PURPOSE:

NSAIDs are commonly prescribed for the treatment of pain and inflammation. Despite the effectiveness of NSAIDs, concerns exist regarding their tolerability. Worldwide health authorities, including the European Medicines Agency, Health Canada, and the US Food and Drug Administration, have advised that NSAIDs be prescribed at the lowest effective dosage and for the shortest duration. Effective lowering of NSAID dosage without compromising pain relief has been demonstrated in randomized, controlled trials of the recently approved NSAID lower-dose submicron diclofenac. Building on previously published work from an independently published systematic review and meta-analysis, a linear dose-toxicity relationship between diclofenac dose and serious gastrointestinal (GI) events was recently demonstrated, indicating that reductions in adverse events (AEs) may be seen even with modest dose reductions in many patients. The objective of the present study was to estimate the potential reduction in risk for NSAID dose-related AEs, corresponding savings in health care costs, and the incremental cost-effectiveness of submicron diclofenac compared with generic diclofenac in the United States.

METHODS:

Our decision-analytic cost-effectiveness model considered a subset of potential AEs that may be avoided by lowering NSAID dosage. To estimate the expected reductions in upper GI bleeding/perforation and major cardiovascular events with submicron diclofenac, our model used prediction equations estimated by meta-regressions using data from systematic literature reviews. Utilities, lifetime costs, and health outcomes associated with AEs were estimated using data from the literature. The face validity of the model structure and inputs was confirmed by clinical experts in the United States. Results were evaluated in 1-way and probabilistic sensitivity analyses.

FINDINGS:

The model predicted that submicron diclofenac versus generic diclofenac could reduce the occurrence of modeled GI events (by 18.0%), cardiovascular events (by 6.9%), and acute renal failure (by 18.8%), leading to a 9.8% reduction in costs of treating AEs. Submicron diclofenac was predicted to be cost-saving, with results relatively insensitive to parameter uncertainty.

IMPLICATIONS:

Submicron diclofenac has the potential to provide clinical and economic value to patients using NSAIDs in the United States. Further investigation regarding the potential effects of submicron diclofenac on the risks for additional NSAID dose-related toxicities should be explored.

A phamacokinetic study in man has been made of a new dosage form of diclofenac hydroxyethylpyrrolidine (DIEP); soluble salt packed in sachets was compared with diclofenac sodium as enteric coated tablets. Oral DIEP 2 X 50 mg showed a significant difference in absorption kinetics (ka, lag time and tmax) as compared to oral diclofenac sodium 2 X 50 mg. A relevant plasma concentration of diclofenac was detected just 15 min after DIEP, while diclofenac sodium produced a measurable plasma concentration only 0.5-1 h after the treatment. Cmax and t1/2 after DIEP and diclofenac sodium were comparable. Comparison of the two AUC values showed that DIEP was bioequivalent to diclofenac sodium (Q = 100%).

BACKGROUND:

This review is an update of a previously published review in Issue 2, 2012 (Derry 2012a). Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter (OTC) analgesics. Diclofenac is an established analgesic, and new formulations using the potassium or epolamine salts, which can be dissolved in water, have been developed for rapid absorption, which may be beneficial in acute migraine. Co-therapy with an antiemetic should help to reduce the nausea and vomiting commonly associated with migraine.

OBJECTIVES:

To determine the efficacy and tolerability of diclofenac, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches in adults.

SEARCH METHODS:

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Relief Database, ClinicalTrials.gov, and reference lists for studies through 27 September 2011 for the original review and 15 February 2013 for the update.

SELECTION CRITERIA:

We included randomised, double-blind, placebo-controlled or active-controlled studies, or both, using self administered diclofenac to treat a migraine headache episode, with at least 10 participants per treatment arm.

DATA COLLECTION AND ANALYSIS:

Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate relative risk (or 'risk ratio') and numbers needed to treat to benefit (NNT) or harm (NNH) compared to placebo or a different active treatment.

MAIN RESULTS:

Five studies (1356 participants, 2711 attacks) compared oral diclofenac with placebo, and one also compared it with sumatriptan; none combined diclofenac with a self administered antiemetic. Four studies treated attacks with single doses of medication, and two allowed an optional second dose for inadequate response. Only two studies, with three active treatment arms, provided data for pooled analysis of primary outcomes. For single doses of diclofenac potassium 50 mg versus placebo (two studies), the NNTs were 6.2, 8.9, and 9.5 for pain-free at two hours, headache relief at two hours, and pain-free responses at 24 hours, respectively.Similar numbers of participants experienced adverse events, which were mostly mild and transient, with diclofenac and placebo. There were insufficient data to evaluate other doses of oral diclofenac, or to compare different formulations or different dosing regimens; only one study compared oral diclofenac with an active comparator (oral sumatriptan 100 mg).

AUTHORS' CONCLUSIONS:

Oral diclofenac potassium 50 mg is an effective treatment for acute migraine, providing relief from pain and associated symptoms, although only a minority of patients experience pain-free responses. Adverse events are mostly mild and transient and occur at the same rate as with placebo.

The authors noticed a marked increase in the incidence of reactionary post-operative haemorrhage after tonsillectomy during the course of 1992. This increase appeared to be related to the introduction of diclofenac as a post-operative analgesic. A retrospective review of casenotes of patients having tonsillectomy under the care of the senior author (P. M. R.) in 1992 revealed that four of the 73 patients (5.5%) receiving diclofenac at induction of anaesthesia suffered reactionary haemorrhage requiring operative control, as compared with two of 293 (0.7%) receiving other analgesics.

RECORD STATUS:

None

CITATION:

Canadian Coordinating Office for Health Technology Assessment. Topical diclofenac sodium. Canadian Coordinating Office for Health Technology Assessment (CCOHTA). 2001

Diclofenac sodium is one of the most prescribed NSAIDs in the world which is frequently used in therapy of musculosceletal diseases. Therefore it is important to justify clinical and literary data about diclofenac hepatotoxicity. We searched for diclofenac versus placebo investigations performed in patients with osteoarthrosis. A method of the search included international databases such as EMBASE, Cochrane Database, databases of medical publishers and search engines. Total amount of patients in all trials was 1121. 583 patients took diclofenac and 538 ones took placebo. Meta-analysis was performed in StatsDirect software. We estimated 95% confidence interval, Q and 12 criteria, Mantel-Haenszel and DerSimonian-Laird statistics and relative risk of adverse reactions. Relative risk of hepatitis in diclofenac group did not differ from placebo. Hereby the fact of diclofenac hepatotoxicity needs more detailed study and genetic factors of risk should be taken into account.

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The efficacy and gastroprotective effects of tizanidine plus diclofenac were compared with placebo plus diclofenac in patients with acute local pain syndromes such as low-back pain. This multicenter, double-masked, placebo-controlled, parallel-group study included patients in the Asia-Pacific region who experienced local pain syndromes of recent onset and clinically discernible muscle spasms. Patients received either tizanidine 2 mg twice daily (BID) with diclofenac 50 mg BID or placebo BID with diclofenac 50 mg BID for 7 days. Efficacy variables (pain at rest, at night, on palpation, and during movement; hardness of muscles on palpation; restriction of body movement and disability due to pain; sleep quality; duration of daytime bed rest) and tolerability (includiug a questionnaire for gastrointestinal adverse effects) were assessed at baseline, and on days 4 and 8. Overall efficacy and tolerability were assessed and a test; for occult blood in the stool was performed on day 8. A total of 405 patients were entered into the study in 12 centers in 6 countries; 361 were assessable. Results revealed that the combination of tizanidine with diclofenac was significantly more effective than diclofenac with placebo for most variables. Overall tolerability was better in patients who received tizanidine with diclofenac, although the difference between groups did not reach statistical significance. However, the frequency of gastrointestinal adverse effects was significantly less in patients who received tizanidine plus diclofenac (12%) compared with patients who received placebo plus diclofenac (32%). The frequency of positive test results for occult blood in the stool was 5% in the former group and 11% in the latter group. The combination of tizanidine with diclofenac was more effective and better tolerated than diclofenac alone in patients with local pain syndromes. This study confirms and extends the results of previous studies suggesting increased efficacy and gastroprotective effects of tizanidine when combined with nonsteroidal anti-inflammatory drugs.

A prospective double-blind randomized trial was conducted on 184 cancer patients with moderate to severe chronic pain to evaluate the analgesic efficacy and tolerability of diclofenac alone (50 mg q.i.d.) or in combination with a weak opioid (codeine 40 mg q.i.d.), or with an anti-depressant (imipramine, 10 or 25 mg t.i.d.). All demographic and clinical characteristics including cancer type, presence of bone metastases, baseline pain severity, neuropathic and nociceptive pain, and depressive state, were well balanced between the three treatment groups. The main analysis of the study was on the VAS scores at visit 2 (day 4). The mean VAS values for both associations imipramine plus diclofenac and codeine plus diclofenac were similar to the association placebo plus diclofenac. Patients on imipramine plus diclofenac and on placebo plus diclofenac were withdrawn mainly for inadequate efficacy, while patients on codeine plus diclofenac discontinued equally for inadequate efficacy or adverse events. In conclusion, in a short-term evaluation the addition of a tricyclic anti-depressant or a weak opioid to diclofenac did not provide further analgesia with respect to diclofenac administration alone.

Pain syndromes of the lumbar spine are one of the main problems in orthopedic practice. The therapeutic effect of NSAIDs is not subject to doubt in this connection. But considering that the application of NSAIDs is frequently associated with side effects, a reduction of dosage would be to the patient's benefit. Clinical studies have shown that concomitant treatment with vitamins B1, B6, B12 and diclofenac leads to a more efficient pain relief than treatment using diclofenac alone and thus provides the possibility of saving NSAIDs. This clinical trial was carried out in order to determine whether these results can also be achieved when a reduced dosage of diclofenac (75 mg daily) is used. 123 patients with acute pain syndromes of the lumbar spine were treated with either B-vitamins and diclofenac or diclofenac alone for a maximum of 7 days. There was the option to terminate therapy in the trial after 3-4 days in the case of total pain relief. 45 patients could stop the treatment due to remission of symptoms. 30 patients belonged to the combination therapy group, the other 15 took diclofenac alone; this difference is statistically significant (p< 0.05). All parameters concerning pain relief and movement of the vertebral column showed statistically significant differences in favour of the B-vitamin-diclofenac-combination, too. The results document the positive influence of B-vitamins on painful vertebral syndromes and indicate that B-vitamins contribute to saving of NSAIDs by shortening the treatment time and reducing daily NSAID-dosage. © 1990 Springer-Verlag.