Ketoprofen

Medical uses

Ketoprofen is generally prescribed for arthritis-related inflammatory pains or severe toothaches that result in the inflammation of the gums.

Ketoprofen topical patches are being used for treatment of musculoskeletal pain.

Ketoprofen can also be used for treatment of some pain, especially nerve pain such as sciatica, postherpetic neuralgia and referred pain for radiculopathy, in the form of a cream, ointment, liquid, spray, or gel, which may also contain ketamine and lidocaine, along with other agents which may be useful, such as cyclobenzaprine, amitriptyline, acyclovir, gabapentin, orphenadrine and other drugs used as NSAIDs or adjuvant, atypical or potentiators for pain treatment.

Efficacy

A 2013 systematic review indicated "The efficacy of orally administered ketoprofen in relieving moderate-severe pain and improving functional status and general condition was significantly better than that of ibuprofen and/or diclofenac." A 2017 Cochrane systematic review investigating ketoprofen as a single-dose by mouth in acute, moderate-to-severe postoperative pain concluded that its efficacy is equivalent to drugs such as ibuprofen and diclofenac.

There is evidence supporting topical ketoprofen for osteoarthritis but not other chronic musculoskeletal pain.

Adverse effects

In October 2020, the U.S. Food and Drug Administration (FDA) required the prescribing information to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in fetuses that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.

Mechanism

Ketoprofen undergoes metabolism in the liver via conjugation with glucuronic acid (glucuronidation) by UGT enzymes, hydroxylation of the benzoyl ring by the CYP3A4 and CYP2C9 enzymes, and reduction of its ketone moiety (a carbonyl functional group, i.e. with carbon-oxygen double bond) by carbonyl reducing enzymes (CREs). Ketoprofen is used for its antipyretic, analgesic, and anti-inflammatory properties by inhibiting cyclooxygenase-1 and -2 (COX-1 and COX-2) enzymes reversibly, which decreases production of proinflammatory prostaglandin precursors.

The patches have been shown to provide rapid and sustained delivery to underlying tissues without significantly increasing levels of drug concentration in the blood when compared to the traditional oral administration.

Chirality and biological activity

Ketoprofen has one stereogenic center in the side chain and hence exists as mirror-image twins. Majority of the profens are marketed as racemic mixtures. For most of the NSAIDs the pharmacological activity resides in the (S)-enantiomers with their (R)-enantiomer virtually inactive. An interesting observation about most profens including ketoprofen is that they undergo unidirectional metabolic inversion, chiral inversion, of the (R)- acid to its (S)-mirror-image version with no other change in the molecule. There have been concerns raised that Ketoprofen can break down into the parent benzophenone molecule in skin exposed to strong summer or tropical UV light and this could pose a theoretical cancer risk. Given such a risk it is better to use other pain killers in such circumstances.

History

The earliest report of therapeutic use in humans is in 1972.

Society and culture

Brand names

Brand names in Albania are Oki and Fastum Gel. The names in Australia include Orudis and Oruvail. It is available in Estonia as Keto, Ketonal, and Fastum Gel; in Finland as Ketorin, Keto, Ketomex, and Orudis; in France as Profénid, Bi-Profénid, Toprec, and Ketum. It can be bought in Indonesia as Kaltrofen; in Ireland as Fastum Gel. In Italy it is sold as Ketodol, Fastum Gel, Lasonil, Orudis, Oki and Okitask; in Greece as Okitask. It is available in Japan in a transdermal patch, Mohrus Tape, made by Hisamitsu Pharmaceutical. In Mexico it is sold as Arthril; in Norway as Zon and Orudis. In Poland as Ketonal, Ketonal active, and Ketolek. In Romania as Ketonal and Fastum Gel; in Russia as ОКИ (OKI), Fastum Gel and Ketonal. In Serbia, Slovenia and Croatia as Knavon and Ketonal. In Spain as Actron and Fastum Gel. It is available in the UK as Ketoflam and Oruvail. Lastly, it is sold in Venezuela as Ketoprofeno as an injectable solution of 100 mg and 150 mg capsules.

In some countries, the optically pure (S)-enantiomer (dexketoprofen) is available; its trometamol salt is said to be particularly rapidly reabsorbed from the gastrointestinal tract, having a rapid onset of effects.

Veterinary medicine

Ketoprofen is a common NSAID, antipyretic, and analgesic used in horses and other equines. It is most commonly used for musculoskeletal pain, joint problems, and soft tissue injury, as well as laminitis. It is also used to control fevers and prevent endotoxemia. It is also used as a mild painkiller in smaller animals, generally following surgical procedures.

In horses, it is given at a dose of 2.2 mg/kg/day. Studies have shown that it does not inhibit 5-lipoxygenase and leukotriene B4, as originally claimed. It is therefore not considered superior to phenylbutazone as previously believed, although clinical signs of lameness are reduced with its use. In fact, phenylbutazone was shown superior to ketoprofen in cases of experimentally-induced synovitis when both drugs were used at labeled dosages.

Ecological problems

Experiments have found ketoprofen, like diclofenac, is a veterinary drug causing lethal effects in red-headed vultures. Vultures feeding on the carcasses of recently treated livestock develop acute kidney failure within days of exposure.

References

References

1. (3 August 2022). "Health product highlights 2021: Annexes of products approved in 2021".
2. (1986). "Ketoprofen: a review of its pharmacologic and clinical properties". Pharmacotherapy.
3. (2006). "Analogue-based Drug Discovery". John Wiley & Sons.
4. (August 2005). "Topical ketoprofen patch in the treatment of tendinitis: a randomized, double blind, placebo controlled study". The Journal of Rheumatology.
5. (2005). "Topical ketoprofen patch". Drugs in R&D.
6. (March 2010). "Ketoprofen absorption by muscle and tendon after topical or oral administration in patients undergoing anterior cruciate ligament reconstruction". AAPS PharmSciTech.
7. (2013). "Efficacy of ketoprofen vs. ibuprofen and diclofenac: a systematic review of the literature and meta-analysis". Clinical and Experimental Rheumatology.
8. (May 2017). "Single dose oral ketoprofen or dexketoprofen for acute postoperative pain in adults". The Cochrane Database of Systematic Reviews.
9. (April 2016). "Topical NSAIDs for chronic musculoskeletal pain in adults". The Cochrane Database of Systematic Reviews.
10. (15 October 2020). "FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications".
11. (21 July 2017). "NSAIDs may cause rare kidney problems in unborn babies".
12. (February 2014). "Carbonyl reduction pathways in drug metabolism". Drug Metabolism Reviews.
13. Ketoprofen. (n.d.). Millennium Web Catalog. Retrieved 1 February 2010, from http://0-online.lexi.com.library.touro.edu {{Webarchive. link. (29 August 2021)
14. Lemke TL, Williams DA, Roche VF, Zito SW. Foyes ''Principles of Medical Chemistry''. 6th ed. Philadelphia: Lippincott Williams and Wilkins; 2008.
15. link. (20 July 2011)
16. (July 2008). "Physical limitations and depressive symptoms: exploring the nature of the association". The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences.
17. (November 1983). "The metabolic chiral inversion of 2-arylpropionic acids--a novel route with pharmacological consequences". The Journal of Pharmacy and Pharmacology.
18. (January 1988). "The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences". Biochemical Pharmacology.
19. (1997). "The impact of stereochemistry on drug development and use". Wiley.
20. (November 1972). "Orudis in management of rheumatoid arthritis and osteoarthrosis of the hip: comparison with indomethacin". British Medical Journal.
21. (2007). "Understanding equine medications: your guide to horse health care and managements". Eclipse Press.
22. (September 1984). "Benoxaprofen does not inhibit formation of leukotriene B4 in a model of acute inflammation". Biochemical Pharmacology.
23. (1991). "The analgesic effect of ketoprofen for use in treating equine colic as compared to flunixin meglumine". Equine Pract.
24. (1994). "Anti-inflammatory effects and pharmacokinetics of ketoprofen in a model of equine synovitis.". Blackwell Scientific Publications.
25. (June 1996). "Effects of pretreatment with ketoprofen and phenylbutazone on experimentally induced synovitis in horses". American Journal of Veterinary Research.
26. (June 2010). "Toxicity of non-steroidal anti-inflammatory drugs to Gyps vultures: a new threat from ketoprofen". Biology Letters.