INTRODUCTION:

The drug diclofenac sodium topical gel is used to treat knee arthritis¹. It belongs to a class of NSAIDs that reduces inflammation on the part of your body that is afflicted, you can apply this gel to your skin as instructed. It belongs to a class of drugs known as NSAIDs and works by reducing inflammation. This medication may also be used for other conditions. In joints that potentially benefit from therapy through the skin, diclofenac sodium topical gel is used to relieve osteoarthritis discomfort².

Your hands and knees are among these joints. Actinic keratosis can also be treated with diclofenac topical gel³. Topical gel formulations continue to be among the most used and significant pharmacological dosage forms. As a result, the therapeutic effects of the medications are successfully obtained, and the systemic adverse effects are either prevented or reduced. The most recent advances in topical formulation are topical semi-solids for systemic medication administration⁴.

In comparison to oral drug delivery systems, topical formulations are used to treat a wide range of illnesses, are simple to give, and have quick effects. Different dose forms, including gel, cream, paste, and others, are available for topical medications⁵. Topical gel formulations are a good choice for drug administration since they are less oily, simple to remove from the skin, and have physicochemical characteristics including pH, Spreadability, rheological properties, release studies.

Osteoarthritis (OA) is a joint disease with a complex origin that eventually results in the loss of joint function and is accompanied by pain, stiffness, reduced mobility, and, in some cases, disability⁶ OA is defined as a painful, inflammatory arthritis of the cartilage1 that is influenced by genetic, immunological, mechanical, and other inflammatory related factors. Clinical evidence has shown anomalies of the synovium, synovial fluid, and subchondral bone, and inflammatory alterations have regularly been found in affected joints, especially with more advanced disease. Reduced mobility, poor quality of life, and a heavy load of both acute and chronic pain are all consequences of OA, particularly of the knee⁷.

The projected lifetime risk of osteoarthritis of the knee is 13.8%, with non-obese males having a risk of 9.6% and obese females having a risk of 23.9%. By the time they reach the age of 60, 9.3% of Americans will have been given a diagnosis of symptomatic knee OA. The median age for knee OA diagnosis is thought to be 55 years old. By the age of 85, nearly one in two persons risk developing symptoms of knee OA, with lifetime risk highest in obese people. Nonsteroidal anti-inflammatory medications (NSAIDs) have both anti-inflammatory and analgesic effects, in part because they prevent prostaglandin production from occurring. One of the most popular treatments for treating the symptoms of OA is the use of NSAIDs. Oral NSAIDs, however, are linked to a higher risk of renal, gastrointestinal, and cardiovascular toxicity⁸.

NSAIDs used topically have lower systemic exposure than NSAIDs taken orally which typically lowers the frequency of gastrointestinal and other related adverse events⁹. For patients with comorbidities, such as the elderly or those who have trouble swallowing oral drugs, this is a crucial factor to take into account¹⁰. Additionally, in patients with knee OA using anticoagulants, as well as in those with renal and/or hepatic dysfunction, heart failure, severe respiratory illness, and other pathological conditions, topical administration is advantageous in delivering pain relief while reducing toxicity¹¹.

As with other NSAIDs, the exact mechanism of action of diclofenac is unknown, however it may be connected to the inhibition of prostaglandin synthetase or cyclooxygenase. There are currently several topical diclofenac formulations available¹².

Methods of Topical Gel:

Patients between the ages of 40 and 85 who had radiographically confirmed primary osteoarthritis of the knee within a year of screening and who scored a 2 or 3 on the Kellgren-Lawrence scale were eligible for inclusion. They also had to be receiving stable analgesic therapy, which means taking an NSAID or acetaminophen at least three days a week for the previous month. Before beginning study treatment, enrolled patients underwent a 3–14-day medication washout period and had to exhibit a "moderate flare" (defined as a baseline minimum pain score of at least 5 on an 11-point numeric rating scale [NRS] and at least a 2 unit worsening from the baseline.

Secondary osteoarthritis (OA) (defined as OA with a specific cause, such as an injury or an effect of obesity, genetics, inactivity, or another disease) or symptomatic chondrocalcinosis (determined by radiographic diagnosis with symptoms present) of the study knee, study drug contraindications or known sensitivity to diclofenac or other NSAIDs, other severe medical condition, and any abnormality that could cloud interpretation of the safety results were the exclusion criteria. Patients were also disqualified if they had undergone significant surgery, suffered substantial knee injury in the past, or had mild knee damage. surgery on the study knee within a year of screening; corticosteroid injection into the primary study knee within 90 days of screening or into any other joint within 30 days of screening; or topical corticosteroid use on the study knee. Examples of minor surgery include cartilage repair, collateral ligament repair, and arthroscopic debridement.

The primary study knee's intra-articular viscosupplementation in the six months before screening, prior use of a stable opioid analgesic, any other painful or incapacitating conditions affecting the knee or leg, incapacitating condition of the hands, and skin disorder with current involvement of the hands or knee were also exclusion criteria. having advanced osteoarthritis (OA) of the knee to the point where all cartilage was eroded (radiographic examination revealed that the joint space was eliminated in both the lateral and medial tibia/femoral compartments); being advised to have knee replacement or knee reconstruction surgery; or experiencing chronic headaches requiring acetaminophen.

Treatment:

An interactive Web-based system randomly assigned patients to receive diclofenac sodium topical gel. To make sure that each therapy group received an equal number of patients, a balanced randomized block design.

The research medicine was applied for the first time under supervision at the study center (around 2 mL, or two pumps of the bottle each knee every 12 2 hours for 4 weeks), but subsequent administrations were self-administered on an outpatient basis. A comprehensive instruction manual was used to teach patients on how to give the study medicine. Patients might begin therapy with the same regimen and maintain it until the study's conclusion if the contralateral knee hurt at any time during the investigation (even at baseline). Based on information from the diclofenac sodium 1.5% solution development program and previously published studies, the study medication dose and frequency as well as the trial's four-week length were chosen.

During the course of therapy, patients were permitted to use acetaminophen (paracetamol) as rescue medicine as needed (up to 1950 mg per day), with the exception of the three days previous to each clinic appointment. At each appointment, the causes of withdrawal were noted. Utilizing an interactive voice response system (IVRS) to get patient reports of study medication administration daily for each dosage and comparing the weights of the study medicine bottles that were supplied and returned, study medication compliance was measured¹³.

Topical Diclofenac Efficacy in Osteoarthritis:

The effectiveness of topical diclofenac in treating chronic pain associated with OA has been shown by thorough reviews and meta-analyses. Recent network meta-analysis of observational studies and randomized controlled trials (RCTs) mostly of knee OA found that topical diclofenac was better to placebo for both pain relief and functional improvement¹⁴.

The most current systematic evaluation of topical diclofenac trials in patients with knee or hand OA was carried out by Wiffen et al. In five 6- to 12-week studies, they found that 59% of patients treated with topical diclofenac gel or solution experienced clinical success (defined as a 50% reduction in pain intensity or an OARSII response) compared to 48% of patients treated with a placebo (carrier alone; risk ratio (RR) 1.2; 95% CI 1.1-1.3). Wiffen et al. showed clinical success (C 50% decrease in pain or patient global rating of very good or outstanding) in five 2- to 6-week investigations in patients with knee OA in 43% treated with topical diclofenac plaster, gel, or solution against 23% with placebo¹⁵.

Topical diclofenac and an oral NSAID were directly compared in three RCTs, and all three found that they provide at least comparable relief from OA pain and other symptoms. In two of these studies, oral diclofenac was utilized. Ibuprofen was employed as the comparative and third. In the aforementioned meta-analysis, both topical vs. oral diclofenac trials were compared side by side. A 12-week double-blind, double-dummy study comparing topical diclofenac solution (1.5% diclofenac sodium in 45.5% dimethyl sulfoxide [DMSO]) with oral diclofenac capsules 50 mg three times per day (the maximum daily dose) in patients with symptomatic primary knee OA (per protocol N = 492) was one of the two topical vs. oral diclofenac studies¹⁶.

Although patients with discomfort in both knees were permitted to apply the topical cream to both, only the knee that had the highest pain at baseline was taken into account when evaluating the effectiveness. Topical and oral diclofenac were associated with similar rates (P [ 0.05) of improvement across all variables of pain (44 vs. 49%), physical function (39 vs. 46%), and stiffness (39 vs. 45%), as well as on a patient global assessment (43 vs. 49%), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at the end of 12-week treatment (or earlier discontinuation). All variables met prespecified criteria for equivalency.

So, according to the most recent research, topical diclofenac decreases OA pain and stiffness and enhances physical function, at least to the same extent as some NSAIDs taken orally. Notably, oral NSAID dosages were employed in two of the three head-to-head tests with topical diclofenac that were lower than the maximum recommended levels. The outcomes of these two trials, however, agreed with those of the study that employed the highest dosage of oral diclofenac as a comparator as well as with research and meta-analyses that also included other topical NSAIDs.

Additionally, it should be highlighted that although the trials included here only looked at effectiveness in a single target joint, patients with polyarticular arthritis in real life may use topical diclofenac on several joints at once. In these circumstances, it is important to carefully observe the dosage recommendations, especially those relating to the maximum daily doses that should be applied to all joints. The topical mode of administration, together with the therapeutic benefits of the active component, may favourably contribute to the perceived pain reduction in OA¹⁷.

Epidemiology:

Even though OA may affect any joint, it most frequently affects the knees, hips, hands, facet joints, and feet. Over 26 million Americans were thought to have OA in 2005, according to estimates. However, the prevalence of OA varies significantly based on the criteria employed, as well as the age, sex, and geographic location analyzed. The highest stated prevalence is based on a radiological case definition of OA. The frequency of hand, hip, and knee osteoarthritis as seen on radiographs¹⁸.

Hand Oa:

According to reports, the prevalence of radiographic hand OA might range from 27 to more than 80%. In research from the Netherlands, distal interphalangeal (DIP) joints showed signs of OA in 75% of women between the ages of 60 and 70, while OA radiological abnormalities were identified in 10-20% of participants between the ages of 40 and 50.8 According to data from the Framingham cohort, the frequency of at least one hand joint having symptomatic osteoarthritis was 13.2% for men and 26.2% for women who were 70 years of age or older. All of the men over 65 in a rural Turkish sample had at least one hand joint that was damaged¹⁹.

Though far less frequent, symptomatic hand OA meets the ACR criteria. In the third National Health and Nutrition Examination Survey (NHANES III) of the United States and the Framingham cohort, it was discovered to be 8% and 7% prevalent, respectively. Rates rose to 13 and 26% for males and women, respectively, among senior people. According to research from Teheran, 2.2% of adults aged 40 to 50 had hand OA, and that number rose to 22.5% by the time a person reached their seventies. Gender differences in this sample demonstrated that women were more commonly impacted than males, in line with numerous researches, including the Framingham cohort. It's interesting to note that data from China based on 13 studies including 29 621 individuals showed that symptomatic OA of the hand was seldom present²⁰.

Knee Oa:

Although it is more prevalent in women, with a female-to-male ratio ranging between 1.5:1 and 4:1, knee involvement happens less commonly than hand OA. Population studies conducted in the USA show that prevalence rates for knee OA are similar to those in Europe. According to this research, 1% of individuals between the ages of 25 and 34 and almost 50% of individuals 75 years and beyond had serious radiographic abnormalities. The prevalence of radiographic knee OA increased from 19.2% among individuals in the Framingham Study over the age of 45 to 43.7% among those over the age of 80. The Dutch Institute for Public Health reported that among those 55 and older, the prevalence of knee OA was 15.6% for men and 30.5% for women.10 Only 12.1% of NHANES III individuals and 16.3% of Johnston County Osteoarthritis Project participants aged 55 to 64 had symptoms of knee OA, respectively.

There is significant regional diversity in the epidemiology of OA. Studies from China that followed the Framingham Study's methodology and criteria discovered that the prevalence of bilateral knee OA and lateral compartment disease was two to three times greater in Chinese cohorts than it was in the Framingham OA study's estimations. The Community Oriented Program for Control of Rheumatic Disorders (COPCORD) studies in Asia found that the prevalence of clinically diagnosed knee OA in this region ranged from 1.4% in urban Filipinos to 19.3% in rural communities in Iran. This divergence could have been caused in part by the physical and socioeconomic surroundings. The COPCORD investigations carried out in Pakistan, Bangladesh, and India notably examined variations between rural and urban populations. In India, the urban population had a crude prevalence of clinically diagnosed knee OA that was greater (5.5%) than that of the rural population (3.3%). In spite of accounting for age and sex distribution, rural areas had a greater frequency. Furthermore, as compared to males from metropolitan areas in China, men aged 60 and older from rural communities had around double the frequency of symptomatic knee OA²¹.

Hip Oa:

Compared to OA in the hands or knees, hip OA is less frequent. In studies from Asia and Africa, the mean prevalence of primary radiographic hip OA is 1.4 and 2.8%, respectively. These numbers are significantly lower than those observed in North America and Europe, where the mean prevalence is 7.2% and 10.1, respectively.18 When examining osteoporotic fractures in women over 65, the prevalence of radiographic hip OA was examined using 11 alternative criteria. Depending on the criterion utilized, the prevalence ranged from 1.8 to 9.4% when the minimum joint gap of 2.5 mm was excluded. In contrast, the study of the Johnston County sample found that the prevalence of symptomatic hip OA ranged from 5.9% in people aged 45 to 54 to 17% in those aged 75 and above²².

Pathology:

The pathophysiology of OA may potentially be influenced by systemic inflammation. Body weight was discovered to be a significant risk factor for developing hand OA in research by Yusuf and colleagues 9(2010). This implies that there may be other effects of obesity than those related to body weight and joint function. This study and others indicate that systemic variables associated with obesity, metabolic syndrome, and atherosclerosis likely have a systemic role in the development of OA, probably through leptin and other adipokines. Research is also being done on the direct effects of aging on cartilage (caused by chondrocyte senescence, DNA damage, aging of the cartilage matrix, oxidative stress, mitochondrial dysfunction, and autophagy), as well as the impact of the endocrine system and estrogen on joint health.

A simple "wear and tear" condition was once assumed to be all that OA was. The breakdown of the joint's articular cartilage and the subsequent inflammation were believed to be caused by chronic overload and poor biomechanics. Stiffness, bruising, and decreased movement followed as a result. We now understand that the causes of OA, which include inflammatory and metabolic variables, are considerably more complicated²³.

Articular cartilage, which suffers substantial degradation throughout the course of the illness, is the structure that OA most noticeably affects. In the intervertebral discs and at the ends of long bones, there is smooth cartilage called articular cartilage. While being able to transmit large loads, it has a low friction articulation surface. Even with slight injuries, cartilage heals very slowly, if at all. This is despite the fact that the collagen within it has a lengthy half-life. Despite the most obvious alterations occurring in the cartilage, the synovium, joint ligaments, and subchondral bone are all impacted along with the cartilage. The pathophysiology of OA is heavily influenced by inflammation, including systemic inflammation and active synovitis.

One explanation is because worn-out cartilage causes the synovial cells to experience a foreign body response. As a result, more cartilage may be destroyed by metalloprotease synthesis, synovial angiogenesis, and the release of inflammatory cytokines. According to some views, the innate immune system and activated synovial macrophages play a crucial role in the development of OA²⁴.

Risk Factors:

Both systemic and local variables influence the likelihood of developing OA. Numerous systemic variables have been found; they may function by making joints more prone to damage, by directly harming joint tissues, or by hindering the process of healing in injured joint tissue. Local variables that have a negative impact on the forces acting on the joint are often biomechanical in origin. Obesity and metabolic diseases, age, sex, ethnicity, and race, genetics, diet, smoking, bone density, and muscular function are only a few of the particular risk factors that have been found. There are a number of risk factors for the onset of OA, although much fewer have been linked to the development of OA. Evidence for these connections is frequently sparse, despite the possibility that variables that encourage the development of a disease can also speed its course. OA often worsens gradually over many years. Additionally, it's possible that vascular disease will both start and speed up the development of the OA condition.

This may be caused by microemboli, stasis, or venous occlusion, which results in an occasional decrease in blood flow through tiny veins inside the subchondral bone. In addition to its direct negative effects on the bone itself, subchondral ischaemia may subsequently impair the transport of nutrients and gas exchange to articular cartilage. Additionally, those who have osteoarthritis have a higher chance of using analgesics like NSAIDs, which raise the risk of cardiovascular disease, and being physically inactive. This may help to clarify why these two diseases are often associated²⁵.

Significant correlations between OA and cardiovascular risk factors including high blood pressure and cholesterol levels have also been shown by studies. However, there is conflicting clinical data linking diabetes with OA. Numerous studies did discover a link between diabetes and OA, and intriguing theories have been put forth to explain this association, such as the idea that high glucose concentrations cause the production of reactive oxygen species and advanced glycation end products, which cause cartilage to deteriorate and degenerate. Further investigation is necessary because other studies were unable to confirm the link²⁶.

Age:

As people age, radiographic and symptomatic OA prevalence and incidence both significantly rise. As a result of several different individual variables, including oxidative damage, cartilage thinning, muscle deterioration, and a decline in proprioception, the association between age and the risk of OA is probably complex. Aging also causes a deterioration in the fundamental biological systems that keep tissues in a state of homeostasis, which impairs the body's ability to respond to stress or joint damage and causes loss and death of joint tissue²⁷.

Gender:

Women are more likely than males to develop knee, hip, and hand OA, and this risk rises sharply at menopause in women. Researchers have hypothesized that hormonal variables may contribute to the development of OA as a result of the latter discovery, however clinical and epidemiologic study findings have not always supported this. Radiographic knee and hip OA or the progression to joint replacement have both been demonstrated to be protected by estrogen or hormone replacement treatment. However, despite the inability to do a single analysis of the studies due to study heterogeneity, a recent systematic review of 16 research identified no conclusive link between sex hormones and radiographic hand, knee, or hip OA in women²⁸.

Smoking:

The link between smoking and OA has been the subject of contradictory reports. Smoking and OA have been linked in some research to a protective relationship, while in other studies, smoking and OA have been linked to higher risks of cartilage loss and knee discomfort. The protective effect of smoking on the development of OA (OR: 0.87; 95% CI: 0.80 -0.94) seen is most likely a myth, according to a new meta-analysis of observational data.31 It could be due to selection bias because many studies have been done in hospitals with control people who have illnesses connected to smoking and who are recruited as participants in studies that are not mainly intended to study smoking²⁹.

Osteoporosis:

Similar to OA, osteoporosis is a frequent bone condition associated with aging. Early findings suggested that having low bone mineral density (BMD) would be protective against OA, however further research has contradicted these conclusions. Increased bone mineral density (BMD) has been consistently linked to the onset of osteoarthritis of the knee (OA) in three studies examining women. This finding is supported by a systematic review and meta-analysis of the risk factors for the onset of osteoarthritis of the knee, as defined by radiology or self-report, in older adults. While a clear molecular foundation and similar pathophysiology have not been found to account for the negative relationship between osteoporosis and osteoarthritis, a hereditary component may help explain why the conditions seldom coexist³⁰.

Local Mechanical Risk Factors:

One of the biggest risk factors for the development of knee OA is a severe knee injury. An increased chance of developing osteoarthritis (OA) and musculoskeletal problems can be brought on by acute injuries such as fractures, dislocations, meniscal and cruciate tears, and fractures. The following increased risk of osteoarthritis (OA) is partly due to changed load distribution within the joint and disturbance of normal biomechanics, in addition to direct damage to local tissues caused by the trauma. If the person already has OA in another joint, the risk is increased much more. The risk of developing osteoarthritis (OA) in the affected joints is increased by repetitive and excessive joint loading that goes along with particular physical activity³¹.

Employees with repetitive pincer grip requirements have a higher chance of developing radiographic hand osteoarthritis (OA), especially in the DIP joint.36 Extended kneeling and squatting puts strain on the bigger joints, which raises the possibility of moderate-to-severe radiographic knee OA. Research looking into the connection between athletic activity and OA thereafter has produced mixed findings. Runners who compete in long distance races may have an increased risk of hip and knee osteoarthritis (OA), according to some evidence. According to some research, moderate recreational jogging and sports involvement do not seem to raise the chance of developing radiographic hip or knee OA in the absence of joint damage³².

The way that weight is distributed over the articular surfaces of the knee is influenced by its mechanical alignment. The medial compartment transmits between 60 and 70 percent of the weight-bearing stress in a knee that is positioned appropriately. The load distribution is affected by any change in a valgus or varus direction. The articular cartilage and other joint tissues are assumed to be under increased stress due to abnormal increases in compartmental loading, which eventually results in degenerative deterioration. The advancement of radiographic knee OA is independently correlated with knee malalignment, as shown by a comprehensive study³³.

Summary:

An essential part in preserving the typical physiological structure and function of articular cartilage is the articular chondrocyte, which is the sensor of articular cartilage homeostasis. Aging and aberrant mechanical stress are two of the many variables that might upset the homeostasis of articular chondrocytes, as evidenced by recent research. The balance between anabolic and catabolic activity in articular cartilage can also be upset by genetic changes in the TGF-b/Smad, Wnt/b-catenin, and Ihh signaling pathways, which can lead to the irreversible breakdown of the extracellular matrix. The majority of osteoarthritis animal models to date have converged on the up-regulation of catabolic enzymes, such as MMP-13 and ADAMTS5, indicating that these enzymes may be useful therapeutic targets in controlling the course of OA.

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Received on 06.11.2023 Modified on 02.03.2024

Research J. Topical and Cosmetic Sci. 2024; 15(1):53-59.

DOI: 10.52711/2321-5844.2024.00010