Comparative Study between Paracervical Block and Non-Steroidal Anti Inflammatory Drug for Relief of Pain during Manual Vacuum Aspiration Procedure.

The incidence of first trimester pregnancy loss is around 10.0-20.0% of registered pregnancies. Manual vacuum aspiration is a safe, effective and acceptable option of treatment for patients diagnosed with first trimester pregnancy loss. Main disadvantage of MVA is the pain caused by manipulation of the cervix, the uterine suction and the cervical dilatation. This study showed the way how the pain and discomfort might be reduced. This was a cross-sectional comparative study was conducted at the obstetrics and Gynecological Department of Sadar hospital, Manikganj, Bangladesh from January 2017 to December 2017. All the consecutive women admitted and diagnosed as incomplete abortion, missed abortion and anembryonic pregnancy (blighted ovum) were included in this study. Sampling technique was purposive sampling. The objective of this study was to compare the effectiveness of paracervical block anesthesia with non-steroidal anti inflammatory drug (NSAID) for relief of pain during the manual vacuum aspiration procedure for the treatment of first trimester pregnancy loss. Total 120 cases were included in this study. Assigned study population were divided into two groups like Group A and Group B. 60 of the study population were included in Group A who were given paracervical block anesthesia 3 minutes before the procedure. Another 60 study population was included in Group B who was given diclofenac 75mg intramuscular injection, 30 minutes before the procedure. Both intraoperative and postoperative pain level was evaluated by using visual analog scale ranged from (0-10 points) 30 minutes after the procedure. At the same time the satisfaction level of the study population were measured by 5 points lickert scale. Regarding clinical profile of the study population it showed no significant difference in case of mean age, mean gestational age and mean duration of the procedure between two groups. The mean intraoperative pain score in Group A was 4.0±1.3, in Group B it was 5.4±1.5 (p=0.001) which was significant. So it showed that paracervical block anesthesia significantly reduced the pain in relation to diclofenac 75mg intramuscular injection. Mean postoperative pain level 30 minutes after procedure in Group A was 2.2±0.4 and in Group B was 2.4±0.4 (p=0.343), where post-operative pain is lower in Group A than Group B. Though this difference is not statistically significant (p=0.343). In Group A 73.0% (n=44) and in Group B 43.0% (n=26) study population were agreed that the procedure was easy. Most common adverse effect was epigastric pain which was 1.7% (n=1) in Group A and 10.0% (n=7) in Group B. Paracervical block significantly reduces intraoperative pain during Manual Vacuum Aspiration (MVA) procedure in the treatment of first trimester pregnancy loss in comparison to intramuscular injection of diclofenac. In conclusion it might be mentioned that regarding paracervical block anesthesia, efficacy is higher and side effects are less. Moreover paracervical block anesthesia is cost effective.

Stability Evaluation of Bracketed Diclofenac Sodium USP in VersaPro™ Cream Base, VersaPro™ Gel Base and PLO Gel Mediflo™ 30 Compound Kit.

Diclofenac Sodium is a nonsteroidal anti-inflammatory drug (NSAID) that has analgesic, anti-inflammatory, and antipyretic properties, and has been found to be effective in treating a variety of acute and chronic pain and inflammatory conditions. A stability study was designed to assess the physical, chemical, and antimicrobial stability of three extemporaneously compounded bracketed Diclofenac Sodium formulations over time using a validated, stability indicating HPLC method. Diclofenac Sodium 1% and 15% were compounded in Medisca VersaPro™ Cream Base, VersaPro™ Gel Base and PLO Gel Mediflo™30 Compound Kit and stored at room temperature, in tightly closed, light resistant, plastic containers for 180 days. The organoleptic properties, pH, viscosity, and Diclofenac Sodium concentration of each formulation were evaluated at predetermined time points. Antimicrobial effectiveness testing of the compounded formulation according to USP <51> was also evaluated at the initial time point and after 180 days. The results demonstrated that all formulations remained within the specified stability criteria for the duration of the study. Therefore, an extended beyond-use-date of 180 days may be assigned to these compounded formulations under the studied conditions.

Use of metamizole and other non-opioid analgesics in Switzerland between 2014 and 2019: an observational study using a large health insurance claims database.

OBJECTIVE: To investigate claims patterns for metamizole and other non-opioid analgesics in Switzerland. To characterise users of these non-opioid analgesics regarding sex, age, comedications and canton of residence. METHODS: We conducted a retrospective descriptive study using administrative claims data of outpatient prescribed non-opioid analgesics of the Swiss health insurance company Helsana between January 2014 and December 2019. First, we evaluated the number of claims and defined daily doses  per year of metamizole, ibuprofen, diclofenac and paracetamol in adults aged 18 years or over. Second, we characterised new users of these non-opioid analgesics in terms of sex, age, claimed comedications and canton of residence. RESULTS: From 2014 to 2019, among the investigated non-opioid analgesics, metamizole showed the highest increase in claims (+9545 claims, +50%) and defined daily doses (+86,869 defined daily doses, +84%) per 100,000 adults. Metamizole users had the highest median age (62 years [IQR: 44-77]) compared to ibuprofen (47 years [IQR: 33-62]), diclofenac (57 years [IQR: 43-71]) and paracetamol (58 years [IQR: 39-75]) users. Metamizole users also more frequently claimed proton pump inhibitors, anticoagulants, platelet aggregation inhibitors and antihypertensive drugs than users of other non-opioid analgesics. While metamizole was most frequently claimed in German-speaking regions of Switzerland, ibuprofen and paracetamol were most frequently claimed in the French-speaking regions and diclofenac in German- and Italian-speaking regions. CONCLUSION: In Switzerland, metamizole was increasingly claimed between 2014 and 2019. Metamizole was most frequently claimed by older adults and patients with comedications suggestive of underlying conditions, which can be worsened or caused by use of nonsteroidal anti-inflammatory drugs. The lack of studies regarding the effectiveness and safety of metamizole in this population warrants further investigation.

Nonsteroidal anti-inflammatory drugs before endoscopic ultrasound guided tissue acquisition to reduce the incidence of post procedural pancreatitis.

Endoscopic ultrasound (EUS) with fine needle aspiration or fine needle biopsy is the gold standard for sampling tissue to diagnose pancreatic cancer and autoimmune pancreatitis or to analyze cyst fluid. The most common reported adverse event of fine needle aspiration and/or fine needle biopsy is acute pancreatitis, which is likely induced by the same pathophysiological mechanisms as after endoscopic retrograde cholangiopancreatography (ERCP). According to the current European Society of Gastrointestinal Endoscopy guideline, nonsteroidal anti-inflammatory drugs are administered prior to ERCP as a scientifically proven treatment to reduce post-ERCP pancreatitis incidence rate. A single suppository of diclofenac or indomethacin prior to EUS guided tissue acquisition (TA) is harmless in healthy adults. Since it is associated with low costs and, most important, may prevent a dreadsome complication, we strongly recommend the administration of 100 mg diclofenac rectally prior to EUS-TA. We will explain this recommendation in more detail in this review as well as the risk and pathophysiology of post-EUS TA pancreatitis.

ß-keto amyrin isolated from Cryptostegia grandiflora R. br. inhibits inflammation caused by Daboia russellii viper venom: Direct binding of ß-keto amyrin to phospholipase A2.

The search for mechanism-based anti-inflammatory therapies is of fundamental importance to avoid undesired off-target effects. Phospholipase A2 (PLA2) activity is a potential molecular target for anti-inflammatory drugs because it fuels arachidonic acid needed to synthesize inflammation mediators, such as prostaglandins. Herein, we aim to investigate the molecular mechanism by which ß-keto amyrin isolated from a methanolic extract of Cryptostegia grandiflora R. Br. Leaves can inhibit inflammation caused by Daboia russellii viper (DR) venom that mainly contains PLA2. We found that ß-keto amyrin neutralizes DR venom-induced paw-edema in a mouse model. Molecular docking of PLA2 with ß-keto amyrin complex resulted in a higher binding energy score of -8.86 kcal/mol and an inhibition constant of 611.7 nM. Diclofenac had a binding energy of -7.04 kcal/mol and an IC50 value of 620 nM, which predicts a poorer binding interaction than ß-keto amyrin. The higher conformational stability of ß-keto amyrin interaction compared to diclofenac is confirmed by molecular dynamics simulation. ß-keto amyrin isolated from C. grandiflora inhibits the PLA2 activity contained in Daboia russellii viper venom. The anti-inflammatory property of ß-keto amyrin is due to its direct binding into the active site of PLA2, thus inhibiting its enzyme activity.

Inhibitory effect of diacerein on diclofenac-induced acute nephrotoxicity in rats via modulating SIRT1/HIF-1α/NF-κB and SIRT1/p53 regulatory axes.

The aim of this study is to explore the potential of repurposing the antiarthritic drug diacerein (DCN) against diclofenac (DCF)-induced acute nephrotoxicity in rats. Rats were divided into four groups: Group I (CTRL) served as the negative control; Group II (DCF) served as the positive control and was injected with DCF (50 mg/kg/day) for three consecutive days (fourth-sixth) while being deprived of water starting on day 5; Group III (DCF + DCN50) and Group IV (DCF + DCN100) were orally administered DCN (50 and 100 mg/kg/day, respectively) for six days and injected with DCF, while being deprived of water as described above. Changes in kidney function biomarkers were assessed. Levels of MDA and GSH along with NO content in kidney tissues were measured as indicators of oxidative stress status. Histopathological changes of the renal cortex and medulla were evaluated. Changes in renal NF-κB and SIRT-1 levels were immunohistochemically addressed. Western blotting was used to estimate the relative expressions of HIF-1α, p53, and active caspase-3. Our results showed that DCN inhibited kidney dysfunction and suppressed oxidative stress, which were reflected in improved kidney architecture, including less tubular degeneration and necrosis in the cortex and medulla. Interestingly, DCN reduced renal HIF-1α, p53, and active caspase-3 expression and NF-κB activation while increasing renal SIRT1 expression. In conclusion, for the first time, DCN counteracts acute kidney injury induced by DCF in rats by its anti-oxidative, anti-inflammatory, antinecrotic, and anti-apoptotic effects in a dose-dependent manner, which are mainly via targeting SIRT1/HIF-1α/NF-κB and SIRT1/p53 regulatory axes.

Betulin Accelerated the Functional Recovery of Injured Muscle in a Mouse Model of Muscle Contusion.

Muscle contusion is an injury to muscle fibers and connective tissues. It commonly happens in impact events, and could result in pain, swelling, and limited range of motion. Diclofenac is one of commonly used nonsteroidal anti-inflammatory drugs to alleviate pain and inflammation after injury. However, it can potentially cause some side effects including gastrointestinal complications and allergy. Betulin is a lupine-type pentacyclic triterpenoid. It is showed to have valuable pharmacological effects, but the physiological effect of betulin on muscle contusion has not been reported. This study aimed to explore the therapeutic effects of betulin on muscle contusion that produced by the drop-mass method in mice. C57BL/6 mice were randomly assigned to control (no injury), only drop-mass injury (Injury), diclofenac treatment (Injury+diclofenac), and betulin treatment (Injury+betulin) groups. Injury was executed on the gastrocnemius of the right hind limb, and then phosphate-buffered saline (PBS), diclofenac, or betulin were oral gavage administrated respectively for 7 days. Results revealed that betulin significantly restored motor functions based on locomotor activity assessments, rota-rod test, and footprints analysis. Betulin also attenuated serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels after muscle injury. Neutrophil infiltration was alleviated and desmin levels were increased after betulin treatment. Our data demonstrated that betulin attenuated muscle damage, alleviated inflammatory response, improved muscle regeneration, and restored motor functions after muscle contusion. Altogether, betulin may be a potential compound to accelerate the repair of injured muscle.

The radiation- and chemo-sensitizing capacity of diclofenac can be predicted by a decreased lactate metabolism and stress response.

BACKGROUND: An enhanced aerobic glycolysis ("Warburg effect") associated with an increase in lactic acid in the tumor microenvironment contributes to tumor aggressiveness and resistance to radiation and chemotherapy. We investigated the radiation- and chemo-sensitizing effects of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac in different cancer cell types. METHODS: The effects of a non-lethal concentration of diclofenac was investigated on c-MYC and Lactate Dehydrogenase (LDH) protein expression/activity and the Heat shock Protein (HSP)/stress response in human colorectal (LS174T, LoVo), lung (A549), breast (MDA-MB-231) and pancreatic (COLO357) carcinoma cells. Radiation- and chemo-sensitization of diclofenac was determined using clonogenic cell survival assays and a murine xenograft tumor model. RESULTS: A non-lethal concentration of diclofenac decreases c-MYC protein expression and LDH activity, reduces cytosolic Heat Shock Factor 1 (HSF1), Hsp70 and Hsp27 levels and membrane Hsp70 positivity in LS174T and LoVo colorectal cancer cells, but not in A549 lung carcinoma cells, MDA-MB-231 breast cancer cells and COLO357 pancreatic adenocarcinoma cells. The impaired lactate metabolism and stress response in diclofenac-sensitive colorectal cancer cells was associated with a significantly increased sensitivity to radiation and 5Fluorouracil in vitro, and in a human colorectal cancer xenograft mouse model diclofenac causes radiosensitization. CONCLUSION: These findings suggest that a decrease in the LDH activity and/or stress response upon diclofenac treatment predicts its radiation/chemo-sensitizing capacity.

Intradermal Sterile Water Injection: Safe and Effective Alternative for Relief of Acute Renal Colic in the Emergency Department.

BACKGROUND: The optimal pain relief method for acute renal colic in the emergency department remains controversial. OBJECTIVE: We compared the safety and efficacy of intradermal sterile water injection (ISWI) to treatment with intramuscular (IM) diclofenac, intravenous (IV) opioids, and IV paracetamol in patients with acute renal colic. METHODS: This randomized, single-blind study included 320 patients with renal colic to one of four treatment groups. The first group received ISWI at four different points around the most painful flank area. Patients in the DI, PARA, and TRAM groups received 75 mg IM diclofenac, 1 g IV paracetamol, and 100 mg IV tramadol, respectively. Pain intensity was measured using a visual analog scale (VAS) before treatment and 15, 30, and 60 min after treatment. RESULTS: VAS scores 15 and 30 min after treatment were significantly lower in group ISWI than in groups DI, PARA, and TRAM. However, there were no significant differences in the decrease in the pain score at baseline and at 60 min after treatment. In addition, fewer patients required rescue analgesia in group ISWI than in group TRAM. However, no significant differences were observed between group ISWI and group DI or PARA in terms of the need for rescue analgesia. Finally, there were significantly fewer adverse events in group ISWI than in groups DI and TRAM. CONCLUSIONS: ISWI had similar efficacy, faster pain relief, and lower need for rescue analgesia compared with diclofenac, paracetamol, and tramadol for the management of acute renal colic. In addition, ISWI was well-tolerated and had no adverse effects.

Effect of preemptive use of a nonsteroidal anti-inflammatory drug and a corticosteroid on the efficacy of inferior alveolar nerve blockade and postoperative pain control in endodontic treatment of molars with symptomatic pulpitis: A randomized double-blind placebo-controlled clinical trial.

AIM: The anaesthetic success rate of an inferior alveolar nerve block (IANB) in mandibular molars with irreversible symptomatic pulpitis can be low, and postoperative pain control in teeth with this diagnosis can be challenging. This study aimed to evaluate the influence of preemptive use of dexamethasone and oral potassium diclofenac on the success of IANB. The influence of these drugs on the intensity of postoperative pain was assessed as a secondary outcome. METHODOLOGY: Eighty-four patients with mandibular molars diagnosed with irreversible symptomatic pulpitis recorded preoperative pain intensity using a cold thermal test and a modified Numerical Rating Scale (mNRS). Sixty minutes before the anaesthetic procedure, patients were randomly assigned to one of three groups based on the medication they received: dexamethasone (4 mg), diclofenac potassium (50 mg), or placebo. All patients received IANB with 4% articaine (1:200 000 epinephrine), and 15 min later, they were evaluated for pain intensity using the cold thermal test. Anaesthetic success was analysed. The pain intensity was then recorded, and endodontic treatment and provisional restoration of the tooth were executed in a single session. Patients were monitored for 6, 12, 24, 48 and 72 h using the mNRS to assess the intensity of postoperative pain. RESULTS: There was a statistically significant increase in anaesthetic success when 4 mg dexamethasone (39.3%) or 50 mg diclofenac potassium (21.4%) was used compared to the placebo group (3.6%) (p < .001), with no significant difference between the two drugs. Regarding postoperative pain, dexamethasone was superior to placebo at 6 h (p < .001), with diclofenac having an intermediate behaviour, not differing between dexamethasone and placebo (p > .05). There was no significant difference amongst the groups at 12 h (p > .05). At 24, 48 and 72 h, the effectiveness of dexamethasone and diclofenac were comparable, and both were superior to placebo (p < .001). CONCLUSION: The use of dexamethasone or diclofenac potassium was favourable in terms of increasing the success rate of inferior alveolar nerve block in cases of mandibular molars with irreversible symptomatic pulpitis and decreased the occurrence of postoperative pain when compared to the use of a placebo.

Influence of Endogenous Substances on Site-II to Site-I Displacement of Diclofenac Bound to Albumin in the Aqueous Humor of Patients with Cataract.

Diclofenac instillation is useful in preventing intraoperative miosis and macular edema caused by postoperative inflammation in cataract surgery; however, optimum efficacy is not attained when the instilled diclofenac strongly binds to albumin in patients' aqueous humor. Therefore, a method that inhibits diclofenac binding and increases the concentration of its free fraction is needed. We conducted a basic study regarding the effects of inhibitors on the binding of instilled diclofenac to albumin and endogenous substances in aqueous humor. Aqueous humor samples from 16 patients were pooled together for analysis. The free fraction of diclofenac was measured using ultrafiltration methods in various experiments with pooled and mimic aqueous humor. Free fraction of diclofenac, a site II drug, in pooled aqueous humor was 0.363 ± 0.013. The binding of diclofenac in the presence of phenylbutazone (PB), a site I inhibitor, was significantly inhibited (free fraction = 0.496 ± 0.013); however, no significant inhibition by ibuprofen, a site II inhibitor, (free fraction = 0.379 ± 0.004), was observed. The unexpected result was due to free fatty acids (FFAs; palmitic acid (PA)) and L-tryptophan (Trp). The inhibition of diclofenac binding by PB in the mimic aqueous humor containing these endogenous substances revealed significant binding inhibition in the presence of PA and Trp. Diclofenac is strongly rebound from site II to site I in the presence of FFAs and Trp in the aqueous humor because FFAs and Trp induce a conformational change in albumin. Therefore, PB significantly inhibits the binding of diclofenac to albumin.

NSAIDs do not reduce severity among post-ERCP pancreatitis patients.

OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAIDs) are the most studied chemoprophylaxis for post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). While previous systematic reviews have shown NSAIDs reduce PEP, their impact on moderate to severe PEP (MSPEP) is unclear. We conducted a systematic review and meta-analysis to understand the impact of NSAIDs on MSPEP among patients who developed PEP. We later surveyed physicians' understanding of that impact. DESIGN: A systematic search for randomized trials using NSAIDs for PEP prevention was conducted. Pooled-prevalence and Odds-ratio of PEP, MSPEP were compared between treated vs. control groups. Analysis was performed using R software. Random-effects model was used for all variables. Physicians were surveyed via email before and after reviewing our results. RESULTS: 7688 patients in 25 trials were included. PEP was significantly reduced to 0.598 (95%CI, 0.47-0.76) in the NSAIDs group. Overall burden of MSPEP was reduced among all patients undergoing ERCP: OR 0.59 (95%CI, 0.42-0.83). However, NSAIDs didn't affect the proportion of MSPEP among those who developed PEP (p = 0.658). Rectal Indomethacin and diclofenac reduced PEP but not MSPEP. Efficacy didn't vary by risk, timing of administration, or bias-risk. Survey revealed a change in the impression of the effect of NSAIDs on MSPEP after reviewing our results. CONCLUSIONS: Rectal diclofenac or indomethacin before or after ERCP reduce the overall burden of MSPEP by reducing the pool of PEP from which it can arise. However, the proportion of MSPEP among patients who developed PEP is unaffected. Therefore, NSAIDs prevent initiation of PEP, but do not affect severity among those that develop PEP. Alternative modalities are needed to reduce MSPEP among patients who develop PEP.

A randomized controlled trial of rectal versus intramuscular diclofenac for post-operative analgesia after open myomectomy.

AIM: To determine the efficacy and safety of rectal versus intramuscularly administered Diclofenac in reducing post-operative pain in the first 24 h after open-myomectomy. METHODS: A single blind, placebo controlled randomized trial consisting of 90 consenting women that had open-abdominal-myomectomy. They were randomized into two-groups (rectal-group and intramuscular-group) of 45 women (1:1 ratio). Rectal-group received 75 mg of Diclofenac suppository 12 hourly for 24 h and placebo (3 ml of intramuscular injection-water) 12hourly for 24 h while intramuscular-group received intramuscular Diclofenac 75 mg 12 hourly for 24 h and placebo (Anusol suppository) 12 hourly for 24 h. Both groups received intramuscular Pentazocine 30 mg 6 hourly for 24 h as primary analgesic after myomectomy. Pain was assessed using a Ten-Point Visual-Analogue-Scale. Participants' satisfaction of the mode of the pain relief was assessed using the Likert-scale after 24 h. The primary outcome was the pain score using the visual-analogue-scale. The secondary outcome-measures were participants' satisfaction after 24 h of administration of the drugs, the need and frequency of rescue-analgesia and maternal-side-effects. RESULT: The baseline socio-demographic characteristics were similar in both groups. There was no statistically significant difference between both groups in pain assessment at 1 h post-myomectomy (p-value > 0.05). However, the pain assessments at 6, 12, 18 and 24 h post-myomectomy were statistically significant with more pain in intramuscular-group when compared to rectal-group. Majority of participants in rectal-group were both very satisfied (35.6 %) and satisfied (55.6 %) when compared to intramuscular-group (11.1 %) and (31,1%) respectively (p-value < 0.05). Also majority of the participants in intramuscular-group were dissatisfied (17.8 %) with none of the participant showing any form of dissatisfaction (p-value < 0.05). Majority of the participant in rectal-group had no drug side effects when compared with intramuscular-group. Epigastric discomfort was commoner in rectal-group while drowsiness was commoner in intramuscular-group. CONCLUSION: Rectal Diclofenac with intramuscular Pentazocine is significantly associated with better effectiveness in pain reduction and maternal satisfaction when compared with intramuscular Diclofenac and intramuscular Pentazocine following open-myomectomy. While epigastric discomfort was the commonest side-effect in rectal-group, drowsiness was commoner in intramuscular-group. TRIAL REGISTRATION: Pan-African-clinical-trial-registry (PACTR); PACTR202206556144219.

Correlation of diclofenac sodium sustained-release capsules in conjunction with function training and VAS score after ankle fracture surgery.

OBJECTIVE: To investigate the effect of Diclofenac sodium sustained-release capsules combined with function training on functional recovery and Visual Analog Scale (VAS) score after surgery for ankle fractures. PATIENTS AND METHODS: The study included 88 patients with ankle fractures who were surgically treated at our institution between October 2019 and October 2021. The individuals were randomized into experimental and control groups, with 44 patients in each group. Following their hospitalization, all patients had surgical therapy. After surgery, patients in the control group received conventional analgesics together with function training, whereas those in the experimental group received Diclofenac sodium sustained-release capsules along with function training. The efficacy of the post-surgical treatment in the two groups was then evaluated using functional recovery and VAS scores. RESULTS: There was no significant difference in the VAS score between the two groups before intervention (p>0.05). After treatment, both groups experienced pain relief, with the VAS score of the experimental group being significantly lower than the control group (p<0.05). The number of patients in the experimental group who fully and partially complied with the study was 19 and 24, respectively, significantly higher than that of 15 and 20 in the control group. Only 1 patient in the experimental group was non-compliant, compared to 9 in the control group. The total compliance rate in the experimental group was 97.73%, much higher than that of 79.55% in the control group (p<0.05). Before the intervention, there was no significant difference in the range of active ankle motion between the two groups (p>0.05). After treatment, there was an improvement in the range of active motion of the ankle in patients from both groups. CONCLUSIONS: After ankle fracture surgery, using Diclofenac sodium sustained-release capsules in conjunction with function training successfully lowers postoperative pain. It also maintains emotional stability and ensures sleep, factors which are helpful in improving patient compliance to treatment and promoting functional recovery of the ankle. The clinical value of this treatment regimen is certain, and it deserves more widespread application.

Diclofenac for acute postoperative pain in children.

BACKGROUND: Many children undergo various surgeries, which often lead to acute postoperative pain. This pain influences recovery and quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs), specifically cyclo-oxygenase (COX) inhibitors such as diclofenac, can be used to treat pain and reduce inflammation. There is uncertainty regarding diclofenac's benefits and harms compared to placebo or other drugs for postoperative pain. OBJECTIVES: To assess the efficacy and safety of diclofenac (any dose) for acute postoperative pain management in children compared with placebo, other active comparators, or diclofenac administered by different routes (e.g. oral, rectal, etc.) or strategies (e.g. 'as needed' versus 'as scheduled'). SEARCH METHODS: We used standard, extensive Cochrane search methods. We searched CENTRAL, MEDLINE, and trial registries on 11 April 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in children under 18 years of age undergoing surgery that compared diclofenac (delivered in any dose and route) to placebo or any active pharmacological intervention. We included RCTs comparing different administration routes of diclofenac and different strategies. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were: pain relief (PR) reported by the child, defined as the proportion of children reporting 50% or better postoperative pain relief; pain intensity (PI) reported by the child; adverse events (AEs); and serious adverse events (SAEs). We presented results using risk ratios (RR), mean differences (MD), and standardised mean differences (SMD), with the associated confidence intervals (CI). MAIN RESULTS: We included 32 RCTs with 2250 children. All surgeries were done using general anaesthesia. Most studies (27) included children above age three. Only two studies had an overall low risk of bias; 30 had an unclear or high risk of bias in one or several domains. Diclofenac versus placebo (three studies) None of the included studies reported on PR or PI. We are very uncertain about the benefits and harms of diclofenac versus placebo on nausea/vomiting (RR 0.83, 95% CI 0.38 to 1.80; 2 studies, 100 children) and any reported bleeding (RR 3.00, 95% CI 0.34 to 26.45; 2 studies, 100 children), both very low-certainty evidence. None of the included studies reported SAEs. Diclofenac versus opioids (seven studies) We are very uncertain if diclofenac reduces PI at 2 to 24 hours postoperatively compared to opioids (median pain intensity 0.3 (interquartile range (IQR) 0.0 to 2.5) for diclofenac versus median 0.7 (IQR 0.1 to 2.4) in the opioid group; 1 study, 50 children; very low-certainty evidence). None of the included studies reported on PR or PI for other time points. Diclofenac probably results in less nausea/vomiting compared to opioids (41.0% in opioids, 31.0% in diclofenac; RR 0.75, 95% CI 0.58 to 0.96; 7 studies, 463 participants), and probably increases any reported bleeding (5.4% in opioids, 16.5% in diclofenac; RR 3.06, 95% CI 1.31 to 7.13; 2 studies, 222 participants), both moderate-certainty evidence. None of the included studies reported SAEs. Diclofenac versus paracetamol (10 studies) None of the included studies assessed child-reported PR. Compared to paracetamol, we are very uncertain if diclofenac: reduces PI at 0 to 2 hours postoperatively (SMD -0.45, 95% CI -0.74 to -0.15; 2 studies, 180 children); reduces PI at 2 to 24 hours postoperatively (SMD -0.64, 95% CI -0.89 to -0.39; 3 studies, 300 children); reduces nausea/vomiting (RR 0.47, 95% CI 0.25 to 0.87; 5 studies, 348 children); reduces bleeding events (RR 0.57, 95% CI 0.12 to 2.62; 5 studies, 332 participants); or reduces SAEs (RR 0.50, 95% CI 0.05 to 5.22; 1 study, 60 children). The evidence certainty was very low for all outcomes. Diclofenac versus bupivacaine (five studies) None of the included studies reported on PR or PI. Compared to bupivacaine, we are very uncertain about the effect of diclofenac on nausea/vomiting (RR 1.28, 95% CI 0.58 to 2.78; 3 studies, 128 children) and SAEs (RR 4.52, 95% CI 0.23 to 88.38; 1 study, 38 children), both very low-certainty evidence. Diclofenac versus active pharmacological comparator (10 studies) We are very uncertain about the benefits and harms of diclofenac versus any other active pharmacological comparator (dexamethasone, pranoprofen, fluorometholone, oxybuprocaine, flurbiprofen, lignocaine), and for different routes and delivery of diclofenac, due to few and small studies, no reporting of key outcomes, and very low-certainty evidence for the reported outcomes. We are unable to draw any meaningful conclusions from the numerical results. AUTHORS' CONCLUSIONS: We remain uncertain about the efficacy of diclofenac compared to placebo, active comparators, or by different routes of administration, for postoperative pain management in children. This is largely due to authors not reporting on clinically important outcomes; unclear reporting of the trials; or poor trial conduct reducing our confidence in the results. We remain uncertain about diclofenac's safety compared to placebo or active comparators, except for the comparison of diclofenac with opioids: diclofenac probably results in less nausea and vomiting compared with opioids, but more bleeding events. For healthcare providers managing postoperative pain, diclofenac is a COX inhibitor option, along with other pharmacological and non-pharmacological approaches. Healthcare providers should weigh the benefits and risks based on what is known of their respective pharmacological effects, rather than known efficacy. For surgical interventions in which bleeding or nausea and vomiting are a concern postoperatively, the risks of adverse events using opioids or diclofenac for managing pain should be considered.

[Investigation of the effect of ethylmethylhydroxypyridine succinate on the effectiveness of non-steroidal anti-inflammatory drugs for visceral and somatic pain in mice and rats]. / Izuchenie vliyaniya etilmetilgidroksipiridina suktsinata na effektivnost' nesteroidnykh protivovospalitel'nykh preparatov pri vistseral'noi i somaticheskoi boli v eksperimente na myshakh i krysakh.

OBJECTIVE: To study the effect of ethylmethylhydroxypyridine succinate (EMHPS) on the analgesic effect of the non-selective cyclooxygenase (COX) inhibitor diclofenac sodium and the selective COX-2 inhibitor etoricoxib in models of acute visceral and somatic pain and to evaluate the possibility of using EMHPS in combination with COX inhibitors to reduce their doses while maintaining analgesic efficiency. MATERIAL AND METHODS: We studied the effect of EMHPS with a single oral administration on the analgesic effects of non-steroidal anti-inflammatory drugs (NSAIDs): the non-selective COX inhibitor diclofenac sodium and the selective COX-2 inhibitor etoricoxib - on models of acute visceral (vinegar writhing test) and somatic pain (formalin test and mechanical hyperalgesia during inflammation) in an experiment on mice and rats. RESULTS: In a model of acute visceral pain in mice, EMGPS (25-100 mg/kg) does not have a significant effect on its severity, but enhances the analgesic effect of diclofenac sodium (0.5 mg/kg) and etoricoxib (1 mg/kg). In the formalin test in rats, which simulates pain during surgical incisions (trauma), EMGPS (25 mg/kg) increases the severity of the analgesic effect of COX inhibitors (1 mg/kg), primarily by reducing pain in the acute phase caused by the effect of formalin on afferent neurons. In a model of mechanical hyperalgesia in rats caused by exudative inflammation after injection of a carrageenan solution into the paw, EMHPS enhances the effect of diclofenac to a greater extent than etoricoxib. CONCLUSION: The data obtained indicate the feasibility of a clinical study of the use of EMGPS in combination with NSAIDs for visceral and somatic pain in order to assess its ability to increase the therapeutic effect of NSAIDs.

The efficacy of intradermal sterile water application in severe renal colic: a randomised clinical trial.

It is important to do a fast and effective treatment for patients with renal colic pain in emergency departments for both patients' comfort and clinicians' patient management. In this study, we aimed primarily to test the efficacy of intradermal sterile water application as a rapid and effective treatment in severe renal colic. This is a single-centre, prospective, randomised controlled trial. Study group consists of patients with severe renal colic related to urolithiasis. Patients were randomly divided into three groups. The first group received only intramuscular diclofenac sodium, the second group received intramuscular diclofenac sodium and intradermal sterile water, and the third group received intramuscular diclofenac sodium together with intravenous fentanyl. Numerical Rating Scale was used to determine the level of pain before and after the treatment at the 1st, 5th, 15th, 30th, 60th and 120th minutes. 95 out of 201 patients with severe renal colic pain randomly divided into 3 groups. The pre-treatment pain severity of the groups was similar (p = 0.228). We found that the decrease in pain intensity was significantly faster in the intradermal sterile water group than the other groups even in the first minute. Percentages of patients who had 50% pain reduction, which is considered as successful treatment, was higher in the intradermal sterile water group (which had 75.9% success rate) in the first 5 min compared to the IM diclofenac sodium group (which had 7.1% success rate) and IV fentanyl group (which had 25% success rate) (p < 0.001). According to the results, pain control was achieved much faster than the other methods with intradermal sterile water injection. All methods were found to be effective in relieving the pain of the patients.

Safety and Efficacy of Oral Nalbuphine on Postoperative Pain in Hemorrhoidectomy Patients: A Randomized, Double-blind, Placebo-controlled, Pivotal Trial.

OBJECTIVES: Severe postoperative pain requiring opioid treatment has been reported in 20% to 40% of hemorrhoidectomy patients. Compared with morphine, nalbuphine offers better hemodynamic stability, a lower risk of respiratory depression, and a lower potential for addiction. Nalbuphine was developed from the intravenous form into an oral form (PHN131) to alleviate moderate-to-severe pain. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled, multiple-dose, parallel-design trial was conducted to evaluate the safety and efficacy of PHN131 in patients undergoing hemorrhoidectomy. Eligible patients were randomly assigned to receive either PHN131 soft capsules containing nalbuphine hydrochloride 60 mg or placebo capsules. Intramuscular diclofenac was the rescue analgesic. Pain was measured by the area under the curve of mean Visual Analog Scale pain intensity scores. RESULTS: Visual Analog Scale results in patients receiving PHN131 were significantly lower than placebo group scores through 48 hours postoperatively (149.2±75.52 vs. 179.6±65.97; P =0.0301). According to Brief Pain Inventory Short-Form scores, the impact of pain on quality of life was significantly smaller for the PHN131 group than for the placebo group. Time to the first use of diclofenac postoperatively was significantly longer in the PHN131 group than in the placebo group. The cumulative dosage of diclofenac in the PHN131 group was only around half of that in the placebo group ( P <0.0001). Drug-related adverse events were mild-to-moderate and resolved by the treatment end. No drug-related severe adverse events were observed. DISCUSSION: Our findings demonstrate that PHN131 is effective and well-tolerated in the treatment of moderate-to-severe post hemorrhoidectomy pain and may provide another option for patients to control their pain.

Improving the efficacy of photodynamic therapy for actinic keratosis: A comprehensive review of pharmacological pretreatment strategies.

BACKGROUND: Photodynamic therapy (PDT) is approved for treatment of actinic keratoses (AKs) and field-cancerisation. Pretreatment with pharmacological compounds holds potential to improve PDT efficacy, through direct interaction with PpIX formation or through an independent response, both of which may improve PDT treatment. OBJECTIVE: To present the currently available clinical evidence of pharmacological pretreatments prior to PDT and to associate potential clinical benefits with the pharmacological mechanisms of action of the individual compounds. METHODS: A comprehensive search on the Embase, MEDLINE, and Web of Science databases was performed. RESULTS: In total, 16 studies investigated 6 pretreatment compounds: 5-fluorouracil (5-FU), diclofenac, retinoids, salicylic acid, urea, and vitamin D. Two of these, 5-FU and vitamin D, robustly increased the efficacy of PDT across multiple studies, illustrated by mean increases in clearance rates of 21.88% and 12.4%, respectively. Regarding their mechanisms, 5-FU and vitamin D both increased PpIX accumulation, while 5-FU also induced a separate anticarcinogenic response. Pretreatment with diclofenac for four weeks improved the clearance rate in one study (24.9%), administration of retinoids had a significant effect in one of two studies (16.25%), while salicylic acid and urea did not lead to improved PDT efficacy. Diclofenac and retinoids demonstrated independent cytotoxic responses, whereas salicylic acid and urea acted as penetration enhancers to increase PpIX formation. CONCLUSION: 5-FU and vitamin D are well-tested, promising candidates for pharmacological pretreatment prior to PDT. Both compounds affect the haem biosynthesis, providing a target for potential pretreatment candidates. KEY WORDS: Photodynamic Therapy, Actinic Keratosis,Pre-tretment,Review,enhancement.