What is the selection process for osteoarthritis pharmacotherapy?

ABSTRACT

Osteoarthritis is the most prevalent joint condition that continues to increase with an ever-aging population and the rising tide of obesity. There are multiple recommendations/guidelines for the management of osteoarthritis. The basis of management should focus on self-management and education, lifestyle modifications, exercise and when appropriate, weight loss. Pharmacotherapy is targeted toward pain palliation with no agents available presently to target prevention and disease modification. The selection of pharmacotherapy should be tailored to the individual, taking into account of personal preferences and interactions with underlying co-morbidities. This editorial provides a guide to the selection process of presently available pharmacotherapy in osteoarthritis.

KEYWORDS:

• Osteoarthritis; management
• guidelines
• knee
• hip
• polyarticular osteoarthritis

1. Introduction

Osteoarthritis (OA) is the most prevailing joint condition. With the uprising trend in the number of individuals affected annually and the expectations that the numbers will continue to rise, it poses tremendous impact on the individuals affected along with substantial consequences on the health-care systems and wider socioeconomic systems [1,2].

The pathophysiology of OA itself has migrated from traditional concepts of a degenerative process. Rather, it is a process of excessive mechanical stress that overwhelms the joints innate reparative potential applied in the setting of systemic susceptibility [3]. It is a complex disease with whole joint involvement, that incorporates associated structural alterations of the articular cartilage, meniscus, synovial membrane, subchondral bone, ligaments, capsule and peri-articular musculature [4]. Osteoarthritis pain pathogenesis itself is an intricate biopsychosocial model that encompasses interactions between catabolic and inflammatory cytokines and sensitization of nociceptive pathways by the activation of primary afferent nerves in response to inflammation or tissue injury [5–8]. Apart from nociceptive pain mechanisms, there is increasing recognition of neuropathic/central pain mechanisms in OA patients [8,9].

Despite individuals experiencing a wide range of clinical symptoms including a reduction in physical function, range of movement restrictions, joint stiffness, joint instability and bony enlargements, joint pain is still the hallmark feature that promotes individuals to seek healthcare intervention. Similarly, pain is the main factor upon which clinical decisions are made in the healthcare setting [7,10].

This editorial aims to discuss the currently available pharmacological therapies for OA and the selection progress behind these agents.

2. Pharmacotherapy for Osteoarthritis

Currently, available management therapies focus on pain alleviation and are regarded as palliative, given the current lack of preventative or curative treatments. Surgery should be regarded as the end of line therapy after failure of response to appropriate, conservative options. The National Institute for Health and Care Excellence (NICE), American Academy of Orthopedic Surgeons (AAOS) and the recently updated Osteoarthritis Society International (OARSI), European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and American College of Rheumatology/Arthritis Foundation guidelines recommend that first-line therapy for OA, whether it is for knees, hip, or polyarticular OA, to focus on conservative therapy with an emphasis toward education, lifestyle modifications with weight loss (in overweight/obese persons), water and land-based exercise, strength training and instilling self-management skills for a chronic disease process [11–16]. The utilization of aids such as orthoses and braces are possible adjuncts to the above strategies in addition to recommended pharmacotherapies (Table 1).

Table 1. Pharmacologic recommendations from NICE, AAOS, OARSI, ACR and ESCEO guidelines for OA.

Pharmacotherapy mainly targets pain with no apparent favorable effect on disease progression. Topical and oral non-steroidal anti-inflammatory drugs (NSAIDs) or Coxibs have taken over from paracetamol as first-line medications and are strongly recommended over other available oral medications [11,17]. Even though NSAIDs/Coxibs are thought to exert effects on some of the inflammatory processes in OA, there are associated potential concerns regarding cardiovascular, gastrointestinal and renal side effects that may limit its use in the OA population, where a substantial proportion of people have multiple health comorbidities [18–20]. Therefore, it is imperative that risk reduction is taken into consideration in the prescription of these medications, whether it be using the lowest dose for the shortest duration possible, or considering other alternatives if there are contraindications.

Whilst paracetamol/acetaminophen is not recommended as first-line treatment given minimal benefit is seen from meta-analysis in OA [17], it is likely that majority of symptomatic OA patients will have trialed the medication in the context of it being readily available over-the-counter and its perceived safety of use. Actual symptomatic relief and possible hepatotoxicity in the individual must be taken account of with ongoing regular usage.

Other pain management alternatives include opioid-based medications, which have demonstrated no clinically meaningful effects on pain, with associated side effects of dizziness, nausea, vomiting and constipation, along with increases in adverse events of cardiovascular events, falls and fractures [11,21,22]. The dependency potential of these medications also raises concern in the setting of the current opioid crisis. In situations where no other pharmacological or surgical options are available, opioids can be considered, but it has been recommended that tramadol should be conditionally used over non-tramadol opioids with a short duration period [13].

Duloxetine, a serotonin-noradrenaline reuptake inhibitor, is another option targeting the concept of central pain sensitization in knee OA. Efficacy has been demonstrated in multiple chronic pain settings. It has only been investigated primarily in knee OA, with no significant differences in effect on pain when indirectly compared with NSAIDs and opioids [23,24]. The use of this drug in OA is generally off-label in most countries.

Intra-articular injection therapies are often utilized especially in the setting of symptomatic monoarthritis, in an attempt by clinicians to minimize the need for systemic therapies. Currently available intra-articular pharmacologic therapies that are not ‘biological’, are corticosteroids and viscosupplements (hyaluronate). In reference to current guidelines for knee OA, intra-articular injections are preferred as the last non-operative alternative where other conservative modalities have failed, or not recommended at all based on their limited efficacy profiles [14,25].

In osteoarthritis, intra-articular corticosteroids do have positive effects over that of placebo, but it is short-lasting of up to 6 weeks duration from Cochrane reviews in terms of pain and function improvements [26,27]. In patients who present with acute OA exacerbations with clinical features of joint effusion and inflammation, intra-articular corticosteroids may be contemplated, but the quality of evidence for corticosteroids, even in the short term is low, with high risk of bias [28]. In patients with indolent OA symptoms, repeated injections are considered inappropriate. Recent studies demonstrated the potential that specific corticosteroid preparations or frequency of injections may accelerate cartilage loss [29,30]. Infection post intra-articular corticosteroid, remains the main adverse event concern with the rate of septic arthritis post arthrocentesis being estimated at 1 in 2000 to 1 in 15,000. Reactive flares to intra-articular corticosteroid can also occur, usually about 6–12 hours post-injection, and resolve spontaneously in up to 3 days [31,32].

The use of exogenous intra-articular viscosupplements is based on the concept that it may restore the viscoelastic properties of the osteoarthritic joint with the added benefit of potential analgesic and anti-inflammatory properties [33]. The main issue with this therapy is that the apparent benefit is seen mainly in trials with a higher risk of bias. There are numerous comparative trials assessing viscosupplementation to that of placebo, corticosteroids, NSAIDS, platelet-rich-plasma and paracetamol. However, the evidence is conflicting. Viscosupplement have been shown to be superior to placebo, corticosteroids and NSAIDs, in terms of knee pain and function [34,35]. However, in general, meta-analysis of viscosupplements has shown that the overall effect size of this injection is small and not of clinical importance [36], and when assessing best-evidence randomized controlled trials, differences between hyaluronic acid and placebo were not observed [37]. In addition to the high cost per injection, there are potential harms ranging from minor side effects including injection site pain, local joint pain and swelling to more serious side effects such as the development of a pseudoseptic reaction, or a flare of crystalline arthritis [38].

Nutraceuticals are popular with their direct marketing and labeling of the products stating its potential benefits for specific chronic conditions. The use of fish oil, vitamin D, glucosamine, chondroitin sulfate are all discouraged in OA guidelines. There is limited evidence of their efficacy in OA, and glucosamine, the most commonly used supplement is now strongly recommended against by OA guidelines [13]. There are concerning publication biases in glucosamine trials with a trend toward a larger effect size in industry-sponsored trials [39]. Lately, there has been more topical focus toward curcumin, the principal curcuminoid extracted from turmeric root (curcuma longa). Curumin is thought to be an inhibitor of nuclear factor-kappa β (NF- κβ) and may have pain reduction effects in OA. A recent double-blind multi-center, randomized placebo controlled trial of a bio-optimized curcuma longa extract showed a significant decrease in knee OA pain, with positive trends for Patient Global Assessment of Disease Activity and serum sColl2-1, a biomarker of cartilage degradation [40]. The study is of short duration with 150 participants, and further large-scale investigational trials are required before conclusive recommendations can be made for this nutraceutical.

The limitations of available pharmacotherapy for OA, has led to investigational use of traditional anti-rheumatic medications along with intra-articular ‘biological’ or blood-derived therapies. Disease modifying agents for anti-rheumatic drugs such as methotrexate and hydroxychloroquine, along with bisphosphonates, tumor necrosis factor (TNF inhibitors) and IL-1 receptor antagonists are not recommended based on failed clinical trials in OA. Despite commercial availability of platelet-rich plasma and stem cell injections, international OA guidelines strongly oppose the employment of these injections in hip and knee OA due to trial heterogeneity and lack of standardization in preparation and techniques [13]. High-quality investigational trials and cost-effective analysis are required, before further advocation of these therapies.

Development of disease-modifying osteoarthritis drugs are under development and trials that act on different aspects of the OA pathway, targeting inflammation, cartilage catabolism/anabolism and increasing cartiage repair. Some promising agents include Sprifermin, a fibroblast growth factor 18, Wnt/β catenin signaling pathway inhibitors and Gene therapy (TissueGene-C) (allogeneic human chondrocytes modified to express transforming growth factor- β1) [41].

3. Expert Opinion

Despite the rising prevalence of OA amongst society, there is no pharmacotherapy that can prevent, halt or reverse disease progression. Symptom control continues to be the goal of treatment in most circumstances; thus, it is imperative that management should incorporate treatment modalities other than pharmacological agents. Care of patients with OA should be patient-specific and tailored to their individual requirements and goals. Clinical algorithms are readily available to aid in OA guideline dissemination to help clinicians to make educated and appropriate decisions toward the care of OA patients [42]. We echo the recommendations and guidelines of the different governing associations, starting with education/self management, weight loss, exercise and physical activity, followed by medications. The decision of medication takes onboard single versus multiple joints with OA symptoms and patient’s comorbidities, with a preference toward topical anti-inflammatories, followed by oral anti-inflammatories with gastroprotection cover. Should anti-inflammatories be contra-indicated, consideration of less preferenced analgesics such as tramadol or intra-articular corticosteroids can be utilized.

Ultimately, there needs to be a shared decision-making approach between the clinician and patient, especially with pharmacotherapy. Patients should be informed of the evidence of benefit in this context and the lack of high-quality clinical trials in many circumstances. Prioritization of patient safety is imperative, regardless of what pharmacotherapy is chosen and regular monitoring of patients’ responses will not only ascertain safety, but also check adherence, and encourage concurrent life-style modifications. Across the board, effective and evidence-proven lifestyle behavior modification strategies are underutilized [43], and this is multi-factorial due to lack of availability of service providers, government support or individual financial limitations.

OA is a chronic disease and should be viewed similar to other chronic pain conditions, where the recommended goals of treatment are aimed at limiting the use of analgesics and concentrating on the incorporation of a biopsychosocial plan to target different aspects of the condition.

Declaration of interest

DJ Hunter provides consulting advice to Pfizer Inc, Eli Lilly and Company, TLCBio and Merck Serono. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscrirpt has not been funded.