What is the systemic absorption of lidocaine patches and diclofenac gel? When should we be most concerned for systemic side effects?

Comment by InpharmD Researcher

Robust data regarding when systemic absorption of topical lidocaine and diclofenac formulations becomes clinically relevant remain sparse; however, both lidocaine patches and diclofenac gel demonstrate relatively low systemic absorption under recommended use. Prescribing information indicates that lidocaine 5% patches result in systemic absorption of approximately 3% of the applied dose, while diclofenac gel 1% produces systemic exposure of approximately 6% relative to oral diclofenac. Despite this limited systemic exposure, both agents retain warnings and precautions in labeling. Lidocaine patch labeling notes increased risk with application to large surface areas, broken or inflamed skin, prolonged use, use beyond the recommended number of patches, external heat exposure, and in patients with hepatic impairment or reduced drug elimination. Diclofenac gel retains NSAID-related precautions including use in patients with cardiovascular disease, renal or hepatic impairment, gastrointestinal bleeding risk, and concomitant interacting medications; concurrent heat application is also not recommended per labeling. Overall, while systemic exposure is low under standard conditions, caution remains warranted in higher-risk populations and in settings that may increase systemic absorption.

Background

According to the prescribing information for Lidoderm (lidocaine), when lidocaine patch 5% is used according to recommended dosing instructions, approximately 3 ± 2% of the applied dose is systemically absorbed, with a mean peak blood concentration of approximately 0.13 mcg/mL, which is about one-tenth of the concentration typically required to treat cardiac arrhythmias. Repeated application of three patches simultaneously for 12 hours daily did not demonstrate accumulation over three days. Despite low systemic absorption with recommended use, increased systemic exposure and toxicity may occur with application to larger areas, prolonged wear beyond recommended duration, use of more than the recommended number of patches, application to broken or inflamed skin, use with external heat sources, smaller patient size, impaired drug elimination, or severe hepatic disease. Lidocaine toxicity may be expected at blood concentrations above 5 mcg/mL, and caution is advised with concomitant use of other local anesthetic-containing products or Class I antiarrhythmic agents. [1]

Consistent with existing prescribing information, the U.S Food and Drug Administration (FDA) issued a 2024 safety communication highlighting the risk of serious injury associated with topical lidocaine products. The communication specifically addressed products marketed for use prior to cosmetic procedures, including laser treatments, tattooing, and piercing. Factors noted to increase risk included application over large areas of skin, use on irritated or broken skin, prolonged application, and covering the treated skin, which may increase absorption of the drug through the skin and have been associated with severe adverse events such as arrhythmias, seizures, and respiratory difficulties. [2]

According to the prescribing information for diclofenac, when diclofenac sodium topical gel 1% is used at the recommended dose of 4 g applied to one knee four times daily, systemic absorption averages approximately 6% of that observed with oral diclofenac, and peak plasma concentrations are approximately 158-fold lower than those seen with oral diclofenac 50 mg administered three times daily. Pharmacokinetic studies conducted under conditions of moderate heat applied prior to gel administration and moderate exercise did not demonstrate clinically relevant differences in systemic absorption or tolerability; however, the effects of heat applied after gel administration have not been evaluated, and concurrent heat use is not recommended per labeling. Despite lower systemic absorption, diclofenac sodium topical gel retains nonsteroidal anti-inflammatory drug (NSAID)-related warnings and precautions. Labeling identifies increased risk in patients with cardiovascular disease or cardiovascular risk factors, prior gastrointestinal ulceration or bleeding, renal impairment, hepatic impairment, heart failure, dehydration, hypovolemia, advanced age, asthma/aspirin sensitivity, or bleeding disorders, as well as in those receiving interacting medications such as oral corticosteroids, aspirin, anticoagulants, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), diuretics, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs). Additional caution is advised with higher doses, prolonged duration of therapy, or concomitant oral NSAID use, and labeling recommends use of the lowest effective dose for the shortest duration possible. [3]

NSAIDs applied topically generally result in only 3-5% of the systemic absorption seen with oral diclofenac products. Interstitial concentration of diclofenac in muscle tissues are often higher after topical application than oral NSAIDs. Pharmacokinetic studies in healthy volunteers showed that peak plasma levels after topical diclofenac were less than 10% of those following oral administration, with maximal plasma concentrations occurring roughly ten times later. [4]

A 2018 review published in the Clinical Liver Disease Journal states lidocaine (Lidoderm) patches can be considered an effective treatment for localized pain in patients with cirrhosis given its low systemic absorption. As such, hepatic adjustment may not be required. Up to three patches can be used at one time, with each patch applied to the affected area for up to 12 hours per day. In contrast, NSAIDs, in general, should be avoided in all patients with cirrhosis. While topical NSAIDs can be considered, again based on theoretically minimal systemic absorption, further studies are needed to elucidate their safety profile in patients with cirrhosis. [5]

References: [1] Lidoderm (lidocaine) 5% patch. Prescribing information. TPU Pharma, Inc.; 2022
[2] U.S Food and Drug Administration (FDA). FDA Warns Consumers to Avoid Certain Topical Pain Relief Products Due to Potential for Dangerous Health Effects. Published March 26, 2024. Accessed April 10, 2026. https://www.fda.gov/news-events/press-announcements/fda-warns-consumers-avoid-certain-topical-pain-relief-products-due-potential-dangerous-health
[3] Diclofenac sodium gel. Prescribing information. Direct_Rx; 2025.
[4] Altman R, Bosch B, Brune K, Patrignani P, Young C. Advances in NSAID development: Diclofenac product using pharmaceutical technology. Drugs. 2015;75(8):859-877.
[5] Rakoski M, Goyal P, Spencer-Safier M, Weissman J, Mohr G, Volk M. Pain management in patients with cirrhosis. Clin Liver Dis (Hoboken). 2018;11(6):135-140. Published 2018 Jul 26. doi:10.1002/cld.711
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What is the systemic absorption of lidocaine patches and diclofenac gel? When should we be most concerned for systemic side effects?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Table 1 for your response.

 

Systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers

Design

Single-center, open-label, multi-dose, randomized three-way cross-over study

N= 39

Objective

To compare the systemic bioavailability and pharmacodynamics of 1% topical diclofenac sodium gel vs 50 mg diclofenac sodium tablets

Study Groups

Topical diclofenac sodium 1% one 1 knee (n= 39)

Diclofenac gel 1% on both knees (n= 39)

50 mg diclofenac sodium tablets (n= 39)

Methods

Inclusion criteria: 50 years and older, healthy patients (as determined via physical examination, vital signs, clinical laboratory work of blood hematology and chemistry)

Exclusion criteria: Previously treated with diclofenac in past 2 weeks (prior to start of study), required treatment with any topical or systemic medication (excluding hormone replacement therapy or contraceptives), pregnant, any other factors that would confound study results or patient welfare, 50% of selected participants had to be 60 years or older and 50-70% had to be women, men and women were randomized separately


Three 7 day treatment arms were  completed with a 14 day washout period in between each arm.

    Treatment A: diclofenac sodium gel 1% on 1 knee

    Treatment B: diclofenac sodium gel 1% on 2 knees

    Treatment C: diclofenac sodium 50 mg tablets

Duration

7 weeks

Outcome measures

Pharmacodynamic: inhibition of COX-1, COX-2, and platelet aggregation.

Safety: incidence rates of treatment-emergent  AE

Baseline Characteristics

Men

50%

White

100%

Mean (SD) age, years

59.9 (5.7)

Mean (SD) BMI, kg/m2

25.6 (2.7)

Results

Treatment

Cmax ng/mL

tmax h

AUC0-24 ng*h/mL

A (n=39)

15.0±7.33

14 (0-24)

233±128

B (n=39)

53.8±32.0

10 (0-24)

807±478

C (n=39)

2270±778

6.5 (1-14)

3,890±1,710

Adverse Events

Four patients reported AE related to topical application (dermatitis, erythema, pruritus, paresthesia)

Three patients reported AE related to oral dose included GI distress (abdominal pain, dyspepsia and eructation)

Study Author Conclusions

Systemic exposure from oral dose was 5 times greater than 1% diclofenac gel applied to both knees, and 17 times greater than diclofenac sodium gel applied to 1 knee. Diclofenac sodium gel 1% applied to one knee suppressed COX-2 significantly. Reduced systemic exposure from topical therapy is suggested to coincide with improved safety.  

InPharmD Researcher Critique

The study had a small sample size with healthy volunteers which does not represent the greater patient population.
References:
[1] [1] Kienzler JL, Gold M, Nollevaux F. Systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers. J Clin Pharmacol. 2010;50(1):50-61.