Journal of Pain & Palliative Care Pharmacotherapy

ISSN: 1536-0288 (Print) 1536-0539 (Online) Journal homepage: http://www.tandfonline.com/loi/ippc20

Oral Versus Topical Diclofenac Sodium in the

Treatment of Osteoarthritis

Vinicius Tieppo Francio, Saeid Davani, Chris Towery & Tony L. Brown

To cite this article: Vinicius Tieppo Francio, Saeid Davani, Chris Towery & Tony L. Brown (2017):
Oral Versus Topical Diclofenac Sodium in the Treatment of Osteoarthritis, Journal of Pain &
Palliative Care Pharmacotherapy, DOI: 10.1080/15360288.2017.1301616

To link to this article: http://dx.doi.org/10.1080/15360288.2017.1301616

Published online: 07 Apr 2017.

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JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY
http://dx.doi.org/./..

ARTICLE

Oral Versus Topical Diclofenac Sodium in the Treatment of Osteoarthritis

Vinicius Tieppo Francio , Saeid Davani, Chris Towery, and Tony L. Brown

ABSTRACT ARTICLE HISTORY

Osteoarthritis (OA) is one of the most common causes of joint pain in the United States and non- Received  November 
steroidal anti-inflammatories (NSAIDs), such as Diclofenac sodium, which is currently available in Revised  January 
two main routes of administration; oral and topical distribution have been established as one of the Accepted  February 
standard treatments for OA. Generally, oral NSAIDs are well tolerated; however our narrative review KEYWORDS
suggests that the topical solution had a better tolerability property than oral Diclofenac sodium, espe- chronic pain;
cially due to side effects of gastrointestinal bleeding with the utilization of the oral format. In addi- musculoskeletal pain;
tion, the topical route may be considered a reasonable selection by clinicians for management of NSAIDs; oral diclofenac;
musculoskeletal pain in those patients with a history of potential risk and adverse side effects. Most osteoarthritis; topical
studies reviewed comparing oral versus topical solution of Diclofenac sodium revealed comparable diclofenac
efficacy, with minimal side effects utilizing the topical route. The key point of this narrative review is
to help clinicians that currently must decide between very inexpensive diclofenac oral presentations
and expensive topical presentations especially in the elderly population and the pros and cons of such
decision-making process.

Introduction associated with repetitive trauma, continuous overuse

and wear and tear, obesity, gender, genetics, as well as
Osteoarthritis (OA) is the most common joint disor-
certain metabolic, collagen, or endocrine disorders.4
der in the United States and one of the most common
The pathophysiology of OA initiates early with articu-
causes of chronic pain due to musculoskeletal injury.1
lar cartilage swelling and development of irregularities
The number of people affected with symptomatic
and microscopic erosions. The chondrocyte response
OA is likely to increase due to the aging of the pop-
results in increased type I and III collagen production,
ulation and the obesity epidemic in North America.
which will become loosely fragmented, consequently
The rapid increase in the prevalence of this already
stimulating the release of intra-articular metallopro-
common disease suggests that OA will have a growing
teinases (MPs), responsible for cartilage degradation,
impact on health care and public health systems in
thinning, and subchondral cyst formation, which fur-
the future.2 Although ascertaining the incidence and
ther produces synovitis, articular inflammation and
epidemiology of osteoarthritis is challenging, recent
pain.5
literature suggests that a substantial proportion of
Standard pharmacological treatment of osteoarthri-
adults worldwide are affected, and the condition has
tis targets symptomatic management of the con-
been on the rise within the last decade.3 Common
dition and most often includes nonsteroidal anti-
joints affected by osteoarthritis include the hip, knee,
inflammatory drugs (NSAIDs). These are widely
shoulder, metacarpals, and the spine. This condi-
employed in musculoskeletal disease, both for their
tion has increased in prevalence over the last quarter
anti-inflammatory as well as their analgesic proper-
century and is expected to continue rising, further bur-
ties.6 Opioids are also widely used for the management
dening the health care system and decreasing patients’
of chronic pain, often due to osteoarthritis7 ; however,
quality of life.2 There are many epidemiological fac-
this topic is beyond the scope of this paper. Diclofenac,
tors associated with OA, and increased risk has been

Vinicius Tieppo Francio, DC, MS, MD/PhD candidate, is with Variety Care Community Health Center, Pain Management Services and Essential Integrative Health in
Oklahoma City, Oklahoma, USA; and the University of Science, Arts and Technology (USAT) College of Medicine Graduate Program in Biomedical Sciences, Montserrat,
British West Indies. Saeid Davani, R.Ph, MD/PhD candidate, and Chris Towery, MPAS, PA-C, NP, MD/PhD candidate, are with the USAT College of Medicine Graduate
Program in Biomedical Sciences, Montserrat, British West Indies. Tony L. Brown, MD, is with the Department of Neurology, College of Physicians and Surgeons,
Columbia University, New York, New York, USA.
CONTACT Vinicius Tieppo Francio, MD/PhD (c) vinicius.francio@usat.edu USAT College of Medicine; Graduate Program (PhD) in Biomedical Sciences, P.O.
Box , S. Mayfield Estate Drive, Olveston, Montserrat, British West Indies.
©  Taylor & Francis Group, LLC
2 V. TIEPPO FRANCIO ET AL.
a classic NSAID available for oral and topical adminis-
tration, is a phenylacetic acid derivative that competes
with arachidonic acid (ARA) for binding to cyclooxy-
genase (COX), resulting in decreased formation of
prostaglandins, which are biomarkers responsible for
inflammation and pain.8 Diclofenac has both analgesic
and antipyretic activities and is generally well toler-
ated; however, there is evidence of increased serious
gastrointestinal and cardiovascular risks with oral
administration.9 Therefore, with the understanding
that diclofenac has been targeted to provide symp-
tomatic management of OA, and considering that
osteoarthritis is the most prevalent joint disorder in
the United States, especially in the elderly population,1
we postulate that for the symptomatic management of
OA in the population at most risk, elderly population
and those with gastrointestinal, cardiovascular, and
renal comorbidities, the utilization of topical diclofenac
is likely superior than oral diclofenac for efficacy, as
well as for decreased adverse risk of gastrointestinal
and cardiovascular effects.
Therefore, the purpose of this narrative review is to
provide a clinical perspective of current research in this
topic to help clinicians who must decide between very
inexpensive diclofenac oral presentations and expen-
sive topical presentations, especially in the elderly pop-
ulation and those at risk.
Methods
The present study is a descriptive narrative
review regarding the symptomatic management
of osteoarthritis and pain with oral versus topical
diclofenac, specially focusing on the population group
at risk, such as the elderly with slower metabolism
rate and subjects with comorbidities with potential
gastrointestinal or cardiovascular risk. The study was
designed to answer the specific questions postulated
by the authors that for the symptomatic management
of OA in the population at most risk, elderly popula-
tion, the utilization of topical diclofenac is potentially
superior than oral diclofenac for efficacy, as well as for
decreased risk of gastrointestinal and cardiovascular
adverse effects. The search strategy utilized was cate-
gorized as a narrative review of the literature, in which
the studies were reviewed, assessed for quality, and
the results were discussed, emphasizing a clinical per-
spective to medical providers in clinical practice and
not a meta-analytical or statistical discussion of results
and methodology. The study describes the data results
and characteristics about the population (patients
with osteoarthritis) and the phenomenon (use of
oral versus topical diclofenac) being studied utilizing
a clinician’s perspective and not a meta-analytical
or statistical review of the literature. Therefore, we
present a discussion of the results summarized by this
descriptive narrative review in which the main key
point is to help clinicians who currently must decide
between very inexpensive diclofenac oral presentations
and expensive topical presentations especially in the
elderly population, discussing the pros and cons of
such decision-making process.
We conducted a review of the literature utilizing the
following search engines: MEDLINE, Google Scholar,
Index Copernicus, EBSCO, and Science Direct. We
used MEDLINE database and other search engines
in which there was unlimited access and publications
were peer-reviewed. We did not utilize the Embase
database due to cost and limited access, although
cross-references between different databases provided
a wide access to resources. We reviewed a total of
65 references, including clinical guidelines, origi-
nal research, and meta-analyses or state-of-the-art
reviews. The results of the data collected are presented
in a narrative format discussing clinical key points. We
chose not to conduct separate sections of results and
discussion, since there are already published meta-
analyses and state-of-the-art reviews that accomplish
such objective; hence, we propose with this narrative
review to provide a clinical perspective for the discus-
sion of the data results. Only peer-reviewed articles
were used in this review published by the MEDLINE
database. The search was restricted to publications
from 1980 to 2016. The search was limited to studies
published in English language. Of the 65 resources
initially reviewed, 28 references were excluded, since
these were found to be incompatible with the scope
and topic of this paper, and utilization of topical and
oral diclofenac were focused on nonmusculoskeletal
etiologies; therefore, these were excluded. The search
strategy for this review was as follows: Step 1: the
reference list of articles identified by the search engines
were searched and triaged into usable relevant pub-
lications. Step 2: the relevant research articles were
then reviewed by the author(s) and summarized into a
relevant data results description emphasizing a clinical
standpoint. Only peer-reviewed articles were included
based on scope, language, relevancy, and content

pertinent to the publication. Step 3: the author(s)
reviewed the articles and summarized the informa-
tion into this narrative review, emphasizing a clinician’s
standpoint regarding the pros and cons of symptomatic
management of osteoarthritis with oral versus topical
diclofenac and the decision-making between these
interventions.
Discussion
In patients suffering from OA, chronic pain is the
symptom most commonly contributing to functional
limitations and disability. The source of the pain
in symptomatic OA is quite complex; therefore, the
appropriate symptomatic management of OA must
be comprehensive, especially when accompanied by
chronic pain syndrome.10 To properly manage the
symptomatology associated with OA, it is fundamental
to have an understanding of the pathophysiology of the
condition. Osteoarthritis is characterized by a loss of
the functional/biochemical integrity of a joint, in which
the key pathological feature is degeneration of articular
cartilage within the joint associated with chondrosis,
subchondral bone sclerosis, osteophyte development,
and chronic low-grade synovial inflammation.11 The
manifestation of joint pain associated with OA has been
linked to articular inflammation and noxious stimula-
tion of A-delta mechanoreceptors in the fibrous capsule
of joints, and C polymodal nerve endings in the syn-
ovium and surrounding joint components.12 The bio-
chemical properties of osteoarthritis articular inflam-
mation relate to an abnormal remodeling of the joint,
spurred by inflammatory cytokines, such as interleukin
(IL)-1, tuor necrosis factor (TNF), IL-8, prostaglandin
E2 (PGE2), vasoactive intestinal peptide (VIP), and
nitric oxide (NO), which are likely attributed to the
synovitis associated with osteoarthritis.13
Oral diclofenac sodium, a commonly used NSAID
for symptomatic management of OA, has both anal-
gesic and antipyretic activities and is efficiently
absorbed from the gastrointestinal tract, metabo-
lized in the liver, and eliminated by urinary and biliary
excretion. The peak plasma concentrations occur
2 hours after oral administration, and it has been
noted that diclofenac has a relatively short elimina-
tion half-life in plasma (1.5 hours), and it persists
in synovial fluid.14 For treatment of osteoarthritis,
diclofenac was equivalent in efficacy to aspirin, diflu-
nisal, indomethacin, sulindac, ibuprofen, ketoprofen,
JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY 3
naproxen, flurbiprofen, mefenamic acid, and piroxi-
cam. The most frequent adverse effects reported for
oral diclofenac were gastrointestinal bleeding, but
these effects were fewer and less serious than occurred
with aspirin or indomethacin. In addition, diclofenac
caused fewer central nervous system reactions than
indomethacin.15 Furthermore, topical diclofenac
solution had a better tolerability property than oral
diclofenac sodium, especially due to side effects of
gastrointestinal bleeding with the utilization of the
oral format.16 As with all NSAIDs, diclofenac exert
its action by inhibition of prostaglandins through the
cyclooxygenase (COX 1 and COX 2) inhibition. Yet,
diclofenac has been recently associated with inhibition
of the thromboxane-prostanoid receptor, affecting
arachidonic acid release and uptake, inhibiting lipoxy-
genase enzymes, and activating the nitric oxide–cyclic
guanosine monophosphate (cGMP) antinociceptive
pathway. Another recent association of the mechanism
of action of diclofenac sodium includes the inhibition
of substance P, inhibition of peroxisome prolifera-
tor activated receptor gamma (PPARγ ), blockage of
acid-sensing ion channels, alteration of interleukin-6
production, and inhibition of N-methyl-d-aspartate
(NMDA) receptor hyperalgesia.17
After oral administration, the systemic absorption
of diclofenac is very rapid. The rate of absorption may
vary depending on the salt form and the time of admin-
istration with respect to food intake. Approximately
60% of diclofenac reaches the systemic circulation.
The main active metabolite is 4-hydroxydiclofenac
and it has anti-inflammatory and anti-analgesic activ-
ities. Diclofenac accumulates in synovial fluid at levels
that eventually exceed plasma levels and that persist
after the plasma levels have substantially decreased.
Diclofenac administered as the sodium salt was
detectable in synovial fluid for up to 11 hours follow-
ing administration of a 50-mg enteric-coated tablet.18
On the other hand, the administration of topical
diclofenac is well absorbed superficially through the
skin due to the dermis being rich in high-molecular-
weight hydrophobic proteoglycans that allow for the
uptake of water and soluble medications. The dense
capillary and skin lymphatics network allows for pen-
etration to deeper subcutaneous fatty tissue where
lipophilic agents may accumulate the drug at the
site of inflammation.19 Systemic penetration of top-
ical agents is dependent on liposolubility, molecular
weight, charge of the molecule, aqueous solubility,
4 V. TIEPPO FRANCIO ET AL.
and the kinetics of the blood flow with reference to
relative anatomic vascularity.19 For this reason, there
is a lower systemic concentration of the drug and
decrease in systemic side effects when used topically.
For optimal efficacy, the NSAID has to penetrate
to the inflamed tissue in a concentration adequate
to exert meaningful anti-inflammatory activity. The
major diclofenac metabolite, 4’-hydroxydiclofenac,
is primarily mediated by cytochrome P450 2C9
(CYP2C9), and 5-hydroxy- and 3 -hydroxydiclofenac
are mediated by CYP3A4. Diclofenac metabolites
undergo glucuronidation or sulfation followed by
biliary excretion and acyl glucuronidation mediated
by UDP-glucuronosyltransferase (UGT2B7) and oxi-
dation mediated by CYP2C8. Approximately 65%
of the dose is excreted in the urine and approxi-
mately 35% in the bile as conjugates of unchanged
diclofenac plus metabolites.20 Oral Diclofenac use
has been linked to innumerous drug interactions
in the general population, affecting the bioavailabil-
ity, absorptions, metabolism, and effectiveness of
the drug. Diclofenac has been recognized to inter-
act with lithium and digoxin, increasing plasma
concentration levels; with angiotensin-converting-
enzyme (ACE) inhibitors and angiotensin receptor
blockers (ARBs), decreasing the antihypertensive
effect; with hydrochlorothiazide, decreasing renal
function; with beta blockers, decreasing antihy-
pertensive effect; with other NSAIDs, increasing
cardiovascular risk and risk of gastrointestinal bleed-
ing; with aspirin, decreasing the levels of diclofenac;
with warfarin, linked to severe hemorrhage; with
methotrexate, increasing level of methotrexate; with
cyclosporine, increasing the risk for neurotoxicity due
to the inhibition of renal prostaglandins by diclofenac;
etc.21
Oral NSAIDs are among the most commonly pre-
scribed drugs worldwide and are responsible for
approximately 25% of all adverse drug reaction reports
to the Food and Drug Administration Agency (FDA).
NSAIDs are widely prescribed for patients with both
arthritic and rheumatic disease—a population at
increased risk for serious gastrointestinal (GI) com-
plications due to long-term medication use. Hence,
the potential selection of the topical administration of
NSAIDs offers the advantage of local, enhanced drug
delivery to the affected inflamed tissues with a reduced
incidence of systemic adverse effects, such as peptic
ulcer disease and GI hemorrhage.22
Topical diclofenac, which is applied to the skin,
penetrates slowly and in small quantities into the
systemic circulation. Its bioavailability and maximal
plasma concentration after topical application are gen-
erally less than 5% versus 15% with oral treatment of
the drug. Compared with oral administration, topical
application leads to relatively high local concentra-
tions in the dermis and subdermal tissues. Diclofenac
applied topically does reach the synovial fluid, likely
due to the percutaneous absorption rate been strongly
influenced by individual skin properties. 23 Applica-
tion of topical diclofenac solution to the knee joint
of patients with OA produced relief of symptoms
equivalent to oral diclofenac in review of many stud-
ies on the efficacy of this drug in its topical versus
oral form. Topical diclofenac use has been reported
to adversely elicit only minor local skin irritation,
but it is associated with a significant reduced risk
of diclofenac-related cardiovascular, GI complaints,
and abnormal laboratory value.19 One specific study
revealed that topical diclofenac was superior to placebo
for pain, physical function, and overall health. The
most common adverse event associated with topical
diclofenac was dry skin (18.2%) and possible irritation.
Fewer digestive system and laboratory abnormalities
were observed with topical diclofenac than with oral
diclofenac, and topical diclofenac appears to play a
potential role as an effective treatment option for
osteoarthritis with efficacy similar to, but tolerability
better than, oral diclofenac.22
Due to the variability of transdermal absorption,
the use of percutaneous enhancers and solvent com-
positions have been shown essential in microemulsion
formulations and preparations containing penetra-
tion enhancers such as dimethyl sulfoxide (DMSO).24
Evaluation in animal models of the effect of vehicle
on topical diclofenac penetration may lead to future
expansion of therapeutic choices. Diclofenac has been
available in several different topical formulations.
These include diclofenac sodium 1% gel, diclofenac
diethylamine gel 1.16%, MIKA diclofenac spray 4%
gel, diclofenac DMSO lotion, and diclofenac epo-
lamine (diclofenac hydroxyethylpyrrolidine) patch.19
Topical diclofenac diffuses into and out of the synovial
fluid. Diffusion into the joint occurs when plasma
levels are higher than those in the synovial fluid, after
which the process reverses and synovial fluid levels are
higher than plasma levels; however, it is not known
whether diffusion into the joint is the reason for the

effectiveness of diclofenac.25 There has also been some
evidence that diclofenac may inhibit L-type calcium
channels, which participate in pain perception.26 From
a clinical perspective, the appropriate management
of OA symptoms has been published in different
clinical guidelines, including the American College
of Rheumatology (ACR)27 and the European League
Against Rheumatism (EULAR)28 guidelines. The uti-
lization of topical versus oral NSAIDs still remains
controversial, with different guidelines expressing
contrasting opinions. The Osteoarthritis Research
International (OARSI)11 recommendations include
the guideline that topical NSAIDs can be effective in
the treatment of osteoarthritis of the knee specifically.
We acknowledge that these trials regarding the short-
duration utilization of diclofenac and other data are not
equivalent to longer-term exposure clinical trials that
have been documented regarding the use of diclofenac
and other NSAIDs regarding both GI and cardiovas-
cular risks, and there is still a lack of appropriate data
with published studies regarding the potential risks
of topical NSAIDs long term or retrospectively. A few
studies have demonstrated potential adverse effects of
topical diclofenac, such as skin irritation, dry skin, and
dermatitis; however, the most recent reviews regarding
the utilization of topical diclofenac for musculoskeletal
symptoms have been positive.29
Topical diclofenac studies shows that there is
evidence through several randomized studies that
topical diclofenac is an efficacious treatment compared
with placebo for a short duration, with clinical effi-
cacy appearing within the first week and duration of
effect up to 12 weeks. The clinical efficacy of topical
diclofenac is likely secondary to local concentration
when applied. Furthermore, according to these guide-
lines, the utilization of topical NSAIDs should be first
line in the population at risk and considered a rea-
sonable option in healthy subjects, compared with the
utilization of oral NSAIDs, mostly due to the gastroin-
testinal and cardiovascular risks.28–30 Furthermore,
according to the 2014 ESCEO guidelines,28 every
patient suffering from symptomatic OA should be
educated about their condition and provided informa-
tion about weight management, obesity, and exercise
program. Physical therapy and other physical modal-
ities should be considered as first line, in addition to
paracetamol, adjunctive glucosamine, and chondroitin
sulfate. If still symptomatic, topical NSAIDs and topi-
cal capsaicin should be tried first to oral NSAIDs due
to the associated cardiovascular and gastrointestinal
JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY 5
risks. However, this guideline did not consider the
cost-related expenses of topical versus oral NSAIDs,
only clinical effectiveness. The efficacy of topical
NSAIDs was established in several randomized trials,
meta-analyses, and reviews,30,31 and the most sub-
stantial evidence show a moderate relief of OA pain.
Recent randomized trials confirmed that the difference
between topical NSAIDs and their oral counterpart is
the better gastrointestinal and cardiovascular safety of
topical delivery; however, these have not been assessed
long term.9,22,32
Considering the population at risk for chronic
utilization of NSAIDs (elderly and those with his-
tory of comorbidities), the decision-making process
for clinicians in selecting the appropriate dose and
drug formulation is quite challenging and evidently
a clinical dilemma with many variables, such as cost,
clinically efficacy, and side effects. Oral NSAIDs carry a
potential higher risk with cardiovascular and gastroin-
testinal aversion; however, these tend to be significantly
less expensive formulations, and due to low cost and
potential clinical efficacy it still may be challenging
to decide the appropriate formulation. With this nar-
rative review, we present the potential benefits of the
topical solution, which has been considered to carry
a much lower adverse risk and still provide symp-
tomatic improvement; however, the elevated cost of
these solutions certainly create a dilemma for the clin-
ician’s decision-making process. Oral diclofenac 50 mg
monthly cost an average of $109.00, in comparison with
topical diclofenac 1% solution costing an average of
$196.00 monthly. We could not find any peer-reviewed
published studies discussing the potential cost-related
barriers and the dilemma regarding this decision-
making process between oral versus topical diclofenac,
and the majority of the data published rely on clinical
efficacy and adverse effects between the two different
methods. Therefore, considering this important lim-
itation regarding a cost analysis and its implications
in the decision-making process between topical versus
oral diclofenac, we recommend further research in
the field focusing on the impact of the cost and the
decision-making process for health care clinicians
managing patients with musculoskeletal pain deciding
between oral versus topical diclofenac formulation.
The adverse effects associated with NSAIDs intake
in patients suffering from OA are still a serious issue,
especially for the elderly, which is the most common
population affected both by OA and by the prevalence
of cardiovascular and gastrointestinal diseases that can
6 V. TIEPPO FRANCIO ET AL.
potentiate risk with the NSAIDs use. Although two
classes of medications, namely, proton pump inhibitors
(PPIs) and prostaglandins, have shown promise to
collaborate treating NSAID-related gastrointestinal
pathology, this is still problematic due to its asymp-
tomatic nature and adherence challenges.33,34 Adverse
effects associated with oral diclofenac, such as dyspep-
sia, diarrhea, abdominal distention, gastrointestinal
bleeding, abdominal pain, and nausea, were reported
significantly more frequently with oral diclofenac
treatment, in comparison with those utilizing topical
solution.35 The improved safety and tolerability of
topical diclofenac highlight the potential impact of the
use of topical solution in the overall treatment of OA.
COX-2 inhibitors are associated with less gastrointesti-
nal risk (although this risk is not completely mitigated)
but greater cardiovascular risk compared with nons-
elective NSAIDs.36 Most studies reviewed comparing
oral versus topical solution of diclofenac sodium
revealed comparable efficacy and topical administra-
tion suggested low occurrence of adverse effects, which
represents a useful alternative to oral management,
especially in patients with increased risk. Therefore,
our initial query that for the symptomatic manage-
ment of OA in the population at most risk, elderly
population, the utilization of topical diclofenac is likely
of potential efficacy, as well as for decreased risk of
gastrointestinal and cardiovascular adverse effects,
and this appears to be well documented by current
literature and by evidence-based clinical guidelines
that support this decision-making process in clini-
cal practice. Clinical guidelines from the American
Geriatrics Society34 recommend appropriate patient
selection after evaluating the risk of gastrointestinal,
cardiovascular, and renal events, using particular
caution in elderly patients prior to initiating pharma-
cological management with oral NSAIDs. According
to the Royal College of Physician’s Guidelines,37 those
at increased gastrointestinal risk should receive a gas-
troprotective agent such as a proton pump inhibitor
in conjunction with oral nonselective NSAID therapy
or be treated with COX-2–selective NSAIDs in the
absence of preexisting cardiovascular risk.
Conclusions
Evidence-based clinical guidelines recommend that
topical NSAIDs, along with acetaminophen and glu-
cosamine/chondroitin sulfate, should be the first phar-
macological options in the management of OA pain
prior to the use of oral NSAIDS, COX-2 inhibitors, and
opioids. The efficacy of diclofenac topical solution was
also evaluated utilizing standardized patient question-
naires with the use of oral and topical solutions. The
topical solution was considered equivalent from that
of oral diclofenac and produced significantly greater
improvements in pain and physical function according
to patient’s questionnaires.31
Although this study has several limitations, we
provide a discussion of results focusing on the clinical
aspect and the decision-making dilemma between
treating patients suffering from musculoskeletal pain
with oral NSAIDs or topical NSAIDs. It is our opinion
that although oral NSAIDs have been considered to
carry a higher adverse risk potential, especially gas-
trointestinal, renal, and cardiovascular, for healthy
individuals without any comorbidities suffering from
acute or chronic musculoskeletal pain or osteoarthri-
tis, oral NSAIDs or acetaminophen together with
glucosamine sulfate and chondroitin sulfate appear
to be still a clinically safe and cost-effective interven-
tion. However, when considering the population at
risk, such as the elderly and those with gastrointesti-
nal, renal, and cardiovascular comorbidities, topical
solutions may be a very reasonable supplementary
method for the management of musculoskeletal pain,
especially in superficial joints, with skin irritation to
the area been reported the most common adverse
reaction, and no reports of major adverse effects when
compared with oral NSAIDs. The topical NSAID
formulations were designed to be safer than oral
NSAIDs, since the medication is mainly delivered
directly to the joints by transdermal absorption where
the pain is located and theoretically should have
less adverse reactions and low potential risk to the
gastrointestinal, renal, and cardiovascular systems.
Although there are few randomized controlled clinical
trials and meta-analyses discussing the use of oral
versus topical NSAIDs, the studies currently avail-
able are not large or with long-term control of the
topical NSAIDs’ potential long-term adverse effects
and mostly emphasize oral diclofenac side effects.
Therefore, we recommend further research in this field
focusing on the impact of the cost of these different
delivery systems (topical versus oral NSAIDs) and
the decision-making process for health care clinicians
managing patients with musculoskeletal pain, as well as
further research regarding long-term potential adverse
effects of topical NSAIDs, and clinical trials comparing
the utilization of these different delivery methods

with the same formulation and for the same medical
condition.
Limitations
This study has potential limitations. We present a
narrative review with discussion of the results with a
clinical perspective and not a statistical standpoint.
There are already currently published studies pre-
senting actual data comparing oral diclofenac with
topical diclofenac, as well as reviews of composite data
with this scope. Therefore, we present in this study
a clinical perspective of the utilization of oral versus
topical diclofenac, rather than a meta-analysis or state-
of-the-art review of the literature of statistical and
epidemiological results that would be mirroring other
published studies. Hence, our goal was to focus on
clinical aspects by reviewing published data with focal
emphasis on medical providers and the decision-
making process in managing pain with topical versus
oral NSAIDs. The key point of this narrative review
is to help clinicians who must decide between rela-
tively inexpensive diclofenac oral options and relatively
expensive topical options, especially in the elderly pop-
ulation, and the pros and cons of such decision-making
process.
Declaration of interest
The authors report no conflicts of interest. The authors alone
are responsible for the content and writing of the article.
ORCID
Vinicius Tieppo Francio http://orcid.org/0000-0001-6513-
0058
References
1. Zang Y, Jordan JM. Epidemiology of osteoarthritis. Clin
Geriatr Med. 2010;26:355–369.
2. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of
the prevalence of arthritis and other rheumatic conditions
in the United States. Part II. Arthritis Rheum. 2008;58:26–
35.
3. Allen K, Golightly Y. Epidemiology of osteoarthritis: state
of the evidence. Curr Opin Rheumatol. 2015;27:276–283.
4. Hochberg M. Osteoarthritis. In: Silman A, Hochberg M,
eds. Epidemiology of the Rheumatic Diseases. Oxford, UK:
Oxford University Press; 2001:206–229.
5. Wollheim FA, Lohmander LS. Pathogenesis and pathology
of osteoarthritis. In: Hochberg MC, Silman AJ, Smolen JS,
JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY 7
Weinblatt ME, Weisman MH, eds. Rheumatology. 4th ed.
St. Louis, MO: Mosby Elsevier; 2008:1711–1728.
6. Hochberg MC. COX-2 selective inhibitors in the treatment
of arthritis: a rheumatologist perspective. Cur Top Med
Chem. 2005;5:443–448.
7. Boudreau D, Von Korff M, Rutter CM, et al. Trends in long-
term opioid therapy for chronic non-cancer pain. Pharma-
coepidemiol Drug Saf. 2009;18:1166–1175.
8. Bookman AAM, Williams KS, Shainhouse JZ, et al. Effect
of a topical diclofenac solution for relieving symptoms
of primary osteoarthritis of the knee: a randomized con-
trolled trial. CMAJ. 2004;171:333–338.
9. Tugwell PS, Wells GA, Stainhouse 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;31:2002–2012.
10. Shaible HG. Mechanisms of chronic pain in osteoarthritis.
Curr Rheumatol Rep. 2012;14:549–556.
11. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI
guidelines for the non-surgical management of knee
osteoarthritis. Osteoarthritis Cartilage. 2014;22:363–388.
12. Kean WF, Kean R, Buchanan WW. Osteoarthritis: symp-
toms, signs and source of pain. Inflammopharmacology.
2004;12:3–31.
13. Alshami AM. Knee osteoarthritis related pain: a narrative
review of diagnosis and treatment. Int J Health Sci (Qas-
sim). 2014;8:85–104.
14. Hui X, Hewitt PG, Poblete N, et al. In vivo bioavailability
and metabolism of topical diclofenac lotion in human vol-
unteer. Pharm Res. 1998;15:1589–1595.
15. Van Walsem V, Pandhi S, Nixon RM, et al. Relative
benefit-risk comparing diclofenac to other traditional non-
steroidal anti-inflammatory drugs and cyclooxygenase-2
inhibitors in patients with osteoarthritis or rheumatoid
arthritis: a network meta-analysis. Arthritis Res Ther.
2015;17:66.
16. Roth S. Diclofenac topical solution compared with oral
diclofenac: a pooled safety analysis. J Pain Res. 2011;4:159–
167.
17. Gan TJ. Diclofenac: an update on its mechanism of action
and safety profile. Curr Med Res Opin. 2010;26:1715–
1731.
18. Fowler PD, Shadforth MF, Crook PR, John VA. Plasma
and synovial fluid concentrations of diclofenac sodium
and its major hydroxylated metabolites during long-term
treatment of rheumatoid arthritis. Eur J Clin Pharmacol.
1983;25:389–394.
19. Nair B. A review of topical diclofenac use in musculoskele-
tal disease. Pharmaceuticals. 2010;3:1892–1908.
20. Holt RJ. Bioequivalence of diclofenac sodium 2% and
1.5% topical solutions relative to oral diclofenac sodium in
healthy volunteers. Postgrad Med 2015;127:581–590.
21. Novartis Pharmaceuticals Voltaren Monograph. Novartis
Web site. https://www.novartis.ca/sites/www.novartis.ca/
files/voltaren_scrip_e.pdf. Last accessed November 13,
2016.
8 V. TIEPPO FRANCIO ET AL.
22. Lee S, Simon A. Efficacy and safety of topical diclofenac
containing dimethylsulfoxide (DMSO) compared with
those of topical placebo, DMSO vehicle and oral diclofenac
for knee osteoarthritis. Pain. 2009;14:238–245.
23. Heyneman C, Lawless-Liday C, Wall GC. Oral versus top-
ical NSAIDs in rheumatic diseases: a comparison. Drugs.
2000;60:555–574.
24. Altman R, Bosch B, Brune K, Patrignani P, Young C.
Advances in NSAID development: evolution of diclofenac
products using pharmaceutical technology. Drugs.
2015;75:859–877.
25. Dehghanyar P. Topical skin penetration of diclofenac after
single- and multiple-dose application. Int J Clin Pharmacol
Ther. 2004;42:353–359.
26. Yarishkin OV. Diclofenac, a non-steroidal anti-
inflammatory drug, inhibits L-type Ca channels in
neonatal rat ventricular cardiomyocytes. Korean J Physiol
Pharmacol. 2009;13:437–442.
27. Hotchberg M. American College of Rheumatology
2012 recommendations for the use of nonpharmaco-
logic and pharmacologic therapies in osteoarthritis of
the hand, hip, and knee. Arthritis Care Res. 2012;64:
465–474.
28. Bruyere O. An algorithm recommendation for the manage-
ment of knee osteoarthritis in Europe and internationally: a
report from a task force of the European Society for Clinical
and Economic Aspects of Osteoporosis and Osteoarthri-
tis (ESCEO). Semin Arthritis Rheum. 2014;44(3):
253–263.
29. Derry S, Moore RA, Rabbie R. Topical NSAIDs for chronic
musculoskeletal pain in adults. Cochrane Database Syst
Rev. 2016;(4):CD007400.
30. Zhang W, Zhang W, Jones A, Doherty M. Efficacy of topical
nonsteroidal anti- inflammatory drugs in the treatment of
osteoarthritis: meta-analysis of randomised controlled tri-
als. BMJ. 2004;329:324–326.
31. Mason L, Moore RA, Edwards JE, Derry S, McQuay H.
Topical NSAIDs for chronic musculoskeletal pain: system-
atic review and meta-analysis. BMC Musculoskel Disord.
2004;5:28.
32. Taylor RS, Fotopoulos G, Malbach H. Safety profile of top-
ical diclofenac: a meta-analysis of blinded, randomized,
controlled trials in musculoskeletal conditions. Curr Med
Res Opin. 2011;27:605–622.
33. Roth SH. Nonsteroidal anti-inflammatory drug gastropa-
thy. We started it—can we stop it. Arch Intern Med.
1986;146:1075–1076.
34. American Geriatrics Society Panel on the Pharmacological
Management of Persistent Pain in Older Persons. Pharma-
cological management of persistent pain in older persons.
J Am Geriatr Soc. 2009;57:1331–1346.
35. Emery P, Zeidler H, Kvien TK, et al. Celecoxib ver-
sus diclofenac in long-term management of rheumatoid
arthritis: randomised double-blind comparison. Lancet.
1999;354:2106–2111.
36. Lanas A, Tornero J, Zamorano JL. Assessment of gas-
trointestinal and cardiovascular risk in patients with
osteoarthritis who require NSAIDs: the LOGICA study.
Ann Rheum Dis. 2010;69:1453–1458.
37. National Collaborating Centre for Chronic Conditions.
Osteoarthritis: National Clinical Guideline for Care
and Management in Adults. London: Royal College of
Physicians; 2008. http://www.nice.org.uk/nicemedia/pdf/
CG059FullGuideline.pdf. Accessed May 5, 2010.