What is the extent of systemic level increase of diclofenac (nonsteroidal anti-inflammatory drug (NSAID)) with patch use in adults with normal renal function?

Systemic Absorption of Diclofenac Patches

Diclofenac patches result in minimal systemic absorption, with plasma concentrations approximately 93% lower than oral administration and steady-state levels of only 1-3 ng/mL—far below concentrations needed for systemic effects. 1, 2

Pharmacokinetic Profile of Topical Diclofenac Patches

Delayed Absorption and Low Plasma Levels

• Diclofenac first appears in plasma at a mean of 4.5 hours after patch application (range 2-8 hours), indicating that initial pain relief occurs before any measurable systemic absorption 2
• Steady-state plasma concentrations are reached before 3 days of application (two patches per day) and remain in the range of 1-3 ng/mL 2
• The bioavailability of diclofenac from patches compared to oral administration (75 mg/day) is approximately 1%, representing a 93% reduction in systemic exposure 1, 2

Extended Half-Life Due to Tissue Reservoir

• The apparent plasma half-life after patch application is 9-12 hours, compared to only 1-2 hours after oral intake 2
• This prolonged half-life indicates the presence of a tissue reservoir under the patch, with diclofenac accumulating locally at the site of application rather than systemically 2
• The delayed elimination is 4- to 6-fold longer compared to oral diclofenac 1

Clinical Implications of Low Systemic Levels

Safety Profile

• Topical diclofenac patches have been specifically developed to avert systemic NSAID-related adverse effects, including cardiovascular, gastrointestinal, and renal risks 3
• Pooled safety data from randomized trials demonstrate similar low rates of adverse effects between topical diclofenac gel and placebo, even in high-risk patients with hypertension, type 2 diabetes, or cardiovascular disease 3
• No drug-related gastrointestinal bleeding, ulcers, or serious cutaneous events have been reported during 15 years of diclofenac patch use 2

Mechanism of Action

• The patch provides pain relief through local accumulation of diclofenac under the site of application, achieving therapeutic concentrations in underlying tissues without systemic effects 2
• Pain relief begins at 1-3 hours after application, before diclofenac appears in plasma, demonstrating purely local action 2
• Substantial concentrations are attained in synovial fluid and local tissues, which are the proposed sites of action for NSAIDs 4

Comparison with Oral Diclofenac

Systemic Exposure Differences

• Oral diclofenac produces significantly higher systemic exposure and is associated with cardiovascular risks, including a 63% increased risk of vascular events (RR 1.63,95% CI 1.12-2.37) compared to placebo 3
• Oral diclofenac carries a 54% increased risk of recurrent myocardial infarction and 140% increased mortality risk in registry studies 3
• The maximum daily dose of oral diclofenac is 150 mg, with higher doses associated with increased gastrointestinal and renal adverse effects 5

Clinical Recommendations

• Topical NSAIDs like diclofenac patches are recommended as first-line pharmacological treatment for localized pain due to their favorable safety profile compared with oral analgesics 3, 6
• For patients requiring NSAID therapy who have hypertension or cardiovascular risk factors, topical diclofenac is a safer alternative to oral diclofenac 3
• Topical diclofenac is particularly beneficial for older adults due to reduced risk of systemic adverse effects 6

Common Pitfalls and Caveats

• Mild application site reactions are the most common treatment-emergent adverse events with topical diclofenac patches 1
• When treating multiple joints or widespread pain, systemic pharmacological treatment may be preferred over topical application 3
• The low systemic levels (1-3 ng/mL) are insufficient to produce systemic anti-inflammatory effects, so patches should only be used for localized conditions 2