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10 Articles in Volume 17, Issue #7
Abuse-Deterrent Opioids: Why Rush to Judgment?
Alcohol Screen Recommended to Reduce Opioid-Induced Respiratory Depression Overdose
Ehlers-Danlos Syndrome: An Emerging Challenge for Pain Management
Guide to Laboratory Testing in Patients With Suspected Rheumatic Disease
Letters to the Editor: Arachnoiditis, Hormone Testing, Ehlers-Danlos Syndrome
Neurocognitive Disorders: Pain Expression in the Face of Mental Deficits
Preemptive and Preventive Analgesia for Chronic Postsurgical Pain
The Effects of Religion and Spirituality on Coping Efficacy for Death and Dying
Topical Nonsteroidal Anti-inflammatory Drugs and Nephrotoxicity: Is There a Safer Option?
Transformative Care for Chronic Pain and Addiction

Topical Nonsteroidal Anti-inflammatory Drugs and Nephrotoxicity: Is There a Safer Option?

Based on limited data, the authors believe prescribers need to use the same precautions for topical NSAIDs that they use for other NSAID preparations.

Prescription and over-the-counter (OTC) nonsteroidal anti-inflammatory drugs (NSAIDs) represent an important component in

 the treatment of acute and chronic pain. The emergence of topical NSAIDs has generated controversial questions about their safety in patients with absolute or relative contraindications to orally administered NSAIDs. OTC NSAIDs generally are considered safe when they are used as directed, but extensive data showing evidence of renal dysfunction (changes in serum urea or creatinine levels, clinically diagnosed kidney disease, and renal failure) illustrates they can cause renal toxicity.1,2 Using non-oral routes of administration to achieve analgesia with reduced plasma concentrations may be an attractive alternative to systemic NSAID exposure, especially in patients who are at greater risk for NSAID-induced toxicity.  

Mechanism of Action of NSAIDs

The pharmacological effect of most NSAIDs is thought to be due to reversible cyclooxygenase 1 and 2 (COX-1 and COX-2) inhibition resulting in downstream inhibition of prostaglandin (PG) synthesis through the arachidonic acid pathway. Specifically, the rate-limiting step of arachidonic acid oxygenation is inhibited, preventing PG G2 and, ultimately, thromboxane A2 and PGE2 from being produced.3 Thromboxane A2 is a potent activator of platelets and a crucial component in the pain and inflammatory response.4 In addition, NSAIDs may exert their analgesic effect by a poorly understood central mechanism.5

Non-acetylated salicylates also may have effects on other inflammatory pathways, such as nuclear factor-κβ.6 Each available NSAID displays variable inhibitory selectivity and potency for the COX enzymes, which explains the different propensities for adverse effects (AEs) between the agents. Aspirin is the only irreversible COX inhibitor due to a covalent bond formed at the active site. The other commercially available NSAIDs are reversible, owing largely to noncovalent binding to COX active sites.3

Mechanisms of NSAID-Associated Toxicities

Gastrointestinal Toxicity

It is important to understand the mechanisms of the major AEs associated with oral NSAID use. The AE profiles of NSAIDs are thought to be based on their unique COX inhibition reactions. Data suggest that both COX (1 and 2) isoforms maintain gastric mucosa, therefore NSAIDs that block COX-1 are not more likely to cause ulceration and bleeding than COX-2 blocking agents.7 Other proposed explanations for NSAID-induced gastrointestinal ulceration and bleeding include a reduction in ATP levels and increases in free oxygen species, both of which alter the protective environment of the intestinal epithelial barrier.8

Cardiovascular Toxicity

COX-2 isoform inhibition has been directly linked to cardiovascular toxicity based on a meta-analysis of 114 double-blind, randomized controlled trials.1 COX-2 inhibition also was found to reduce the renal clearance of the major metabolite of PGI2 (prostacyclin).9 PGI2 and PGE2 both play a large role in vascular tone and, more importantly, platelet aggregation, which explains the increased incidence of cardiovascular AEs. Other proposed explanations for NSAID-associated cardiovascular toxicity includes COX-2 mediated inhibition of cardiac angiogenesis as well as attenuation of ATP-mediated stress priming within the cardiac myocyte following hypoxic insult.10

Renal Toxicity

NSAIDs have been linked to acute and chronic renal failure, tubulointerstitial nephritis, papillary necrosis, pre-renal azotemia, and acute tubular necrosis.11 The 2 primary PGs that modulate renal function are PGE2 and PGI2.12 PGE2 decreases sodium reabsorption in the loop of Henle. The decrease in sodium reabsorption is responsible for the natriuresis required to maintain adequate renal perfusion. At the distal nephron, PGI2 enhances potassium secretion through the renin-angiotensin system as it stimulates renin release.12

PGI2 also plays a major role in the vasodilation of the afferent arteriole, resulting in an increase in renal blood flow through the glomerulus.12 Inhibition of PGI2 or PGE2 inhibits renin release in the juxtaglomerular apparatus, decreasing glomerular filtration rates. Specifically, COX-2 inhibition has been found to decrease renin secretion from the macula densa induced by a decrease in NaCl.13

Along with these hemodynamic changes, NSAIDs can cause direct tubular damages. It is important to note that analgesic-induced nephrotoxicity (AIN) consists of a chronic renal papillary and medullary necrosis.14 This is direct damage to the renal physiology, unlike the pharmacodynamic effects of afferent arteriole dilation. NSAIDs may precipitate papillary necrosis due, in part, to decreases in blood flow to the renal medulla.15,16 To summarize, NSAID inhibition of the COX enzymes plays a multifactorial role in causing renal toxicities via hemodynamic changes and/or direct tubular damage.

Topical NSAIDs

Indications/Applications of Topical NSAIDs

Topical NSAIDs have been proven to be effective in multiple different disease states. According to the large, randomized, double-blind, placebo-controlled trial of patients with osteoarthritis (OA) of the knee, Simon et al found no statistically significant difference between topical and oral diclofenac with respect to Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) scores of pain, functioning, and stiffness.17

In another randomized controlled trial, Tugwell et al found that the use of topical diclofenac was equally as efficacious in reducing pain from baseline and improving function in patients with OA of the knee.18

Available Topical Products

In the United States, 6 topical NSAID products are commercially available as either OTC or prescription treatments for pain (Table 1).  Most topicals use diclofenac as the active anti-inflammatory agent, with concentrations varying between 1% and 3% of the drug in differing bases and delivery vehicles. Treatment guidelines for osteoarthritis have recognized the value of topical NSAID treatment and, rightfully, transitioned these agents to higher recommendation levels or places in their respective treatment algorithms.19,20

Systemic Absorption of Topical NSAIDs

For a topical NSAID to be successful, it must demonstrate therapeutic action at the target site. It is unknown whether the efficacy may be due to direct local absorption or a result of systemic absorption and distribution throughout the vasculature.

According to the clinical data reported in the prescribing information of diclofenac 1% (Voltaren) gel, the average systemic exposure of diclofenac sodium is 5.8% of that of the oral counterpart.21 When higher doses were applied topically, serum drug concentrations approached 23% that of the oral systemic exposure. To achieve the higher percentage of system absorption, it would require a patient to use 13.5 inches of Voltaren gel (12 g) 4 times a day.21

Incidence of Systemic AEs with Topical NSAIDs

A study from 2010 compared the systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers.22 This 7-week, single-center, randomized, open-label, multiple-dose, 3-way crossover study showed differences in typical topical exposure (1 knee, 16 g daily), maximum topical exposure (2 knees and 2 hands, 48 g daily), and exposure to oral diclofenac (150 mg daily). The total AUC0-24 was reported as 233 + 128 ng x h/mL, 807 + 478 ng x h/mL, and 3,890 + 1,710 ng x h/mL, respectively, showing a larger systemic effect from oral diclofenac.

Oral diclofenac inhibited platelet aggregation as well as COX-1 and COX-2, whereas topical diclofenac did not inhibit platelet aggregation and inhibited COX-1 and COX-2 less than oral diclofenac did. Systemic exposure of topical diclofenac sodium gel 1% was 5- to 17-fold lower than that of oral diclofenac, making them less pronounced but not absent (Table 2).23

Incidence of Nephrotoxicity With Topical NSAIDs

Otsuka et al assessed the impact of long-term application of S-flurbiprofen plaster (SFP) on kidney function in a multicenter, open-label, uncontrolled prospective study.24 They treated 201 osteoarthritis patients with the same oral NSAID for 2 weeks as an observational period, then switched the patients to a 40-mg SFP patch (101 patients) or an 80-mg SFP patch (100 patients) for 52 weeks. They measured plasma concentrations at 4, 8, and 12 weeks after initiation of therapy to determine systemic exposure.

The investigators examined serum creatinine (SCr), blood urea nitrogen (BUN), and urinalysis results at 2 and 4 weeks after therapy initiation and at 4-week intervals for 52 weeks. They observed small but statistically significant decreases in estimated glomerular filtration rate (eGFR) at 52 weeks in those taking the 40-mg dose and at 44 and 52 weeks in those taking the 80-mg dose. Abnormal changes in BUN, SCr, and urinalysis results were higher in the 80-mg group, but they were small and not statistically significant.24

The safety of topical diclofenac using dimethyl sulfoxide (DMSO) as a permeability enhancement vehicle was compared to topical placebo, DMSO alone, and oral diclofenac.17 In this study, both oral and topical diclofenac showed a mean change in SCr and creatinine clearance (CrCl), but oral diclofenac resulted in a greater mean change. The mean change in SCr was -0.4 µmol/L for topical diclofenac and 3.1 µmol/L for oral diclofenac.

The percent of patients that went from normal (within normal limits at baseline) creatinine to abnormal (above the upper limit of normal) was 2.8% with topical diclofenac and 7.2% with oral diclofenac. The mean change in CrCl was 0.4 mL/min for topical diclofenac and -2.4 mL/min for oral diclofenac. The percent of patients that went from normal CrCl to abnormal was 7.6% for topical diclofenac and 7.2% in oral diclofenac.  

Roth and Fuller also evaluated the safety of topical diclofenac compared with oral diclofenac.25 Again, oral diclofenac was associated with significantly greater increases in SCr (10.3% oral vs 8.2% topical) and decreases in CrCl (84.2% oral vs 81.3% topical), but the differences between the oral diclofenac and topical diclofenac groups were not significant.25

The Kidney Disease Improving Global Outcomes guidelines for the evaluation and management of chronic kidney disease recommend judicious use of NSAID therapy with the shortest duration and lowest dose possible in patients whose calculated CrCl has dropped below 60 mL/min/1.73m2.26  In addition, these guidelines recommend against using NSAIDs for those with calculated CrCl below 30 mL/min/1.73m2, concurrently with lithium, or with renin-angiotensin-aldosterone blocking agents (ie, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers).

Unfortunately, these recommendations do not provide detailed guidance for treating patients with pain who require anti-inflammatory drug therapy. The guidelines also do not provide any direction on the use of topically administered NSAIDs in patients with impaired kidney function).


Oral NSAID nephrotoxicity has been well-described. Guidelines support the analgesic efficacy of topical NSAID therapy in specific disease states, such as osteoarthritis and low back pain, and is supported by well-controlled clinical trials. Regrettably, data is lacking on the relative safety of these agents, especially in patients who are most prone to NSAID-induced AEs. Given the lack of separation between oral and topical NSAIDs on renal function parameters, as illustrated by both the Simon and Tugwell studies,17,18 continued use of topical NSAIDs in patients with pre-existing renal compromise may be ill-advised.

Certainly, well-controlled, prospective studies are warranted. An ideal safety trial would eliminate or account for confounding variables contributing to any renal decline. Such a trial preferably would include patients with mild to moderate renal impairment because oral NSAIDs are still used by that population. Some common variables to account for may include advanced age (>60 years),27 hydration status, additional concurrent nephrotoxic medications, lifestyle changes, ethnicity, malnutrition, and even dietary sodium intake. There is a belief that topical NSAIDs should have a smaller incidence of nephrotoxicity due to their reduced systemic absorption, but in clinical practice, they are associated with a significant amount of renal decline and nephrotoxicity. We believe prescribers need to use the same precautions for topical NSAIDS that they use for other NSAID preparations.

Last updated on: September 27, 2017
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