“Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain associated with a variety of indications, including arthritic conditions, but their usefulness is often limited by dose-dependent adverse events such as gastrointestinal disturbances, cardiovascular events, and renal toxicity. The risk of such effects could be reduced by the use of topical formulations, which offer the potential to deliver analgesic concentrations locally, at the site of inflammation, while minimizing systemic concentrations… Meta-analyses have confirmed the efficacy and safety of these [TOPICAL] preparations. However, it is important to recognize that pharmacokinetics [and] absorption from topical formulations can vary markedly, even between different formulations of the same drug, depending on the agent, the underlying disorder, and the site of application. It is therefore essential to consider the patient, the drug, and the drug delivery mechanism when selecting a topical NSAID preparation.”

Am J Ther. 2015 Sep-Oct;22(5):388-407

Topical Nonsteroidal Anti-Inflammatory Drugs: The Importance of Drug, Delivery, and Therapeutic Outcome.

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Managing Osteoarthritic Pain with Topical NSAIDs

Osteoarthritis (OA) is a leading cause of pain and disability worldwide. Due to the rapid aging of the world’s population, OA of the hands, knees, and lower back is expected to be one of the major challenges to maintaining physical function and quality of life in the elderly. Topical NSAIDS are expected to be at the forefront of providing relief from osteoarthritic pain while avoiding systemic exposure – an important consideration in a patient population with frequent co-morbidities and age-related decline in renal and hepatic function.

The best available evidence indicates that topical NSAIDs have a moderate effect on the relief of osteoarthritic pain, comparable to that of oral NSAIDs but with a better risk-to-benefit ratio. International clinical practice guidelines recommend topical NSAIDs on par with or ahead of oral NSAIDs for pain management in patients with knee and hand osteoarthritis, and as the first-line choice in persons aged ≥ 75 years.

Primary symptoms of OA include joint pain, stiffness, and movement limitation with occasional effusion and variable degrees of local inflammation. Treatment goals are to manage pain, reduce inflammation and maintain joint function. NSAIDs are central to the pharmacological management of OA. However, frequent or prolonged use of oral NSAIDs in chronic conditions such as OA raises tolerability and safety concerns, especially in more vulnerable populations such as the elderly and those with predisposing co-morbidities including high cardiovascular risk, type 2 diabetes and renal dysfunction. Oral NSAIDs are associated with age- and dose-related risks of gastrointestinal, cardiovascular, renal and hepatic adverse events.

Topical NSAIDs operate under the same mechanism of action as oral NSAIDs but with localized absorption and effect. Topical NSAIDs provide analgesic concentrations at the site of pain/inflammation, while avoiding systemic distribution of drug at physiologically active levels.

Systematic reviews and meta-analyses reporting on the efficacy and safety of topical NSAIDs found that most evidence exists for topical ketoprofen and diclofenac. “Topical NSAIDs are effective and should be recommended as a first-line intervention for mild to moderate pain associated with musculoskeletal disorders.”

The National Institute for Health and Clinical Excellence (2014) recommends that for hand and knee OA, topical NSAIDs should be considered for pain relief ahead of oral NSAIDs, COX-2 inhibitors, or opioids. The Osteoarthritis Research Society International reported topical NSAIDs are appropriate to treat knee OA in patients with or without co-morbidities.

In the treatment of acute musculoskeletal pain (e.g., sprains, strains, and overuse injuries) in adults, topical NSAIDs were found to provide significantly higher rates of clinical success (more patients with ≥50% pain reduction) than topical placebo during short-term use (less than 7 days), with an efficacy comparable to that of oral NSAIDs. Topical NSAIDs were well tolerated during short-term use.

The balance of lipophilic and hydrophilic components in gel-based formulations allows for faster diffusion across the skin and greater absorption in local tissues when compared with ointments and creams. Gels have better cosmetic acceptability since they spread and vanish more readily and are devoid of fatty components that leave a greasy residue. When assessed for ease of application, rate of penetration, after-feel, and scent, ketoprofen gel scored higher than diclofenac and piroxicam.

Pain Manag. (2018) 8(2), 115–128

Consensus recommendations for managing osteoarthritic pain with topical NSAIDs in Asia-Pacific

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Topical Therapies in the Management of Chronic Pain

Chronic pain, whether localized or generalized, is a widespread, often debilitating condition affecting > 25% of adults. Topical therapies offer advantages over systemically administered medications, including the requirement of a lower total systemic daily dose for patients to achieve pain relief, site-specific drug delivery, and avoidance of first-pass metabolism, major drug interactions, and systemic side effects. Topical NSAIDs have been shown to have a lower incidence of gastrointestinal complaints than oral formulations. In patients with neuropathic pain, topical formulations have been shown to be useful in the treatment of postherpetic neuralgia and diabetic peripheral neuropathic pain, and in relieving patient pain due to complex regional pain syndrome. Data suggest that topical therapies may offer a well-tolerated alternative to systemic therapies in the treatment of patients with chronic, localized musculoskeletal and neuropathic pain.

Postgrad Med. 2013 Jul;125(4 Suppl 1):25-33.

Topical therapies in the management of chronic pain.

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Comparison of Analgesic Activities of Compounded Topical Creams and Voltaren® Gel in Chronic Non-cancer Pain

Pharmacologic treatment of chronic pain is challenging. Oral therapy may require multiple medications; each has side effects, dose limitations, and limited efficacy. Compounded topical formulations have evolved as potential treatment options. The objective of a study was to evaluate the efficacy of 2 compounded topical creams, “Cream I” and “Cream II,” in patients with chronic extremity, joint, musculoskeletal, neuropathic, or other chronic pain conditions and compare their efficacy with Voltaren® gel. The primary efficacy outcome was the change in visual numeric pain intensity score from pretreatment to posttreatment. Cream I contained flurbiprofen 20%, tramadol 5%, clonidine 0.2%, cyclobenzaprine 4%, and bupivacaine 3%. Cream II contained flurbiprofen 20%, baclofen 2%, clonidine 0.2%, gabapentin 10%, and lidocaine 5%. The Voltaren® gel contained 1% diclofenac sodium. A total of 2177 patients were evaluated, 826 males and 1351 females. During their medical treatment, 1141 patients received Cream I, 527 patients received Cream II, and 509 patients received Voltaren® gel. After treatment, the pain intensity score decreased by 37% with Cream I, by 35% with Cream II, and by 19% with Voltaren® gel. Cream I and Cream II did not differ significantly in efficacy, and both were significantly more effective than Voltaren® gel.

Am J Ther. 2015 Sep-Oct;22(5):342-9.

Retrospective Evaluation on the Analgesic Activities of 2 Compounded Topical Creams and Voltaren® Gel in Chronic Noncancer Pain.

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To avoid the risks of COX-2 inhibitors, our pharmacy can compound topically applied NSAIDs such as ibuprofen and ketoprofen. Topical NSAIDs have a safety profile which is superior to oral formulations. Topical NSAID administration offers the advantage of local, enhanced delivery to painful sites with a reduced incidence of systemic adverse effects.

Topical preparations can be customized to contain a combination of medications to meet the specific needs of each patient.

This study concluded that topical NSAIDs, when used for the treatment of pain resulting from strains, sprains or sports or overuse-type injuries, can provide good levels of pain relief without the systemic adverse events associated with oral NSAIDs.

Cochrane Database Syst Rev. 2010 Jun 16; 6: CD007402.

Topical NSAIDs for acute pain in adults.

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“Topical non-steroidal anti-inflammatory drugs have a lower incidence of gastrointestinal adverse effects than the same drugs when they are taken orally. The low incidence of systemic adverse effects for topical NSAIDs probably results from the much lower plasma concentration from similar doses applied topically to those administered orally. Topical application of ibuprofen resulted in measurable tissue concentrations in deep tissue compartments, more than enough to inhibit inflammatory enzymes.”

BMJ. 1995 Jul 1;311(6996):22-6

Topical non-steroidal anti-inflammatory drugs and admission to hospital for upper gastrointestinal bleeding and perforation: a record linkage case-control study.

Free full text article available at bmj.com:

//bmj.bmjjournals.com/cgi/content/full/311/6996/22

This study concludes that topical NSAIDs have not been associated with renal failure.

QJM. 1995 Aug;88(8):551-7

Non-steroidal anti-inflammatory drugs and hospitalization for acute renal failure.

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The following article concludes: “Topical non-steroidal anti-inflammatory drugs are effective in relieving pain in acute and chronic conditions.”

BMJ. 1998 Jan 31;316(7128):333-8

Quantitative systematic review of topically applied non-steroidal anti-inflammatory drugs.

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“The systemic concentrations of ketoprofen have also been found to be 100 fold lower compared to tissue concentrations below the application site in patients undergoing knee joint surgery. Topically applied ketoprofen thus provides high local concentration below the site of application but lower systemic exposure.”

Pharm Res. 1996 Jan;13(1):168-72

Percutaneous absorption of ketoprofen from different anatomical sites in man.

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Sever disease is the most common cause of heel pain in pre-pubertal children. This inflammatory condition is a result of minor repetitive trauma and typically occurs during a growth spurt or at the beginning of a new sports season. A case report described the use of topical ketoprofen 10% gel to relieve pain and inflammation.

Phys Ther. 2006 Mar;86(3):424-33

Ketoprofen gel as an adjunct to physical therapist management of a child with Sever disease.

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