare no conflict of interest.

Research involving human participants and/or animals

Not applicable.

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