Characteristics of the Included Studies

Definition of PEP

Risk ratio (95% CI)

Sotoudehmanesh et al., 2007, Iran

Amylase >3× ULN, 24 h post‐ERCP, with epigastric pain, back pain, and epigastric tenderness

Montaño Loza et al., 2007, Mexico

Amylase >3× ULN, 2 h post‐ERCP, sharp pain irradiating to the back, and nausea or vomiting

Döbrönte et al., 2012, Hungary

Amylase, lipase >3× ULN, 24 h post‐ERCP, new pancreatic‐type pain, and prolonged hospitalization

Döbrönte et al., 2014, Hungary

Multicenter prospective randomized placebo‐controlled trial

Amylase, lipase ≥3× ULN, 24 h post‐ERCP, new typical upper abdominal pain requiring prolonged hospitalization

A'rpa'd Patai et al., 2015, Hungary

Amylase ≥3× ULN, 24 h post‐ERCP, pancreatitis‐type pain, and extension of hospitalization ≥2 nights

Levenick et al., 2016, USA

Prospective double‐blind placebo‐controlled trial

New-onset upper abdominal pain, increased lipase level > 3 × ULN, 24 h after onset of pain, hospitalization for at least 2 nights

Hosseini et al., 2016, Iran

Serum amylase levels ≥3 × ULN, and the patient presented with abdominal pain, nausea, and vomiting

Shafique et al., 2016, Pakistan

Randomized, double-blinded, placebo-controlled study

Epigastric pain with guarding and/or vomiting, an elevated pancreatic enzyme (serum amylase) level greater than four‐fold the ULN (>400 IU/L)

UÇAR et al., 2016, Turkey

Prospective, randomized controlled study

Amylase >3× ULN, and new‐onset or worsened abdominal pain lasting more than 24 h post‐ERCP

Arain et al., 2013, India

Randomized controlled clinical trial 

Amylase ≥3× ULN within 24 h post‐ERCP, new upper abdominal pain, and hospitalization for at least two nights 

Design

N= 372

Objective

Study Groups

Diclofenac (n= 124)

Indomethacin (n= 122)

Naproxen (n= 126)

Inclusion Criteria

Exclusion Criteria

Methods

Duration

Outcome Measures

Baseline Characteristics

Diclofenac (n= 124)

Indomethacin (n= 122)

Age, years

Female/Male

ERCP indications

Common bile duct stone

Bile duct stricture

Pancreatic cancer

55 (45.1%) 

60 (47.6%)

40 (31.7%)

26 (20.7%)

Pre-ERCP markers

Amylase, U/l

Lipase, U/l

lipoxin A4, pg/ml

Resolvin E1, pg/ml

60.0 ± 24.2 

38.6 ± 17.1

307 ± 27

448 ± 32

29 (23.4%)

95 (76.6%)

32 (26.2%)

90 (73.8%)

30 (23.8%)

96 (76.2%)

122 (98.4%)

0

2 (1.6%)

118 (96.7%)

1 (0.8%)

3 (2.5%)

120 (95.2%)

2 (1.6%)

4 (3.2%) 

4 (3.2%)

19 (15.3%)

101 (81.5%)

4 (3.3%)

9 (7.4%)

109 (89.3%) 

9 (7.1%)

12 (9.5%)

105 (83.4%)

91 (73.4%)

31 (25%)

2 (1.6%)

89 (72.9%)

32 (26.3%)

1 (0.8%)

88 (69.8%)

34 (27%)

4 (3.2%)

Results

Endpoint

Diclofenac (n= 124)

Indomethacin (n= 122)

Naproxen (n= 126)

p-value

115 (94.2%)

3 (2.4%)

2 (1.7%)

2 (1.7%)

0.001

-

-

- 

Post-ERCP markers

Amylase, U/l

Lipase, U/l

lipoxin A4, pg/ml

Resolvin E1, pg/ml

107.0 ± 61.8

0.183

0.597

-

-

Mild PEP, a hospital stay after developing PEP that was less than three days; moderate PEP, a hospital stay of 4–10 days; severe PEP, a hospital stay of more than 10 days or the presence of complications requiring a pancreatectomy 

Adverse Events

Study Author Conclusions

InpharmD Researcher Critique

Rectal Indomethacin Versus Rectal Diclofenac Sodium for Reducing Pain Associated with Diagnostic Office Hysteroscopy

Design

Prospective study

N= 83

Objective

To study the effect of rectal diclofenac sodium and indomethacin during diagnostic office hysteroscopy

Study Groups

Indomethacin (n = 29)

Diclofenac Sodium (n = 27)

No Medication (n = 27)

Inclusion Criteria

Aged 18-45 years; indication for office hysteroscopy (infertility or recurrent miscarriage)

Exclusion Criteria

Patients with known cardiac disease, gastritis/peptic ulcer, asthma, acute porphyria, hepatitis, or renal failure; women undergoing menopause; allergy to indomethacin or NSAIDs; possible pregnancy; lower genital tract infection; lactating women

Methods

Patients were sorted based on the medication they received: 100 mg rectal indomethacin, 100 mg rectal diclofenac sodium, and no medication. The latter served as the control group. All patients in the first two groups took the medication one hour before the procedure. Pain perception was evaluated during, immediately after, and 30 minutes post-procedure using a visual analogue scale (VAS), ranging from 0 (no pain) to 10 (worst pain). The operator explained the scale before the procedure and patients reported their pain scores three times. Patients remained in the clinic until pain subsided and were discharged pain-free. Adverse effects were documented. 

Duration

December 2018 to March 2018

Outcome Measures

Baseline Characteristics

Indomethacin (n= 29)

Diclofenac Sodium (n= 27)

Age, years

Body mass index, kg/m²

Gravida * (IQR)

Indication

Infertility

Recurrent abortion

Both

75%

25%

0

81.%

18.5%

0

65.4%

23.1%

11.5%

Abbreviations: IQR= interquartile range 

*p= 0.047

Results

Endpoint* 

Indomethacin (n = 29) 

Diclofenac Sodium (n = 27) 

No Medication (n = 27)

p-value

5.33 ± 3.57

5 (0 - 10)

4.82 ± 2.99

4.5 (1 - 10)

4.91 ± 2.79

5 (0 - 10)

1.83 ± 2.54

0 (0 - 8)

1.32 ± 1.90

0 (0 - 5.5)

1.61 ± 2.10

1 (0 - 7)

0.71 ± 1.50

0 (0 - 6)

0.29 ± 0.58

0 (0 - 2)

0.64 ± 1.45

0 (0 - 7)

Adverse Events

One patient in the diclofenac group had flushing, itching, and dizziness. One patient in the indomethacin group had a vasovagal reaction; she developed bradycardia, hypotension, dizziness, faintness, and sweating.

Study Author Conclusions

There is no statistically significant beneficial effect of either medication compared with any medication with regard to mean pain scores during and after diagnostic office hysteroscopy.

InpharmD Researcher Critique

Limitations of the study include the lack of randomization and a placebo control group, as well as reliance on subjective pain perception for results. The small sample size across the three groups is also a constraint. Additionally, exploration of alternative dosages or administration timings was not conducted, potentially impacting the efficacy of 100 mg rectal NSAIDs administered one hour pre-operation.

A Comparative Study on Relieving Post-Episiotomy Pain with Diclofenac and Indomethacin Suppositories or Placebo

Design

Randomized, double-blinded intervention groups compared to single-blinded no treatment group

N= 90

Objective

To compare the effectiveness of the diclofenac suppository with the indomethacin suppository and placebo groups, when relieving pain after episiotomy

Study Groups

Diclofenac (n= 30)

Indomethacin (n= 30)

No Suppository (n= 30)

Inclusion Criteria

Women aged 18-35 years old with 2nd-degree episiotomy to aid normal vaginal delivery, without epidural analgesia; parity of 1 to 4; gestational age of 36-42 weeks; birth weight of 2.5 to 4 kg

Exclusion Criteria

Extensive tears of the vagina or labia; suffer from asthma, porphyria, peptic ulcer or other internal problems including cardiac, renal, hepatic; past medical history of hemorrhoids; recorded as taking strong pain killers prior to referral or in daily life

Methods

Eligible and enrolled participants were provided diclofenac or indomethacin suppositories during the routine rectal examination after recovery from the episiotomy. All episiotomies were second-level with the same technique of interrupted sutures using coated 2/0 catgut. All patients recovered within 1 hour after delivery. Suppositories were provided in envelopes coded as "A" or "B" for double blinding. For those not given a suppository "C" was labeled on an empty envelope and researchers in the postpartum room were unaware of treatments. Researchers inquired about pain via 2 methods at 1, 2, 4, 6, and 12 hours after suppository use. Patients were asked about the episiotomy pain location which was scored as the pain score method: 0= no pain; 1= pain only while moving and no pain while resting/sitting; 2= pain while moving and sitting and no pain while resting; 3= pain while moving, sitting, and resting; 4= severe and unbearable pain while moving, sitting, and resting. Patients were also given a 10 cm chart numbered to mark their pain out of a scale of 0-10 with 0= no pain and 10 = most severe pain as the visual analogue method (pain level). 

Duration

Study performed in 2010

Outcome Measures

Pain scores and pain level

Baseline Characteristics

Diclofenac

(n= 30)

Indomethacin

(n= 30)

Suppository Free

(n= 30)

Maternal Age, years

Labor duration, hours

Gestational age, weeks

Parity

Baby birth weight, g

No significant difference between groups

Results

Diclofenac 

Indomethacin

Mean Pain Score (Pain Score Method)*

1 hr 

2 hr

4 hr

6 hr

12 hr

0.4

0.4

0

0.1

0.2

0.4

0.4

0.1

0.1

0.1**

1.7

1.7

1.7

1.5

1.4

Mean Pain Level (Visual Analogue Method)*

1 hr 

2 hr

4 hr

6 hr

12 hr

1.25

1

0**

0.25

1

1.5

1.25

1

0.75

0.25**

4.5

4.25

3.75

3.25

3.25

* Data were presented as graph plots from which precise data was unretrievable. Available data is estimated to nearest 0.25 based on bar graph figures. 

**Significant difference between diclofenac and indomethacin groups

Mean pain scores had significat difference between groups (p< 0.05) mainly due to the suppository free group

Mean pain levels had signficant differences between groups (p< 0.05) except at the 12th hour

Adverse Events

Not reported

Study Author Conclusions

We recommend the use of a diclofenac suppository (maximum two suppositories) for all episiotomy cases, without internal problems, in 4-hour intervals

InpharmD Researcher Critique

This was a small prospective study evaluating subjective outcomes of episiotomy pain. While patients with epidural analgesia or records of pain medication history were not included, there was no discussion of any other medications used during the delivery and post-operative hours. Additionally, pain scores and levels specific to episiotomy pain may have been difficult for patients to differentiate immediately following delivery. Based on the half-lives and findings of this small study, larger prospective studies evaluating safety comparisons and duration of action would be beneficial.  

Comparison of the efficacy of diclofenac and indomethacin suppositories in treating perineal pain after episiotomy or laceration: a prospective, randomized, double-blind clinical trial

Design

Prospective, randomized, double-blind clinical trial

N= 200

Objective

To compare the results in terms of effectiveness, side effects, and patient satisfaction when diclofenac and indomethacin suppositories were used for the relief of perineal pain after episiotomy or tearing during childbirth 

Study Groups

Diclofenac (n= 100)

Indomethacin (n= 100)

Inclusion Criteria

Pregnant women who had given birth vaginally and had had a mediolateral episiotomy or a second- or three-degree tear

Exclusion Criteria

Known allergy to the study drugs, a history of peptic ulcer disease or gastrointestinal bleeding, asthma, porphyria, salicylates hypersensitivity, significant cardiac, renal, or hepatic disease, a history of drug dependence, regular use of analgesic drugs before and during pregnancy, multiparous women with a history of postpartum hemorrhage or any other major postpartum complication 

Methods

Women in the delivery suite received 10 ml of 2% lidocaine HCl for local anesthesia before episiotomy or vaginal tear repair. Suturing followed using standardized techniques and materials known to affect post-treatment pain. Patients were randomly assigned 1:1 before delivery to two treatment groups. The first group received a single 100 mg diclofenac suppository, while the second group received two 100 mg indomethacin suppositories, 12 hours apart. Suppositories were inserted into the rectum during routine post-episiotomy examination.

Pain ratings in both groups were recorded at 1, 3, 6, 9, 12, and 24 hours post-drug insertion. A single investigator or obstetric nurse conducted all observations to reduce inter-observer variation. Pain intensity was self-reported using a 10 cm visual analog scale (VAS), ranging from 0 (no pain) to 10 (worst imaginable pain).

Duration

October 2003 to January 2004

Outcome Measures

Baseline Characteristics

Diclofenac (n = 100)

Indomethacin (n = 100)

Maternal age, years

27.83 ± 3.39

Gestational age, weeks

Parity

Parity 0

Parity 1+

40% 

60%

37% 

63%

Fetal weight, g

Second or third-degree tear, n

Local anesthetic only, n

Vaginal infiltration with local anesthetic, n

Results

Endpoint

Indomethacin (n = 100)

VAS at 24 h

Additional analgesic request at 24 h, n

Additional paracetamol, g

Overall satisfaction score

Adverse Events

Rectal administration of diclofenac and indomethacin caused a few localized reactions such as pruritus, burning, and exacerbation of hemorrhoids; none of these needed any additional treatment.

Study Author Conclusions

Since the two analgesics were rated similarly and gave satisfactory pain relief, diclofenac may be preferred because it is administered in a single dose and requires less nursing time to dispense and is a substantially less costly alternative to the new pain treatment technologies currently in use.

InpharmD Researcher Critique

The effects of indomethacin, diclofenac, and acetaminophen suppository on pain and opioids consumption after cesarean section

Design

Randomized, double-blind clinical trial

N= 120 

Objective

To compare the effects of indomethacin, diclofenac, and acetaminophen suppositories on postoperative pain and opioid usage after cesarean section

Study Groups

Diclofenac (n= 30)

Indomethacin (n= 30)

Acetaminophen (n= 30)

Placebo (n= 30)

Inclusion Criteria

Pregnant patients volunteered to cesarean surgery with the American Society of Anesthesiologists Classification (ASA) I or II

Exclusion Criteria

Patients with kidney diseases, pregnancy hypertension, active peptic ulcers, a history of abdominal surgery, history of cardiovascular disease, or twin pregnancy

Methods

Patients were randomized to receive either indomethacin (50 mg), diclofenac (50 mg), and acetaminophen (325 mg) suppositories or placebo suppositories. Surgeries were performed under spinal anesthesia using hyperbaric 5% lidocaine, with continuous monitoring of vital signs. Following surgery, patients received suppositories according to their assigned group and received the study drug Q6H for 24 hours. Pain severity was assessed using a visual analog scale (VAS), and pethidine (meperidine; 0.5 mg/kg) was administered in case of severe pain (VAS > 5). Opioid usage in the 24 hours post-surgery was recorded from patient records. The patients,  anesthesia nurse, nurse prescribing medicine, and data analyzer were all blinded to the group assignments. 

Duration

Study: 2007 

Intervention: 24 hours 

Outcome Measures

Baseline Characteristics

Diclofenac

(n= 30)

Indomethacin 

(n= 30)

Acetaminophen 

(n= 30)

Placebo 

(n= 30) 

Age, years

Duration of operation, min 

Results

Endpoint

Diclofenac

(n= 30)

Indomethacin 

(n= 30)

Acetaminophen

(n= 30)

Placebo

(n= 30) 

p-value

Pain starting time, min 

First dose of meperidine*, min

Total meperidine* dose in 24 h, mg

Pain intensity**

1 h postop 

12 h postop

24 h postop

4.73 ± 2.16

1.97 ± 1.38

0.97 ± 0.85

4.60 ± 1.94

1.41 ± 2.50

1.30 ± 0.95

5.47 ± 1.53

3.87 ± 1.59

1.97 ± 1.27

6.57 ± 1.43

4.97 ± 1.33

3.10 ± 1.37

<0.001

<0.001

<0.001

*Non FDA approved brand of meperidine (Pethidine) was utilized. 

**Pain intensity based on visual analog scale criteria 

Adverse Events

A total of 7 patients experienced complications: 6 vomiting, and 1 itching. The placebo group had the most complications (3 patients), while the acetaminophen and diclofenac groups had 1 case each.

Study Author Conclusions

InpharmD Researcher Critique

Comparison of diclofenac sodium with indomethacin suppositories for mediolateral episiotomies

Design

Prospective, randomized, one-side blinded study

N= 70

Objective

Study Groups

Diclofenac (n= 35)

Indomethacin (n= 35)

Inclusion Criteria

Exclusion Criteria

Methods

Duration

Outcome Measures

Baseline Characteristics

Diclofenac (n= 35)

Indomethacin (n= 35)

Age, years

Length, cm

Gravida

Parity

Live birth

Primigravida

Multigravida

MLE length, cm

MLE reoperation duration, min

3.6 ± 0.6

20 ± 3

3.7 ± 0.5

19.8 ± 3.2

Results

Endpoint

Diclofenac (n= 35)

Indomethacin (n= 35)

p-value

1-hour pain score

VRS

VAS

2.6 ± 0.5

4.9 ± 0.8

3.4 ± 0.6

6.6 ± 1.2

24-hour pain score

VRS

VAS

1.2 ± 0.4

2.4 ± 0.9

2 ± 0.7

4 ± 1.3

< 0.05

A positive correlation was obtained between the first and 24th hour VRS and VAS by Spearman correlation analysis (rs= 0.9, n= 70, p= 0.000).

Adverse Events

Study Author Conclusions

The two analgesics were effective after episiotomy repair, however, diclofenac sodium suppositories may be the preferred choice because they were more effective.

InpharmD Researcher Critique

Comparison of diciofenac and indomethacin suppositories in rheumatoid arthritis

Design

Prospective, double-blind, cross-over study

N= 30

Objective

To evaluate the efficacy and local and systemic tolerability of suppositories of diclofenac sodium

Study Groups

Diclofenac (n= 14)

Indomethacin (n= 16)

Inclusion Criteria

Exclusion Criteria

Severe hepatic or kidney disease, manifest diabetes, ulcus ventriculi en duodeni, colitis ulcerosa, parkinsonism and epilepsy

Methods

Voltaren (diclofenac) 100 mg suppositories were compared against matching indomethacin 100 mg suppositories via randomized groups; the first group was treated with diclofenac 100 mg for 6 days, then placebo for 2 days, then indomethacin 100 mg for 6 days, whereas the other group was treated in the opposite order. Acetaminophen 500 mg was used as a rescue analgesic if needed, and concomitant treatment was continued during the trial period. Severity of disease was rated from 1 (very poor) to 5 (very good) by the patient and physician. Pain at rest was rated from 1 (no pain) to 5 (intolerable).

Duration

14 days

Outcome Measures

Global assessment of disease status, duration of morning stiffness, rheumatic pain

Baseline Characteristics

Study cohort (N= 30)

Age, years

Weight, kg

Pain scores

At rest

On movement

No pain at rest

1.9 ± 1.1

3.0 ± 1.1

12 (40%)

Duration of morning stiffness, min

Pain intensity

Results

Endpoint

Diclofenac*

Indomethacin*

Duration of morning stiffness, min

Pain intensity

At rest

On movement

1.5 ± 0.8

2.9 ± 0.9

1.5 ± 0.8

2.3 ± 0.7

Rescue analgesics taken, tablets

10

10

*Final evaluation consisted of 10 and 14 patients for diclofenac and indomethacin, respectively, due to six withdrawals.

Patient's opinion on disease state was improved by both diclofenac (p< 0.01) and indomethacin (p< 0.01) compared to baseline. Similarly, both treatments improved disease status (p= 0.062) according to physician evaluation.

Both treatments shortened the duration of stiffness statistically significantly (p< 0.005).

Adverse Events

Common Adverse Events (diclofenac vs. indomethacin): Gastrointestinal symptoms (gastric pain, 3 vs. 2; meteorism, 3 vs. 3), central nervous system-related symptoms (headache, 3 vs. 5; vertigo, 2 vs. 2), and allergies (skin rash, 2 vs. 2) were common.

Serious Adverse Events: N/A

Reasons for withdrawal include heartburn, diarrhea, and nausea for diclofenac and diarrhea for indomethacin. Itching started after indomethacin on Day 8 during placebo, and continued up to withdrawal on Day 11 for one patient.

Study Author Conclusions

The status of the disease was statistically significantly improved during both diclofenac sodium and indomethacin, the two drugs being equally effective. The effects on pain at rest and on movement, as well as on morning stiffness, were equally good with both drugs, as compared to the situation before the treatment. When compared to each other, no statistically significant difference was found between the two drugs. Also the amount of rescue analgesics used was the same at both treatments.

InpharmD Researcher Critique

Some symptoms reported were already present prior to treatment. This was a small study that likely lacked power and regimens trialed prior to study initiation, as well as other baseline characteristics, were not described.