Article, Urology

Does lidocaine as an adjuvant to morphine improve pain relief in patients presenting to the ED with acute renal colic? A double-blind, randomized controlled trial

a b s t r a c t

Objective: Renal colic (RC) is a common clinical presentation in the emergency department (ED). Prompt and ef- fective pain control is one of the first responsibilities of emergency physicians. The aim of this study was to eval- uate the Analgesic effect of adding lidocaine to morphine compared to morphine alone in patients presenting to the ED with RC.

Methods: In a double-blind, randomized controlled trial, a total of 110 adult patients of both sexes, aged 18 to 50 years, who presented to the ED with signs and symptoms suggestive of RC were randomly assigned into 1 of 2 groups. Patients in group A received morphine (0.1 mg/kg) plus lidocaine (1.5 mg/kg), whereas those in group B received morphine (0.1 mg/kg) plus normal saline 0.9% as placebo. All patients were asked to rate the intensity of their pain and nausea on a 0- to 10-point visual analog scale before and at 5, 10, 30, 60, and 120 minutes after intervention.

Results: There was a statistically significant time trend decline in both groups for both pain and nausea scores (P b

.01). Repeated-measures analysis showed a significant effect for the interaction between group and time of per- sistent pain (P = .034), but there was no significant group effect in this regard (P = .146). Median times to being pain free in the group receiving morphine plus lidocaine and in the group taking morphine alone were 87.02 mi- nutes (95% confidence interval [CI], 74.23-94.82) and 100.12 minutes (95% CI, 89.95-110.23), respectively (P =

.071). Repeated-measures analysis also showed a significant group effect for nausea (P = .038), but there was no interaction between group and time in this regard (P = .243). The median nausea-free times in the group receiv- ing morphine plus lidocaine and the group receiving morphine alone were 26.6 minutes (95% CI, 14.16-39.03) and 58.33 minutes (95% CI, 41.85-74.82), respectively. This time difference was statistically significant (P b .001). Conclusions: Using lidocaine may be recommended as an effective, safe, and inexpensive adjuvant to morphine in improving nausea and reducing the time needed to achieve pain and nausea relief in patients visiting the ED with acute RC.

(C) 2015

  1. Introduction

Renal colic (RC) is a common clinical presentation in the emergency department (ED) [1]. Worldwide, more than 12% of people will

? Conflict of interest: None.

?? Funding: Research Deputy of Mazandaran University of Medical Sciences.

* Corresponding author at: Department of Emergency Medicine, Imam Khomeni Hospi- tal, Amir Mazandarani Boulevard, Sari, Iran. Tel.: +98 9355952357; fax: +98 1133254541.

E-mail address: [email protected] (S.M. Hosseininejad).

experience this condition in their lifetime, with a recurrence rate of 50% [2]. Annually, RC affects approximately 1.2 million people and ac- counts for 1% of all ED visits and hospitalizations [3]. Urinary tract ob- struction caused by calculi is the most common cause of RC occurrence. The classical clinical presentation of a ureteric colic is the sudden onset of colicky pain beginning in the flank and radiating to the groin. Humans have described this as the worst pain they have ever experienced [1,4]. Because of the intense nature of the pain associ- ated with RC, prompt and effective pain control is one of the first re- sponsibilities of emergency physicians and the main issue in the

0735-6757/(C) 2015

management of these patients until spontaneous stone passage occurs or surgical intervention is started [5,6]. Given that the most Kidney stones will pass spontaneously, conservative management, including observation with analgesia, remains the preferred approach for these patients [1].

Many pharmacologic agents including nonsteroidal anti- inflammatory drugs, opioids, antispasmodics, and antidiuretic hor- mones can be administered for pain management in RC [6,7]. Nonethe- less, the most effective analgesic regimen has not been determined [8]. Use of opioids is still routine clinical practice for pain control in patients with acute RC and reported to be effective. However, opioids have a problematic side effect profile that includes respiratory depression, nau- sea, vomiting, and hypotension [1,9]. These side effects, which usually increase with increases in the opioid dose, are known to possibly lead to inadequate pain management in patients using opioids [10]. The ad- dition of Adjuvant analgesics to opioids is a strategy that can lead to bet- ter pain control with fewer adverse effects [11].

Lidocaine is a local anesthetic and is thought to exert its analgesic ef- fect by various mechanisms, including inhibition of central and peripheral voltage-dependent sodium (Na) channels, G protein-coupled receptors, and N-methyl-D-aspartate receptors [12-15]. The times to onset of action and elimination half-life of lidocaine after an intravenous (IV) bolus ad- ministration are 2 to 5 minutes and 1.5 to 2 hours, respectively. Lidocaine is mainly metabolized by the liver and excreted by the kidneys. The max- imum bolus dose of lidocaine for adults is 300 mg [16-18].

intravenous lidocaine has proven to be effective in management of acute and chronic pain [19-22]. Likewise, IV lidocaine can also be effec- tively used to treat both central and visceral pain. Based on these char- acteristics, it seems that under conditions where opioids are either ineffective or associated with undesirable complications, the IV lido- caine may be the appropriate choice [18].

Lidocaine has also been stated to augment opioid-mediated analge- sic effects and induce an opioid-sparing effect by interacting with the u and ? Opioid receptors [12].

In previous studies, IV administration of lidocaine was associated with better pain control and lower morphine requirements after sur- gery [23-25]. Moreover, the results of some animal studies regarding synergistic interactions for antinociception and the analgesic advan- tages of combining of topical, epidural, or intrathecal lidocaine and opi- oids [26-28] encouraged us to question whether similar advantages might be seen intravenously in patient with acute RC pain. The only published clinical trial regarding the use of IV lidocaine in patients with RC showed that this modality provides a rapid and significant re- duction in pain intensity compared to morphine [29], but the combina- tion of lidocaine and morphine was not evaluated.

Because of the importance of pain control in patients with RC, the likelihood that lidocaine could provide additional pain relief in a safe manner in this situation, and the limited evidence that supports the ef- ficacy of lidocaine in RC pain management, the aim of the study was to evaluate the Analgesic effects of the addition of lidocaine to morphine compared to morphine alone in patients presenting to the ED with RC.

  1. Methods

After obtaining approval from the Mazandaran University of Medical Sciences Ethics Committee and informed consent from all patients, a consecutive sample of patients with signs and symptoms suggestive of RC were enrolled in this prospective, double-blind randomized con- trolled study. Patients were aged 18 to 50 years, of both sexes, and pre- sented to the ED of Imam Khomeini Hospital, Sari, Iran, between December 2012 and July 2013. The first diagnosis of RC had been made by an emergency medicine specialist, based on history and clinical findings, and confirmed with positive Urine analysis for hematuria or by identifying the pelvi-ureteric stone using ultrasonography or radiologic imaging including the kidney, ureters, and bladder.

Patients with a history of asthma, substance abuse, cardiac disease, kidney or Liver failure, confirmed or suspected pregnancy, multiple pre- vious ED admissions due to RC (N 3 times in a year), use of any analgesics or spasmolytics in the previous 4 hours before admission, hemodynam- ic instability, and prior known allergy to lidocaine or morphine were ex- cluded from the study. Patients whose diagnoses were not confirmed via the methods described above were also excluded.

Patients who fulfilled the inclusion criteria were randomly allocated into group A (n = 55) and group B (n = 55) by sealed envelope tech- nique. Patient allocation was performed by a nurse who was unaware of the study groups, according to numbers generated by the computer-generated list. Group A received morphine (0.1 mg/kg) plus lidocaine (1.5 mg/kg); group B received morphine (0.1 mg/kg) plus nor- mal saline 0.9% as placebo. In both groups, drugs were given as a Bolus infusion over a period ranging from 2 to 4 minutes by a nurse who was blinded to group assignment. All patients were asked to rate the in- tensity of their pain on a 0- to 10-point Visual analog scale , in which 0 indicates “no pain” and 10 indicates the “severest imaginable pain,” before the intervention and 5, 10, 30, 60, and 120 minutes after intervention. Assessed at the same time were the presence or absence of vomiting and nausea (along with nausea intensity) using a VAS (0, no nausea; 10, worst imaginable nausea). The evaluation of pain inten- sity and the occurrence of any side effects such as nausea, vomiting, and so forth had been done and recorded by an emergency medicine resi- dent who was blinded to the patient allocation into the 2 study groups. In this study, the primary end point was the comparison of changes in the VAS pain intensity score at 5, 10, 30, 60, and 120 minutes after in- tervention between groups. Secondary end points were the comparison of changes in the VAS nausea intensity score over the same time inter- vals as well as comparison of the incidence of side effects between the groups. This study is registered in the Iranian Registry of Clinical Trials

Database (IRCT201404196803N7).

  1. Statistical analysis

Data were tested for normal distribution using the Shapiro-Wilk test. Comparisons were tabulated as mean +- SD, median (interquar- tile range) or as percentages for the descriptive baseline characteris- tics of the 2 groups. The ?2 or Fisher exact test was used to statistically analyze the categorical data being compared between the 2 groups; continuous data were statistically analyzed using the t test and the Mann-Whitney U test. The primary efficacy data on pain and nausea scores (according to VAS) were examined using intention-to-treat analysis. Using a general linear model, the VAS scores of the 2 groups were compared by repeat-measurement anal- ysis of variance test. Time of evaluation was considered as a within- subject factor and intervention state (morphine plus lidocaine and morphine plus normal saline) as a between-subject factor. The Time groups (interaction term) were considered as group differences (between morphine plus lidocaine and morphine plus normal sa- line) in their responses over time. Mauchly’s sphericity test was used to test for equality of variances. In addition, the Kaplan-Meier method was used to assess the occurrence of pain-free and nausea- free effects according to time without pain/nausea for patients tak- ing each intervention. The median pain-free/nausea-free time from intervention initiation to the onset of freedom from pain and nausea in patients was determined by log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with the Cox models, which were adjusted for covariates believed to be potential con- founders for the pain-free/nausea-free time. Based on our study, var- iables we used for modeling were age, body mass index (BMI), stone size, hydronephrosis, and history of urolithiasis and lithotripsy. P <=

.05 was considered statistically significant. Data were analyzed using IBM SPSS statistics version 16 (IBM, Armonk, NY) and Stata version 10 (StataCorp LP, College Station, TX).


Basic demographic and clinical characteristics for the study population


Group A (morphine plus lidocaine, n = 47)

Group B (morphine plus normal saline, n = 42)


Age (y)

37.91 +- 10.76

37.95 +- 12.6


Sex (female/male)





26.92 +- 3.44

26.1 +- 3.3


Residency (urban/rural)







2 (4.3)

2 (4.8)


18 (38.3)

11 (26.2)


27 (57.4)

29 (69)

Stone side


Right kidney

21 (44.7)

20 (47.6)

Left kidney

19 (40.4)

17 (40.5)

Both kidneys

7 (14.9)

5 (11.9)

Stone size (mm)

7.6 +- 3.1

8.2 +- 2.4



17 (36.2)

18 (42.9)


History of urolithiasis

23 (54.8)

21 (44.7)


History of lithotripsy

7 (14.9)

10 (23.8)


Pain VAS score before the intervention, median (interquartile range)

10 (8-10)

10 (9-10)


Nausea VAS score before the intervention, median (interquartile range)

5 (0-7)

5 (0.75-7.25)


a “Low” educational attainment includes every level of educational attainment up through high school graduate; “High” education attainment means college graduate.

  1. Results

A total of 128 consecutive samples of patients who presented to our ED with signs and symptoms suggestive of RC were screened during the study period. Of these, 11 patients did not meet the inclusion criteria, and 7 patients declined to participate in the study. The remaining 110 patients were randomly allocated to 2 groups. Of these, 21 patients were lost to follow-up during the study period. In total, 89 patients com- pleted the present study, and data from all these patients were analyzed (Fig. A; Appendix A).

Image of Fig. 1

Fig. 1. Pain score trend (according to VAS) before and after interventions in patients with acute RC. Repeated-measures analysis showed a significant effect for time (P b .01) and for the interaction between group and time (P = .034). No significant group effect existed (P = .146).

Basic demographic and clinical characteristics of the patients in the 2 groups (group A, morphine plus lidocaine; group B, morphine plus nor- mal saline) are presented in the Table. No significant difference was de- tected in average age (37.91 +- 10.76 vs 37.95 +- 12.6; P = .992), sex ratio (11/36 vs 7/35; P = .641), BMI (26.92 +- 3.44 vs 26.1 +- 3.3; P =

.314), hydronephrosis proportion (36.2% vs 42.9%; P = .662), and the

stone size (7.6 +- 3.1 vs 8.2 +- 2.4; P = .685) between the 2 groups. In addition, there were no significant differences between 2 groups in terms of the history of urolithiasis and lithotripsy (P N .05).

Figs. 1 and 2 show the mean values of the preintervention and post- intervention VAS parameters of each group. As shown in Fig. 1, there was a statistically significant time trend toward decline in both groups (within-subject or time-effect differences) for pain scores (P b .01). Pain scores in the group receiving both morphine and lidocaine were

Image of Fig. 2

Fig. 2. Nausea score trend (according to VAS) before and after interventions in patients with acute RC. Repeated-measures analysis showed a significant effect for time (P b .01) and group (P = .038). No significant interaction existed between group and time (P = .243).

lower than those for the group that only received morphine, but neither the between-subject differences nor group effect was statistically signif- icant between the groups (P = .146). The groups have nonparallel lines that decline over time and progressively move away from each other. The reduction slope for the morphine plus lidocaine group was greater than for the group solely receiving morphine (group time interaction or interaction effect) (P = .034), indicating that the magnitude of the differences between the 2 groups was not constant over time. Fig. 2 shows that a statistically significant time trend decline (within-subject differences or time effect) occurs for nausea scores as well (P b .01). The nausea scores in the group receiving morphine and lidocaine were lower than for the morphine group alone; there was a statistically significant difference between groups (between-subject differences or group effect) (P = .038). The reduction slope for the morphine plus li- docaine group was greater than that of the control group, but this differ- ence was not statistically significant (no interaction effect) (P = .243). These results indicate that there was an overall difference across groups for all time points.

The median for pain-free time (the time from receiving analgesic to

feel pain free) in the morphine plus lidocaine group was 87.02 minutes (95% CI, 74.23-94.82) (Kaplan-Meier method); this time was 100.12 mi- nutes in the group receiving only morphine (95% CI, 89.95-110.23) (P =

.071, log-rank test). Multivariable Cox proportional hazards model was used to determine the independent effects of lidocaine in pain- free time and included terms for age, BMI, stone size, hydronephrosis, and history of urolithiasis and lithotripsy. From this Cox regression analysis, the only independent predictor of pain-free time was lidocaine. Adding of lidocaine to morphine decreased the pain-free time, with an adjusted HR of 0.57 (95% CI, 0.33-1.001; P = .051). The median nausea-free time in patients administered morphine plus lidocaine was 26.6 minutes (95% CI, 14.16-39.03) (Kaplan-Meier method) and in patients adminis- tered morphine alone was 58.33 minutes (95% CI, 41.85-74.82), which was significantly different (P b .001, log-rank test). Multivariable Cox proportional hazards model was used to determine the independent ef- fects of lidocaine in nausea-free time and included terms for age, BMI, stone size, hydronephrosis, and history of urolithiasis and lithotripsy. From this Cox regression analysis, the independent predictors of nausea-free time were lidocaine and BMI. Adding of lidocaine to mor- phine significantly decreased nausea-free time, with an adjusted HR of

0.054 (95% CI, 0.32-0.9; P = .019). No lidocaine-related adverse effects were observed in this study.

  1. Discussion

We evaluated the analgesic effects of lidocaine plus morphine com- pared with morphine alone in patients presenting to the ED with RC. One of the major findings of this study was that no statistically signifi- cant differences were observed between groups, despite a significant time trend decline in pain intensity in both groups. It is noteworthy that patients receiving morphine plus lidocaine had shorter time to reach a pain-free state in comparison with the morphine group. The other main finding was that the patients in the lidocaine plus morphine groups had milder nausea and a shorter time to reach the nausea-free period. A study conducted by Soleimanpour et al [29] comparing the an- algesic effects of IV morphine vs IV lidocaine in patients presenting to the ED with RC showed that patients who received lidocaine had signif- icant pain relief vs the comparison group. Furthermore, 11 patients in the morphine group and no patients in the lidocaine group experienced nausea and vomiting [29]. In a case series study, 8 intractable RC pa- tients who were resistant to treatment with nonsteroidal anti- inflammatory drugs or morphine were successfully treated using IV li- docaine, with no patients experiencing serious adverse events [30].A study by Iguchi et al [31] that aimed to evaluate the effects of local injec- tion of lidocaine into the Trigger points of patients experiencing RC showed that this intervention was significantly superior to Conventional treatment (combination of IV butylscopolamine and sulpyrine) in RC

pain management. A case study reported by Nikiforov et al [32] de- scribed the successful treatment of persistent RC pain in a pregnant woman who did not respond to treatment with IV opioids, using subcu- taneous paravertebral block with lidocaine.

A recent study by Alebouyeh et al [23] showed that adding lidocaine 1% to a 20-mg morphine infusion significantly decreased the patients’ pain intensity and opioid consumption after the surgery compared with patients who received 10 mg of morphine plus lidocaine and to the control group, without having side effects. In this study, nausea, vomiting, and sedation scores were not statistically different among the study groups [23], which is inconsistent with the results of our study. One possible explanation for this is that the combination of lido- caine and morphine was infused during the study period in the earlier study, but patients in our study received only a single bolus dose of lido- caine in combination with morphine [23].

In our study, the pain intensity in the 2 groups decreased similarly up to 5 minutes after the beginning of the intervention. After the 5-minute point, the decrease in pain intensity in patients who received morphine plus lidocaine was greater than that of the morphine plus normal saline group for all time points. This result is in broad agreement with the onset time and Duration of action of lidocaine after IV bolus ad- ministrations, which are 2 to 5 minutes and 1.5 to 2 hours, respectively [17,18]. Although no significant group effect has been demonstrated in this study, the amount of time it took patients who received a combina- tion of lidocaine and morphine to attain a pain-free state was shorter than that for the group only receiving morphine with normal saline. Al- though this time difference was statistically insignificant, we believe that an approximate 13-minute difference in median for pain-free time is significant in terms of clinical practice. The present study’s find- ings indicate that a sample size of 78 in each group would be required to detect statistically significant differences in VAS change between 2 groups, assuming 80% power, a 2-tailed ? of .05, mean (SD) change in VAS score of 8.44 (2.1) in the lidocaine plus morphine group, vs 7.19 (3.1) in the morphine alone group. Relatively, small sample size in our study may be a possible explanation for this insignificant result. Hence, future studies with larger sample sizes are warranted.

Intravenous lidocaine is used extensively in the clinical setting for the management of postoperative pain, refractory headache, postherpetic neuralgia, neuropathic and centrally mediated pain, and poststroke pain syndrome [22,23,33-35]. The results of a meta- analysis showed that IV administration of lidocaine can decrease post- operative pain intensity and the incidence of nausea and vomiting [36]. In a case study by Ferrini and Paice [37], a patient with primitive neuroectodermal tumor and severe Neuropathic pain resistant to mor- phine and other adjuvant treatments was successfully treated using a single IV lidocaine (1.5 mg/kg).

Lidocaine changes the tone of sympathetic smooth muscle through reduction in the transmission from the afferent sensory pathway. Eventually, considerable reduction in pain is achieved via IV administration of lidocaine [29]. It is interesting to point out that the analgesic properties of lidocaine persist even after decreases in plasma levels. In other words, even in low doses, lidocaine sup- presses evoked potential and demonstrates strong results in analge- sia [38,39,16]. Because of efficacy of lidocaine in both central and visceral pain management, IV administration of this analgesic may be considered as a choice in cases where opioids are either ineffec- tive or associated with unacceptable side effects [18]. Nonetheless, as local anesthetics and opioids have different sites and mechanisms of action, it is believed that coadministration of these drugs improves analgesic and opioid-sparing effects by interacting with the u and ? opioid receptors [12].

The results of our study showed that adding lidocaine to morphine significantly decreased nausea and shortened the time needed to reach the nausea-free period. The antinausea effect of lidocaine could possibly be related to its anti-inflammatory properties. It has been pre- viously shown that lidocaine has significant anti-inflammatory

properties [40]. This anti-inflammatory property may reduce the in- flammation triggered by afferent stimulation of the parasympathetic nervous system to the vomiting center, thereby reducing nausea and vomiting [41]. Another possible explanation may be that lidocaine re- duces serotonin levels. Serotonin, as a main neurotransmitter compo- nent of the Inflammatory process, promotes pain from tissue injuries through action on multiple receptor subtypes [42]. Serotonin can sensi- tize the vagal afferent nerves and trigger nausea and vomiting [43]. On the other hand, it has been shown that lidocaine can reduce serotonin concentrations [42,44,45]. Nevertheless, no experimental evidence ex- ists for the aforementioned explanation, requiring further studies to de- termine the mechanism by which lidocaine’s antinausea effect can be explained.

In this study, no lidocaine-related adverse effects were observed. Al- though most adverse effects that have been reported in the literature, including transient mild dizziness, constipation, perioral numbness, and minimal slurring of speech, are mild and temporary [18,29], in pa- tients with cardiac or Hepatic dysfunction and in use with advanced age, lidocaine should be administered with caution and under continuous monitoring [46]. The side effects of IV lidocaine are predictable and pro- vide adequate safety margins. Because of the short half-life of lidocaine, the symptoms of toxicity are transient and rapidly reversible (the most common side effects are generally mild and central nervous system re- lated), adding to its popularity among physicians working in the emer- gency medicine setting [18]. Lidocaine-triggered toxic manifestations occur when its plasma concentrations reach 5 ug/mL. However, doses between 1 and 5 mg/kg result in plasma concentrations of 2 ug/mL that are safely below toxic levels [38,16]. Note that the toxic dose of li- docaine may change in terminally ill patients [47].

One limitation of this study was that we only use a single dose of li- docaine as an adjunct to morphine in patients presenting to the ED with

RC. We are not certain whether higher doses or lidocaine infusion may be able to provide more favorable results, demanding further research. We also did not measure the lidocaine plasma concentration in this study, so for an optimal dose of administration, further study to mea- sure the lidocaine plasma concentration is recommended. To add this, loss to follow-up cases in this study was 21 (8 in morphine plus lido- caine, and 13 in morphine plus normal saline groups), among which 15 cases were excluded due to unconfirmed diagnosis of RC. The rest cases (2 in morphine plus lidocaine and 4 in morphine plus normal sa- line groups) made a small ratio. Although most of the lost to follow-up cases had unconfirmed diagnosis, we examined all of them for possible confounders and found no significant differences between them and study groups in terms of age, sex, preintervention pain and nausea VAS scores, stone size, and history of urolithiasis and lithotripsy. Thus, the risk of substantial bias is unlikely.

  1. Conclusion

Using lidocaine may be recommended as an effective, safe, and inex- pensive adjuvant to morphine in improving nausea and reducing the time to achieve pain and nausea relief in patients presenting to the ED with acute RC. Further well-designed randomized clinical trials to con- firm the safety and efficacy of lidocaine as an adjunct in the treatment of RC pain are warranted.


The financial support of Research Deputy of Mazandaran University of Medical Sciences is gratefully acknowledged. In addition, the authors wish to thank all the study participants for their tremendous coopera- tion and support.

Appendix A

Fig. A. CONSORT diagram of patients’ randomization, intervention, and analysis.


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