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ORIGINAL ARTICLE
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Comparison of the effects of midazolam, dexamethasone, ondansetron and propofol on the prevention and control of opioid-induced pruritus after spinal anaesthesia with bupivacaine combined with fentanyl in femoral fracture surgery


1 Department of Anesthesiology, Arak University of Medical Sciences, Arak, Iran
2 Department of Orthopedic Surgery, Arak University of Medical Sciences, Arak, Iran
3 Department of Anesthesiology, Student Research Committee, Arak University of Medical Sciences, Arak, Iran

Date of Submission26-Feb-2022
Date of Acceptance29-Jul-2022
Date of Web Publication23-Sep-2022

Correspondence Address:
Esmail Moshiri,
Department of Anesthesiology, Arak University of Medical Sciences, Arak
Iran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aihb.aihb_45_22

  Abstract 


Introduction: The present study set out to compare the effects of midazolam, dexamethasone, ondansetron and propofol on the prevention and control of opioid-induced pruritus after spinal anaesthesia with bupivacaine and fentanyl as adjuvants in femoral fracture surgery. Materials and Methods: This double-blind clinical trial study was conducted on 136 patients who were scheduled for orthopaedic surgery in Valiasr Hospital of Arak. The patients were randomly divided into four groups (ondansetron, midazolam, dexamethasone and propofol) with a block randomisation pattern. Blood pressure, heart rate, oxygen saturation, the incidence of pruritus, nausea, vomiting and sedation level were monitored and recorded intraoperatively and postoperatively in recovery and every 2 h until 12 h postoperatively. Data were then analysed with SPSS 20. Results: From 10 min to 60 min, blood pressure was lower in the midazolam group, while it was lower in the propofol group from 60 min to 105 min. In general, blood pressure in the midazolam group was lower than that in the other groups (P = 0.001). Furthermore, pruritus was observed less in the midazolam group than in the other groups (P < 0.05). Sedation level was higher in the midazolam group than in the other groups (P < 0.05). Conclusion: Midazolam reduced pruritus and increased sedation in patients. On the other hand, a decrease in blood pressure was observed in the midazolam group, which did not require any special treatment. According to the results of the present study, after midazolam, propofol and dexamethasone, and finally ondansetron, respectively, were effective in controlling pruritus after spinal anaesthesia, but the efficacy and effectiveness of midazolam were higher than that in the other groups. As such, this drug is recommended to be used in such procedures. Of course, it should be mentioned that the final decision depends on the
patients' physical conditions and the anaesthesiologist's discretion.

Keywords: Bupivacaine, dexamethasone, femoral fracture, fentanyl, midazolam, ondansetron, opioid-induced pruritus, propofol, spinal anaesthesia



How to cite this URL:
Modir H, Moshiri E, Azami M, Modir A. Comparison of the effects of midazolam, dexamethasone, ondansetron and propofol on the prevention and control of opioid-induced pruritus after spinal anaesthesia with bupivacaine combined with fentanyl in femoral fracture surgery. Adv Hum Biol [Epub ahead of print] [cited 2022 Dec 2]. Available from: https://www.aihbonline.com/preprintarticle.asp?id=356797




  Introduction Top


Neuraxial injection of opioids in various surgeries provides adequate analgesia, but the use of opioids for analgesia in spinal anaesthesia is associated with complications such as pruritus, nausea and vomiting.[1],[2] Pruritus – with an incidence rate of about 30%–100% – has been introduced as the most common cause of neuraxial opioid injection.[3] The incidence rate of pruritus is observed to range from 83% in postpartum women to 69% in non-pregnant patients, including men and women.[4] In orthopaedic surgeries, the incidence of pruritus from the neuraxial injection is reported to be 30%–60%.[5]

Pruritus begins shortly after neuraxial opioid analgesia. The time depends on the type and dose of administered opioid.[6] The mechanism of pruritus in patients is not known, but it is very similar to the activation of the central opioids receptor than the release of histamine because naloxone, naltrexone or nalorphene (a partial agonist) can be used for treatment.[7]

The treatment of neuraxial opioid-induced pruritus still remains a major problem. A variety of drugs with different effects have been used to control pruritus after spinal anaesthesia, including 5-hydroxytryptamine 3 receptor antagonists (5HT3 antagonists), opioid antagonists, propofol, nonsteroidal anti-inflammatory drugs and droperidol.[8] The mechanism of pruritus is not yet fully understood. The interaction between opioids and 5HT3 receptors plays an important role in pruritus following neuraxial opioid use.[8] As such, it seems that the preventive use of 5HT3 antagonists such as ondansetron can prove effective in treating pruritus caused by a neuraxial injection of opioids.[9] Antagonists of 5HT3 receptors are antiemetics with greater safety and fewer side effects. Amongst their side effects, mention can be made of restlessness and insomnia, but they do not have the extrapyramidal side effects seen with other common antiemetics. The effect of intrathecal use of fentanyl on postoperative pain control has been well established. Unfortunately, intrathecal or epidural use of fentanyl – due to the appearance of some effects – might be limited. Pruritus has been reported to occur intermittently after using this drug, especially after caesarean section. This type of pruritus is somewhat difficult to treat and will usually have a poor response to treatment.

Several studies have pointed to the role of ondansetron in the prevention of opioid-induced pruritus. Ondansetron is a selective antagonist for the 5HT3 blocker, which is highly effective in the treatment and prevention of nausea and vomiting.[10] Propofol is currently the most common intravenous agent used in anaesthesia.[11] The administration of lower than necessary doses of propofol for the hypnotic effects of propofol is as effective as naloxone in reducing cholestatic pruritus and treating intrathecal opioid-induced pruritus, despite the fact that not all previous studies have confirmed this effect of propofol.[12]

Midazolam is a relatively short-acting benzodiazepine with anti-anxiety, sedative, anticonvulsant and muscle relaxant effects. This medication can enhance gamma-aminobutyric acid (GABA) inhibitory neurons in the dorsal horn neurons and thus inhibit opioid-induced pruritus. In a study in 2017, Makarem et al. investigated the relative effectiveness of intravenous midazolam injection over propofol to reduce intrathecal-sufentanil pruritus and stated that midazolam is better than propofol in preventing intrathecal sufentanil pruritus with no side effects.[13] Dexamethasone is a corticosteroid medication that is mostly used to manage nausea and vomiting caused by opioids. Various studies have shown the effect of dexamethasone on reducing the severity of meperidine-induced pruritus. However, in general, the mechanism of dexamethasone in the management of pruritus remains unknown. Banihashem et al. conducted a study on the effect of dexamethasone on nausea and vomiting and meperidine-induced pruritus after caesarean delivery and concluded that prophylactic use of dexamethasone reduces the severity of pruritus while it does not reduce the incidence of pruritus in general.[14] Kung et al. studied the effects of intravenous ondansetron on the prevention versus treatment of neuraxial morphine-induced pruritus and found that ondansetron reduced the incidence and severity of pruritus.[15] In their study in 2002, Yazigi et al. concluded that prophylactic IV ondansetron was effective in reducing the incidence and severity of nausea and vomiting, but not pruritus, following caesarean delivery with intrathecal morphine in the two study groups.[16]

Therefore, based on the above-mentioned studies and the different results obtained in previous research and the fact that to date, the drugs used in the current study have not been used together in the prevention and control of post-spinal pruritus, it seems that carrying out additional research in this regard may be useful. As such, the present study was designed and conducted in an effort to compare the effect of dexamethasone, midazolam, ondansetron and propofol in the prevention and control of pruritus after spinal anaesthesia with bupivacaine combined with fentanyl.


  Materials and Methods Top


The current study was a randomised, double-blind clinical trial conducted on 136 patients who were candidates for femoral fracture surgery at Valiasr hospital of Arak. The study began after getting the informed consent as well as the required approval by the Research Council and the Ethics Committee of Arak University of Medical Sciences by IR.ARAKMU.REC.1398.313. Moreover, the study protocol is registered at the Iranian Registry Clinical Centre by IRCT20141209020258N141. The inclusion criteria were as follows: Aged 18–65 years, American Society of Anaesthesiologists Class I and II, candidate for femoral fracture surgery, no history of any skin disease with generalised pruritus, no complaint of pruritus before surgery, no history of drug abuse, absence of seasonal allergies and allergies to any of the drugs used in this study, no history of long-term use of corticosteroids, no movement disease, no glucose tolerance, no diabetes and no neuromuscular diseases. The exclusion criteria included failure in anaesthesia method, use of other methods and dissatisfaction.

In the operating room, the patients were initially monitored with a non-invasive sphygmomanometer, electrocardiogram and pulse oximetry. All patients received 10 mL/kg of normal saline before any intervention. Spinal anaesthesia was performed in the sitting position with a 25-G Quincke needle into the space between the third and fourth lumbar vertebrae. 15 mg hyperbaric bupivacaine 0.5% (Abureihan Pharmaceutical Co.) 50 μg (1 ml) of fentanyl (CaspianTa'amin Co.) was administered in all groups. After that, the patients were randomly divided into four groups with block randomisation patterns. It should be mentioned that the drugs for each group were prescribed in the form of bolus and intravenous infusion, and to create blindness, the patients did not know about the administered drug. In addition, to make the collector of the data unaware of the type of administered drugs, bolus and infusion syringes, as well as infusion sets, were covered with foil. After calculating their amount, the required drugs were drawn into 50 mL syringes and administered at the desired dose. An anaesthesiologist monitored the administration and required dose for each patient. The amounts of drugs prescribed in each group were specified as follows: Group 1 (ON) received 4 mg of ondansetron (Tehran Shimi Pharmaceutical Co., Iran) as a bolus and then 50 ml of distilled water by infusion at a rate of 25 mL/h.[17] In Group 2 (P), propofol was administered at an initial dose of 10 mg and then at a dose of 10 μg/kg of body weight/min (the amount of intravenous infusion was poured into a 50 ml syringe at the above-mentioned dose and administered in millilitre/hour.[17] Group 3 (D) received 8 mg of dexamethasone[14] followed by 50 ml of distilled water in the form of infusion at a rate of 25 mL/h. Group 4 (M) received 0.03 mg/kg midazolam as a bolus and 0.02 mg/kg/h as an infusion[13] (the amount of intravenous infusion was poured into a 50 ml syringe and administered at the above-mentioned dose in millilitre/hour).

Blood pressure, heart rate and oxygen saturation were measured every 5 min for the first half-hour and then every 15 min until the end of the procedure. In case systolic blood pressure dropped to below 100 mmHg or more than 20% of the initial systolic pressure, an attempt was made to prevent further decreased by increasing the rate of normal saline infusion and using 5–10 mg of intravenous ephedrine. The incidence of pruritus, nausea and vomiting and the amount of sedation was assessed and recorded intra- and postoperatively in the recovery and every 2 h until 12 h postoperatively. The degree of pruritus was assessed by visual scale, receiving a score of 0–10 with its interpretation as follows: 0 = no pruritus, 1–3 = low pruritus, 4–7 = average pruritus and 8–10 = severe pruritus.[17] The patients with a pruritus score of more than 4 received naloxone at a dose of 0.33 μg/kg intravenously.[17] Furthermore, the patients in all groups were compared with one another in terms of the amount of sedation created intraoperatively and up to 12 h postoperatively by recording the Ramsay scores. After entering the data into SPSS SPSS version 20 (IBM Corp., Armonk, USA), statistical analysis was performed as needed using the statistical tests of Chi-square, ANOVA and repeated measures analysis of variance.


  Results Top


The present study was a randomised, double-blind clinical trial conducted on 136 patients who were candidates for femoral fracture surgery at Valiasr Hospital of Arak. The patients were randomly divided into four groups midazolam, dexamethasone, ondansetron and propofol.

The minimum and maximum age of the patients WAS respectively found to be 20 and 52 years, with the mean age of 35.22 ± 5.94 years. The mean body mass index was found to be 25.84 ± 2.03. In addition, 80 patients (58.8%) were male and 56 (41.2%) were female. No statistically significant difference was found to exist amongst the four groups in terms of the percentage of oxygen saturation, duration of surgery, mean heart rate, the incidence of nausea and vomiting and the dose of administered naloxone (P > 0.05). The groups were similar in terms of age, sex and body mass index.

According to the results presented in [Table 1], there was a statistically significant difference in mean blood pressure from 10 to 120 min after the onset of surgery between the 4 groups (P < 0.05). Blood pressure was lower in the midazolam group from 10 to 60 min, while it was lower in the propofol group from 60 to 105 min. In general, as the repeated measures test showed, blood pressure in the midazolam group was lower than that in the other groups (P = 0.001).
Table 1: Comparison of mean and standard deviation of blood pressure in the study groups

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Based on the results presented in [Table 2], there was a statistically significant difference at all times between the four groups (P < 0.05). Pruritus was less observed in the midazolam group than in the other groups [Figure 1].
Figure 1: Comparison of pruritus in the study groups.

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Table 2: Comparison of mean and standard deviation of pruritus in the studied group

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According to the results presented in [Table 3], there was a statistically significant difference in sedation between the four groups from 60 min after the start of surgery until the recovery (P < 0.05). It should be mentioned that sedation was higher in the midazolam group than in the other groups.
Table 3: Comparison of mean and standard deviation of Ramsay score in the study groups

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  Discussion Top


The current study was a randomised, double-blind clinical trial carried out on 136 patients who were scheduled for femoral fracture surgery at Valiasr Hospital of Arak. The patients were randomly divided into four groups midazolam, dexamethasone, ondansetron and propofol.

From min 10 to 60, blood pressure was lower in the midazolam group while it was lower in the propofol group from min 60 to 105. In general, blood pressure in the midazolam group was lower than that in the other groups. Furthermore, pruritus was less observed in the midazolam group than in the other groups. The sedation level was higher in the midazolam group than in the other groups. All in all, midazolam led to a decrease in pruritus while it increased patient sedation. Midazolam is a relatively short-acting benzodiazepine with anti-anxiety, sedative, anticonvulsant and muscle relaxant effects. This medication can enhance GABA inhibitory neurons in the dorsal horn neurons and thus inhibit opioid-induced pruritus.[13]

In 2017, Mahouri et al. compared the effect of ondansetron with propofol on intrathecal opioid-induced pruritus in elective caesarean section. The results of their study showed that ondansetron and propofol at doses lower than the hypnotic dose were well tolerated.[17] Considering the effect of both drugs on the treatment of pruritus caused by intrathecal fentanyl, both of them can be used clinically. Their results were consistent with those of the current study, but in the current study, midazolam was more effective.

In their study, Makarem et al. investigated intravenous injections of midazolam and propofol to reduce pruritus caused by intrathecal administration of sufentanil. They came to the conclusion that midazolam was better than propofol in preventing intrathecal sufentanil-induced pruritus without any side effects.[13] The results of the study by Makarem et al.[13] were in tandem with those of the present study.

Sane et al. investigated the efficacy of ondansetron for treatment or prophylaxis of intrathecal fentanyl-induced pruritus. They came to the conclusion that prophylactic ondansetron can reduce the incidence of pruritus, nausea and vomiting intra- and postoperatively caused by intrathecal fentanyl with Marcaine.[18] It should, however, be mentioned that ondansetron was effective in the current study, but midazolam was more effective in reducing pruritus.

The results of another study[19] showed that the use of ondansetron and granisetron could reduce the incidence and severity of pruritus as well as the need for medical treatment to relieve this complication (i.e. pruritus). They went on to say that the effect of granisetron was much greater than that of ondansetron. The results of their study were similar to those of the current study. Banihashem et al. conducted a study on the effect of dexamethasone on nausea and vomiting and meperidine-induced pruritus after caesarean delivery and concluded that though prophylactic use of dexamethasone reduced the severity of pruritus, it did not reduce the incidence of pruritus in general.[14] In the current study, all the study drugs reduced pruritus, but the effect of midazolam was greater.


  Conclusion Top


Midazolam reduced pruritus and increased sedation in patients. On the other hand, a decrease in blood pressure was observed in the midazolam group, which did not require any special treatment. Based on the results of the current study, after midazolam, propofol and dexamethasone, and finally ondansetron, respectively, were effective in controlling pruritus after spinal anaesthesia, but the efficacy and effectiveness of midazolam were higher than that in the others. Therefore, this drug can be recommended to be used in such procedures. Of course, it should be mentioned that the final decision depends on the patients' physical conditions and the anaesthesiologist's discretion.

Acknowledgement

This article is the result of a general medicine thesis with Ethics code number of IR.ARAKMU.REC.1398.313 and its clinical trial code number of IRCT20141209020258N141. The authors, hereby, would to express their gratitude to clinical research council in Valiasr hospital as well as the vice chancellor for research and technology of Arak University of Medical Sciences for their financial and moral support.

Financial support and sponsorship

This study was supported by Arak University of Medical Sciences.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Tian X, Niu K, Cao H, Zhan G, Zhang Y, Xu F, et al. Pruritus after continuous administration of epidural morphine for post-cesarean delivery analgesia: A case control study. BMC Pregnancy Childbirth 2021;21:60.  Back to cited text no. 1
    
2.
Cevikbas F, Steinhoff M, Ikoma A. Role of spinal neurotransmitter receptors in itch: New insights into therapies and drug development. CNS Neurosci Ther 2011;17:742-9.  Back to cited text no. 2
    
3.
Szarvas S, Harmon D, Murphy D. Neuraxial opioid-induced pruritus: A review. J Clin Anesth 2003;15:234-9.  Back to cited text no. 3
    
4.
Bonnet MP, Marret E, Josserand J, Mercier FJ. Effect of prophylactic 5-HT3 receptor antagonists on pruritus induced by neuraxial opioids: A quantitative systematic review. Br J Anaesth 2008;101:311-9.  Back to cited text no. 4
    
5.
Koju RB, Gurung BS, Dongol Y. Prophylactic administration of ondansetron in prevention of intrathecal morphine-induced pruritus and post-operative nausea and vomiting in patients undergoing caesarean section. BMC Anesthesiol 2015;15:18.  Back to cited text no. 5
    
6.
Youssef N, Orlov D, Alie T, Chong M, Cheng J, Thabane L, et al. What epidural opioid results in the best analgesia outcomes and fewest side effects after surgery?: A meta-analysis of randomized controlled trials. Anesth Analg 2014;119:965-77.  Back to cited text no. 6
    
7.
Miller R. Spinal, epidural and caudal anesthesia. In: Miller's Anesthesia. Miller's Anesthesia. Philadelphia: Churchill Livingstone; 2020. p:1611-25.  Back to cited text no. 7
    
8.
Sultan P, Gutierrez MC, Carvalho B. Neuraxial morphine and respiratory depression: Finding the right balance. Drugs 2011;71:1807-19.  Back to cited text no. 8
    
9.
Hirmanpour A, Safavi M, Honarmand A, Hashemi Yazdi SH, Pourreza A. Ondansetron and Metoclopramide Can Prevent Intrathecal Sufentanil-Induced Pruritus. Arch Anesth & Crit Care. 2018;4:409-16.  Back to cited text no. 9
    
10.
Nazari S, Nazari S, Shayan A, Shobeiri F, Ahmadi Nia Tabesh R. Comparison of the effects of ondansetron, vitamin B6 and ginger rhizome in nausea and vomiting of pregnancy: A randomized clinical trial. Iran J Obstet Gynecol Infertil 2018;21:29-35.  Back to cited text no. 10
    
11.
Charuluxananan S, Kyokong O, Somboonviboon W, Lertmaharit S, Ngamprasertwong P, Nimcharoendee K. Nalbuphine versus propofol for treatment of intrathecal morphine-induced pruritus after cesarean delivery. Anesth Analg 2001;93:162-5.  Back to cited text no. 11
    
12.
Liu X, Zhang J, Zhao H, Mei H, Lian Q, ShangGuan W. The effect of propofol on intrathecal morphine-induced pruritus and its mechanism. Anesth Analg 2014;118:303-9.  Back to cited text no. 12
    
13.
Makarem J, Mireskandari SM, Jafarzadeh A, Rahbar Nikoukar L, Aghaii S. Intravenous midazolam as more effective than propofol for preventing pruritus after intrathecal sufentanil in surgical patients: A randomized blinded trial. Anesth Pain Med 2017;7:e37535.  Back to cited text no. 13
    
14.
Banihashem N, Hasannasab B, Alereza H. Does dexamethasone prevent subarachnoid meperidin-induced nausea, vomiting and pruritus after cesarean delivery? Saudi J Anaesth 2013;7:138-41.  Back to cited text no. 14
    
15.
Kung AT, Yang X, Li Y, Vasudevan A, Pratt S, Hess P. Prevention versus treatment of intrathecal morphine-induced pruritus with ondansetron. Int J Obstet Anesth 2014;23:222-6.  Back to cited text no. 15
    
16.
Yazigi A, Chalhoub V, Madi-Jebara S, Haddad F, Hayek G. Prophylactic ondansetron is effective in the treatment of nausea and vomiting but not on pruritus after cesarean delivery with intrathecal sufentanil-morphine. J Clin Anesth 2002;14:183-6.  Back to cited text no. 16
    
17.
Mahouri AS, Hasani E, Rezai H, Aghasi L↱. A comparison of the effect of ondansetron and propofol on intrathecal opioidinduced itch in elective ↱cesarean section↱. J Babol Univ Med Sci 2017;20:7-12.  Back to cited text no. 17
    
18.
Sane S, Mahoori A, Valizad Hasanloei MA, Karami N, Poormohammad R. Efficacy of intravenous ondansetron on pruritus after intrathecal opioid in cesarean section with spinal anesthesia. Stud Med Sci 2016;27:148-54.  Back to cited text no. 18
    
19.
Siddik-Sayyid SM, Aouad MT, Taha SK, Azar MS, Hakki MA, Kaddoum RN, et al. Does ondansetron or granisetron prevent subarachnoid morphine-induced pruritus after cesarean delivery? Anesth Analg 2007;104:421-4.  Back to cited text no. 19
    


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