European Review for Medical and Pharmacological Sciences 2011; 15: 943-949 Ketoprofen 2.5% gel: a clinical overview S. COACCIOLI Rheumatology Unit, Santa Maria General Hospital, Terni (Italy) Abstract. – Ketoprofen (KP), a non- therefore, with fewer serious adverse events steroidal anti-inflammatory drug (NSAID), pos- (AEs)2. Current guidelines produced by the Euro- sesses analgesic, antipyretic and anti-inflamma- pean League Against Rheumatism (EULAR) and tory properties. Oral KP is widely used in mus- culoskeletal pain and inflammation in muscles the Osteoarthritis Research Society International and joints, including arthritis pain, osteoarthritis, (OARSI) suggest that topical NSAIDs are pre- stiffness of the joints, soft tissue rheumatism, ferred over oral NSAIDs for patients with mild to and sports injuries. In common with all NSAIDs, moderate knee or hand OA with few affected oral KP has been associated with systemic ad- joints, and/or a history of sensitivity to oral verse events and in particular gastrointestinal NSAIDs3,4. The favourable benefit/risk ratio of disorders. Topical application of the active ingre- dient is locally effective and at the same time topical NSAIDs has been further confirmed by a minimises the risk of systemic adverse events. recent Cochrane meta-analysis of 47 randomized Pharmacokinetic studies show that serum levels studies5. Because there are a number of topical of the active ingredient following topical KP formulations of NSAIDs currently available, 2.5% gel are less than 1% of those reported after there is a need to summarize the evidence sup- oral dosing, thereby providing good levels of porting the effectiveness and safety of each for- pain relief without the systemic adverse events mulation. In fact, the results of a recent systemat- normally associated with oral NSAIDs. In com- parative studies, topical KP 2.5% gel twice daily ic review highlighted that topical NSAIDs may showed clinical benefits in patients with a range vary significantly in their pharmacokinetic and of musculoskeletal conditions. KP 2.5% gel is pharmacodynamic properties, as well as in their generally well tolerated but the treated skin area efficacy/safety profile1. should not be exposed to direct sunlight, includ- Ketoprofen (KP), a widely used NSAID, is ef- ing solarium (sunbeds), during the treatment fective and well-tolerated in the treatment of and for 2 weeks afterwards as topical photosen- acute and chronic pain, of both rheumatic and sitization has been reported. To our knowledge, 6 this is the first overview on the use of topical KP traumatic origin, as well as postoperative pain . (tKP) 2.5% gel which includes data from both The clinical experience with this drug is exten- clinical trials and from ‘real-life’ clinical practice. sive6, and a number of different formulations are available - including capsules, suppositories, in- Key Words: jectable solutions, sustained release formulations, 7 Ketoprofen, Gel, NSAIDs, Pain, Topical treatment, and a topical gel . To our knowledge, this is the Musculoskeletal. first overview on the use of topical KP (tKP) 2.5% gel which includes data from both clinical trials and from “real-life” clinical practice. Methodology Introduction We first performed a systematic search using MEDLINE (last updated February 2011). The The use of topical non-steroidal anti-inflam- search terms included, but were not limited to, matory drugs (NSAIDs) in relieving pain in pa- ketoprofen AND gel; topical NSAIDs AND pain tients with acute and chronic musculoskeletal were used. Articles were chosen based on their disorders, including osteoarthritis (OA), ten- relevance, as judged by the Author and search re- donitis, and muscle strains is well established1. sults were supplemented with a search of Com- Topical formulations of NSAIDs have analgesic pany reports held in a proprietary database, by effects similar to that of oral formulations, but manually searching the reference list of identi- are associated with less systemic exposure and, fied articles. Corresponding Author: Stefano Coaccioli, MD; e-mail: [email protected] 943 S. Coaccioli Product Development and Indications in the urine following daily application of tKP KP is a NSAIDs which belongs to the group of was 2.6% of the initial dose applied and the ap- substituted 2-phenyl propionic acids [2-(3-ben- parent half-life of unchanged KP was 17.1 ± 9.1 zoylphenyl)-propionic acid]. It was first synthe- hours, and no accumulation was reported10. An- sized in 1967 at Rhone-Poulenc Research Labo- other study, conducted to determine the concen- ratories, Paris, and was approved for clinical use tration of KP in the synovial fluid following topi- as an oral formulation in France and the United cal application, showed that KP concentrations Kingdom in 1973. It is now available in more were comparable with those following intramus- than 100 countries worldwide. There is a wealth cular administration11. of clinical experience with tKP and it is estimat- In 2002, KP 2.5% gel was used as a standard ed that the therapeutic experience of KP exceeds reference to measure the percutaneous absorption 3 million patient/year8. In the 10 years from Jan- by human skin in two in vitro studies. The first uary 1998 to January 2008, more than 140 mil- study compared the percutaneous absorption (af- lions patients were treated with tKP gel. ter a 24-hour contact) of KP 2.5% gel alone or in The main indication for tKP 2.5% gel is the combination with sunscreen, through human skin local treatment of musculoskeletal pain and in- compared with other two gel formulations (Table flammation in muscles and joints (contusions, I)12. The second study was carried out using ver- distortions, strains, stiff neck, and lumbago). The tical Franz diffusion cells, and the extent of KP topical release of the active molecule is locally diffusion was determined using a validated effective, and because of the low systemic HPLC method13. Systemic absorption of tKP bioavailability is associated with fewer adverse 2.5% gel was relatively low, with the plasma lev- events (AEs) than with systemic formulations1. els about 100-fold lower, and the local tissue lev- Importantly, tKP should only be used on intact els 100-fold higher than those reported following skin (as single or repeated application) to avoid the oral administration. any irritant action on mucosa and scarred skin. In common with other NSAIDs, the pharma- codynamic activity of KP relies on the inhibition Pharmacokinetics and Pharmacodynamics of the metabolism of arachidonic acid. KP is one The pharmacokinetic profile of tKP after topi- of the most powerful inhibitors of cyclooxyge- cal application has been extensively studied in nase (COX)14 and the inhibition of prostaglandins vitro and in vivo. In one of the first studies, tKP synthesis gives it its anti-inflammatory, anal- was applied to the entire surface of the knee once gesic, and antipyretic effects1. In addition, KP is a day for three days in patients scheduled for sur- characterized by other pharmacological effects gical intervention. KP concentrations in the plas- that may be relevant to its anti-inflammatory and ma, synovial fluid and tissue were determined by analgesic activities. It is a powerful inhibitor of HPLC9 KP was detected in the plasma 2 hours bradykinin (an important chemical mediator of after the administration and its concentration re- pain and inflammation)15; it stabilises the lysoso- mained constant for 12 hours. Local tissue con- mal membranes against the osmotic damage16 centrations at the site of application were about and it prevents the release of lysosomal enzymes 100-fold higher than the plasma concentrations. that mediate the tissue destruction in the inflam- KP levels in the knee joint were considered to be matory reactions8. In an unpublished report, the a result of a direct transcutaneous diffusion, effect of tKP 2.5% gel on prostaglandin concen- rather than a plasma diffusion. In a 10-day study trations in the synovial fluid and on the platelet in 10 healthy volunteers, the total amount of KP output of tromboxane B2 (TXB2) was measured Table I. Percutaneous absorption of tKP 2.5% (expressed as µg) gel alone or in combination with sunscreeen, through human skin in comparison with ethylhexyl methoxycinnamate 3% and phenylbenzimidazole sulfonic acid 3% after a 24-hour contact12. Receptor fluid Epidermis Dermis Total Ethylhexyl methoxycinnamate 3% 17.16 ± 3.00 9.83 ± 1.85 1.31 ± 1.18 28.30 ± 3.34 KP 2.5% + sunscreen 6.19 ± 1.92 8.77 ± 1.43 0.66 ± 0.32 15.62 ± 3.27 KP 2.5% alone 10.13 ± 3.75 12.23 ± 3.30 0.86 ± 0.48 23.22 ± 5.07 Phenylbenzimidazole sulfonic acid 3% 12.56 ± 4.65 10.60 ± 3.51 1.00 ± 0.54 24.17 ± 9.29 944 Ketoprofen 2.5% gel: a clinical overview in patients with joint effusion17. Inhibition of According to these results, and the overall im- platelet COX activity was comparable to that ob- proved efficacy/safety ratio when compared with served after an oral administration of KP, with a oral administration, the topical treatment with significant reduction in the synovial concentra- NSAIDs, including KP, should be considered as tions of PGE2 and 6-keto-PGF1alpha. a first-line treatment for the management of knee and hand osteoarthritis3,4,36,37. Efficacy The efficacy of tKP gel has been studied in a Safety and Tolerability series of controlled trials versus placebo or other Overall tKP 2.5% gel is well tolerated38. Re- analgesic drugs such as diclofenac or etofena- sults of meta-analyses, conducted in a wide range mate, in a broad range of patients, with acute of patients, consistently show that local and sys- and chronic painful conditions (sport lesions, temic adverse events associated with the admin- low back pain, tendonitis, osteoarthritis of the istration of tKP are rare and in most cases knee and hand, soft tissue rheumatic pain).