A Double-Blind, Randomized Controlled Trial of Pre-incision Wound Infiltration Using Diclofenac Versus Bupivacaine for Post-operative Pain Relief in Open Thyroid and Parathyroid Surgery.

BACKGROUND: Pre-incision wound infiltration using NSAID is an alternative method to manage post-operative pain in surgery. It is postulated that NSAID delivered peripherally exerts efficient analgesic and anti-inflammatory effect with minimal systemic complication. This study explored the efficacy of using diclofenac for wound infiltration in open thyroidectomy and parathyroidectomy as compared to conventional agent, bupivacaine. METHODOLOGY: The study was designed as a double-blind, randomized controlled trial involving 94 patients who underwent open thyroidectomy or parathyroidectomy in Hospital Pulau Pinang, Malaysia, from November 2015 to November 2016. The study compared the efficacy of pre-incision wound infiltration of diclofenac (n = 47) versus bupivacaine (n = 47) in post-operative pain relief. Wound infiltration is given prior to skin incision. Mean pain score at designated time interval within the 24-h post-operative period, time to first analgesia, total analgesic usage and total analgesic cost were assessed. RESULTS: Ninety-four patients were recruited with no dropouts. Mean age was 49.3 (SD = 14.2) with majority being female (74.5%). Ethnic distribution recorded 42.6% Chinese, 38.3% Malay, followed by 19.1% Indian. Mean duration of surgery was 123.8 min (SD = 56.5), and mean length of hospital stay was 4.7 days (SD = 1.8). The characteristics of patient in both groups were generally comparable except that there were more cases of total thyroidectomy in the diclofenac group (n = 31) as compared to the bupivacaine group (n = 16). Mean pain score peaked at immediate post-operative period (post-operative 0.5 h) with a score of 3.5 out of 10 and the level decreased steadily over the next 20 h starting from 4 h post-operatively. Pre-incision wound infiltration using diclofenac had better pain control as compared to bupivacaine at all time interval assessed. In the resting state, the mean post-operative pain score difference was statistically significant at 2 h [2.1 (SD = 1.5) vs. 2.8 (SD = 1.8), p = 0.04]. During neck movement, the dynamic pain score difference was statistically significant at post-operative 1 h [2.7 (SD = 1.9) vs. 3.7 (SD = 2.1), p = 0.02]; 2 h [2.7 (SD = 1.6) vs. 3.7 (SD = 2.0), p = 0.01]; 4 h [2.2 (SD = 1.5) vs. 2.9 (SD = 1.7), p = 0.04], 6 h [1.9 (SD = 1.4) vs. 2.5 (SD = 1.6), p = 0.04] and 12 h [1.5 (SD = 1.5) vs. 2.2 (SD = 1.4), p = 0.03]. Mean dose of tramadol used as rescue analgesia in 24 h duration was lower in the diclofenac group as compared to bupivacaine group [13.8 mg (SD = 24.9) vs. 36.2 mg (SD = 45.1), p = 0.01]. The total cost of analgesia used was significantly cheaper in diclofenac group as compared to bupivacaine group [RM 3.47 (SD = 1.51) vs. RM 13.43 (SD = 1.68), p < 0.01] or [USD 0.83 (SD = 0.36) vs. USD 3.21 (SD = 0.40), p < 0.01]. CONCLUSION: Pre-incision wound infiltration using diclofenac provides better post-operative pain relief compared to bupivacaine for patient who had underwent open thyroidectomy or parathyroidectomy. Diclofenac is cheap and easily available in the limited resource setting. This approach offers a superior alternative for post-operative pain relief as compared to bupivacaine.

Evaluation of the treatment costs and duration of topical treatments for multiple actinic keratosis based on the area of the cancerization field and not on the number of lesions.

BACKGROUND: The cost of topical treatments for actinic keratosis (AK) has historically been evaluated in relation to the number of lesions requiring treatment or simply by the price of a single tube/sachet of the drug used. OBJECTIVE: To demonstrate a new method of costing topical treatments in AK, which takes into account the actual cancerization area treated. METHODS: In order to evaluate the actual cost of each treatment, the official approval status of the drug was used to estimate the amount of cream needed per one cm2 . This value was then applied to the hypothetical cancerization area sizes to demonstrate the impact of the size treated on the actual cost of treatment. The price considered was the ex-factory price in Italy. RESULTS: Areas which could be treated with a single tube/sachet of Metvix® , Picato® , Aldara® , Solaraze® and Zyclara® were 200, 25, 25, 33.3 and 200 cm2 , respectively. For the treatment of smaller areas (<100 cm2 ), treatment with Metvix® was the most costly topical option in Italy. However, for the treatment of cancerization areas larger than 100 cm2 , Metvix® was the least expensive treatment option. Treatment with Metvix® was least long, requiring a single day of treatment for an area of up to 200 cm2 , compared with up to 224 days of treatment with Aldara® for the treatment of a similar size. CONCLUSION: Changing treatment costing strategy in the management of multiple AKs towards costing per cancerization area instead of costing per lesion is a much more accurate representation of the 'real world cost' for AK.

Cost-efficacy analysis of 3% diclofenac sodium, ingenol mebutate, and 3.75% imiquimod in the treatment of actinic keratosis.

Actinic keratosis (AK) is a clinical condition characterized by keratinocytic dysplastic lesions of the epidermis, affecting individuals chronically exposed to sunlight. Topical therapies allow the treatment of a whole area of affected skin and currently include diclofenac sodium gel, 5-fluorouracil cream, 5-fluorouracil and acetylsalicylic acid solution, imiquimod cream, and ingenol mebutate gel. Due to the comparable efficacy of 3% diclofenac, ingenol mebutate, and 3.75% imiquimod in treating AK multiple lesions, a pharmacoeconomic evaluation of cost-effectiveness of the three treatments was needed. A cost-efficacy analysis comparing 3% diclofenac sodium with ingenol mebutate and 3.75% imiquimod was performed. In this analysis, efficacy data were combined with quality-of-life measurement derived from previous studies as well as the costs associated with the management of these lesions in Italy. Patients' demographics and clinical characteristics were assumed to reflect those from the clinical studies considered.

Cost-effectiveness of Ingenol Mebutate Gel for the Treatment of Actinic Keratosis in Greece.

PURPOSE: The present study aimed to perform a cost-effectiveness analysis of ingenol mebutate (IM) versus other topical alternatives for the treatment of actinic keratosis (AK). METHODS: The analysis used a decision tree to calculate the clinical effects and costs of AK first-line treatments, IM (2-3 days), diclofenac 3% (for 8 or 12 weeks), imiquimod 5% (for 4 or 8 weeks), during a 24-month horizon, using discrete intervals of 6 months. A hypothetical cohort of immunocompetent adult patients with clinically confirmed AK on the face and scalp or trunk and extremities was considered. Clinical data on the relative efficacy were obtained from a network meta-analysis. Inputs concerning resource use derived from an expert panel. All costs were calculated from a Greek third-party payer perspective. FINDINGS: IM 0.015% and 0.05% were both cost-effective compared with diclofenac and below a willingness-to-pay threshold of €30,000 per quality-adjusted life-year (QALY) (€199 and €167 per QALY, respectively). Comparing IM on the face and scalp AK lesions for 3 days versus imiquimod for 4 weeks resulted in an incremental cost-effectiveness ratio of €10,868 per QALY. IM was dominant during the 8-week imiquimod period. IM use on the trunk and extremities compared with diclofenac (8 or 12 weeks) led to incremental cost-effectiveness ratios estimated at €1584 and €1316 per QALY accordingly. Results remained robust to deterministic and probabilistic sensitivity analyses. IMPLICATIONS: From a social insurance perspective in Greece, IM 0.015% and IM 0.05% could be the most cost-effective first-line topical field treatment options in all cases for AK treatment.

Cost-Effectiveness and Cost-Utility Analysis of Ingenol Mebutate Versus Diclofenac 3% and Imiquimod 5% in the Treatment of Actinic Keratosis in Spain. / Análisis de coste-efectividad y coste-utilidad de ingenol mebutato versus diclofenaco 3% e imiquimod 5% en el tratamiento de la queratosis actínica en España.

OBJECTIVE: To perform a cost-effectiveness and cost-utility analysis of ingenol mebutate in the treatment of actinic keratosis in Spain. METHODS: We used an adapted Markov model to simulate outcomes in a cohort of patients (mean age, 73 years) with actinic keratosis over a 5-year period. The comparators were diclofenac 3% and imiquimod 5%. The analysis was performed from the perspective of the Spanish National Health System based on direct costs (2015 retail price plus value added tax less the mandatory discount). A panel of experts estimated resources, taking unit costs from national databases. An annual discount rate of 3% was applied. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: The effectiveness of ingenol mebutate-with 0.192 and 0.129 more clearances gained in treatments for face and scalp lesions and trunk and extremity lesions, respectively-was superior to diclofenac's. The total costs of treatment with ingenol mebutate were lower at € 551.50 (face and scalp) and € 622.27 (trunk and extremities) than the respective costs with diclofenac (€ 849.11 and € 844.93). The incremental cost-effectiveness and cost-utility ratios showed that ingenol mebutate was a dominant strategy vs diclofenac. Ingenol mebutate also proved to be more effective than imiquimod, based on 0.535 and 0.503 additional clearances, and total costs of € 551.50 and € 527.89 for the two drugs, respectively. The resulting incremental cost-effectiveness ratio was € 728.64 per clearance gained with ingenol mebutate vs imiquimod. CONCLUSIONS: Ingenol mebutate was a dominant treatment option vs diclofenac and was efficient vs imiquimod (i.e., more effective at a higher cost, achieving an incremental cost-utility ratio of<€30000/quality-adjusted life-years).

A cost-utility analysis of ingenol mebutate gel for the treatment of actinic keratosis: a Scottish perspective.

BACKGROUND: Actinic keratosis (AK) is a UV-induced, pre-malignant skin condition that is common in adults over 60 years of age with fair skin in Scotland. The most commonly prescribed first-line treatment for AK in Scotland is currently diclofenac gel (3 %). Ingenol mebutate gel is a recently developed topical therapy available in two strengths for the treatment of AK lesions on the face and scalp (150 mcg/g once daily for 3 consecutive days) or trunk and extremities (500 mcg/g once daily for 2 consecutive days). OBJECTIVE: To compare the cost-effectiveness of two strengths of ingenol mebutate gel developed to treat AK lesions on the face and scalp (150 mcg/g once daily for 3 consecutive days) or trunk and extremities (500 mcg/g once daily for 2 consecutive days) with other first-line AK therapies including diclofenac gel, 5-FU, 5-FU/salicylic acid, and cryotherapy for the first-line treatment of AK in adult patients, from the perspective of the National Health Service (NHS) in Scotland. METHODS: A cost-utility analysis was conducted using a decision-tree approach to calculate the costs and benefits of different treatment strategies for AK on the face and scalp or trunk and limbs over a 12-month time horizon. Data on the relative efficacy of treatments were obtained from a systematic literature review and meta-analysis. Utility scores and resource-use data were obtained from published sources. RESULTS: Over 12 months, ingenol mebutate 150 mcg/g gel and 500 mcg/g gel were cost-effective compared with the most commonly used topical therapy in Scotland, diclofenac (3 %) gel, at a willingness-to-pay threshold of £20,000 per QALY, with a minimal additional cost of £43 and £105, respectively per QALY gained. CONCLUSIONS: Ingenol mebutate gel is a cost-effective therapy for the first-line treatment of AK from a Scottish NHS perspective.

A randomized clinical trial of photodynamic therapy with methyl aminolaevulinate vs. diclofenac 3% plus hyaluronic acid gel for the treatment of multiple actinic keratoses of the face and scalp.

BACKGROUND: A gel containing diclofenac and hyaluronic acid (DHA) and photodynamic therapy with methyl aminolaevulinate (MAL-PDT) are widely used treatments for actinic keratoses (AKs). OBJECTIVES: The aim of this single-centre, open-label, prospective, nonsponsored, randomized controlled clinical trial was to compare the treatment results and cost-effectiveness of MAL-PDT and DHA. METHODS: Patients with multiple AKs of the face and scalp were randomized to receive MAL-PDT or DHA. After 90 days, the overall complete remission (CR) rate of patients and the CR rate of lesions according to thickness score were assessed, and patients and an investigator scored the cosmetic outcome. In addition, patients scored their overall satisfaction with the treatment. Patients with CR of all lesions were followed up for 12 months. RESULTS: Two hundred patients with a total of 1674 AKs were enrolled. The lesion CR rates at 3 months were 85·9% with MAL-PDT and 51·8% with DHA (P < 0·0001). AKs of all thicknesses were significantly more responsive to MAL-PDT. The patient CR rates at 3 months were 68% with MAL-PDT and 27% with DHA. At the 12-month examination, the number of patients with CR reduced to 37 with MAL-PDT and seven with DHA. Rating of cosmetic outcome was very good or excellent in the vast majority of patients with both treatments. The analysis of cost-effectiveness showed that the costs per patient with CR at 3 months and at 12 months are €566·7 and €1026·2, respectively, with MAL-PDT and €595·2 and €2295·6, respectively, with DHA. CONCLUSIONS: Efficacy, cosmetic outcome and patients' overall satisfaction with MAL-PDT are superior in comparison with DHA. MAL-PDT is more expensive but it is more cost-effective.

Cost-effectiveness analysis of topical treatments for actinic keratosis in the perspective of the Italian health care system.

Actinic keratosis (AK) is the most common cutaneous malignant neoplasm and its prevalence continues to increase. According to the most recent findings, AK is currently considered the initial stage, in situ, of squamous cell carcinoma. Field-directed therapies for AKs are the preferred treatment since they have the advantage to clear the clinically visible lesions and also subclinical lesions within the cancerous field. We assessed the cost-effectiveness of topical treatments for AKs including 3% diclofenac in 2.5% hyaluronic acid (HA) gel, imiquimod 5% cream and photodynamic therapy with methyl aminolevulinate (MAL-PDT) in the perspective of the Italian Health Care System (SSN). We used a decision tree analytical approach and efficacy data were drawn from published clinical trials. Cost was evaluated from the SSN perspective during a time horizon of 3 months. A responder was defined as a patient with all lesions clinically cleared and showing an excellent cosmetic result. Based on the applied model, the cost per complete responder was calculated. Diclofenac 3% in HA was less expensive (Euro 256) than MAL-PDT (Euro 320) and imiquimod (Euro 342). Effectiveness was similar and better for diclofenac 3% in HA and MAL-PDT (0.813%) in comparison to 0.734% of imiquimod, respectively. The one-way and probabilistic sensitivity analyses confirmed the results of base case scenario. Based on this cost-effectiveness model, diclofenac 3% in HA can be considered the treatment of choice for AK lesions and surrounding field under a pharmacoeconomic point of view.

[Postoperative multimodal pain management : Cost-minimisation analysis from a hospital's point of view]. / Multimodale postoperative Schmerztherapie : Kostenminimierungsanalyse aus Krankenhausperspektive.

BACKGROUND: Adequate pain management after major surgery is important to improve patients' quality of life and to support the healing process. Since the cost for pain management is included in the DRG system for hospital reimbursement, hospitals should aim to provide adequate postoperative pain management at the lowest possible cost. In this study we compare two multimodal pain management schemes for postoperative pain management in a cost-minimisation analysis. METHODS: In a decision analytic model two treatment regimes for postoperative pain management are compared in a cost-minimisation analysis: diclofenac + morphine vs paracetamol vs morphine. The study is performed from the perspective of a public hospital. Due to the short time horizon costs are not discounted. RESULTS: Assuming comparable effectiveness for adequate postoperative pain management, the expected value in the decision tree model for the combination diclofenac + morphine is 13.37 EUR and for the combination paracetamol + morphine 32.23 EUR, respectively. The results are robust under various one- and two-way sensitivity analyses. CONCLUSION: With no contraindications given the combination diclofenac + morphine is more cost-effective for postoperative pain management after major surgery compared to paracetamol + morphine.

[Pharmaco-economic efficiency of the treatment of patients with acute vertebrogenic lumbar pain syndrome].

The aim of the study was to evaluate pharmaco-economic efficiency of two therapeutic schemes for the treatment of acute vertebrogenic lumbar pain syndrome. One hundred patients (including 77 women) with this syndrome caused by vertebral osteochondrosis (VO) were examined. Mean age of the patients was 41.00 +/- 8.33, mean duration of exacerbation 6.92 +/- 4.55 days. The majority of the patients had roentgenologic stage II VO. Patients of one group (n=50) were given intramuscular injections of ketorol (1 ml twice daily for 5 days) and diclofenac-retard (100 mg per os twice daily for 10 days). The second group (n=50) received ketorol and nise (100 mg twice daily for 10 days). This treatment was followed by 10 seances of phonophoresis using 1% hydrocortisone ointment. The clinical efficiency of therapy was evaluated based on the visual analog scale and in terms of Lasagne symptom, muscular syndrome index, Schober test, Thomayer's symptom, vertebrogenic syndrome coefficient. Pharmaco-economic analysis included calculation of direct medical care expenses and cost index/efficiency. The efficiency of therapy in group 2 (restoration of lumbar vertebral column mobility and alleviation of pain) was higher than in group 1 while the number of adverse effects was lower and the periods of remission longer. Combined therapy with ketorol and nise per unit efficiency was more expensive but the total cost of the management of one case including all yearly relapses suggested its advantages over the alternative treatment with ketorol and diclofenacin terms of clinical and pharmaco-economic efficiency.

Pharmacoeconomic analysis of the treatment of multiple actinic keratoses.

Actinic keratosis (AK) is common and lesions may progress to squamous cell carcinoma. The choice of therapy depends mainly on 2 factors: the efficacy of therapeutic options and the number of lesions present. Cryotherapy alone is suitable for treating a few lesions, whereas topical medications, photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA), or either in combination with cryotherapy are appropriate for treating multiple (>15) lesions. When combinations are necessary, the total cost to treat multiple AKs to 100% clearance becomes important. This report provides a simple pharmacoeconomic analysis of 4 FDA-cleared therapies (imiquimod, diclofenac, 5-fluorouacil [5-FU], and ALA PDT) for AK given in combination with cryotherapy. This analysis assumes standard costs of procedures and office visits (based on April 2007 reimbursement data) and 2 treatment courses (medications: imiquimod, diclofenac, 5-FU) or sessions (ALA PDT) of each modality followed by cryotherapy to 100% clearance. The total cost of each combination is $725.17 for ALA PDT, $845.07 for diclofenac, $942.13 for 5-FU, and $1,473.39 for imiquimod. When phase III trial efficacies of the 4 modalities are considered, the actual cost of using imiquimod or diclofenac increases because additional treatments may be required. Among these 4 FDA-cleared therapies for multiple AK lesions, ALA PDT is the least expensive treatment and imiquimod is the most expensive treatment under the stated assumptions.

Prospective randomized trial of pre-emptive analgesics following ambulatory inguinal hernia repair: intravenous ketorolac versus diclofenac suppository.

BACKGROUND: A pre-emptive non-steroidal anti-inflammatory drug is routinely given to patients undergoing ambulatory inguinal hernia repair. The present prospective randomized trial was undertaken to compare the efficacy of intravenous ketorolac and rectal diclofenac for ambulatory inguinal hernia repairs. METHODS: Between June 1999 and February 2001, a total of 108 patients who underwent ambulatory inguinal hernia repairs under general anaesthesia were recruited. Patients were randomized to receive either intravenous ketorolac 30 mg immediately prior to induction of general anaesthesia (n = 54) or rectal diclofenac 50 mg after signing consent at the Day Surgery Centre (n = 54). RESULTS: The demographic features, hernia types, anaesthetic time, dosage of anaesthetic medication and operative details of the two groups were comparable. There was no significant difference in total amount of analgesic consumption and linear analogue pain scores after operation. With regard to recovery variables, the respective times taken to regain ambulation and micturition were similar in both groups. CONCLUSION: Diclofenac suppository 50 mg and intravenous ketorolac 30 mg provided equivalent postoperative analgesia following ambulatory inguinal hernia repair under general anaesthesia. Diclofenac suppository is an economical alternative to intravenous ketorolac. In the interests of cost containment rectal diclofenac could be considered the non-steroidal anti-inflammatory drug of choice for pre-emptive analgesia.

The economic consequences of NSAID-induced gastropathy: the French context.

The costs of treating gastroduodenal ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs) are shown to increase the total cost of NSAID treatment to the Assurance-Maladie, the French national health insurance system. This increased cost is termed the iatrogenic cost factor, and is defined as the ratio of the shadow price of an NSAID to its reimbursed cost. The shadow price is calculated from estimates of the incidence of NSAID-induced gastropathies, the cost of the drug, and the hospital and ambulatory costs of treating the gastropathies. The resulting iatrogenic cost factors are estimated as 1.36 for naproxen, 1.48 for sulindac, 1.65 for diclofenac, 1.67 for piroxicam, 2.00 for ketoprofen, and 2.12 for etodolac.

The economic consequences of NSAID-induced gastropathy in the United Kingdom and commentary on the article by G. de Pouvourville.

The iatrogenic cost factor of treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) is defined as the increase in cost resulting from NSAID-induced gastroduodenal ulcers. The iatrogenic cost factor of NSAIDs for the National Health Service (NHS) in the United Kingdom was calculated using the model of de Pouvourville (1992). The cost factor is defined as the ratio of the shadow price of the NSAID to the NHS price. The shadow price is calculated from the incidence of NSAID-induced gastroduodenal ulcers and the costs of treating them and the price of the drugs. The NHS iatrogenic cost factors of 10 NSAIDs were similar to those calculated by de Pouvourville for the French national health insurance system, Assurance-Maladie, and ranged from 1.08 for diclofenac/misoprostol to 2.38 for ibuprofen.