28 J Contemp Med Sci | Vol. 9, No. 1, January-February 2023: 28–34 Original Comparison of Rectal Suppository and Intramuscular Morphine for Management of Patients with Renal Colic Referred to the Emergency Department: A Randomized Double-blinded Controlled Trial Arash Ardestani Zadeh1, Mohammadreza Moonesan2, Fatemeh Taheri1, Davood Arab1*, Tahmineh Mokhtari3,4* 1Clinical Research Development Unit, Kowsar Educational, Research and Therapeutic Hospital, Semnan University of Medical Sciences, Semnan, Iran. 2Department of Emergency Medicine, Kosar Hospital, Semnan University of Medical Sciences, Semnan, Iran. 3Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, China. 4Department of Histology and Embryology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China. *Correspondence to: Tahmineh Mokhtari (Email: mokhtari.tmn@gmail.com), Davood Arab (Email: drdavoodarab@semums.ac.ir) Abstract Objectives: To compare the analgesic effects of rectal suppository morphine (RSM) with intramuscular morphine (IMM) in patients suffered from renal colic referred to emergency ward (EW). Methods: In a controlled, randomized, clinical trial, 74/90 patients with renal colic referred to the EW between March 2016 and March 2017 were randomly enrolled into two groups of RSM (10 mg) and IMM (10 mg/mL). Vital signs and severity of pain were recorded at admission time (0), 15, 30 and 60 min after treatment. Results: The results showed that there was a significant decrease in VAS score of RSM group compared to IMM group after 30 and 60 min of administration (P < 0.05). Furthermore, no significant difference was recorded in vital signs, except there was a significant decrease in heart rate (15 and 60 min) and respiratory rate (60 min) of RSM group compared to IMM group (P < 0.05) and no side effects were recorded during the investigation. Conclusion: In conclusion, the use of rectal route of morphine had higher efficiency compared to the IM route of morphine in relieving pain of patients with renal colic. Although, decreased heart and respiratory rates were recorded, the values were in normal range. As well, no major complications were recorded for each method. Keywords: Renal Colic, morphine; pain management, suppositories, injections, intramuscular ISSN 2413-0516 Introduction Urolithiasis has been shown to be a common disease with inci- dence of 8–15% in North Americans and Europeans for centu- ries.1 Approximately 2.4/1000 people in Iran suffer from renal colic, whereas it differs from 0.5 to 2 in every 1000 ones in other countries.2 The mean cost of urolithiasis and renal colic was estimated about 2.1 billion dollars in 2000.3 Recently, it has been reported that changes in individuals’ diet and lifestyle leads to increase in incidence of renal colic worldwide.4 Renal colic as a frequent disorder usually presents as an acute and severe pain in the flanks due to obstruction of the urinary flow via a stone or the passage of a stone from the uri- nary tract, which can radiate to the abdomen and genitalia.5,6 This type of pain is often defined as the worst pain which patient has ever experienced.7,8 The mechanism of pain is associated with the enhanced pressure in the urinary tract along with construction of urethral smooth muscles and enhanced pressure in the regional blood flow.9 A wide range of analgesics are used to manage the pain. In emergency ward (EW), opioids and non-steroidal anti-inflam- matory drugs (NSAIDs) are most frequent to relieve the pain.10 According to the literature, stable doses of opioids can provide analgesic impacts for weeks or years and efficiency, low cost, and titration possibility make them popular for managing pain.3,11 The high doses of opiates administered systemically has been shown to be related to different side effects e.g., res- piratory depression, vomiting, nausea, sedation, and pru- ritus.12 On the other hand, the human rectum is a body cavity in which drugs can be retained and absorbed easily and is effective rather than orally, especially in cases with nausea and vomiting.13 As a most common type of opioids, morphine is an anal- gesic with a direct impact on the central nervous system (CNS) and the most powerful analgesic drugs in managing and curing severe, acute and chronic pains.14 Different routes of morphine have been used to control pain in patients following operation or in emergency department.15-17 Morphine suppos- itories administered via rectal route are one of the newly released morphine forms. Different doses of 5, 10, 20, and 30 mg of morphine can be contained in each rectal suppository. It has been shown that about two-thirds of rectal morphine can be absorbed via the gastrointestinal tract and then, it paases through portal vein to be metabolized in the liver. The max- imum effects of rectal route has been recorded 20–60 min fol- lowing administration.12 The administration of suppository morphine is often for- gotten by clinicians seeking to use the oral routs18 and to the best of our knowledge, there was no previous study to com- pare the analgesic effect of rectal suppository morphine (RSM) with intramuscular morphine (IMM) to relieve pain in patients with renal colic. Materials and Methods Study Population This study was a randomized, controlled, clinical trial was per- formed between March 2016 and March 2017. Ninety patients with renal colic (18 to 55 years) referred to EW of Kosar Hos- pital (Semnan University of Medical Sciences, Semnan, Iran) were randomly selected, but 74 patients were eligible to be enrolled. This trial was approved by Ethics Committee of (Submitted: 01 December 2022 – Revised version received: 22 December 2022 – Accepted: 02 January 2023 – Published online: 26 February 2023) mailto:mokhtari.tmn@gmail.com mailto:drdavoodarab@semums.ac.ir 29J Contemp Med Sci | Vol. 9, No. 1, January-February 2023: 28–34 A.A. Zadeh et al. Original Suppository or Intramuscular Morphine for Pain Control in Renal Colic Semnan University of Medical Sciences (5/1/2016). Written informed consent form was signed by all subjects to accept that they had adequate information about the investigation. The study was registered at Iranian registry of clinical trial (IRCT number: IRCT2015111825098N1). Inclusion and Exclusion Criteria In this study, 90 patients referred to EW with main complaint of flank pain, and the patients who clinically diagnosed for renal colic were selected. The inclusion criteria were defined as all cases with acute severe flank pain that radiated to ipsilateral groin or abdomen. Then, the urinary stone was confirmed through ultrasonography, computed tomography (CT) scan, or intravenous (IV) pyelography, or the patients with stone passage and the patients were selected for investigation. The exclusion criteria was described as follows: patients with history of allergy to opioids, addiction, fever ≥38ºC, unstable hemodynamic status, liver failure, cardiac or respira- tory failure, evidence of peritoneal inflammation, renal failure or kidney transplantation, aortic aneurysm or dissection, pregnancy, receiving any analgesia within 6 h before the study and age <18 and >55 years. An emergency medicine specialist performed all evalua- tions. Sixteen cases were excluded from the study due to the above exclusion criteria. Randomization and Intervention In this study, a convenience sampling was used to select 90 patients (74 were eligible). Then, patients were randomly allo- cated into two groups (37 in each group) using permuted bal- anced block randomization in a completely random manner. For this purpose, six blocks of four were used in which the structure of each block was four-way, the combination of two methods of interference in a perfectly balanced way. To random assignment of blocks to each group a random digits table was carried out. Therefore, a list of eligible participants (n = 74) was prepared and according to this list each case was randomly enrolled in the study group, respectively. No addi- tional matching was performed and one of the investigators scheduled for randomization before the initiation of study. None of participants and data analysts knew about the groups. The treatment groups were defined as below: SS-MP group (n = 37): Patients received 10 mg morphine suppository (Opirec® 10 mg, Aburaihan pharmaceutical Co.). IM-MP group (n = 37): Patients received 10 mg mor- phine intramuscularly (IM) (Morphine Sulfate 10 mg/mL, Daou Pakhsh pharmaceutical Co.). Procedures and Evaluations Data were collected using a designed checklist containing the factors as below to make the assessments: A: Patient’s demographic information including age, gender and weight. B: History of similar pain, history of urinary stones and Main data including vital signs (blood pressure [BP], respira- tory and heart rate [HR] and axillary temperature) and severity of pain using a 10-centimeter visual analogue scale (VAS). VAS was used for evaluation of the pain severity was in several time points of admission time (0), 15, 30 and 60 min after administration of medications. VAS is a measurement instrument that tries to measure a pain severity scored 0 (no pain) -10 clinical observation.19 Clinically, the difference of VAS score between 0 and 15 min (0–15), 0 and 30 min (0–30), 0 and 60 min (0–60) time points were calculated and com- pared in two groups of morphine routes. Moreover, other var- ibales including HR, BP (systolic and diastolic), respiratory rate, and the side effects of drugs (secondary outcomes including drowsiness, nausea & vomiting, facial flushing, and dizziness) were investigated in defined time points. After gath- ering the data, the VAS scores of different time points were compared. After 60 min, if the severity of pain did not relief by 50%, 5 mg/IM morphine was used to relive the pain. In this study, four patients were excluded due to missing or incon- sistent data (n = 3 in RSM group and n = 1 in IMM group) during the study and data of 70 cases were analyzed. Due to incomplete information and data in the questionnaire, patients were excluded from the study (Figure 1). Sample Size Estimation and Statistical Analysis Using the findings of the study performed by Safdar et al. (2006) reporting an average reduction of one hour of pain equal to 5.0 ± 1.6 in patients with intramuscular morphine injection compared with the average further reduction of 6.0 ± 1.6 in patients with morphine suppository in term of VAS, set- ting the statistical power and confidence levels to be 95%, a sample size of 136 people (68 in each group) was estimated to be enough using G*Power.3.1 software. But conservatively up to 7 people were added in each group to deal with possible data loss.20 Data were analyzed using SPSS (ver. 22). Mean, standard deviation, frequency and percentage were used to summarize the data in tables. The analysis of variance (ANOVA) for repeated measures models applied to compare the two groups. Fisher’s exact tests and Chi-square were used to determine the differences in the qualitative data. In addi- tion, T- test was used for evaluation of differences in the quan- titative data. Significant level was defined as P < 0.05. Results In this study, the data of 70/74 cases (n = 3 in RSM group and n = 1 in IMM group were excluded) with renal colic treated Fig. 1 CONSORT flow diagram. 30 J Contemp Med Sci | Vol. 9, No. 1, January-February 2023: 28–34 Suppository or Intramuscular Morphine for Pain Control in Renal Colic Original A.A. Zadeh et al. between the two groups (P = 0.030). In addition, there were no significant differences in HR of two groups based on time points of 0 (P = 0.116) and 30 (P = 0.139), but significant decreases were seen in time point of 15 (P = 0.04) and 60 min (P = 0.014) in RSM group compared to IMM group. Com- paring two groups showed that there was no significant dif- ference in terms of changes in the respiratory rate (per min) between the two groups (P = 0.622). Based on time points, respiratory rate was significantly decreased in 60 min (P = 0.017) in RSM group compared to the IMM group. How- ever, in the other time points no differences was observed (0: P = 0.799, 15: P = 0.291, 30: P = 0.605, and 60: P = 0.855, respectively) (Table 2 and Figure 1). No major complications were reported in two groups. Discussion In this investigation, we aimed to compare the influence of rectal and IM morphine/pain management in patients with renal colic. In EW, management of patients with colic pain is one of the most important part of caring system.21 NSAIDs and opioids as well as the combination of spasmolytic and anti-inflammatory drugs have been recorded to be mostly used for pain control of these patients.10,22,23 Among these, nar- cotics such as morphine, tramadol, codeine and meperidine have long been used.20,24,25 Morphine, as an opioid analgesic, has been used for pain control of patients with renal colic given by different routes.26,27 Morphine administered with IV route is a drug of choice to manage pain in acute renal colic.28 Nevertheless, the other routes of morphine administration, e.g., oral, IM and rectal are available to relieve pain in different conditions.29,30 Studies have proven that IM administration of opioids has been considered to be safer than IV.31 Although, oral and par- enteral narcotics are used usually for pain relief in EW or fol- lowing surgical procedures, these routs can exacerbate the incidence of sedation, vomiting, and nausea, which ultimately delays recovery.32-34 Thus, non-parenteral route of analgesic drugs, especially their rectal route has been suggested in dif- ferent studies.13,35,36 According to the literature, it has been proved that rectal route morphine results less analgesia and lower pain scores compared to its IV administration.34,37 The findings of both groups showed the similarity in the different demographic features including age, gender, weight, Table 1. Comparing the characteristics of patients with renal colic based on study groups Groups P-value SS-MP (n = 34) IM-MP (n = 36) N (%) or Mean ± SD* (range) N (%) or Mean ± SD (range) Age (year) 37.75 ± 10.92 (18–68) 38.89 ± 10.46 (18–60) 0.329 Gender (male) 24 (70.6) 29 (80.6) 0.331 Weight (Kg) 79.88 ± 14.17 84.3 ± 23.41 0.446 History of urinary stones 23 (67.6) 22 (61.1) 0.568 History of simmilar pain 22 (64.7) 22 (61.1) 0.756 Axillary temperature ( °C) 36.76 ± 0.53 36.76 ± 0.32 0.543 Opioids for pain relief 3 (8.8%) 9 (25) 0.73 SD: Standard deviation; UPJ: Ureteropelvic junction. with morphine administered via IM or rectal routes were considered. The demographic features of cases with renal colic in two groups were compared (Table 1). The mean age of patients in RSM group was 37.75 ± 10.92 year (18 to 55) and IMM group was 38.89 ± 10.46 year (18 to 55). No significant difference was reported in the mean age of two groups (Table 1, P = 0.329). As well, 24 patients (70.6%) in RSM group and 29 patients (80.6%) in IMM group were male and no significant differences were seen in the distribution of sex in two groups (Table 1, P = 0.331). The mean weight of patients in RSM group was 79.88 ± 14.17 Kg and in IMM group was 84.3 ± 23.41 Kg and no differences was recorded in the weight of patients in two groups (Table 1, P = 0.446). The history of urinary stones and similar pains were compared between two groups as was shown in Table 1. No significant differences were reported in the distribution of history of uri- nary stones (Table 1, P = 0.568) and similar pains (Table 1, P = .756) of patients in two treatment groups. Furthermore, frequency of extra doses of opioids was not significant in two groups (Table 1, P = 0.073). Using chi-square test, no signifi- cant differences were observed in the distribution of side effects in both groups (Table 1, P = .599). All these results proved that two groups were similar in these characteristics before the treatment period. The mean VAS score, systolic BP (mmHg), diastolic BP (mmHg), HR (bpm), and respiratory rate (per min) were compared in two groups (Table 2, Figure 2). A significant dif- ference was observed in terms of pain intensity between two groups (P = .017). Also, there were significant differences in VAS score of two treatment groups according to time points of 30 (P = .037) and 60 (P = 0.027) after treatment; but no differences were recorded in time point of 0 (P = 0.58) and 15 (P = 0.083). There was a significant difference in the mean VAS score difference of 0–30 (P = 0.001) and 0–60 (P = 0.001) time points; but no significant difference was recorded for mean VAS score difference of 0–15 min (P = 0.083). Based on the results, no significant difference was also observed between groups for systolic (P = 0.201) and diastolic pressure (P = 0.350). As well, no significant difference was seen in the mean systolic pressure (P = 0.762, P = 0.068, P = 0.072 and P = 0.232, respectively), diastolic pressure (P = 0.345, P = 0.506, P = 0.222, and P = 0.105, respectively) on different time points of 0, 15, 30, and 60. In addition, significant differ- ence was observed in terms of changes in the HR (per min) 31J Contemp Med Sci | Vol. 9, No. 1, January-February 2023: 28–34 A.A. Zadeh et al. Original Suppository or Intramuscular Morphine for Pain Control in Renal Colic Table 2. Comparing the vital signs and pain severity (VAS) between two groups based on different time points, including admission time (0), 15, 30 and 60 min after drugs administration Groups SS-MP (n = 34) IM-MP (n = 36) P-value Mean ± SD* Mean ± SD VAS score 0 8.26 ± 1.79 9 ± 1.26 0.116 15 min after treatment 5.95 ± 1.78 6.73 ± 1.97 0.139 30 min after treatment 4.32 ± 2.58 5.58 ± 2.38 0.018 60 min after treatment 2.58 ± 2.95 4.19 ± 3.03 0.081 Systolic pressure (mmHg) 0 124.38 ± 10.31 127.27 ± 16.38 0.762 15 min after treatment 116.56 ± 10.44 123.64 ± 14.32 0.068 30 min after treatment 113.75 ± 11.33 120 ± 12.82 0.073 60 min after treatment 115.31 ± 9.91 119.55 ± 12.14 0.232 Diastolic pressure (mmHg) 0 79.38 ± 7.0 79.32 ± 11.37 0.848 15 min after treatment 76.88 ± 6.02 77.14 ± 11.37 0.988 30 min after treatment 72.5 ± 8.37 77.5 ± 11.73 0.889 60 min after treatment 72.5 ± 7.53 77.73 ± 10.99 0.888 Heart rate (bpm) 0 78.4 ± 7.59 82.55 ± 8.23 0.115 15 min after treatment 76.4 ± 6.67 81.59 ± 7.08 0.04 30 min after treatment 76.6 ± 6.6 81.86 ± 7.32 0.073 60 min after treatment 75.23 ± 6.42 81.55 ± 8.15 0.017 Respiratory rate (per min) 0 18.21 ± 2.11 18.48 ± 2.6 0.779 15 min after treatment 17.14 ± 0.81 17.76 ± 2.23 0.291 30 min after treatment 16.79 ± 1.76 17.19 ± 1.91 0.073 60 min after treatment 16.93 ± 1.77 17.05 ± 2.01 0.017 *SD: Standard deviation. and also history of urinary stones and similar pain. Based on the findings of present study, rectal route of morphine could decrease the VAS score significantly compared to the IMM group. Additionally, the score differences of 0–30 and 0–60 showed significant improvement in RVS group. Taken together, administration of rectal route of morphine could be successful in the management of pain in patients with renal colic. Although the mean heart and respiratory rate decreased in rectal route group compared to IM group, these criteria were within normal range in this group, which were not a cause for concern. As well, no serious complications have been reported in these two groups. Based on the literature, efficiency of different routes of morphine have been compared in a wide range of painful con- ditions. To show the efficiency and safety of morphine admin- istered via rectal route in relieving pain, Rahimi et al. (2016) used preemptive suppository morphine after laparoscopic cholecystectomy in a placebo-controlled study. The results from VAS score proved that administration of morphine sup- pository was effective in analgesic requirements following lap- aroscopic cholecystectomy.12 In a randomized controlled trial, Butler et al. (2017) evaluated the effects of belladonna and opium suppositories for reduction of pain in vaginal surgery and showed that these drugs are safe to use following this sur- gery.37 As well, Cole et al. (1990) demonstrated that morphine hydrogel suppository appears to be effective in management of postoperative pain.38 Studies to compare the different routes of morphine espe- cially the rectal and intramuscular routes of morphine are so limited. Guldbrand and Mellstrom (1995) compared the rectal rout of morphine-scopolamine with IM route as a premedica- tion in healthy children scheduled for minor ENT surgery. Their findings indicated that administration of rectal route of drug worked better and resulted in slightly less post-operative pain and nausea. They suggested to use rectal route of mor- phine-scopolamine as a premedication for minor ENT sur- gery on children as a good alternative compared to the IM route.39 Additionally, in a study by Wilkinson et al. (1992), the effectiveness of rectal vs. oral sustained-release morphine were compared in the patients with cancer. They found no signifi- cant difference between the oral and the rectal route in meas- urements based on VAS score or side effects. As well, they recommended to use the rectal route of morphine, when the oral route is not accessible for long time.40 The bioavailability of IM morphine is roughly complete (100%), whereas the bio- availability of rectal morphine is only 50–60%.41,42 Therefore, the poorer rectal bioavailability leads to lower plasma concen- trations of morphine compared with the IM application. How- ever, the evidence showed that the rectal and IM morphine reached the peak plasma concentration after 30 min and 1 hour, respectively, indicating that the absorption was rapid in the rectal route.43 According to the results, no major complications were recorded for two forms of administrations. The safety and 32 J Contemp Med Sci | Vol. 9, No. 1, January-February 2023: 28–34 Suppository or Intramuscular Morphine for Pain Control in Renal Colic Original A.A. Zadeh et al. Fig. 2 Comparing the vital signs and pain severity between two groups based on different time points including admission time (0), 15 min, 30 min, and 60 min after drug administration. effectiveness of morphine suppository in relieving pain have been proven in different studies. Westerling et al. evaluated the bioavailability and absorption of rectally administered morphine in 21 healthy women undergoing gynaecological operations and demonstrated that the mean bioavailability was 31% (range 12%–61%) and none of the cases showed any clinical sign of respiratory depression.43 Furthermore, Babul et al. (2013) compared the safety and effectiveness of controlled‐release morphine tablets and suppositories in pain management of patients with cancer and reported that controlled‐release morphine suppositories provides pain control comparable to that provided by tablets when received every 12 h at a 1/1 dose ratio, and suggested a reli- able alternative approach of pain management for patients unable to take oral opioid medications.44 In an experimental study by Barnhart et al. (2000), the systemic bioavailability and therapeutic plasma levels of morphine following IV and IM administration as well as respiratory, cardiovascular, and analgesic values were compared in dogs. No differences were recorded in analgesia values and vital organs e.g., res- piratory and cardiovascular between control and morphine groups.45 33J Contemp Med Sci | Vol. 9, No. 1, January-February 2023: 28–34 A.A. Zadeh et al. Original Suppository or Intramuscular Morphine for Pain Control in Renal Colic Fig. 3 The schematic summary of the study. Conclusion Our findings indicated that the use of rectal morphine suppos- itories may be more effective in diminishing pain in cases referred to EW with renal colic compared with IM route in EW. Since the morphine suppositories are due to no adverse impact on the vital signs of patients and also have no other major complication, we recommend to use rectal route of morphine as a safe and more effective method in relieving pain of renal colic patients in EW (Figure 3). Limitation One of our study limitations was that the possibility of evalu- ating other variables attributed to alterations of pain severity. One of these limitations is the differences in the level of educa- tion and awareness of the patients under study that may have been effective in expressing the severity of pain based on VAS. On the other hand, there are several variables that affect the pain severity, which of course has not been possible to con- sider all of them in one study. Acknowledgments We would like to thank the Clinical Research Development Unit of Kowsar Educational and Research and Therapeutic Center of Semnan University of Medical Sciences for pro- viding facilities to this work. 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