Oral Administration Of Non-steroidal Anti-inflammatory Drugs Research Articles

Transport of Non-Steroidal Anti-Inflammatory Drugs across an Oral Mucosa Epithelium In Vitro Model.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed drugs to treat pain or fever. However, oral administration of NSAIDs is frequently associated with adverse effects due to their inhibitory effect on the constitutively expressed cyclooxygenase enzyme 1 (COX-1) in, for instance, the gastrointestinal tract. A systemic delivery, such as a buccal delivery, of NSAIDs would be beneficial and additionally has the advantage of a non-invasive administration route, especially favourable for children or the elderly. To investigate the transport of NSAIDs across the buccal mucosa and determine their potential for buccal therapeutic usage, celecoxib, diclofenac, ibuprofen and piroxicam were tested using an established oral mucosa Transwell® model based on human cell line TR146. Carboxyfluorescein and diazepam were applied as internal paracellular and transcellular marker molecule, respectively. Calculated permeability coefficients revealed a transport ranking of ibuprofen > piroxicam > diclofenac > celecoxib. Transporter protein inhibitor verapamil increased the permeability for ibuprofen, piroxicam and celecoxib, whereas probenecid increased the permeability for all tested NSAIDs. Furthermore, influence of local inflammation of the buccal mucosa on the transport of NSAIDs was mimicked by treating cells with a cytokine mixture of TNF-α, IL-1ß and IFN-γ followed by transport studies with ibuprofen (+ probenecid). Cellular response to pro-inflammatory stimuli was confirmed by upregulation of cytokine targets at the mRNA level, increased secreted cytokine levels and a significant decrease in the paracellular barrier. Permeability of ibuprofen was increased across cell layers treated with cytokines, while addition of probenecid increased permeability of ibuprofen in controls, but not across cell layers treated with cytokines. In summary, the suitability of the in vitro oral mucosa model to measure NSAID transport rankings was demonstrated, and the involvement of transporter proteins was confirmed; an inflammation model was established, and increased NSAID transport upon inflammation was measured.

Effect of Diclofenac Mouthwash on Postoperative Pain after Periodontal Surgery.

Non-Steroidal AntiInflammatory Drugs (NSAIDs) are widely used drugs for the management of pain. Oral administration of NSAIDs has various adverse events like gastrointestinal alterations - nausea, dyspepsia and gastrointestinal bleeding, hepatotoxicity and blood dyscrasias. As orally given NSAIDs are associated with systemic side effects, it is preferred to alleviate pain and inflammation using topical medication. Thus, recently the focus has been on the development of topical administration of NSAIDs in the form of gels, toothpastes and rinses. To determine if diclofenac mouthwash, would be a better alternative to its systemic administration post surgery, in terms of patient acceptance and to minimize the adverse effects of orally administered drug. The study was designed as a single blinded, randomized, controlled clinical trial. Thirty chronic periodontitis patients scheduled for full mouth flap surgeries were randomized to receive either Diclofenac Mouthwash (MW) or Diclofenac Tablets (TB), post surgery. The MW group patients (15) were advised to rinse undiluted 15 ml solution for 30 secs, twice daily for three days. TB group (15) was advised to take 50 mg tablet twice daily for three days. A 10 point Visual Analog Scale (VAS) and Wong Baker Facial Rating Scale (FRS) was recorded to measure the pain perception by the patients. Gingival status was assessed by the Modified Gingival Index (MGI) at Baseline and seventh day. Data pertaining to pain perception were analysed using repeated measures of ANOVA (Analysis of Variance) with post-hoc LSD test. Intra group comparisons showed a significant reduction in pain, post surgery. Inter group comparisons showed a significant reduction only in the MGI scores of MW group, when compared to TB group. Intergroup comparisons showed no significant reduction in pain scores between both the groups, stating that diclofenac mouthwash is as effective as oral administration. Diclofenac mouthwash is a better alternative to the systemic administration post surgery, in terms of patient acceptance and to minimize the adverse effects of orally administrated drug.

Pain relief during minor procedures: a challenge for gynaecologists.

Common gynaecological problem as abnormal uterine bleeding and postmenopausal bleeding require evaluation by sampling of the endometrial tissue which was initially done by dilatation and curettage (D&C). The D&C has been substituted by outpatient procedures like endometrial suction curette biopsy, aspiration by Karman's cannula or fractional curettage or hysteroscopically guided biopsy. Other minor procedure which can be conducted in outpatients settings are suction termination, cervical biopsy, saline infusion sonography, etc. The major limitation in successful completion of the procedure is pain management. Patients frequently experience moderate to severe pain during these gynaecologic procedures and in some cases the severity of pain makes it impossible to take adequate sample in biopsy. Most patients can tolerate pain to complete necessary procedures but studies show that pain scores with cervical biopsy and cervical curettage range from four to six on a 10-point visual analogue scale (VAS)1,2. Endometrial biopsies have shown VAS scores ranging from five to seven3,4. Pain on VAS more than six suggests the need of pain relief. The choice of anaesthesia and analgesia is dependent on effectiveness, cost, safety, and side effects. Other factors are related to the patient's and physician's preferences. General anaesthesia provides analgesia, amnesia and a hypnotic effect and provides adequate operating conditions for cervical dilatation and uterine intervention but it is associated with increased mortality and morbidity. Lichtenberg et al5 showed that only 10 per cent of clinics use general anaesthesia, so local anaesthesia becomes a dominant method with 58 per cent use in clinics and 32 per cent use of intravenous sedation with local anaesthesia. The paracervical block with local anaesthetic agents is one of the most common procedures used since 19256. Paracervical anaesthetics block transmission of pain through sympathetic and parasympathetic sensory fibres, before these fibres enter the uterus at the level of the internal cervical os6. Most commonly used agent is one per cent lignocaine injected at 5 and 7 O’clock position on the cervix. Paracervical block is a convenient, safe, simple, and effective anaesthetic technique for curettage being used by most clinicians with or without additional analgesia. Tangsiriwatthana et al6 assessed the efficacy of paracervical block for cervical dilatation and uterine intervention, and stated that no local anaesthetic agent prevented pain as well as general anaesthesia. There was no evidence that paracervical block reduced pain compared to alternative regional anaesthetic methods or systemic analgesics and sedatives. In most studies pain score was more than six during the procedure when using placebo implying the need of pain relief6. The study of Acmaz and colleagues7 assessed the analgesic efficacy of preoperative oral dexketoprofen trometamol, intravenous paracetamol, lidocaine spray, pethidine and diclofenac sodium on fractional curettage procedure. A total of 144 mutiparous women were randomly allocated to the six groups. Though significant pain reduction was achieved for both intra- and postoperative periods by using analgesics but lidocaine spray was the best choice for reducing pain score during curettage procedure. All analgesic procedures were significantly effective for reducing pain in post operative period. The authors advocated the use of lidocaine spray as the first choice analgesic and pethidine as the second choice analgesic in the fractional curettage procedure. Lidocaine spray produces significant pain relief even in the absence of clinically significant serum levels as it is proposed to act by reduction of generation and conduction of peripheral pain impulses in dysfunctional or damaged nociceptors situated directly below the application site2. The addition of 10 per cent lidocaine spray to a paracervical block safely decreased perceived pain during first-trimester surgical abortion, as compared to paracervical block alone8. Non steroidal anti-inflammatory drugs (NSAIDs) show their effect by cyclooxygenase inhibition, thereby decrease the release of prostaglandins and do not discriminate between the two enzymes cyclooxygenase (COX)-1 and -29. The administration of oral NSAIDs like tramadol, naproxen, ibuprofen, and mefenamic acid with or without the adjunctive use of paracervical block or intrauterine anaesthesia prior to minor gynaecologic surgery has been introduced in recent years. Dexketoprofen trometamol, the active enantiomer of racemic ketoprofen, is a relatively new NSAID with analgesic and antipyretic properties9. When compared with ketoprofen, dexketoprofen it possesses the advantages of faster onset of action, increased potency, and fewer gastrointestinal side effects. Diclofenac also belongs to NSAID group and has been shown to be effective in reducing intra- and post operative pain after fractional curettage as in the present study7. This has been consistent with a prior study which has demonstrated effectiveness of NSAIDs in such procedures9. Pethidine is a phenylpiperidine derivative with a chemical structure similar to local anaesthetics. Because of its local anaesthetic effect on peripheral nerves it may be the ideal analgesic for curettage. In the present study, pethidine was given subcutaneously while in previous studies, it was given intramuscularly or intrathecally for postoperative pain after caesarean section or other perineal surgery10,11,12. Paracetamol primarily acts upon the central nervous system by inhibiting central cyclooxygenase. It probably has an indirect effect on the serotoninergic system13. Paracetamol is considered safe and can cross the blood brain barrier13. Most of the analgesics are effective in providing post-procedure pain relief in gynaecological procedures. The analgesics led to a reduction in pain score by 40-50 per cent in the study of Acmaz et al7, but lidocaine puffs provided the best pain relief than the other analgesics or placebo. It is observed that during colposcopy treatment cocaine spray before treatment resulted in better pain relief14. In the recent Cochrane reviews6,14 the existing literature regarding pain control for intrauterine interventions as hysteroscopy, first trimester abortion, intrauterine device (IUD) insertion and hysterosalpingography (HSG) has been evaluated, and both the reviews have concluded that optimal methods for pain control are unclear as results of different researches in this field are not consistent. This could be due to heterogeneity in methods and reporting. Many studies were not well designed, the comparator used varied as placebo, local block or no medication. Measurement of pain relief varied as multiple outcomes were used as 10 or 20 cm VAS. While most studies compared difference in mean or median pain scores between intervention and control groups, several compared proportions of patients who reported pain above a predefined cut-off point. Many studies gave importance to need of additional analgesics as a criterion of pain relief measurement. Pain measurements were taken at different times across studies, ranging from one measurement during the procedure to a total of seven measurements prior, during, and after procedures6,14. The analgesics have complications like nausea, vomiting, rashes, bradycardia, and stomach complaints reported in 2-10 per cent cases5. This study7 also had similar rate of complications in all the groups. Strengths of the study by Acmaz et al7 were: randomized placebo controlled trial which was double blind with a power of 80 per cent, many confounding variables were taken into consideration as stringent inclusion criteria, no misoprost or analgesics prior to intervention, only multiparous patients enrolled, exclusion of patients of chronic pelvic pain and performance of procedure by same gynaecologist. The study had limitations also. The number of patients in control group receiving placebo via different modes of administration was small to make adequate comparisons with each study group. The authors in their previous study2 recommended paracervical block as the best method for reducing pain scores in intra- and postoperative periods during curettage procedures. So paracervical block should also have been taken into account while recommending the suitable pain relief technique. Operator's perception of analgesics and patient's satisfaction should also have been included as a parameter for making a choice of best available pain relief modality. In conclusion, though topical lidocaine spray appears promising, there is still no consensus established on which type of analgesia should be used in patients undergoing fractional curettage and endometrial biopsy. More randomized controlled trials with large number of subjects are needed for its use to be recommended.

Non-steroidal anti-inflammatory drugs for the treatment of cancer cachexia: A systematic review

Background: Cancer cachexia is a devastating syndrome of advanced malignancy which negatively impacts on patients’ morbidity, mortality and quality of life. Chronic inflammation is a key characteristic of cancer cachexia. Therefore, non-steroidal anti-inflammatory drugs (NSAIDs) may be able to break the cycle of cachexia. Aim: To systematically review the literature on the use of NSAIDs for the treatment of cachexia in advanced cancer patients. Design: All titles retrieved through searching were downloaded to a reference management database, duplicates were removed and the remaining citations were checked for eligibility. Full copies of all eligible articles were obtained and reviewed. Data sources: Electronic searches (from inception up to 09/2011) included CINAHL, MEDLINE, EMBASE, and Web of Science. Reference lists from reviewed articles, trial registers and abstracts from relevant conferences were searched. Eligibility criteria were (a) Randomised Controlled Trial; (b) participants were adults with cancer with weight loss or a clinical diagnosis of cachexia; (c) administration of oral NSAIDs. Results: Four studies were included. These studies provided some evidence of positive therapeutic effect on quality of life, performance status, inflammatory markers, weight gain and survival, but there was insufficient evidence demonstrated for their widespread use in practice. Conclusions: Insufficient studies have been performed to allow a conclusion to be formed with regard to the effectiveness of NSAIDs in the treatment of cachexia in advanced cancer. Major challenges in this patient cohort include the lack of uniformity of inclusion criteria across studies and the frailty of the patients recruited.