Diclofenac, the active substance of Diclofenac sodium 4% Spray Gel (DicloFlex®), is well known with respect to its overall clinical properties. Numerous products in various pharmaceutical forms and strengths, including topical preparations containing Diclofenac, have already been authorized and marketed world-wide.
Diclofenac has successfully been used for many years for the relief of pain and inflammation in various conditions such as musculoskeletal disorders like sprain, strain, contusion caused by blunt traumatisation of the joints and/or muscles, mostly by accident or in sports, soft-tissue rheumatic disorders with symptoms of tendinitis and bursitis, such as periarthropathia humeroscapularis (PHS syndrome) or tennis elbow, acute conditions in degenerative joint diseases (osteoarthritis) and rheumatoid arthritis (AHFS 2002, Dollery (Ed) 1991; Martindale 2002).
Evidence for efficacy of topically administered diclofenac formulations in the indication "relief of pain and inflammation following acute and chronic blunt trauma of small and medium sized joints and periarticular structures" is provided by numerous published studies (Mucha et al. 1987, ;Buchier-Hayes et al. 1990, Moore et al. 1998, Fioravanti et al. 1999, Galer et al. 2000; Mahler et al. 2002; Predel et al. 2004). In the meantime there are several metaanalysis regarding topical diclofenac formulations and other topical NSAID'S conducted clinical trials available. The 2 most important ones are discussed in the following (2, 8).
Objective
In order to review the effectiveness and safety of topical NSAID'S - which are still regarded by some people as ineffective despite the numerous clinical trials which proofed efficacy as well as safety of the topical NSAID'S and despite the worldwide licensed status of topical NSAID'S. Such people believe that NSAID's cannot permeate through the skin barrier. Moore et al were one of the first scientists who conducted a metaanalysis of all valuable randomised trials in order to check if permeability of topical NSAID'S through the skin barrier in humans is possible and to evaluate the effectiveness and safety of topical administered NSAID'S as well (2).
Methodology
Data of 86 randomized trials involving 10.160 patients were evaluated. 75% of the reports showed quality scores of 3 or more on a scale of 1 to 5.
Results
Moore et al could demonstrate that topical administered NSAID'S have a significant efficacy and superiority over placebo in the treatment of acute pain conditions (soft tissue trauma, strains, and sprains) as well as in chronic pain conditions (osteoarthritis, tendonitis). Furthermore in acute as well as in chronic pain local and systemic side effects of topical administered NSAID's have had a low incidence and were not even different from placebo (2).
Conclusion
In this metaanalysis Moore et al could demonstrate that there are already numerous randomized clinical trials of excellent quality available in which sufficiently could be proven, that topical administered NSAID'S in placebo-controlled trials are effective against acute and chronic pain. Furthermore since topical administered NSAID'S can only be effective if they are able to permeate the skin the conclusion of Moore's metaanalysis can only be , that topical administered NSAID'S can indeed permeate the skin.
Mason published several metaanalysis with NSAID's recently (8, 11). They could proof - like Moore (2) did before - that local adverse events, systemic adverse events as well as the numbers withdrawing due to an adverse event were the same for topical NSAID and placebo.
Moreover in one of these metaanalysis with 1500 patients suffering from chronic musculoskeletal pain from 14 trials Mason et al. demonstrated, that in 3 of the evaluated trials with 764 patients in which a topical NSAID was compared with an oral NSAID there was no difference in efficacy between the oral and the topical NSAID (8).
Also current evidence-based recommendations for the management of osteoarthritis support the use of topical NSAID's as a therapeutic option potentially with fewer gastrointestinal risks than with oral NSAID's.
TOPICAL NSAID'S offer the advantage of enhanced drug delivery to affected tissues with a reduced incidence of systemic drug reaction
Patients suffering from rheumatic disease are at increased risk for serious gastrointestinal complications since NSAIDs are widely prescribed for this population (30). Therefore there is urgent need to offer patients suffering from rheumatic disease an NSAID-formulation with the lowest risk for adverse drug reaction possible (30). Topically applied NSAIDs have a superior safety profile to oral formulations. Adverse drug reaction associated with topical NSAID application occur in approximately 10%-15% of patients and are primarily cutaneous in nature (rash and pruritus at site of application). GI adverse drug reactions are rare with topically applied NSAIDs, compared with a 15% incidence reported for oral NSAIDs (30).
Furthermore topical administration of NSAIDs like Diclofenac sodium 4% Spray Gel (DicloFlex®) offers the advantage of local, enhanced drug delivery to affected tissues with a reduced incidence of systemic adverse drug reaction, such as peptic ulcer disease and GI haemorrhage (30, 9, 10). NSAIDs administered topically permeate slowly and in small quantities into the systemic circulation; bioavailability and maximal plasma NSAID concentration after topical application are generally less than 5%-15% compared with equivalent oral administration (30). Systemic availability of Diclofenac sodium 4% Spray Gel (DicloFlex®) in plasma is 50-fold lower than after oral VOLTAREN® 50 mg tablets (10, 31).
Product formulations have a dramatic impact, not only on absorption rates but also on penetration depth. Furthermore compared with oral administration, topical application leads to relatively high NSAID concentrations in the skin. Concentrations achieved in the muscle tissue below the site of application are variable, but are at least equivalent to that obtained with oral administration (30). Following application of the same amount of the active substance Diclofenac, after 8 hours Diclofenac sodium 4% Spray Gel (DicloFlex®) permeated through the skin to a 20 times higher extend than VOLTAREN® EMULGEL whilst after 8 hours 78% of VOLTAREN® EMULGEL has still not left the stratum corneum (9).
Marked interindividual variability was noted in all studies with NSAIDs applied topically. Percutaneous absorption may be strongly influenced by individual skin properties. In general, interpretation of clinical studies measuring efficacy of topical NSAIDs in rheumatic disease states is difficult because of a remarkably high placebo response rate, use of rescue paracetamol, and significant variability in percutaneous absorption and response rates between patients (30).
Because of the marked interindividual variability of NSAIDs applied topically positive treatment outcomes after topical NSAIDs reported in patients with chronic rheumatic disease range from 30 to 95%, with considerable inter patient variability (29).On average, 1 out of 3 patients using topical NSAIDs will achieve a successful outcome who would not have done so had they used a placebo (29).
There are not only unpublished studies available (26, 28) in which has been proven, that NSAID's like Diclofenac administered topically are effective in rheumatic disorders but there is also clinical evidence, that NSAIDs applied topically are as effective as oral NSAIDs in the treatment of chronic rheumatic diseases (28). Mason et al. demonstrated in one of their metaanalysis with 1500 patients suffering from chronic musculoskeletal pain from 14 trials, that in 3 of the evaluated trials with 764 patients in which a topical NSAID was compared with an oral NSAID there was no difference in efficacy between the oral and the topical NSAID (8). Bouchier-Hayes et al. 1990, Burnham et al. 1998, and Bolton et al. 1989 came to the same results (Bouchier-Hayes et al. 1990, Burnham et al. 1998 and Bolton et al. 1989). Consequently in Germany as well as in other countries a topical diclofenac formulation for cutaneous administration (VOLTAREN® EMULGEL®) has been approved for the treatment of rheumatic disorders for decades.
The topical application of Diclofenac sodium 4% Spray Gel (DicloFlex®) was demonstrated to be superior to the per oral administration of diclofenac in terms of higher levels in the peripheral target tissues and reduced systemic load at the same time (9, 10). Therefore it can be assumed that Diclofenac sodium 4% Spray Gel (DicloFlex®) is in rheumatic disorders as effective as in the treatment of patients suffering from musculoskeletal disorders such as sprain, strain and contusion caused by blunt traumatisation of the joints.
Diclofenac sodium 4% Spray Gel (DicloFlex®) therefore meets the full potential of a medicinal product for treatment of acute musculoskeletal disorders.