Can patients with GI issues who are unable to take oral NSAIDs take topical NSAIDs?

Comment by InpharmD Researcher

Data suggests topical NSAIDs can be used in patients with gastrointestinal risk factors since there is limited systemic absorption. However, topical NSAIDs can still cause GI adverse events at lower incidences than oral NSAIDs. Topical NSAIDs may not be ideal for patients with widespread pain or for prolonged periods.

  

PubMed: topical nsaid gi risk = 22 results;

Background

Guidelines by the Osteoarthritis Research Society International (OARSI) on the management of osteoarthritis recommend the use of topical nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with gastrointestinal comorbidities. However, topical NSAIDs may not be appropriate in patients with widespread pain, since there is a risk of exceeding the total recommended NSAID dose. [1]

A 2018 meta-analysis reviewed the efficacy and safety of topical NSAIDs for the treatment of osteoarthritis. Since topical NSAIDs are not systemically absorbed, they tend to have a more favorable safety profile in terms of gastrointestinal and renal adverse events; however, they can have topical adverse effects. A total of 31 randomized controlled trials involving 11 topical NSAIDs reported adverse events. The results of this meta-analysis showed topical NSAIDs did not result in a significantly higher risk of gastrointestinal or cardiovascular adverse events. Three observational, case-control studies evaluated the risk of serious systemic adverse events (e.g., GI bleeding, perforation, symptomatic peptic ulcers, and acute renal failure) associated with the use of topical NSAIDs. The risks of GI bleeding (odds ratio [OR] 1.45, 95% confidence interval [CI] 0.84 to 2.50), acute renal failure (OR 1.33, 95% CI 0.79 to 2.24) and symptomatic peptic ulcers (OR 1.00, 95% CI 0.60 to 1.70) were not significant. [2]

Another review suggests topical NSAID formulations can be used to reduce gastrointestinal adverse events, but topical NSAIDs may be impractical for systemic pain and they may be ineffective for long-term pain relief. Topical NSAIDs can produce high concentrations of the drug in local tissue with low systemic exposure as measured via plasma concentration. Topical NSAIDs also avoid first-pass metabolism and the GI tract since they are absorbed locally. Other strategies to prevent gastrointestinal complications associated with NSAIDs include using proton-pump inhibitors or H2 blockers, using misoprostol, opting for COX-2 selective NSAIDs, or using lower-dose oral NSAIDs. Not all of these options are practical. [3], [4], [5]

A review on the safety and efficacy of topical versus oral NSAIDs also found more gastrointestinal side effects in patients receiving oral NSAIDs. Studies that compared topical NSAIDs to placebo generally found a similar incidence of gastrointestinal adverse events between the groups, but oral NSAIDs consistently showed a higher incidence of gastrointestinal events compared to topical formulations. [4]

References:

[1] Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019;27(11):1578-1589. doi:10.1016/j.joca.2019.06.011
[2] Zeng C, Wei J, Persson MSM, et al. Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies. Br J Sports Med. 2018;52(10):642-650. doi:10.1136/bjsports-2017-098043
[3] Goldstein JL, Cryer B. Gastrointestinal injury associated with NSAID use: a case study and review of risk factors and preventative strategies. Drug Healthc Patient Saf. 2015;7:31-41. Published 2015 Jan 22. doi:10.2147/DHPS.S71976
[4] Klinge SA, Sawyer GA. Effectiveness and safety of topical versus oral nonsteroidal anti-inflammatory drugs: a comprehensive review. Phys Sportsmed. 2013;41(2):64-74. doi:10.3810/psm.2013.05.2016
[5] McPherson ML, Cimino NM. Topical NSAID formulations. Pain Med. 2013;14(suppl 1):S35-S39. doi:10.1111/pme.12288
Literature Review

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

Can patients with GI issues who are unable to take oral NSAIDs take topical NSAIDs?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→


Please see Table 1 for your response.

 

Equivalence Study of a Topical Diclofenac Solution (Pennsaid®) Compared with Oral Diclofenac in Symptomatic Treatment of Osteoarthritis of the Knee: A Randomized Controlled Trial

Design

Randomized, double-blind, double-dummy, controlled, equivalence trial

N= 604

Objective

To compare the safety and efficacy of a topical diclofenac solution versus oral diclofenac in relieving the symptoms of primary osteoarthritis (OA) of the knee

Study Groups

Topical diclofenac (n= 303)

Oral diclofenac (n= 301)

Inclusion Criteria

Adults aged 40-85 years old; symptomatic primary osteoarthritis of the knee; radiographic examination showing OA within three months; mild symptoms based on the Western Ontario and McMaster Universities (WOMAC) pain score

Exclusion Criteria

Pregnancy; secondary arthritis; chondrocalcinosis with a history of pseudogout; fibromyalgia; previous major surgery to the knee or recommendation for knee replacement/reconstruction; recent intraarticular viscosupplementation; current or recent corticosteroid use (orally, intramuscularly, or topically); topical product use at the application site; allergy to NSAIDs; severe, uncontrolled cardiac, renal, hepatic, or other systemic disease; documented recent gastroduodenal ulcer or GI bleeding

Methods

Participants were randomized 1:1 to receive either topical diclofenac (1.5% w/w) solution 50 drops (~1.55 mL) TID or oral diclofenac capsules 50 mg TID for up to 12 weeks. Persons randomized to topical diclofenac also received placebo capsules, and persons randomized to oral diclofenac received a placebo solution (consisting of the vehicle dimethyl sulfoxide). 

Before randomization, patients underwent a washout period of 3-10 days where all current NSAIDs, narcotic analgesics, acetaminophen, and other prohibited medications/therapies were discontinued. Throughout the study, concomitant medications, including NSAIDs, acetaminophen, and other analgesic medications, were not allowed during the study, but patients were allowed to continue low-dose aspirin (up to 325 mg/day) for cardiovascular prophylactic purposes.

Duration

Physician-assessed evaluations were conducted at weeks 1, 6, and 12

Outcome Measures

Primary: pain and physical function, as measured by the WOMAC index; patient global assessment (PGA) score, a 0-100 visual analog scale

Safety: adverse events

Baseline Characteristics

  

Topical diclofenac (n= 311)

Oral diclofenac (n= 311)

  

Age, years

 64 ± 10 63 ± 10  

Female

178 (57%) 178 (57%)  

Weight, kg

 88 ± 18 88 ± 21  

WOMAC index

Pain score (0-500)

Physical function score (0-1700)

Stiffness score (0-200)

 

286 ± 88

971 ± 295

124 ± 47

 

289 ± 98

984 ± 331

124 ± 47

  

PGA score (0-100)

 69 ± 19 70 ± 21  
 

Results

  

Topical diclofenac (n= 303)

Oral diclofenac (n= 301)

p-value

Change from baseline

WOMAC pain score

WOMAC physical function score

WOMAC stiffness score

PGA score

 

-118 ± 121

-348 ± 400

-45 ± 58

-27 ± 31

 

-134 ± 127

-438 ± 426

-52 ± 61

-32 ± 32

 

0.10

0.008

0.14

0.08

Patients with improvement from baseline

WOMAC pain score

WOMAC physical function score

WOMAC stiffness score

PGA score

 

41%

36%

37%

39%

 

46%

45%

42%

46%

 

0.10

0.008

0.14

0.08
 

Adverse Events

   Topical diclofenac (n= 311)

Oral diclofenac (n= 311)

 p-value

Gastrointestinal events

Abdominal pain

Constipation

Diarrhea

Dyspepsia

Flatulence

Melena

Nausea

Vomiting

35%

12%

8%

9%

15%

10%

1%

8%

2%

48%

22%

10%

17%

26%

17%

2%

13%

2%

0.0006

0.0008

0.40

0.001

0.001

0.009

0.36

0.04

0.56

Dermatologic events

Dry skin

Rash

Pruritis

Vesiculobullous rash

 

27%

12%

6%

5%

 

1%

2%

0.6%

0

 

<0.001

<0.001

<0.001

<0.001

Study Author Conclusions

Application of this topical diclofenac solution to the knee of patients with OA produced relief of symptoms equivalent to oral diclofenac, with minor local skin irritation, but significantly reduced incidence of diclofenac-related GI complaints and abnormal laboratory values.

InpharmD Researcher Critique

A strength of this study is the relatively large sample size (sufficiently powered) and the use of validated tools. The authors conducted an intention-to-treat (ITT) and per-protocol analysis of the collected data; the presented data is from the ITT analysis.



References:

Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of a topical diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol. 2004;31(10):2002-2012.