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
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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
Osteoarthritis (OA) is one of the most common causes of joint pain in the United States and non- steroidal anti-inflammatories (NSAIDs), such as Diclofenac sodium, which is currently available in two main routes of administration; oral and topical distribution have been established as one of the standard treatments for OA. Generally, oral NSAIDs are well tolerated; however our narrative review suggests that the topical solution had a better tolerability property than oral Diclofenac sodium, espe- cially due to side effects of gastrointestinal bleeding with the utilization of the oral format. In addi- tion, the topical route may be considered a reasonable selection by clinicians for management of musculoskeletal pain in those patients with a history of potential risk and adverse side effects. Most studies reviewed comparing oral versus topical solution of Diclofenac sodium revealed comparable 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.
ARTICLE HISTORY Received November Revised January Accepted February
KEYWORDS
chronic pain;
musculoskeletal pain;
NSAIDs; oral diclofenac;
osteoarthritis; topical
diclofenac
Introduction
Osteoarthritis (OA) is the most common joint disor- der in the United States and one of the most common causes of chronic pain due to musculoskeletal injury. The number of people affected with symptomatic OA is likely to increase due to the aging of the pop- ulation and the obesity epidemic in North America. The rapid increase in the prevalence of this already common disease suggests that OA will have a growing impact on health care and public health systems in the future. Although ascertaining the incidence and epidemiology of osteoarthritis is challenging, recent literature suggests that a substantial proportion of adults worldwide are affected, and the condition has been on the rise within the last decade. Common joints affected by osteoarthritis include the hip, knee, shoulder, metacarpals, and the spine. This condi- tion has increased in prevalence over the last quarter century and is expected to continue rising, further bur- dening the health care system and decreasing patients’ quality of life. There are many epidemiological fac- tors associated with OA, and increased risk has been
associated with repetitive trauma, continuous overuse and wear and tear, obesity, gender, genetics, as well as certain metabolic, collagen, or endocrine disorders. The pathophysiology of OA initiates early with articu- lar cartilage swelling and development of irregularities and microscopic erosions. The chondrocyte response results in increased type I and III collagen production, which will become loosely fragmented, consequently stimulating the release of intra-articular metallopro- teinases (MPs), responsible for cartilage degradation, thinning, and subchondral cyst formation, which fur- ther produces synovitis, articular inflammation and pain.
Standard pharmacological treatment of osteoarthri- tis targets symptomatic management of the con- dition and most often includes nonsteroidal anti- inflammatory drugs (NSAIDs). These are widely employed in musculoskeletal disease, both for their anti-inflammatory as well as their analgesic proper- ties. Opioids are also widely used for the management of chronic pain, often due to osteoarthritis ; however, this topic is beyond the scope of this paper. Diclofenac,
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 USATCollege 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) [email protected] USATCollege of Medicine; Graduate Program (PhD) in Biomedical Sciences, P.O. Box ,S.MayfieldEstateDrive, Olveston, Montserrat, British West Indies.
© Taylor&FrancisGroup,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. 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. 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
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.
the United States, especially in the elderly population,
1
We conducted a review of the literature utilizing the
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
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. 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. 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. 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
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. 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. 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.
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
(PGE2), vasoactive intestinal peptide (VIP), and
after the plasma levels have substantially decreased.
nitric oxide (NO), which are likely attributed to the synovitis associated with osteoarthritis.
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. For treatment of osteoarthritis, diclofenac was equivalent in efficacy to aspirin, diflu- nisal, indomethacin, sulindac, ibuprofen, ketoprofen,
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. 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. 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. 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. 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
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. 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. 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.
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-
to the inhibition of renal prostaglandins by diclofenac;
tion enhancers such as dimethyl sulfoxide (DMSO).
Evaluation in animal models of the effect of vehicle
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
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. 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
ulcer disease and GI hemorrhage.
22
whether diffusion into the joint is the reason for the
effectiveness of diclofenac. There has also been some evidence that diclofenac may inhibit L-type calcium channels, which participate in pain perception. From a clinical perspective, the appropriate management of OA symptoms has been published in different clinical guidelines, including the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) guidelines. The uti- lization of topical versus oral NSAIDs still remains controversial, with different guidelines expressing
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, 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
contrasting opinions. The Osteoarthritis Research
long term.
9,22,32
International (OARSI) 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
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-
symptoms have been positive.
29
tomatic improvement; however, the elevated cost of
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. Furthermore, according to the 2014 ESCEO guidelines, 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
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. Adverse effects associated with oral diclofenac, such as dyspep-
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
sia, diarrhea, abdominal distention, gastrointestinal
to patient’s questionnaires.
31
bleeding, abdominal pain, and nausea, were reported significantly more frequently with oral diclofenac treatment, in comparison with those utilizing topical solution. 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. 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 Society 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, 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
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
JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY 7
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