Management of moderate to severe knee osteoarthritis

INTRODUCTION — 

All patients with knee osteoarthritis (OA) should have appropriate interventions that include a combination of nonpharmacologic and pharmacologic treatment modalities. In contrast to patients with mild knee OA, patients with moderate to severe knee OA generally require additional interventions given the degree of functional impairment and impact on quality of life.

The management of moderate to severe knee OA is reviewed here. Separate topic reviews on OA as well as knee pain include the following:

●(See "Pathogenesis of osteoarthritis".)

●(See "Epidemiology and risk factors for osteoarthritis".)

●(See "Clinical manifestations and diagnosis of osteoarthritis".)

●(See "Overview of the management of osteoarthritis".)

●(See "Management of knee osteoarthritis".)

●(See "Comorbidities that impact management of osteoarthritis".)

●(See "Approach to the adult with unspecified knee pain".)

●(See "Approach to the adult with knee pain likely of musculoskeletal origin".)

●(See "Total knee arthroplasty".)

DEFINITIONS — 

These definitions are based on the severity of the impact of the disease on the person rather than on radiographic severity in line with a person-centered approach to management and the fact that symptoms and radiographic findings are not necessarily well correlated and that imaging is not usually required for diagnosis [1]. (See "Overview of the management of osteoarthritis", section on 'Mechanisms of pain'.)

●Mild knee OA – Patients with mild knee OA have low levels of or intermittent knee pain with relatively well-preserved joint function and quality of life. (See "Management of knee osteoarthritis", section on 'Mild knee osteoarthritis'.)

●Moderate to severe knee OA – Patients with moderate to severe OA have persistent pain which significantly impairs functionality, activity participation, and quality of life.

OVERALL APPROACH — 

As with mild knee OA, nonpharmacologic interventions, focusing on education, exercise, and weight management, are first-line therapies for patients with moderate to severe knee OA (algorithm 1). Other nonpharmacologic measures that may be considered include knee braces and walking aids as well as psychologic interventions. Additional medications may be required, including oral nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular steroids, and duloxetine. Surgery is generally reserved for refractory symptoms.

There are also general principles of management that apply to all patients with OA, including education, self-management, and goal-setting, which are discussed separately in detail. (See "Management of knee osteoarthritis", section on 'General principles' and "Overview of the management of osteoarthritis", section on 'General principles' and "Overview of the management of osteoarthritis", section on 'Monitoring and assessment'.)

Nonpharmacologic measures

Exercise — In all patients with moderate to severe knee OA, we suggest exercise for pain relief and functional improvements. Evidence suggests that exercise is safe and effective [2,3], with no research study reporting any serious adverse events related to exercise. A meta-analysis of 4 trials including 240 participants showed that exercise has beneficial effects on pain, even for patients with severe disease awaiting total knee replacement [4]. An individual participant data meta-analysis of 31 randomized trials in knee and hip OA found that people with more severe symptoms (higher pain and worse physical function at baseline) generally benefited more from exercise than those with less severe symptoms [5]. Importantly, radiographic joint appearance did not moderate exercise effects, suggesting that benefits can be obtained even in those with advanced structural changes.

A variety of different types of therapeutic exercise can bring health benefits to patients with knee OA including strengthening, aerobic exercise, neuromuscular exercise, and mind-body exercise such as tai chi and yoga. As muscle weakness is a feature of knee OA, strengthening programs, particularly targeting the quadriceps muscle, can be useful. Inclusion of balance exercises in a therapeutic exercise program may be warranted in people with knee OA when an increased fall risk is identified. Aquatic exercise has been associated with fewer adverse events compared with land-based exercises [6] and is a good option for patients with moderate to severe pain, due to the lower load on the knees when in water. However, the best form of exercise is still unclear, and the choice therefore should depend on identified impairments and patient preference. The optimal dose, including intensity, of therapeutic exercise needed for clinical benefits in people with knee OA is also largely unknown, but two to three times per week is generally recommended. As many patients with knee OA are physically inactive [7], increasing levels of general physical activity is also important. Undertaking at least 45 minutes of moderate to vigorous physical activity per week may improve or sustain high physical function over time [8] while walking >6000 steps per day may protect against functional decline [9]. Given that effects of exercise can decline over time, attention should be paid to optimizing adherence. Individual barriers and facilitators to exercise should be identified and addressed.

Technology-enhanced exercise interventions, including telehealth (videoconferencing) and internet-based home exercise programs, may increase access and adherence [10-16]. In a recent randomized trial of 394 people with knee OA, an exercise program delivered via telehealth by physiotherapists produced similar pain and function outcomes compared with the same program delivered via in-person consultation [16]. In fact, telehealth was superior for some secondary outcomes, including change in physical activity, participant ratings of convenience and satisfaction, and adherence to the exercise program. Randomized trials of self-directed, unsupervised online physical activity programs and yoga programs delivered similar benefit in pain and function when compared with OA education controls [11,15]. Additional information regarding exercise for knee OA can be found separately. (See "Management of knee osteoarthritis", section on 'Exercise'.)

Knee braces — Valgus (or unloader) knee bracing has been used to shift the load from the medial compartment with intent to relieve pain and improve function in patients with medial tibiofemoral (TF) joint OA. Our approach is to try a brace, as an adjunct to the core treatments, for patients who are amenable to this intervention and likely to comply with the treatment. Patients with medial TF OA who are more physically active and usually younger may experience greater improvements with unloader knee bracing.

In a meta-analysis of six randomized trials, the use of a brace compared with standard care (no orthosis use) was associated with a moderate improvement in both pain and function, while overall small improvements in pain were found when valgus bracing was compared with an orthosis control group (neutral knee brace, neoprene knee sleeve, or insoles) [17]. There was great heterogeneity in the comparator and in the prescription of braces across the six studies included in the meta-analysis. In a randomized trial including 80 patients with medial knee OA comparing valgus bracing with a neutral brace, there was a small but statistically significant decrease in pain in the brace group [18]. With regard to soft braces, there is limited evidence in support of their use. A meta-analysis including three low-quality randomized trials with variable follow-up of 6, 16, and 24 weeks found that there was a moderate improvement in pain and a small to moderate improvement in function with soft bracing compared with standard care [19-21].

In general, up to 25 percent of patients experience minor complications of bracing such as slipping and poor fit [17]. In addition, relatively low compliance rates (45 to 58 percent in parallel-group studies) may also hamper optimal results in clinical practice.

Patellofemoral (PF) taping and bracing, on the other hand, aim at reducing joint stress in patients with symptoms arising from the PF joint and the presence of patellar malalignment (see "Patellofemoral pain"). There is evidence that patellar taping markedly improves pain in the short term [22,23], while PF bracing seems a more appealing option for long-term use such as in patients with PF OA [24]. However, a crossover trial did not find differences in pain reduction when PF OA participants wore a specific type of off-the-shelf brace with or without the realigning strap applied [24]. In another study, OA patients who wore the brace for a mean of 7.4 hours daily for six weeks experienced small improvement in pain compared with a no-brace control group [25]. The brace group also had a greater reduction in PF bone marrow lesion volume, suggesting a potential structure-modifying effect. Pooled analysis of these two studies found no significant effect of bracing on pain/function in PF OA [26].

Walking aids — We suggest a walking stick (cane) in the contralateral hand (unaffected side) for patients with significant mobility impairment due to OA, balance impairments, a history of falls, and/or moderate to severe pain resistant to other treatment options. However, the data supporting the use of canes have been conflicting. One randomized trial found that use of a cane daily for two months led to small improvements in pain in patients with knee OA [27]. A subsequent study in 79 patients with medial knee OA found that using a cane daily for three months did not improve pain or reduce medial bone marrow lesion volume compared with no cane use [28]. If a walking aid is recommended, it is important to ensure that it is the correct height for the patient and that they receive instruction on the appropriate technique to use.

Psychologic interventions — Consistent with guideline recommendations, we refer patients for psychologic interventions such as cognitive-behavioral therapy (CBT), including pain-coping skills training if appropriate and if the service is available [29-31]. Chronic knee pain and its impact on functionality often lead to various levels of psychologic distress which, in turn, has a negative impact on symptoms [32]. CBT and other psychologic interventions have shown a beneficial effect on pain and physical and psychologic disability, especially in patients with chronic pain [33]. In addition, coupling cognitive behavioral strategies to exercise training and/or weight loss interventions has resulted in improved adherence and optimized outcomes in clinical trials with knee OA patients and in the general population [34,35]. CBT may also be used for sleep disturbances; in one randomized trial, combination CBT for insomnia and pain improved both sleep outcomes and pain severity when compared with CBT for pain alone [36]. Additional details regarding CBT and other psychotherapy can be found separately. (See "Overview of psychotherapies", section on 'Cognitive and behavioral therapies'.)

Internet-based methods for providing psychosocial support with pain-coping skills training, such as the painTRAINER program, may also be effective. In a trial including 148 patients aged 50 years or older with knee pain and disability for at least three months, patients were randomized to either an intervention or a control group [37]. Both groups had access to Internet-based educational material, but the intervention group also received interactive online training in pain-coping skills as well as videoconferencing sessions with a physiotherapist for home exercise. At three months, the intervention group reported significantly more improvement in pain and function compared with the control group, which was sustained for at least six months.

Pharmacologic measures

Oral NSAIDs — We use oral nonsteroidal anti-inflammatory drugs (NSAIDs) as needed in patients with moderate pain who have insufficient relief with topical NSAIDs or in patients with symptomatic OA in multiple joints. Patients with persistent, disabling pain may need regularly scheduled NSAIDs, although the risk of systemic toxicity needs to be carefully taken into consideration when higher doses and longer duration of use are required. In patients with risk factors for gastrointestinal toxicity (eg, advanced age, hypertension, concomitant aspirin use), we use either celecoxib or a nonselective NSAID with a proton pump inhibitor (PPI) in the lowest dose and shortest duration possible to control symptoms. In patients with a higher risk of gastrointestinal complications, such as past history of gastric ulcer, or with the presence of multiple risk factors, a cyclooxygenase 2 (COX-2) selective NSAID (coxib) in combination with a PPI may be used; however, we prefer to avoid using NSAIDs in these circumstances. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

Choice and use of oral NSAID — The choice of NSAID is based upon a variety of factors including adverse effect profile, patient comorbidities, cost to patient, and patient preference regarding frequency of administration. Some studies suggest that diclofenac 150 mg/day and etoricoxib 60 mg/day are the most effective NSAID regimens in knee OA, albeit with increased risk of adverse events, with efficacy varying greatly across different NSAIDs and doses [38-40]. In patients suitable for nonselective NSAIDs, we usually initiate treatment with either naproxen, meloxicam, diclofenac, or ibuprofen based on the considerations above. In patients with inadequate pain relief, regular NSAID use with gradual increase in dose may be necessary, as a dose-response effect has been observed for some NSAIDs, such as celecoxib, diclofenac, and naproxen [39]. Careful monitoring for side effects, including kidney impairment, hypertension, and gastrointestinal and cardiovascular symptoms, is necessary in these circumstances (table 1). Switching to another NSAIDs may be advantageous for some patients, although there is limited evidence supporting this approach. We usually pursue other treatment options for patients with refractory symptoms despite the use of NSAIDs on a regular basis and discontinue NSAIDs if they have no significant benefits. (See "NSAIDs: Therapeutic use and variability of response in adults", section on 'Dosing and duration'.)

Efficacy of oral NSAIDs — The greater efficacy of nonselective NSAIDs and coxibs compared with placebo and with acetaminophen in the treatment of OA (particularly with respect to pain relief) has been shown in randomized trials of individual drugs and in meta-analyses of randomized trials [39,41-45]. In a 2015 meta-analysis of data from 137 randomized trials comparing the efficacy of NSAIDS with other therapies for knee OA, all of the NSAIDs examined were found to be more effective for pain reduction when compared with acetaminophen [42]. In addition, ibuprofen and diclofenac were as effective at reducing pain as intra-articular corticosteroids or hyaluronic acid. However, this study had many limitations, including the short-term follow-up period of only three months. Another large network meta-analysis comparing NSAIDs and acetaminophen with placebo for the treatment of pain for either hip or knee OA found that NSAIDs improved estimates of pain when compared with placebo or acetaminophen [39]. In patients on chronic NSAIDs, discontinuing NSAIDs and engaging in a telephone-based CBT program was inferior to continuing NSAIDs at 4 and 14 weeks; however, the differences between the groups were small, and patients' global perceptions of pain and function were similar between the groups at 14 weeks [46].

Adverse effects of oral NSAIDs — Patients should be informed of the potential cardiovascular, gastrointestinal, and other major risks of both nonselective NSAIDs and selective COX-2 inhibitors. In order to minimize toxicity, intermittent short- to mid-term use as required, in the minimal dose necessary to control symptoms, should be preferred over long-term fixed doses. (See "Nonselective NSAIDs: Overview of adverse effects" and "NSAIDs: Adverse cardiovascular effects" and "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity".)

Inadequate response to oral NSAIDs or NSAIDs contraindicated

Duloxetine — For patients with symptomatic OA in multiple joints who have not responded satisfactorily to nonpharmacologic treatment and NSAIDs (or have contraindications preventing their use), we suggest a trial of duloxetine [47]. Sensitization of the central nociceptive processing has been increasingly recognized as a potential contributor to pain in knee OA patients. We do not routinely perform quantitative sensory testing to assess peripheral and central sensitization, but we consider a more widespread type of pain suggestive of sensitization. The analgesic efficacy of duloxetine has been variably demonstrated in randomized trials and is presumably related to the modulation of endogenous pain inhibitory pathways through the selective inhibition of serotonin and norepinephrine reuptake [48,49]. In a meta-analysis of eight trials assessing the effect of serotonin-noradrenaline reuptake inhibitors (SNRIs), SNRIs (mostly duloxetine) had small effects on pain and function up to 13 weeks, with low certainty of evidence [50]. Its efficacy was also demonstrated in patients already taking chronic oral NSAIDs with inadequate pain relief [51]. We use 60 mg once daily, with a lower starting dose (30 mg) and gradual increase to improve tolerability [52]. Nausea may occur in 6 to 15 percent of patients; other side effects are fatigue, constipation, dry mouth, diarrhea, somnolence, and dizziness. In contrast to the findings from the meta-analysis, an open-label trial that included 133 patients with chronic hip and knee OA did not detect a statistically significant difference in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores at 3 and 12 months' follow-up when comparing duloxetine plus usual care with usual care alone [48]. However, limitations to the trial include a high dropout rate, and many participants in the intervention group stopped taking duloxetine.

Interventional procedures targeting the genicular nerve — If expertise is available, a genicular nerve block or ablation may be offered for patients with symptomatic knee OA who have not responded satisfactorily to nonpharmacologic treatment and NSAIDs and for patients who have contraindications preventing their use. We suggest considering genicular nerve interventions for patients who have failed other treatment options and in those for whom surgery is not an option. However, our experience with these procedures is still limited as it is not widely available, and we do not use this treatment.

The superior medial genicular nerve, superior lateral genicular nerve, and inferior medial genicular nerve are localized using musculoskeletal ultrasound or fluoroscopy. Subsequently, these nerves are ablated using radiofrequency or chemical blocks (eg, local anesthetics, alcohol, or glucocorticoids). Systematic reviews indicate that both radiofrequency ablation and chemical ablation are effective, but most studies are small, and direct comparisons between these techniques are not available [53-56]. In a randomized trial of 54 patients with chronic knee OA, radiofrequency ablation of the genicular nerve resulted in better pain relief, improved function, and increased muscle strength compared with sham procedure at three months [57]. A separate randomized trial of 59 patients with symptomatic knee OA demonstrated that genicular nerve block with bupivacaine and Celestone Chronodose led to improvement in pain scores compared with normal saline injections, although the absolute effect was modest and diminished over 12 weeks of follow-up [58]. Studies assessing the efficacy and safety of repeated injections for genicular nerve interventions are an area of further study.

Limited role of intra-articular glucocorticoid injections — We recommend against routine use of intra-articular glucocorticoid injections for patients with knee OA. We limit the use of intra-articular injections to patients with moderate to severe pain and contraindications to or failure of other treatment options who are seeking short-term pain relief. This procedure, either as a single injection or multiple repetitive injections, is not routinely recommended in our clinical practice. When indicated, we usually use 40 mg of triamcinolone or methylprednisolone, although other formulations such as betamethasone can also be used. Although there are conflicting results across trials, it seems that there is no superiority of one formulation over others [59] and no difference between 40 and 80 mg of triamcinolone [60]. Serial injections (every three months) are discouraged due to potential negative effects on the progression of cartilage damage in knee OA patients, although it is unclear if the difference in cartilage loss between the groups is of clinical relevance [61]. (See "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?".)

A few large trials have demonstrated short-term improvements in pain relief with intra-articular glucocorticoid injections [42,62]. In a Cochrane review, a single glucocorticoid injection into the knee has been shown to provide short-term pain reduction of small to moderate magnitude for up to six weeks postinjection [62]. After this period, effects on knee pain and function are similar to that obtained with placebo injection. A randomized trial including 140 patients with symptomatic knee OA and ultrasound features of synovitis found that injections of 40 mg triamcinolone acetonide every 12 weeks for two years were no different compared with placebo injections in terms of pain reduction [61]. Although the rate of adverse events associated with intra-articular injections in the short term are generally low [63], longer term data suggest that there may be negative structural implications. In the aforementioned study, patients who received two years of intra-articular triamcinolone injections were found to have significantly greater cartilage volume loss measured by magnetic resonance imaging (MRI) [61]. Other observational studies have shown conflicting results in terms of the effects of intra-articular injections on knee OA progression [64,65]. Patients with greater pain, presence of effusion, and less structural severity may be more likely to benefit from intra-articular steroids, but data are contradictory across studies [66].

In addition, intra-articular glucocorticoid injections appear to be less effective for pain relief compared with physical therapy. In a trial including 156 patients with symptomatic radiographic knee OA, patients were randomly assigned to receive either intra-articular glucocorticoid injections or physical therapy [67]. At one year, patients who received physical therapy had greater improvements in pain and functional disability compared with patients in the glucocorticoid injection group as assessed by the total score on the WOMAC. While the magnitude of the absolute between-group difference was small, 18.8 units (95% CI 5.0-32.6) on a 0 to 240 scale, the number needed to treat for clinically relevant benefits with physical therapy over injection was estimated at between 4 and 7.

Surgery for refractory symptoms — Severe joint damage, chronic pain sensitization, and presence of extra-articular factors, particularly psychosocial issues, can all negatively influence the treatment response and should be assessed and addressed accordingly. (See "Overview of the management of osteoarthritis", section on 'Factors affecting response to therapy'.)

We refer patients to surgery when significant joint-related symptoms persist despite the use of nonsurgical interventions. Surgical treatment is dominated by total knee replacement, and osteotomy is an alternative for younger patients with varus or valgus knee and predominantly unicompartmental disease.

We do not refer patients to arthroscopic surgery involving debridement and/or partial meniscectomy, as it has been shown to have no benefit over control treatment in addition to the real potential for important adverse events including thrombotic events and mortality [68,69]. (See "Total knee arthroplasty", section on 'Indications' and "Overview of surgical therapy of knee and hip osteoarthritis".)

THERAPIES LACKING EFFICACY OR OF UNCERTAIN BENEFIT — 

Therapies lacking efficacy or of uncertain benefit are discussed elsewhere. (See "Management of knee osteoarthritis", section on 'Therapies lacking efficacy or of uncertain benefit'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoarthritis".)

PATIENT PERSPECTIVE TOPIC — 

Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Knee osteoarthritis".)

SUMMARY AND RECOMMENDATIONS

●Definitions – Patients with moderate to severe knee osteoarthritis (OA) have persistent pain which significantly impairs functionality, activity participation, and quality of life. In contrast, patients with mild knee OA have low levels of or intermittent knee pain with relatively preserved joint function and quality of life. (See 'Definitions' above.)

●Nonpharmacologic measures

•Exercise for all patients – In all patients with moderate to severe knee OA, we suggest exercise for pain relief and functional improvements (algorithm 1) (Grade 2C). A variety of exercise types can be beneficial. Aquatic exercise has been associated with reduced rates of adverse events compared with land-based exercises and is a good option for patients with moderate to severe pain due to the lower load to the knees. (See 'Exercise' above.)

•Assistive devices in selected patients – In patients with moderate to severe medial tibiofemoral (TF) OA, we suggest use of a valgus (or unloader) knee brace as an adjunct to other core treatments (Grade 2C). Patients with medial TF OA who are more physically active and usually younger may experience greater improvements with unloader knee bracing. (See 'Knee braces' above.)

In patients with significant mobility and/or balance impairments, a history of falls, and/or moderate to severe pain resistant to other treatment options, we suggest a walking stick (cane) in the contralateral (unaffected side) (Grade 2C). (See 'Walking aids' above.)

•Psychologic interventions – We refer patients for psychologic interventions, such as cognitive-behavioral therapy and pain-coping skills training if appropriate and if the service is available. The use of a freely available internet-based program is also a reasonable option. (See 'Psychologic interventions' above.)

●Pharmacologic measures

•Oral nonsteroidal anti-inflammatory drugs (NSAIDs) – In patients with moderate to severe knee OA or who have symptomatic OA in multiple joints (eg, hip and spine), we suggest oral NSAIDs at the lowest dose and shortest duration possible (Grade 2B). The choice of NSAID is based upon a variety of factors including adverse effect profile, patient comorbidities, cost to patient, and patient preference regarding frequency of administration. (See 'Oral NSAIDs' above.)

•Duloxetine – For patients with OA in multiple joints and concomitant comorbidities for whom oral NSAIDs are contraindicated and for patients who have not responded satisfactorily to NSAIDs, we suggest duloxetine 60 to 120 mg daily (Grade 2B). We start with a lower initial dose of 30 mg and gradually increase to improve tolerability. (See 'Duloxetine' above.)

•Limited role of intra-articular glucocorticoid injections – We do not recommend routine intra-articular glucocorticoid injections for patients with knee OA (Grade 2C). We limit the use of intra-articular injections to patients with moderate to severe pain and contraindications to or failure of other treatment options who are seeking short-term pain relief. (See 'Limited role of intra-articular glucocorticoid injections' above.)

●Surgery for refractory symptoms – We refer patients to surgery when significant joint-related symptoms persist despite the use of nonsurgical interventions. (See 'Surgery for refractory symptoms' above.)