Comparison of the postoperative analgesic effects of intrathecal Clonidine and Fentanyl as adjuvant: Mata Analysis of randomized control trials

Background: Intrathecal clonidine and fentanyl added to bupivacaine prolongs the postoperative analgesic effects for below umbilicus surgery. However, the overall effect of clonidine and fentanyl mixed with spinal anesthesia is not harmonized. Therefore, the aim of this Meta - analysis was to assess the post operative analgesic effects of intrathecal clonidine and fentanyl for different randomized control trials of study. Methods: Pubmed, Cochrane Review, EMBASE, and Google Scholar were searched and a total of four studies have been selected for Meta – Analysis. Three authors engaged independently to extract data on the efficacy of intrathecal clonidine and fentanyl for lower abdomen and limb surgeries. The statistical analysis was accomplished by RevMan (version 5.3) software. The overall efficacy of intrathecal clonidine and fentanyl were pooled by Forrest plot, table, and figure with 95% confidence interval. Results: The pooled effect size mean difference of intrathecal clonidine versus fentanyl was 83.57(95 % CI, 29.33 to 137.82) minutes. Furthermore, the lowest and highest mean difference of effect size was 10.60 and 175.98 minutes respectively. Conclusion: Intrathecal clonidine as adjuvant to bupivacaine gave the prolonged postoperative analgesia in comparison to intrathecal fentanyl. So it is recommended to use clonidine as intrathecal adjuvant when we consider the extended postoperative analgesia.

turn, to increase duration of analgesia and quality of blockage, adjuvant of intrathecal clonidine and opioids are appropriate [2]. Different studies have been found that intrathecal midazolam, neostigmine, opioids and clonidine put together the prolongation of subarachnoid block and reduction of postoperative analgesic consumption [3][4][5][6][7].
Specifically, addition of low doses of clonidine and fentanyl in intrathecal could be associated with lesser incidence of adverse effects [8]. However, intrathecal opioids with bupivacaine connected with side effects of nausea, vomiting, pruritus, respiratory depression and urinary retention in favor of clonidine which has not this property [9].
Amongst the opioids, fentanyl could be the choice of adjuvant because of its potency, rapid onset and short duration of action with lesser incidence of respiratory depression [8,10]. Even though rising number of published trials with small number of patients paying attention on post operative analgesic effects to intrathecal clonidine and fentanyl, full up to date evidence in larger population is lucking so far. Therefore, it was the aim of this Meta analysis performed to confirm their conclusion using at large sample size.

Study selection
A literature search was conducted in Pubmed, Cochrane review, EMBASE and Google scholar data bases and articles which are relevant to our study were identified. The search was performed by three authors (FH, AH, SE) independently with asking the key words of intrathecal, clonidine, fentanyl and postoperative analgesia. In the middle of citation extracted, abstracts were reviewed to recoup the clinical studies of randomized control trials on intrathecal adjuvant of clonidine and fentanyl. Articles that were related, by title and abstract were right to used in full text to determine those that provided sufficient information to be included in our Meta-analysis.

Inclusion and exclusion criteria
The trials included in our Meta analysis: patients undergoing spinal anesthesia were assigned to at least two groups, including Clonidine alone as an adjuvant to local anesthetics and Fentanyl alone as an adjuvant to local anesthetics. So, all randomized control trial studies investigating the efficacy of intrathecal clonidine (50 µg) compared with intrathecal fentanyl (25 µg) for patients under went to lower abdomen and extremity surgery.

Outcome of interest
The primary outcome of interest was duration of Analgesia. The secondary outcomes of interest were duration of sensory and motor blockage.

Data extraction
Data from qualified studies were extracted independently by authors and summarized into a spreadsheet. Discrepancies were resolved by agreement. For each of the included studies, the following information was extracted; First author's name, year of the study, numbers of patients/study participants, total volume for spinal anesthesia, and types of surgery (Table 1).
· Sensory block: the time of regression to S1 from the maximum sensory block level

Results
We have found 817 abstracts through electronic data base search. Among this studies 756 were excluded due to the abstracts or full text information did not related to the topic interest. Eventually, four articles fulfilled our eligibility criteria and were subjected to Notes: * values are mean ± standard deviation.

Discussion
Spinal anesthesia is a type of neuraxial regional anesthesia which covers for lower limb analgesic time. [16,17] It was also supported by other different studies which gave the evidence of 50 µg clonidine to intrathecal bupivacaine made the lengthening of analgesic duration in comparison to 25 µg fentanyl with bupivacaine [18][19][20].
In regarding to secondary outcomes of interest Mata analysis study, the sensory and motor duration of block is significantly prolonged in intrathecal clonidine group compared to fentanyl. This was consistent with many different studies [19,21,22]. However, there was not considerable inter sub group differences of block duration between the motor and sensory.
The means of clonidine related potentiation of spinal sensory block is reported to be reliant on presynaptic (decrease transmission) and postsynaptic (hyper polarization) action. It activates the α2 receptors with blocking of Aδ and C nerve fibers at substantia gelatinosa of spinal cord to generate analgesia [23,24]. Fentanyl is the preferred opioid drug for regional anesthesia with action on µ1 and µ2 receptor agonist. It is highly potent drug due to high lipid solubility [25,26] despite some related complications of nausea, vomiting, and pruritus [27].
According to some study, even at higher dose of clonidine (450 µg) only in intrathecal, didn't result muscle weakness and motor block [28] , but combination to spinal bupivacaine caused significant enhancement of the strength and duration of motor block [29,30]. Tilkar et al study compared clonidine and fentanyl added to intrathecal bupivacaine and reached as conclusion of clonidine was more helpful than fentanyl in pain-relieving properties [31].
Even though different studies have been used intrathecal clonidine from dose of 15 µg to150 µg , the 50 µg intrathecal clonidine was provided the extended postoperative analgesia with minimal side effects compared to fentanyl [32][33][34].
There are a number of limitations to our Meta analysis. It was possible to miss some studies which satisfied the inclusion criteria, and number of studies to be excluded as the full text was unavailable. In addition, there was significant heterogeneity to duration of analgesia, duration of sensory block and duration of motor block with considering different doses of bupivacaine drug and types of surgery.

Conclusion
Addition of 50 µg clonidine to intrathecal bupivacaine, put forward the longer duration of postoperative analgesia than 25 µg of fentanyl. So, it is recommended to use clonidine when we consider the extended duration of postoperative analgesia.

Declarations Acknowledgments
We would like to thank Mr. Awoke in department of Microbiology for helping with suggestion on meta-analysis and systematic review.

Availability of data and materials
No additional data are required; all information is clearly presented in the main manuscript.
Authors' contributions FT: Conception of research protocol, study design, literature review, data collection, data extraction, data analysis and interpretation, and drafting manuscript.
AH, SE: literature review, data collection and extraction, and reviewing manuscript. All authors have read and approved the manuscript.

Competing interests
The authors declare that they have no competing interests.

Consent for publication
Not applicable.

Ethics approval and consent to participate
We have meta-analyzed evidences obtained from randomized controlled studies.
Therefore, this study did not require approval from ethical committee.