The impact of diclofenac suppositories on postcesarean section pain: a systematic literature review

doi:10.21203/rs.3.rs-4969765/v1

Download PDF

Systematic Review

The impact of diclofenac suppositories on postcesarean section pain: a systematic literature review

https://doi.org/10.21203/rs.3.rs-4969765/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this older preprint version

Read the latest preprint version →

Background: Managing postoperative pain after cesarean section is imperative, as acute postoperative pain is considered a risk factor for chronic postoperativepain. We investigatedthe role of diclofenac suppositories in postoperative pain management after cesarean section.

Methods: For this systematic review, we searched PubMed, Scopus, the Cochrane Library, Google Scholar, and two other clinical trial registers from database inception up to July 23 to July 26, 2024. We included randomized controlled trials and other studies in whichdiclofenac suppositories were administeredas an intentional intervention. We excluded studies not reported in English and without a focus on the principal medicine (diclofenac suppository). Two researchers independently selected studies and evaluated the risk of bias with RoB-2 according to PRISMA-2020 guidelines. Primary outcomes included pain severity or intensity measured with validated clinical scales. We synthesized the studies narratively.

Findings: From 203 records, we selected 16 studies. Discrepancies in the study design or its reporting were observed. The visual analogue scale (VAS) is a frequently used pain assessment tool. Diclofenac suppositories were compared under three broad categories: placebo, other nonsteroidalanti-inflammatory drugs (NSAIDs), opioids andopioid-like medicines. The combination of pain medicines (multimodal analgesia) was central to most ofthe studies; however, heterogeneity and risk of bias undermine the reliability of these findings.

Interpretation: The combination of diclofenac suppositories with other NSAIDs, which are usually opioids such as morphine, meperidine or pentazocine, reduces the need for rescue pain medicines.

Obstetrics & Gynecology

Clinical Pharmacology

Diclofenac

Pain Measurement

Cesarean section

Visual analogue scale

Analgesia

Population – Patients in the Cesarean section

Intervention – diclofenac suppository

Comparison – opioids

Outcome – lower pain scores and a reduced need for more pain medications

Research question – the effectiveness of diclofenac suppositories in preventing postoperative pain and reducing the consumption of pain medicines in cesarean section patients.

Managing postoperative pain after cesarean section is imperative, as acute postoperative pain is considered a risk factor for chronic postoperative pain (1, 2) and psychosocial disorders in mothers. It affects the healing time and may also have an impact on breastfeeding. The American Pain Society and the American Society of Anesthesiologist recommend the use of opioids postoperatively. Adjunctive treatment, including NSAIDs and/or acetaminophen, may be administered preoperatively for caesarean section patients as systemic pharmacologic therapy. In addition to transversus abdominal plane block (regional anesthetic technique) and epidural surgery with a local anesthetic (with or without opioid) or intrathecal opioid as neuraxial anesthetic techniques, local techniques involve local anesthetic at the incision site (3).

Currently, there is no best choice for practice in regard to the time needed to administer diclofenac suppositories, whether preoperatively or postoperatively. It is unclear what the general practice is and whether preoperative administration is associated with better pain relief postoperatively and greater patient satisfaction than immediate postoperative administration or administration upon request. Collecting trustworthy data in an open, succinct manner is crucial to enabling women to make evidence-based decisions and to improve practice guidelines. This allows for objective counseling of women scheduled for cesarean section. An evidence synthesis of all available randomized controlled trials and related studies is part of this assessment, which aims to examine the effectiveness of diclofenac suppositories in managing postoperative pain.

The results of this review will contribute toward streamlining the use of suppository diclofenac perioperative. As a consequence, there will be a reduction in the incidence of severe acute postoperative pain. No systematic review has assessed the role of the suppository diclofenac in reducing acute postoperative pain or its impact on the overall opioid consumption of patients after cesarean section.

The primary objective of this review was to examine the role that diclofenac suppositories play in postoperative pain management after cesarean section. Thus, this systematic review aimed to answer the following questions.

What is the impact of diclofenac suppositories on postoperative pain?

What is the impact of diclofenac suppositories on opioid consumption?

What is the appropriate strategy for the use of diclofenac suppositories to combat postoperative pain?

Does diclofenac suppository provide satisfactory pain relief in comparison to other nonopioids?

Does diclofenac suppositories provide satisfactory pain relief equal to opioids?

Eligibility criteria

Types of studies: We included all published randomized controlled trials (RCTs). We also included other types of studies, such as cross-sectional, prospective cohort studies, that assessed the research query. The language English was selected for the search. We did not exclude studies on the basis of the date of publication. We excluded studies that used diclofenac at any other dosage form aside from suppositories. We also excluded studies in which diclofenac suppository was merely a baseline adjunct treatment but not the principal medicine of interest.

Types of participants: We included women of any age who underwent either emergency or elective cesarean section under either regional or general anesthesia. ASA I and II. Studies that used an accepted pain assessment tool according to the American Pain Society guidelines.

Types of interventions: Studies in which interventions described the use of diclofenac suppositories either as a one-time therapy or at a particular frequency. The interventions may have been monotherapy or in combination with other analgesics.

The main categories of approaches were diclofenac suppository single-dose preoperative; diclofenac suppository single-dose immediate postoperative; diclofenac suppository 4-hourly or 6-hourly; and diclofenac suppository therapy compared with intrathecal morphine, IV acetaminophen (paracetamol), acetaminophen suppository, tramadol suppository, morphine suppository, IV/IM meperidine (pethidine), and IM pentazocine.

Types of outcome measures: Primary outcomes included the following:

Pain scores were measured with a numerical pain rating scale, visual analog scale, verbal rating scale or a combination of these. Patient satisfaction was also an issue.

Secondary outcomes: Side or adverse effects and request for rescue analgesic medicines.

Information sources

We conducted electronic searches for eligible studies within each of the following databases and registries:

Scopus (entries from 1994 to 2024) assessed on 24^th July 2024

PubMed (entries from 1995 to 2023) assessed on 24^th July 2024

Cochrane Central Register of Controlled Trials (entries from 1994 to 2024) assessed on 25^th July 2024.

The US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov/) was used to assess the case of patients on 25^th July 2024.

The International Clinical Trials Registry Platform (apps.who.int/trialsearch/) 2013 to 2015 - assessed on 26^th July 2024.

The European Union Clinical Trials Register (www.clinicaltrialsregister.eu/) was accessed on 26^th July 2024.

Google Scholar was used to assess the case on 26^th July 2024.

Search strategy

Scopus was searched with the parameters outlined below. The data gathered spanned from 1994 to 2024.

Query 1 - {suppository} AND diclofenac AND postoperative AND caesarean* AND section)

The records were limited by the following criteria: English, final, journal, article and abstract-title-keyword. This search was performed on 23^rd July 2024. Twenty-six results were exported.

Query 2 – {rectal} AND diclofenac AND postoperative AND pain AND caesarean section

The records were limited by the following criteria: English, final, journal, article and abstract-Title-Keywords. The search was performed on 24^th July 2024. Twenty-two results were exported.

The PUBMED was searched with the parameters outlined below. The data gathered spanned from 1995 to 2023.

Query 1 - diclofenac suppository postoperative pain caesarean section

The filter applied was abstractly available. This search was performed on 23^rd July 2024. Twenty-two results were exported.

Query 2 – rectal diclofenac postoperative pain caesarean section

The filter applied was abstractly available. This search was performed on 24^th July 2024. Fifteen results were exported.

The Cochrane Library was searched for controlled clinical trials on 25^th July 2024 with the query “Query 1 - diclofenac suppository postoperative pain caesarean section”. The data gathered spanned from 1994 to 2024. Forty-one reports were exported. Similarly, query 2 – rectal diclofenac postoperative pain caesarean section, which was used for the search on 25^th July 2024, also yielded four results.

The U.S. National Institutes of Health Ongoing Trials Register was also searched (www.clinicaltrials.gov).

Query:

condition/disease – cesarean section

intervention – diclofenac suppository

other terms – caesarean section; pain

The date on which this search was performed was July 25, 2021. Two results were retrieved. One was already captured by a Scopus search (2024), and the other was still enrolling participants.

The International Clinical Trials Registry Platform (apps.who.int/trialsearch/) was searched using the queries below. The data gathered spanned from 2013 to 2015.

Query 1 - diclofenac suppository postoperative pain, cesarean section

The date on which this search was performed was July 26, 2021. There were four results exported.

Query 2 – rectal diclofenac postoperative pain cesarean section

The search was performed on 26^th July 2024. No results were retrieved.

The EU Clinical Trials Register was searched at www.clinicaltrialsregister.eu/. No entries were found for either query that had been previously used for the other databases. The date on which this search was ^{performed was} July 26, 2021.

A Google Scholar search was carried out with the same queries. The search was performed on 26^th July 2024. Thirty-one results were obtained.

Selection process

Two researchers (SAA and PKAA) independently screened the titles and authors of all the records retrieved from the databases and registries. Duplicate records were eliminated through the first screening procedure, as were out-of-scope records and records that were simply unsuitable for the review. The resulting records after the first screening were subsequently screened according to the inclusion criteria, and the titles and abstracts were used for inclusion in the review. Inconsistencies were discussed until a consensus was obtained. Articles were flagged as yes, no or maybe. The term “maybe” was assigned to articles that did not fully meet the inclusion criteria. All articles that were assigned a “Yes” were subsequently included, and a review of their full text was performed. If necessary, a third researcher was consulted to make the final decision. Next, the researcher (SAA) independently screened the full-text articles for synthesis. PKAA reviewed the results of the full-text synthesis.

Data collection process

After modifying the data collection forms used by Marc Suhrcke and colleagues (4) and Ashdad and Khan (5,6), we designed a data extraction form, which was used for this systematic review. One author used this tool to extract data from eligible studies. The extracted data were reviewed by another author, and any discrepancies were resolved through discussion. When information regarding any of the above was unclear, we contacted the third reviewer.

Data items

Primary outcomes were categorized as pain intensity or severity, pain during the immediate postoperative period and subjective reporting of pain.

Methods of Outcome Measurement and Assessment

Any of the measures and assessment tools accepted by the American Society of Anesthesiologists, which was further accepted by the American Pain Society as appropriate for pain measurement, were eligible for inclusion (3).

Specifically, the visual analog scale (VAS) and numerical rating scale (NRS) were used.

For these scales, pain was subclassified into no pain, 0, mild pain, 1-3, moderate pain, 4-6 and severe pain; 7-10 or a mean score was used for analysis.

Timing of the outcome measurement

Studies that assessed pain intensity or severity within 24-48 hours after surgery were eligible. According to other studies, this is a critical period for optimizing pain management because the anesthesia would have worn out. No restrictions were placed on the number of times the pain was assessed. We extracted information relating to the characteristics of the included studies, and the results followed this pattern.

1. Study design and characteristics

Study context (location) and duration

Study design (e.g., Double-blind randomized controlled trial, control trial, cross-sectional study, etc.)

Funding sources, if available.

2. Patient group characteristics

Qualitative descriptors of each category, if used (e.g., first-time cesarean section, elective or emergency cesarean section patients, age, etc.).

The group was used as a control category in the analyses, and what unique characteristics made them the control group?

Methods of collecting data (e.g., retrospective, involving recall; time points at which exposure data were collected).

The sample size for each exposure group at each measurement point was included in the analysis.

Dose/strength of interventional drugs used and route of administration.

Any additional parameters used to derive each category or exposure measure.

Any additional data not listed above that characterize and quantify the different patterns of the groups.

Duration/length of exposure period at study baseline and follow-up (directly reported or data that can be used for calculations).

Risk of bias assessment

We assessed the risk of bias in the included studies using the revised Cochrane ‘Risk of bias’ tool for randomized trials (RoB 2.0) (7,8). RoB 2.0 is structured into a fixed set of domains of bias, focusing on different aspects of trial design, conduct, and reporting. Within each domain, a series of questions ('signaling questions') aim to elicit information about features of the trial that are relevant to the risk of bias. A proposed judgment about the risk of bias arising from each domain is generated by an algorithm based on answers to the signaling questions. The judgment can be 'Low' or 'High' risk of bias or can express 'Some concerns' (7,8). RoB 2.0 addresses five specific domains: bias arising from the randomization process; bias due to deviations from intended interventions; bias due to missing outcome data; bias in the measurement of the outcome; and bias in the selection of the reported result. Two review authors jointly applied the tool to each included study and recorded supporting information and justifications for judgments of risk of bias for each domain. Any discrepancies in judgments of risk of bias or justifications for judgments were resolved by discussion to reach a consensus between the first two review authors, with a third review author consulted in cases where a consensus could not be reached. Following the guidance given for RoB 2.0, we derived an overall summary 'Risk of bias' judgment (low risk of bias; some concerns; high risk of bias) for each specific outcome, whereby the overall RoB for each study was determined by the highest RoB level in any of the domains that were assessed (8).

Synthesis

Due to the heterogeneity of the studies included, the synthesis was performed narratively. Interventions were categorized into 4 dimensions:

Diclofenac suppository only vs control studies, combination therapy of nonopioids, diclofenac suppository vs opioids.

Meta-analyses could not be performed due to the heterogeneity of the interventions (clinical diversity) (9,10), settings, study designs and outcome measures. We compared the methods and results sections of the published papers. We used the following questions:

What things seem to be agreed upon by the majority of the papers?

What are the areas of disagreement?

What theories, hypotheses, or concepts seem to be coming up repeatedly? How are they connected or disconnected from each other?

We also used our knowledge of the clinical area to identify where trial investigators had not reported commonly used outcome measures.

What types of research designs have been used?

Scopus and PubMed are the largest databases from which most studies can be identified. In addition, the Cochrane Library and the other aforementioned registries were searched for studies to include in this systematic literature review to reduce the risk of reporting biases (11).

We used Cochrane guidelines on systematic reviews and GRADEpro software to assess certainty in the body of evidence for the outcomes of all the included studies.

Our search of the databases and registries mentioned earlier yielded a total of 203 studies. After removing 114 duplicates, we screened 89 studies. Fifty-four ineligible studies were removed due to reasons such as irrelevance to the scope of the review or unpublished trials. These studies included examining the effect of aromatherapy, specifically lavender oil. One such analgesic was suppository diclofenac, which was requested by the placebo group for complete analgesia (12). Similarly, in other studies, suppository diclofenac was an extra analgesic requirement. These studies were more focused on the effects of other agents, such as intrathecal betamethasone, lidocaine, and PCA with morphine and diamorphine (13–18), as well as preassessment tools for pain (19). Two papers reported severe anaphylactic shock in patients receiving the suppository diclofenac after cesarean section (20,21). One study reported the effect of the suppository diclofenac on shivering instead of pain (22). One study was ineligible because it considered all other abdominal surgeries instead of cesarean section; this was the study population for this systematic review (23). Of the 35 studies that remained, twenty-six had full-text documents. Some studies were ineligible because they were not written in the English language (24–28). Therefore, twenty studies were included in this systematic literature review. (Figure 1)

Descriptive analysis

This section provides a descriptive analysis of the articles included in the review. Figure 1 displays the authors, year of publication, and number of citations. The systematic literature review spans 30 years from 1994–2024. The study by Olofsson C. I. and colleagues has the most citations (29), followed by that of Lim N. L. and colleagues (30) as well as Dennis A. R. and colleagues (31).

All the keywords, principally author and index keywords, are summarized in Fig. 2 for co-occurrence. The weight of the frames is based on occurrence; the score is related to the average citation. Notably, there are double-blind procedures, randomized controlled trial, drug efficacy studies, and suppository.

International coauthorship was 10%, and the average number of citations per document was 18.2. There was no single-authored document. There were 5.6 authors per document. Six studies, representing 30% of the included studies, were conducted in Nigeria and Iran (Fig. 3).

The largest set of connected authors is shown below. This finding shows that a strong community of researchers has focused on a common goal (Fig. 4).

Literature Classification

Summary characteristics of the studies

Study design

Thirteen of the selected studies identified their study design as randomized (29, 30, 32–42). Randomized controlled trials are the gold standard for studying interventional effects (43, 44). Assuring the validity and reliability of results in clinical trials requires the fundamental design element of randomization. Randomization minimizes selection bias by randomly allocating individuals to distinct treatment groups, guaranteeing that the groups are comparable at the start of the experiment (45–47). This approach helps to evenly distribute known and unknown confounding factors among the groups, limiting the potential for these factors to distort the results. The perceived effects of care can be distorted in either way, appearing larger or smaller than they are, if sufficiently disguised random allocation is not used. These distortions can have a size that is equal to or greater than the effects that need to be identified (48).

Consequently, discrepancies in results can be more safely ascribed to the treatment being studied rather than to extraneous factors (44). In addition to improving the scientific rigor and validity of the trial's conclusions, randomization encourages the use of statistical tests that presuppose random allocation. However, in the case of rare diseases, alternative clinical trials may be undertaken given the difficulty in recruiting participants for such studies (49). One study reported the use of a quasiexperimental approach (40). In quasiexperimental studies, participants are not randomly assigned to groups. These studies are used when randomization is not feasible (50), but they are more prone to bias than RCTs, even though some studies state otherwise (51). Considering the topic of this systematic literature review, cesarean section did not fall into the category of such rare conditions, as cesarean section has a high prevalence rate in recent years (52–54). Therefore, researchers who wish to study the interventional effects of pain relief medicines for cesarean section should use randomized studies.

Six studies were identified as controlled studies (31, 33–35, 38, 42), while four studies were identified as placebo controlled (31, 33–35). A popular research design in experimental research for ascertaining the impact of a variable or treatment on an outcome of interest is the controlled study (55). Comparing two or more groups that receive different treatments is what it entails. One group was the experimental group and received the intervention or treatment, while the other group was the control group and received a placebo or did not receive any treatment at all. To minimize bias and establish causal links between variables, this design is crucial (56). Therefore, controlled studies should include participants who lack exposure or who are without the outcome of interest (57).

Nine studies used the double blinding approach (29–34, 38, 42, 58). Four studies used a single blinding approach (35–37, 59). In a single-blind study, participants are not familiar with whether they are in the experimental or control group, but the researchers do (60, 61). Single blinding indicated that the outcomes may be influenced by experimenter effects such as observer bias. However, in a double-blind study, neither the participants nor the researchers knew who was in which group. This approach helps prevent bias from both the participants' and the researchers' expectations (60). Although a meta-epidemiological review of meta-analyses could not find enough evidence of the impact of blinding or nonblinding on effect sizes, it was still recommended that blinding be performed as a methodological safeguard in trials as well as cause-and-effect studies (62).

Two of the selected studies used a comparative study design approach (41, 63). A comparative study is a research approach that focuses on comparing at least two groups, variables or phenomena to determine similarities, differences, and patterns (64). Such research design is common in a wide range of disciplines, such as sociology, medicine, education, and economics, for examining connections, hypotheses, or the effect of one variable on others. This was essentially an observational study (65). While controlled studies rely on establishing causality and using manipulation of variables, comparative studies, in the broader sense, tend to concentrate on observation and assessment without changes in the subjects’ environment. Comparative studies are very effective; however, they are not without their drawbacks. There is always the issue of confounding factors that are not well addressed, and this would cause bias in the results. However, the use of such data can hinder the elucidation of cause-and-effect relationships because the recorded differences could be due to influences other than those under investigation. Since comparative analysis underpins randomized controlled trials, the term “comparative studies” should not be used casually; rather, researchers have to be specific about the study design for such interventional studies in cesarean section (66).

Two studies did not specify the study design by using the terms “randomized”, “double-blind”, “single-blind”, “prospective” or “comparative”; however, the procedures outlined in the Patients and Methods section alluded to an attempt at a randomized prospective study (67, 68). Additionally, two studies used the term “clinical trial”, probably due to the unstructured randomization performed in these studies.(59, 69)

Table 1

Literature classification and risk of bias
Authors	Study design	Context	Focus	Hypothesis	Sample size	Setting	Population	Risk of Bias
Bakhsha et al., 2016	Randomized Double-blind Clinical trial	Iran	Independent or Combination administration of nonopioid analgesics	Combination of analgesic agents offers better analgesia	90	Sayyad Shirazi teaching Hospital, Gorgon, Iran	Cesarean section with spinal anesthesia	High risk of bias
Olateju and Faponle, 2016	Double-blind randomized placebo-controlled trial	Nigeria	Effective multimodal approach to an existing practice	Combination of analgesic agents offers better analgesia	116	Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife	Elective or emergency Cesarean section with spinal anesthesia	High risk of bias
Darvish et al., 2014)	Not stated	Iran	The efficacy of nonopioids against opioids	Nonopioids(diclofenac and acetaminophen combination) can provide better analgesia to single opioid administration	120	Amiralmomenin hospital, Tehran, Iran	Elective cesarean section with spinal anesthesia	High risk of bias
Dahl et al., 2002)	Randomized, double-blinded, placebo-controlled study	Norway	NSAIDs (Diclofenac suppository) vs opioid (morphine)	Diclofenac suppositories reduce opioid consumption postcesarean section without major effects	82	Baerum Hospital	Elective cesarean section with spinal anesthesia	High risk of bias
Lim and Pan, 2001	Randomized double-blind study	Singapore	Analgesic efficacy of single dose diclofenac suppository	NSAIDs (Diclofenac suppository can reduce PCEA consumption/requirement)	48	Changi General Hospital	Elective cesarean section with regional anesthesia	High risk of bias
Dennis and Hobbs, 1995	Double-blind placebo‐controlled study	UK	NSAIDs (Diclofenac suppository) as adjunct postoperative analgesia	NSAIDs (Diclofenac suppository) reduces extra analgesic requirements	50	University hospital	Elective cesarean section with spinal anesthesia	High risk of bias

Literature classification and risk of bias

Authors	Study design	Context	Focus	Hypothesis	Sample size	Setting	Population	Risk of Bias
Akbari and Isazadehfar, 2012	Double-blind clinical trial study	Iran	Suppositories for postoperative analgesia	Suppositories reduce extra analgesic requirements	120	Ardebil Alavi Hospital	Elective cesarean section with spinal anesthesia	High risk of bias
Ofor et al., 2022	Single-blind randomized controlled trial	Nigeria	NSAIDs (diclofenac suppository) vs combination of Diclofenac suppository and pentazocine	Combination of analgesic agents offers better analgesia	200	ESUT-TH Hospital	Elective and emergency cesarean section with spinal anesthesia	High risk of bias
Garba et al., 2021	Single-blind, randomized trial.	Nigeria	NSAIDs combinations vs NSAIDs and Opioid	Combination of analgesic agents offers better analgesia	193	Usmanu Danfodiyo University Teaching Hospital (UDUTH), Sokoto	Elective or emergency Cesarean section with spinal anesthesia	High risk of bias
Cardoso, Carvalho and Tahamtani, 2002	Not stated	Brazil	Route and strength of Diclofenac for postoperative pain	The route of administration has an impact on the analgesia achieved	186	Hospital Maternidade Santa Joana, São Paulo	Cesarean section with spinal anesthesia	High risk of bias
Joshi Vyankatesh et al., 2013	Prospective, randomized, single blind	India	Diclofenac suppository vs Tramadol suppository	Do suppositories work the same way; suppository stability and efficacy between opioid-like (tramadol) and nonopioids (diclofenac)	60	Hospital	Elective or emergency Cesarean section with spinal anesthesia	High risk of bias
Ede et al., 2024	Prospective randomized, double blind, placebo-controlled study	Nigeria	NSAIDs (diclofenac suppository) vs combination of Diclofenac suppository and pentazocine	Combination of analgesic agents offers better analgesia	120	Alex Ekwueme Federal University Teaching Hospital, Abakaliki	Elective or emergency Cesarean section with spinal anesthesia	High risk of bias

Literature classification and risk of bias

Authors	Study design	Context	Focus	Hypothesis	Sample size	Setting	Population	Risk of Bias
Fatemeh Abbasalizadeh, 2012)	Randomized Clinical trial	Iran	Diclofenac suppository vs Morphine IM	NSAIDs (Diclofenac suppoository) as an alternative to opioids (Morphine IM)	120	Taleghani Hospital of Tabriz	Cesarean section	High risk of bias
Eleje et al., 2015	Open-label, quasirandomized clinical trial	Nigeria	Effective multimodal approach to an existing practice	Combination of analgesic agents offers better analgesia	67	Obstetrics and Gynecology complex of the Madonna University, Elele, Nigeria	Cesarean section with general or spinal anesthesia	High risk of bias
El Khiary et al., 2024	Comparative prospective interventional clinical study	Egypt	Independent or Combination administration of nonopioid analgesics	Combination of analgesic agents offers better analgesia	48	Zagazig University Maternity Hospita	Cesarean section	High risk of bias
Onuorah, Fyneface-Ogan and Aggo, 2018	Prospective, randomized, comparative study.	Nigeria	Route and strength of Diclofenac for postoperative pain	The route of administration has an impact on the analgesia achieved	88	University of PortHarcourt Teaching Hospital	Cesarean section with spinal anesthesia	High risk of bias
Sorrori et al., 2006	Clinical trial	Iran	Diclofenac suppository vs Pethidine	Alternative analgesia	240	Alzahrah Hospital, Isfahan, Iran	Cesarean section patients	High risk of bias
Mahdavi and Momenzadeh, 2016	Clinical trial	Iran	Comparison between Opioid and nonopioid suppository	suppository stability and efficacy between opioids (morphine) and nonopioids (diclofenac)	100	Shariati Hospital, Iran	Elective cesarean section with spinal anesthesia	High risk of bias

Literature classification and risk of bias

Authors	Study design	Context	Focus	Hypothesis	Sample size	Setting	Population	Risk of Bias
Luthman and White, 1994	Double-blind randomized controlled trial	UK	NSAIDs (Diclofenac suppository) as adjunct postoperative analgesia	NSAIDs (Diclofenac suppository) reduces extra analgesic requirements	50	Northampton General Hospital	Elective cesarean section patients	High risk of bias
Olofsson et al., 2000	randomized double-blind study	Sweden	NSAIDs (Diclofenac suppository) as adjunct postoperative analgesia	NSAIDs (Diclofenac suppository) reduces extra analgesic requirements	50	Karolinska Hospital, SE-17176, Stockholm, Sweden	Elective cesarean section with spinal anesthesia	High risk of bias

Interventions

Some hypotheses were revealed in this systematic literature review. Principally, ten of the studies used diclofenac suppositories independently, while comparing them to either a placebo, another opioid or nonopioid suppository, or intravenous analgesic administration. The hypothesis that diclofenac suppositories reduce extra analgesic requirements was explored in these studies. Three studies compared diclofenac suppository to a placebo (29, 31, 42). Akbari and Isazadehfar compared it to a placebo in one group and to indomethacin and acetaminophen suppositories in two other groups (58). Akbari and Isazadehfar specifically highlighted the important role of diclofenac and indomethacin, both of which are nonsteroidal anti-inflammatory drugs (NSAIDs), in delaying the time needed before patients request additional pain medicines (opioids).

Two studies explored the concept of the route of administration by using diclofenac suppository and intramuscular (IM) diclofenac (41, 68).

Abbasalizadeh and colleagues compared diclofenac suppository with intramuscular morphine. Intramuscular morphine administration for postcesearean section pain is a well-known practice (70). However, in this study, Abbasalizadeh and colleagues concluded through their findings that diclofenac may be more effective than IM morphine (39). In contrast, Mahdavi and colleagues used morphine suppositories (59), while Sorrori and colleagues compared morphine suppositories with IM pethidine (69).

Eight of the studies considered the concept that the combination of analgesic agents offers better analgesia than does independent pain medicine administration (32, 33, 35, 36, 38, 40, 63, 67). There are differences in the focus on this hypothesis. For instance, Bakhsha and El Khiary assessed the impact of combining diclofenac suppositories with acetaminophen, a widely used analgesic (71), with acetaminophen only. Acetaminophen was administered intravenously; hence, there were different routes of administration but rather synergistic effects from the different mechanisms of action of the two agents (32, 63).

Ofor, Eleje, and Ede explored the concept of the adjunctive use of diclofenac suppositories. In their studies, a combination of diclofenac and pentazocine was compared to a combination that received only pentazocine (35, 38, 40). Garba J. A. and colleagues tweaked this concept slightly by comparing the diclofenac-pentazocine combination to the diclofenac-acetaminophen combination (36). Pentazocine is a mixed-action agonist antagonist of opioid receptors (72). It is also known to be a mu (73) and kappa receptor agonist (74). It is more potent than codeine but less potent than morphine (75) and may have fewer hepatotoxic and renal toxic effects (75). In other conditions, such as acute pancreatitis, pentazocine has been postulated to be a better analgesic than diclofenac (76). It has been established that this drug possesses a strong degree of analgesia with minimal accompanying psychomimetic effects or human drug dependency.

One study compared diclofenac suppositories administered independently to another group that received a tramadol suppository (37). Vegard Dahl also compared a combination of diclofenac and acetaminophen suppositories with another group that received a placebo suppository with an acetaminophen suppository (34). The query “Do suppositories work the same way; suppository stability and efficacy between opioid-like drugs (tramadol) and nonopioids (diclofenac)” may strike a chord in these studies.

Lim N. L. and colleagues explored the use of diclofenac as an adjunctive therapy to patient-controlled epidural analgesia (PCEA) (30). Their findings indicated that the suppository reduces the consumption of ropivacaine and fentanyl, which are the medicinal agents in the PCEA device.

Pain measurements and rating scale

Seventeen studies used the visual analog scale (VAS) as a pain assessment tool, while three (36, 42, 59) used the numerical rating scale (NRS). Vegard Dahl also used an additional verbal rating scale (34). The visual analog scale (VAS) is one of the most frequently used tools for assessing changes in the character and intensity of experimentally induced pain (77). In clinical practice, the percent pain reduction, as evaluated by the VAS, is often used to quantify the effectiveness of treatment (78, 79). It is also popular in the gynecological space (80, 81).

Both the VAS and NRS are reliable for assessing pain severity, but there is not a significant difference between them (77, 82, 83). The verbal rating scale is postulated to be less sensitive than the verbal rating scale (83).

VAS scores can be analyzed using a number of methods, including distribution-based methods, distribution-free methods, categorization methods and descriptive methods only (77). Aggregated self-reported pain intensity change, as the core index, is employed in most clinical trials and is the ‘gold standard’ for measuring change (77). Another approach to the analysis of VAS scores is to categorize the VAS score into a small number of levels: none, mild, moderate, severe and unbearable (77). Nonparametric methods do not specify any probability distribution for the response variable and hence are called distribution-free methods. Rather, they are derived from the orderings or ranks that we assigned to the VAS scores rather than the actual scores. Hence, they are suitable for ordinal results (77). When using the VAS, continuous ordinal regression is recommended to have more discriminating power when covariates are highly influential and is thus preferred. Nevertheless, if the spread of the VAS score is not extremely skewed, then more traditional linear methods, such as linear regression (and its analogs), can be used. The Wilcoxon and t tests are less powerful by nature than the other tests and should be ignored (77).

Findings reported by the various studies

Diclofenac-only pain management as a suppository or injectable agent

Dennis concluded that diclofenac suppositories prolong the mean time to first analgesia by more than 5 hours (31). Another study concluded that diclofenac suppositories produced better analgesia than morphine suppositories (59). Moreover, Onuorah reported that suppository diclofenac administered through the rectal route is as efficacious as intramuscular diclofenac injection for post-Cesarean section analgesia, with equal levels of patient satisfaction and acceptability (41). However, Cardoso expressed a different opinion by demonstrating that when diclofenac is combined with small doses of spinal morphine, its intramuscular administration offers better postoperative analgesia than does the rectal route. Additionally, it was observed in that study that diclofenac seems to have a ceiling effect on the efficacy of this drug when used for immediate postoperative pain management; no advantages were observed with doses larger than 50 mg intramuscularly (68).

Diclofenac suppository vs other NSAIDs

Khiary concluded that the combination of acetaminophen and diclofenac has stronger and longer analgesic effects than does the single use of each drug (63). Akbari suggested the use of indomethacin and diclofenac suppositories since there was a significant decrease in pain scores and opioid usage, especially in these groups, compared with the control group (58). Vegard Dahl concluded that diclofenac suppositories of 100 mg twice daily after cesarean section are opioid sparing (34). Bakhsha and Darvish concurred in their conclusion that combination management of pain would have better efficacy in postoperative pain control and cause a reduction in additive analgesia than independent diclofenac suppository management (32, 67).

Diclofenac suppository vs opioids or opioid-like pain medicines

Abbasalizadeh concluded that the suppository diclofenac is considerably more effective than the suppository IM morphine at relieving post-CS pain (39). Eleje concluded that diclofenac combined with pentazocine significantly reduced pain and increased patient satisfaction and earlier mobilization during the postcaesarean period compared to pentazocine alone (40). This conclusion was confirmed by Ede, Olateju, and Ofor, who reiterated that the adjuvant rectal diclofenac is superior to pentazocine alone for the management of pain after cesarean section. Fewer patients had moderate to severe pain at 24–48 hours postoperation. In addition, maternal satisfaction with pain management is better with diclofenac suppositories (33, 35, 38). Furthermore, although the combination of analgesics provided adequate analgesia, the pentazocine-diclofenac combination may be associated with additional side effects (36). Another study reported that diclofenac suppositories are better alternatives than tramadol because they are devoid of nausea and vomiting and have a longer duration (37). According to Lim, a single administration of 100 mg of diclofenac suppository is effective at reducing post-Cesarean epidural local anesthetic/opioid requirements by 33% for the first 24 hr postoperatively (30).

Table 2

Interventions and pain measurement characteristics
Authors	Tools	Number of Pain measurements	Duration of Pain measurements (h)	Diclofenac only	Combination drug	Comparison drugs − 1	Comparison drugs − 2	Strength of Diclofenac suppository	Frequency of administration of Diclofenac suppository
Bakhsha et al., 2016	VAS	6	24	Yes	Yes with 500 mg IV Acetaminophen	1000 mg IV Acetaminophen	None	100 mg	not stated
Olateju and Faponle, 2016	VAS	4	24	No	Yes with 30 mg IM Pentazocine 6 hourly	30 mg IM Pentazocine 6 hourly alone	None	100 mg	12 hourly
Darvish et al., 2014)	VAS	Not stated	Not stated	No	Yes with 1000 mg IV Acetaminophen	20 mg IM Meperidine (Pethidine)	None	Not stated	4 hourly
Dahl et al., 2002)	VAS & VRS	9	32	No	Yes with 1000 mg Acetaminophen suppository	Placebo with 1000 mg Acetaminophen suppository	None	100 mg	12 hourly
Lim and Pan, 2001	VAS	4	24	No	Yes with PCEA (ropivacaine and fentanyl)	No suppository with PCEA (ropivacaine and fentanyl)	None	100 mg	Single administration
Dennis and Hobbs, 1995	VAS	8	48	Yes	No	Placebo	None	100 mg	Single administration then after 16 h
VAS – visual analog scale, NRS – numerical rating scale

Interventions and pain measurement characteristics

Authors	Tools	Number of Pain measurements	Duration of Pain measurements (h)	Diclofenac only	Combination drug	Comparison drugs − 1	Comparison drugs − 2	Strength of Diclofenac suppository	Frequency of administration of Diclofenac suppository
Akbari and Isazadehfar, 2012	VAS	3	24	Yes	No	Placebo	Acetaminophen (325 mg) and Indomethacin (50 mg) Suppositories	50 mg	6 hourly
Ofor et al., 2022	VAS	5	48	No	Yes with 30 mg IM Pentazocine 6 hourly	60 mg IM Pentazocine 6 hourly	None	100 mg	12 hourly
Garba et al., 2021	NRS	4	24	No	Yes with 60 mg IM Pentazocine	600 mg IM Acetaminophen 6 hourly and 100 mg Diclofenac suppository	None	100 mg	12 hourly
Cardoso, Carvalho and Tahamtani, 2002	VAS	12	6	Yes	No	50 mg IM Diclofenac	75 mg IM Diclofenac	50 mg	single administration
Joshi Vyankatesh et al., 2013	VAS	10	10	Yes	No	100 mg Tramadol suppository	None	100 mg	Single administration
Ede et al., 2024	VAS	4	48	No	Yes with 30 mg IM Pentazocine 6 hourly	Anusol suppository plus 30 mg IM Pentazocine	None	75 mg	12 hourly

Interventions and pain measurement characteristics

Authors	Tools	Number of Pain measurements	Duration of Pain measurements (h)	Diclofenac only	Combination drug	Comparison drugs − 1	Comparison drugs − 2	Strength of Diclofenac suppository	Frequency of administration of Diclofenac suppository
Fatemeh Abbasalizadeh, 2012)	VAS	3	24	Yes	No	10 mg IM Morphine	None	100 mg	8 hourly
Eleje et al., 2015	VAS	Not stated	Not stated	No	Yes with 30 mg IM Pentazocine	30 mg IM Pentozocine 6 hourly alone	None	100 mg	12 hourly
El Khiary et al., 2024	VAS	6	24	Yes	Yes with 500 mg IV Acetaminophen	1000 mg IV Acetaminophen	None	100 mg	Single administration
Onuorah, Fyneface-Ogan and Aggo, 2018	VAS	11	24	Yes	No	100 mg IM Diclofenac	None	100 mg	Single administration
Sorrori et al., 2006	VAS	4	26	Yes	No	IM Pethidine	None	100 mg	8 hourly
Mahdavi and Momenzadeh, 2016	NRS	9	24	Yes	No	Morphine suppository 10 mg	None	100 mg	Single administration
Luthman and White, 1994	quasi NRS	10	24	Yes	No	Placebo	None	100 mg	single administration
Olofsson et al., 2000	VAS	12	12	Yes	No	Placebo	None	50 mg	8 hourly
VAS – visual analog scale, NRS – numerical rating scale

Table 3

Certainty of assessment **Question**: Diclofenac suppository compared to placebo, other NSAIDs or opioids for postoperative pain after cesarean section
Pain severity or intensity (assessed with: VAS or NRS; Scale from: 0 to 10)
Certainty assessment							№ of patients		Effect		Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Diclofenac suppository	placebo or other NSAIDs or opioids	Relative (95% CI)	Absolute (95% CI)	Certainty	Importance
20	randomized trials	serious^a	not serious	not serious	not serious	all plausible residual confounding would reduce the demonstrated effect	1221	1098	-	0 (0 to 0)	⨁⨁⨁⨁ High	IMPORTANT
Reduced rescue medicine consumption (assessed with: Device or Volume of Injectables)
13	randomized trials	serious^a	not serious	not serious	not serious	all plausible residual confounding would reduce the demonstrated effect	it was expressed as time to request for extra pain medicines, or the cumulative dose (mg) of opioids or opioid-like pain medicines requested by patients				⨁⨁⨁⨁ High	IMPORTANT
Patient Satisfaction (assessed with: NRS or VRS)
6	randomized trials	serious^a	not serious	not serious	not serious	none	363/1221 (29.7%)	362/1098 (33.0%)	not estimable		⨁⨁⨁◯ Moderate	IMPORTANT
6	randomized trials	serious^a	not serious	not serious	not serious	none	363/1221 (29.7%)	0.0%	not estimable		⨁⨁⨁◯ Moderate	IMPORTANT

CI confidence interval, Explanations - a. Most studies were silent on how randomization was performed, lacked the use of preplanned analysis methods and did not estimate the effect of assignment to interventions.

Study Design

This systematic literature review revealed strengths and weaknesses that are noteworthy. Concerning the areas in which the literature was classified, most of the studies used some form of randomization to eliminate bias; however, there were omissions in their reports. Currently, guidelines concerning the roll-out of randomized control trials do not accept the mere mention of randomization. It is expected that researchers will provide evidence of randomization. Therefore, researchers must mention key terms related to randomization, such as “computer-generated” and “concealed allocation to treatment”(48), and ensure that these measures are taken in their research to reduce the risk of bias. Additionally, double blinding is strongly advised. The term "pilot" refers to a particular kind of study that is similar to the intended trial in elements such as having a control group and randomization, whereas the term "feasibility" should be used as a general term for exploratory studies. However, studies designated "pilots" must have goals and objectives distinct from those of primary trials in addition to a plan for further research. It is not appropriate for researchers to refer to a trial that assesses a therapy effect as a "pilot."

The role of diclofenac in postoperative pain management

Undoubtedly, diclofenac suppositories have become a mainstay for postoperative analgesia. Postoperative pain severity is reduced, which eventually culminates in a prolonged period before patients request additional analgesics. Because they prevent prostaglandin synthesis, NSAIDs have been used increasingly frequently to lessen pain. By lowering the chemical mediators of pain that produce painful impulses, these medications indirectly influence pain alleviation in addition to their direct anti-inflammatory and analgesic actions. Furthermore, NSAIDs do not result in respiratory depression or other opioid side effects, including ileus, nausea, or drowsiness (69). The elimination half-life of the drug is comparatively shorter; therefore, there is unlikely to be drug build-up within the body (84). Its use as an analgesic has the advantages of requiring a short time to onset of action as well as a long interval to the next dose. When introduced intramuscularly, it is no less effective than and often more effective than numerous narcotic and spasmolytic combinations (68,84). With diclofenac, a great deal of clinical experience has been obtained, confirming its safety profile. Compared to other NSAIDs, it is well tolerated and rarely causes stomach ulcers or other severe adverse effects. Diclofenac is therefore one of the rare NSAIDs prescribed as a "first choice" for the management of both acute and long-term inflammatory and painful conditions (84–86). One review posited that indomethacin may be superior to diclofenac; however, the route of administration has not been clearly determined (87)

Because its effectiveness is equal to or better than that of opioids, this hypothesis cannot be confirmed in this systematic literature review because there is not enough experimental evidence to support its effectiveness. A combination regimen that incorporates diclofenac suppository is strongly advised because it has been proven to be more effective than administering opioids or opioid-like agents alone (24,88,89) or any one NSAID alone (90). Pentazocine and pethidine have hemodynamic effects, as they have been shown to increase blood pressure (91). Opioids have well-known side effects (89); hence, reduced opioid use is a goal in most postoperative pain management.

Other findings

The findings of this review showed that combination therapy enhances patient satisfaction and could be an effective substitute for opioids. Based on the type of cesarean section incurred, it was deduced that elective surgeries accounted for a greater percentage of all surgeries, and a significant proportion of the patients had a history of previous cesarean section. Some of the limitations of the studies included were the expensive nature of the study and the duration of assessment, which can prolong hospital stays. All the studies had a high risk of bias, principally due to the lack of appropriate analysis methods for estimating the effect of assignment to interventions, the absence of randomization techniques and the lack of analysis according to a prespecified plan. Most study findings favor the efficacy of the analgesic combination in the management of pain after cesarean delivery.

The results of this study have several implications for maternal satisfaction and pain management during the process of cesarean section. Principally, the satisfaction of mothers with the use of analgesics depends not only on the effectiveness of pain reduction but also on other factors, including neonatal status and the psychological status of the patient at the time of assessment; thus, there should be an interdisciplinary approach to pain interventions. Moreover, there is a need for comprehensive pain assessment tools that can assess pain at rest and during movement. Taken together, these results point to a need for enhanced patient satisfaction approaches that incorporate more of the physical and mental aspects of pain.

Limitations of the review

A few limitations of this review include the use of risk of bias for randomized controlled trials, although not all the studies were randomized controlled trials. A limited number of databases and registers were used. Additionally, we were unable to perform a meta-analysis.

Recommendations for future research

Long-term data monitoring and patient-oriented methodology can improve the validity of the results and their usability in practice. In addition, identifying factors that influence treatment outcomes means that future studies will have to apply those aspects in the design of treatment plans to develop more individualized treatments. Studies should distinguish between emergency and elective cesarean section patients because there could be variations in pain perception depending on the type of cesarean section and whether it was general anesthesia or spinal anesthesia. Research could become progressively targeted at pain as a unique experience and use personal genetic and genomic charts that would estimate the patient’s reaction to pain and pain-relieving medications. Factors that predict the onset of chronic pain after C-sections and how these risk factors can be managed could also be studied.

Registration of the protocol: A protocol was not prepared.

Support: No external funding

Conflict of interest: None declared

Availability of data: Upon request from the authors

Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. The Lancet. 2006 May 13;367(9522):1618–25.
Sharma LR, Schaldemose EL, Alaverdyan H, Nikolajsen L, Chen D, Bhanvadia S, et al. Perioperative factors associated with persistent postsurgical pain after hysterectomy, cesarean section, prostatectomy, and donor nephrectomy: a systematic review and meta-analysis. PAIN. 2022 Mar;163(3):425.
Chou R, Gordon DB, de Leon-Casasola OA, Rosenberg JM, Bickler S, Brennan T, et al. Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. The Journal of Pain. 2016 Feb 1;17(2):131–57.
Suhrcke M, Stuckler D, Suk JE, Desai M, Senek M, McKee M, et al. The Impact of Economic Crises on Communicable Disease Transmission and Control: A Systematic Review of the Evidence. PLOS ONE. 2011 Jun 10;6(6):e20724.
Arshad RN, Abdul‐Malek Z, Roobab U, Qureshi MI, Khan N, Ahmad MH, et al. Effective valorization of food wastes and by‐products through pulsed electric field: A systematic review. J Food Process Engineering. 2021 Mar;44(3):e13629.
Khan M, Khan N, Begum S, Qureshi MI. Digital future beyond pandemic outbreak: systematic review of the impact of COVID-19 outbreak on digital psychology. foresight. 2024;26(1):1–17.
RoB 2: A revised Cochrane risk-of-bias tool for randomized trials | Cochrane Bias [Internet]. [cited 2024 Aug 10]. Available from: https://methods.cochrane.org/bias/resources/rob-2-revised-cochrane-risk-bias-tool-randomized-trials
Sterne JA, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. bmj [Internet]. 2019 [cited 2024 Aug 10];366. Available from: https://www.bmj.com/content/366/bmj.l4898.short
9.5.1 What is heterogeneity? [Internet]. [cited 2024 Aug 20]. Available from: https://handbook-5-1.cochrane.org/chapter_9/9_5_1_what_is_heterogeneity.htm
Schroll JB, Moustgaard R, Gøtzsche PC. Dealing with substantial heterogeneity in Cochrane reviews. Cross-sectional study. BMC Med Res Methodol. 2011 Dec;11(1):1–8.
Chandler J, Cumpston M, Li T, Page MJ, Welch V. Cochrane handbook for systematic reviews of interventions. Hoboken: Wiley [Internet]. 2019 [cited 2024 Aug 20]; Available from: https://dariososafoula.wordpress.com/wp-content/uploads/2017/01/cochrane-handbook-for-systematic-reviews-of-interventions-2019-1.pdf
Olapour A, Behaeen K, Akhondzadeh R, Soltani F, Al Sadat Razavi F, Bekhradi R. The Effect of Inhalation of Aromatherapy Blend containing Lavender Essential Oil on Cesarean Postoperative Pain. Anesth Pain Med. 2013 Summer;3(1):203–7.
Naghibi T, Dobakhti F, Mazloomzadeh S, Dabiri A, Molai B. Comparison between intrathecal and intravenous betamethasone for post-operative pain following cesarean section: a randomized clinical trial. Pak J Med Sci. 2013 Apr;29(2):514–8.
Habibi A, Alipour A, Baradari AG, Gholinataj A, Habibi MR, Peivandi S. The Effect of Adding Lidocaine to Patient Controlled Analgesia with Morphine on Pain Intensity after Caesarean Section with Spinal Anesthesia: A Double-Blind, Randomized, Clinical Trial. Open Access Maced J Med Sci. 2019 Jun 30;7(12):1946–50.
Anwari JS, Butt A, Alkhunein S. PCA after subarachnoid block for cesarean section. Middle East J Anaesthesiol. 2004 Jun;17(5):913–26.
Skilton RW, Kinsella SM, Smith A, Thomas TA. Dose response study of subarachnoid diamorphine for analgesia after elective caesarean section. Int J Obstet Anesth. 1999 Oct;8(4):231–5.
Stacey R, Jones R, Kar G, Poon A. High-dose intrathecal diamorphine for analgesia after Caesarean section. Anaesthesia. 2001 Jan;56(1):54–60.
Cowan CM, Kendall JB, Barclay PM, Wilkes RG. Comparison of intrathecal fentanyl and diamorphine in addition to bupivacaine for caesarean section under spinal anaesthesia. Br J Anaesth. 2002 Sep;89(3):452–8.
Buhagiar L, Cassar OA, Brincat MP, Buttigieg GG, Inglott AS, Adami MZ, et al. Predictors of post-caesarean section pain and analgesic consumption. J Anaesthesiol Clin Pharmacol. 2011 Apr;27(2):185–91.
Hadar A, Holcberg G, Mazor M. [Anaphylactic shock after diclofenac sodium (Voltaren)]. Harefuah. 2000 Feb 1;138(3):211–2, 270.
Razzaque M, Crowhurst JA, Plaat F. Angio-oedema following rectal diclofenac after caesarean section. Int J Obstet Anesth. 2001 Apr;10(2):135–8.
Khezri MB, Bandari AM, Asefzade S, Atlasbaf A. The effect of diclofenac na supp on postoperative shivering in patients undergoing elective cesarean section surgery. Pak J Med Sci. 2011;27(5):1145–8.
Rab A, Parveen S, Ali A, Nawaz A, Gul S, Musadaq M. Comparison Of Diclofenac Suppository with Injection Tramadol In Postoperative Pain: Diclofenac Suppository with Injection Tramadol in Postoperative Pain. Pakistan BioMedical Journal. 2022 Jun 30;46–9.
Hidaka I, Asai, T, Miki, T, Kubota, T, Kawachi S. Combined use of intrathecal morphine and diclofenac suppository for postoperative analgesia after caesarean section. Masui The Japanese journal of anesthesiology. 2003;52(10):1056‐1061.
Molaei B, Fallah, R, Kazemi, A, Rashtchi, V, Soltani S. Comparison of the effect of diclofenac suppository and intravenous paracetamol on post cesarean pain and bleeding. Journal of zanjan university of medical sciences and health services. 2018;26(117):1‐11.
Gooshe SMR, Oulapour A, Javaherfouroosh F, Safari HG, Bakhtiari N. A comparison of the effects of diclofenac sodium suppository, intravenous paracetamol and the combination on acute pain after cesarean surgery under spinal anesthesia. 2022 [cited 2024 Aug 8]; Available from: https://journals.sbmu.ac.ir/isacc/index.php/iranesthesia/article/download/467/454/1624
Lotfalizade M, Zirak, N, Ghomian, N, Ebrahimi, F, Mohammadnejad M. Comparison of the effects of diclofenac suppository and tramadol injection and the combination of these two drugs on pain after spinal anesthesia for cesarean. Iranian journal of obstetrics, gynecology and infertility. 2015;17(131):1‐5.
Mallah F, Saleh P, Hajiagaei N. Comparing Analgesic Effects of Intravenous Acetaminophen، Suppository Diclofenac and Intramuscular Tramadol in Pain Control after Cesarean Delivery. Med J Tabriz Uni Med Sciences Health Services. 2014 Jun 25;36(2):80–5.
Olofsson CI, Legeby MH, Nygårds EB, Ostman KM. Diclofenac in the treatment of pain after caesarean delivery. An opioid-saving strategy. Eur J Obstet Gynecol Reprod Biol. 2000 Feb;88(2):143–6.
Lim NL, Lo, WK, Chong, JL, Pan A. Single dose diclofenac suppository reduces post-Cesarean PCEA requirements. Journal canadien d’anesthesie [Canadian journal of anaesthesia]. 2001;48(4):383‐386.
Dennis AR, Leeson Payne, CG, Hobbs G. Analgesia after caesarean section. The use of rectal diclofenac as an adjunct to spinal morphine. Anaesthesia. 1995;50(4):297‐299.
Bakhsha F, Niaki AS, Jafari SY, Yousefi Z, Aryaie M. The Effects of Diclofenac Suppository and Intravenous Acetaminophen and their Combination on the Severity of Postoperative Pain in Patients Undergoing Spinal Anaesthesia During Cesarean Section. J Clin Diagn Res. 2016 Jul;10(7):UC09-12.
Olateju SO, Adenekan, AT, Olufolabi, AJ, Owojuyigbe, AM, Adetoye, AO, Ajenifuja, KO, Olowookere, SA, Faponle A. PENTAZOCINE VERSUS PENTAZOCINE WITH RECTAL DICLOFENAC FOR POSTOPERATIVE PAIN RELIEF AFTER CESAREAN SECTION- A DOUBLE BLIND RANDOMIZED PLACEBO CONTROLLED TRIAL IN A LOW RESOURCE AREA. Middle East journal of anaesthesiology. 2016;23(4):443‐448.
Dahl V, Hagen, IE, Sveen, AM, Norseng, H, Koss, KS, Steen T. High-dose diclofenac for postoperative analgesia after elective caesarean section in regional anaesthesia. International journal of obstetric anesthesia. 2002;11(2):91‐94.
Ofor IJ, Enebe JT, Ofor NE, Onyia CN, Omeke CA, Nevo CO, et al. Pentazocine with rectal diclofenac versus pentazocine alone for pain relief following caesarean delivery in Enugu, Nigeria: A randomized controlled trial. J Int Med Res. 2022 May;50(5):3000605221102092.
Garba JA, Panti AA, Nnadi DC, Ango IG, Tunau KA, Bello S, et al. The efficacy of pentazocine + diclofenac versus paracetamol + diclofenac for post- caesarean section analgesia. Niger Postgrad Med J. 2021 Sep;28(3):187–92.
Joshi Vyankatesh S, Vyavahare Ramesh D, Khade Ganesh DS, Jamadar NP. Comparative study of analgesic efficacy of rectal suppository of tramadol versus diclofenac in suppressing postoperative pain after Cesarean section. Int J Health Care Biomed Res. 2013;1(2):32–7.
Ede EES, Olaleye AA, Irechukwu JC, Nwaedu UN, Ejikeme BN, Ali VC, et al. Adjuvant Rectal Diclofenac for Post Operative Analgesia after Caesarean Section—A Randomized Controlled Study. Open Journal of Obstetrics and Gynecology. 2024 Apr 3;14(4):591–609.
Fatemeh Abbasalizadeh. A pilot study of the efficacy of diclofenac suppository and intramuscular morphine for relieving the post-cesarean pain. Afr J Pharm Pharmacol [Internet]. 2012 May 8 [cited 2024 Aug 7];6(17). Available from: http://www.academicjournals.org/ajpp/abstracts/abstracts/abstract%202012/8%20May/Abbasalizadeh%20et%20al.htm
Eleje G, Egeonu R, Obianika C, Mbachu I, Okohue J, Osuagwu I, et al. Diclofenac and Pentazocine versus Pentazocine alone for Post-Operative Analgesia in Cesarean Section. International Journal of Medicine and Health Development. 2015 Dec 15;20:2–10.
Onuorah CM, Fyneface-Ogan S, Aggo AT. The efficacy of Diclofenac for post caesarean section analgesia: comparison of rectal and intramuscular routes. Nigerian Journal of Medicine. 2018;27(3):272–6.
Luthman J, Kay, NH, White J. The morphine sparing effect of diclofenac sodium following caesarean section under spinal anaesthesia. International journal of obstetric anesthesia. 1994;3(2):82‐86.
Granholm A, Alhazzani W, Derde LPG, Angus DC, Zampieri FG, Hammond NE, et al. Randomised clinical trials in critical care: past, present and future. Intensive Care Med. 2022 Feb 1;48(2):164–78.
D’Agostino RB, Kwan H. Measuring Effectiveness: What to Expect without a Randomized Control Group. Medical Care. 1995;33(4):AS95–105.
Efird J. Blocked Randomization with Randomly Selected Block Sizes. International Journal of Environmental Research and Public Health. 2011 Jan;8(1):15–20.
Bulpitt CJ. Randomised Controlled Clinical Trials. Springer Science & Business Media; 2012. 288 p.
Broglio K. Randomization in Clinical Trials: Permuted Blocks and Stratification. JAMA. 2018 Jun 5;319(21):2223–4.
Kunz R, Oxman AD. The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials. BMJ. 1998 Oct 31;317(7167):1185–90.
Cornu C, Kassai B, Fisch R, Chiron C, Alberti C, Guerrini R, et al. Experimental designs for small randomised clinical trials: an algorithm for choice. Orphanet J Rare Dis. 2013 Mar 25;8(1):48.
Pavolovich Panko P, Curtis JD, Gorrall BK, Little TD, Pavolovich Panko P, Curtis JD, et al. Alternatives to Randomized Control Trials: A Review of Three Quasi-experimental Designs for Causal Inference. Actualidades en Psicología. 2015 Dec;29(119):20–8.
Waddington H, Aloe AM, Becker BJ, Djimeu EW, Hombrados JG, Tugwell P, et al. Quasi-experimental study designs series—paper 6: risk of bias assessment. Journal of Clinical Epidemiology. 2017 Sep 1;89:43–52.
Yaya S, Uthman OA, Amouzou A, Bishwajit G. Disparities in caesarean section prevalence and determinants across sub-Saharan Africa countries. glob health res policy. 2018 Jul 2;3(1):19.
Landau R. Post-cesarean delivery pain. Management of the opioid-dependent patient before, during and after cesarean delivery. Int J Obstet Anesth. 2019;39:105–16.
Landau R, Bollag L, Ortner C. Chronic pain after childbirth. International Journal of Obstetric Anesthesia. 2013 Apr 1;22(2):133–45.
Concato J, Shah N, Horwitz RI. Randomized, Controlled Trials, Observational Studies, and the Hierarchy of Research Designs. New England Journal of Medicine. 2000 Jun 22;342(25):1887–92.
Grimes DA, Schulz KF. Compared to what? Finding controls for case-control studies. The Lancet. 2005 Apr 16;365(9468):1429–33.
Song JW, Chung KC. Observational Studies: Cohort and Case-Control Studies. Plastic and Reconstructive Surgery. 2010 Dec;126(6):2234.
Akbari GA, Entezariasl, M, Isazadehfar K. Comparison of the effects of indomethacin, diclofenac and acetaminophen suppositories on pain score and pethidine usage after cesarean section. Journal of isfahan medical school [Internet]. 2012;30(179). Available from: https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01043764/full
Mahdavi A, Telkabadi Z, Aleyasin A, Agha Hosseini M, Safdarian L, Momenzadeh A. Comparison of Morphine Suppository and Diclofenac Suppository for Pain Management After Elective Caesarean Section. Acta Med Iran. 2016 Nov;54(11):709–12.
Holman L, Head ML, Lanfear R, Jennions MD. Evidence of Experimental Bias in the Life Sciences: Why We Need Blind Data Recording. PLOS Biology. 2015 Jul 8;13(7):e1002190.
Hróbjartsson A, Thomsen ASS, Emanuelsson F, Tendal B, Rasmussen JV, Hilden J, et al. Observer bias in randomized clinical trials with time-to-event outcomes: systematic review of trials with both blinded and non-blinded outcome assessors. International journal of epidemiology. 2014;43(3):937–48.
Moustgaard H, Clayton GL, Jones HE, Boutron I, Jørgensen L, Laursen DRT, et al. Impact of blinding on estimated treatment effects in randomised clinical trials: meta-epidemiological study. BMJ. 2020 Jan 21;368:l6802.
El Khiary SS, Sarhan AMM, Shazly SA, Fouad TA. The Effects of either Diclofenac Suppository , Intravenous Acetaminophen or their Combination on the Severity of Postoperative Pain in Patients Undergoing Spinal Analgesia during Cesarean Section. Zagazig University Medical Journal. 2024 Jan 1;30(1.1):46–53.
Caramani D. Comparative Politics. Oxford University Press; 2017. 647 p.
Kumar R, Khan A, Chatterjee P. Types of observational studies in medical research. Astrocyte. 2014 Jul 1;1:154–9.
Collier D. The Comparative Method [Internet]. Rochester, NY; 1993 [cited 2024 Aug 15]. Available from: https://papers.ssrn.com/abstract=1540884
Darvish H, Memar Ardestani B, Mohammadkhani Shali S, Tajik A. Analgesic Efficacy of Diclofenac and Paracetamol vs. Meperidine in Cesarean Section. Anesth Pain Med. 2014 Feb;4(1):e9997.
Cardoso MMSC, Carvalho JCA, Tahamtani SMM. [Intramuscular versus rectal diclofenac associated with low dose spinal morphine for post-cesarean analgesia.]. Rev Bras Anestesiol. 2002 Nov;52(6):666–72.
Sorrori ZZ, Sharami, SH, Heidarzadeh, A, Shokri L. The comparison between suppository diclofenac and pethidine in post-cesarean section pain relief: a randomized controlled clinical trial. Journal of research in medical sciences. 2006;11(5):292‐296.
Kanazi GE, Aouad MT, Abdallah FW, Khatib MI, Adham AMBF, Harfoush DW, et al. The analgesic efficacy of subarachnoid morphine in comparison with ultrasound-guided transversus abdominis plane block after cesarean delivery: a randomized controlled trial. Anesth Analg. 2010 Aug;111(2):475–81.
Ayoub SS. Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action. Temperature [Internet]. 2021 Oct 2 [cited 2024 Aug 15]; Available from: https://www.tandfonline.com/doi/abs/10.1080/23328940.2021.1886392
King CD, Goodin B, Glover TL, Riley JL, Hou W, Staud R, et al. Is the pain-reducing effect of opioid medication reliable? A psychophysical study of morphine and pentazocine analgesia. PAIN®. 2013 Mar 1;154(3):476–83.
Shu H, Wang Z, Ye F, Li Q, Dou Y, Lin Y, et al. High-dose pentazocine antagonizes the antinociception induced by high-dose morphine. Life Sciences. 2015 Jun 1;130:1–6.
Ribeiro-Dasilva MC, Shinal RM, Glover T, Williams RS, Staud R, Riley JL, et al. Evaluation of menstrual cycle effects on morphine and pentazocine analgesia. PAIN®. 2011 Mar 1;152(3):614–22.
Rabbani AH, Hayat K, Gardezi FH, Waheed A, Zahra A. A comparison of nalbuphine and pentazocine in controlling post-operative pain in dogs. Matrix Sci Med. 2018;2(2):15–20.
Mahat NB, Zubaidi SA, Kyaw SHH, Nah SA. Paediatric surgical response to an ‘adult’ covid-19 pandemic. Med J Malays. 2021;76(3):284–90.
Heller GZ, Manuguerra M, Chow R. How to analyze the Visual Analogue Scale: Myths, truths and clinical relevance. Scandinavian Journal of Pain. 2016 Oct 1;13(1):67–75.
Carlsson AM. Assessment of chronic pain. I. Aspects of the reliability and validity of the visual analogue scale. Pain. 1983;16(1):87–101.
Kane RL, Bershadsky B, Rockwood T, Saleh K, Islam NC. Visual Analog Scale pain reporting was standardized. Journal of Clinical Epidemiology. 2005 Jun 1;58(6):618–23.
Begum MstR, Hossain M. VALIDITY AND RELIABILITY OF VISUAL ANALOGUE SCALE (VAS) FOR PAIN MEASUREMENT. 2019 Nov 8;2:394–402.
Stourač P, Kuchařová E, Křikava I, Malý R, Kosinová M, Harazim H, et al. Establishment and evaluation of a post caesarean acute pain service in a perinatological center:retrospective observational study. Ceska Gynekol. 2014 Nov 1;79(5):363–70.
Shafshak TS, Elnemr R. The Visual Analogue Scale Versus Numerical Rating Scale in Measuring Pain Severity and Predicting Disability in Low Back Pain. JCR: Journal of Clinical Rheumatology. 2021 Oct;27(7):282.
Breivik EK, Björnsson GA, Skovlund E. A comparison of pain rating scales by sampling from clinical trial data. The Clinical journal of pain. 2000;16(1):22–8.
Todd PA, Sorkin EM. Diclofenac Sodium. Drugs. 1988 Mar 1;35(3):244–85.
Narouze S, Benzon HT, Provenzano D, Buvanendran A, De Andres J, Deer T, et al. Interventional spine and pain procedures in patients on antiplatelet and anticoagulant medications: guidelines from the American Society of regional anesthesia and pain medicine, the European Society of regional anaesthesia and pain therapy, the American Academy of pain medicine, the International neuromodulation Society, the North American neuromodulation Society, and the world Institute of pain. Regional Anesthesia & Pain Medicine. 2018;43(3):225–62.
Naz S, Memon NY, Sattar A, Baloch R. Diclofenac rectal suppository: an effective modality for perineal pain. J Pak Med Assoc. 2016 Aug;66(8):1005–8.
Murdoch I, Carver AL, Sultan P, O’Carroll JE, Blake L, Carvalho B, et al. Comparison of different nonsteroidal anti-inflammatory drugs for cesarean section: a systematic review and network meta-analysis. Korean J Anesthesiol. 2023 Dec;76(6):597–616.
Sia ATH, Thomas E, Chong JL, Loo CC. Combination of suppository diclofenac and intravenous morphine infusion in post-Caesarean section pain relief - A step towards balanced analgesia? SINGAPORE MED J. 1997;38(2):68–70.
Rashid M, Jaruidi HM. The use of rectal diclofenac for post-cesarean analgesia. Saudi Med J. 2000 Feb;21(2):145–9.
Munishankar B, Fettes, P, Moore, C, McLeod G. A double-blind randomised controlled trial of paracetamol, diclofenac or the combination for pain relief after caesarean section. International journal of obstetric anesthesia. 2008;17(1):9‐14.
Tammisto T, Takki S, Toikka P. A COMPARISON OF THE CIRCULATORY EFFECTS IN MAN OF THE ANALGESICS FENTANYL, PENTAZOCINE AND PETHIDINE. British Journal of Anaesthesia. 1970 Apr 1;42(4):317–24.

The authors declare no competing interests.

Download PDF

Version 1

posted

You are reading this older preprint version

Read the latest preprint version →

The impact of diclofenac suppositories on postcesarean section pain: a systematic literature review

Status:

Version 1

Abstract

Figures

The PICO was used to generate a research question

Rationale

Objectives

METHODS

RESULTS

Descriptive analysis

Literature Classification

Study design

Interventions

Pain measurements and rating scale

Findings reported by the various studies

Diclofenac-only pain management as a suppository or injectable agent

Diclofenac suppository vs other NSAIDs

Diclofenac suppository vs opioids or opioid-like pain medicines

DISCUSSION

Declarations

References

Additional Declarations

Status:

Version 1