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 "Total knee arthroplasty".)
●(Related Pathway(s): Knee osteoarthritis: Management in adults.)
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 . (See "Overview of the management of osteoarthritis", section on 'Mechanisms of pain'.)
●Mild knee osteoarthritis – Patients with mild knee osteoarthritis (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 osteoarthritis – 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 osteoarthritis (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 psychological interventions. Additional medications may be required, including oral nonsteroidal antiinflammatory drugs (NSAIDs), intraarticular steroids, and duloxetine. Surgery is generally reserved for refractory symptoms. (Related Pathway(s): Knee osteoarthritis: Management in adults.)
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'.)
Exercise — In all patients with moderate to severe knee OA, we suggest exercise for pain relief, functional improvements, and joint protection. There is evidence that exercise is effective  and safe , 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 .
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 falls risk is identified. 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 . 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 , 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  while walking >6000 steps per day may protect against functional decline .
Technology-enhanced exercise interventions may be useful for some patients and increase access. Several internet-based home exercise programs for knee OA have been described in the literature [9-12]. As an example, a randomized trial found that a six-month freely available self-directed online strengthening exercise and physical activity program (www.mykneeexercise.org.au) improved pain and function more than online education in people with knee OA . 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 use a brace, as an adjunct to the other 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, 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) . 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 . 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 [15-17].
In general, up to 25 percent of patients experience minor complications of bracing such as slipping and poor fit . 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 presence of patellar malalignment (see "Patellofemoral pain"). There is evidence that patellar taping markedly improves pain in the short term [18,19], while PF bracing seems a more appealing option for long-term use such as in patients with PF OA . 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 . On the other hand, another study found small improvement in pain in the group that wore the brace for a mean of 7.4 hours daily for six weeks compared with a no-brace control group. In addition, the brace group had greater reduction in PF bone marrow lesion volume, suggesting a potential structure-modifying effect .
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 . 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 .
Psychological interventions — We refer patients for psychological interventions for pain-coping skills training if appropriate and if the service is available. Chronic knee pain and its impact on functionality often lead to various levels of psychological distress which, in turn, has a negative impact on symptoms . There is evidence showing that psychological interventions, particularly cognitive behavioral therapy (CBT), result in significant improvements in pain and physical and psychological disability in patients with chronic pain . It aims at teaching patients ways to best cope with chronic pain through the modification of pain-related thoughts, behaviors, and emotions. 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 [26,27]. These interventions are conditionally recommended by the American College of Rheumatology and Arthritis Foundation guidelines [28,29] and by the Osteoarthritis Research Society International (OARSI) guideline .
Internet-based methods for providing psychosocial support with pain-coping skills training 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 . 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. The program painTRAINER is freely available for patients to use at www.painTRAINER.org.
Oral NSAIDs — We suggest oral NSAIDs, preferably on an as-needed basis, in patients with moderate pain who have insufficient relief with topical NSAIDs or have symptomatic OA in multiple joints such as the hip and spine. Patients with persistent, disabling pain may need continuous as opposed to as-needed NSAIDs use, 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 NSAIDs with a proton pump inhibitor (PPI). We use a cyclooxygenase (COX)-2 selective NSAID (coxib) in combination with a PPI in patients with higher risk of gastrointestinal complications, such as past history of gastric ulcer, or with presence of multiple risk factors, although we strongly recommend avoiding 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, with efficacy varying greatly across different NSAIDs and doses [32,33]. 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 (table 1). Switching to another NSAIDs may be advantageous for some patients, although there is limited evidence supporting this approach. We usually consider other treatment options for patients with refractory symptoms despite the use of NSAIDs on a regular basis. (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 [33-38]. 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 . In addition, ibuprofen and diclofenac were as effective at reducing pain as intraarticular 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, acetaminophen, or placebo for the treatment of pain for either hip or knee OA found that all of the NSAIDs included in the analysis improved estimates of pain when compared with placebo or acetaminophen .
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 NSAIDs (or have contraindications preventing their use), we suggest duloxetine. 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 demonstrated in some, but not all, randomized trials and is presumably related to the modulation of endogenous pain inhibitory pathways through the selective inhibition of serotonin and norepinephrine reuptake . In a meta-analysis of three trials, the relative risk of experiencing a 30 and 50 percent improvement in pain intensity with duloxetine compared with placebo was 1.49 (95% CI 1.31–1.70) and 1.69 (95% CI 1.27–2.25), respectively . Its efficacy was also demonstrated in patients already taking chronic oral NSAIDs with inadequate pain relief . The effective dose studied, and that is also used in our clinical practice, was 60 to 120 mg once daily, with a lower starting dose (30 mg) and gradual increase to improve tolerability . Nausea occurred in 6 to 15 percent of patients; other side effects were 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 Universities Osteoarthritis Index (WOMAC) pain scores at 3 and 12 months' follow-up when comparing duloxetine plus usual care with usual care alone . However, limitations to the trial include a high dropout rate, and many participants in the intervention group stopped taking duloxetine.
Genicular nerve block — For patients with symptomatic knee OA who have not responded satisfactorily to NSAIDs (or have contraindications preventing their use), a genicular nerve block may be considered if expertise is available. We suggest considering genicular nerve block for patients who have failed other treatment options and in those for whom surgery is not an option. However, our experience with this intervention 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 chemicals (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 [43,44]. A randomized trial of 59 patients with symptomatic knee OA demonstrated that genicular nerve block with bupivacaine and celestone chronodose (versus normal saline injections) led to improvement in pain scores, although the absolute effect was modest and diminished over 12 weeks of follow-up . Studies assessing the efficacy and safety of repeated injections for genicular nerve block are lacking.
Limited role of intraarticular glucocorticoid injections — We recommend against routine use of intraarticular glucocorticoid injections for patients with knee OA. We limit the use of intraarticular 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  and no difference between 40 and 80 mg of triamcinolone . 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 . (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 intraarticular glucocorticoid injections [35,49]. 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 post-injection . 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 . Although the rate of adverse events associated with intraarticular injections in the short term are generally low , longer term data suggest that there may be negative structural implications. In the aforementioned study, patients who received two years of intraarticular triamcinolone injections were found to have significantly greater cartilage volume loss measured by magnetic resonance imaging (MRI) . Other observational studies have shown conflicting results in terms of the effects of intraarticular injections on knee OA progression [51,52]. Patients with greater pain, presence of effusion, and less structural severity may be more likely to benefit from intraarticular steroids, but data are contradictory across studies .
In addition, intraarticular 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 intraarticular glucocorticoid injections or physical therapy . 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.
Refractory symptoms — Severe joint damage, chronic pain sensitization, and presence of extraarticular 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'.)
Surgery — 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 [55,56]. (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
●Patients with moderate to severe knee osteoarthritis (OA) have persistent pain which significantly impairs functionality, activity participation, and quality of life. This is in contrast to patients with mild knee OA who have low levels of or intermittent knee pain with relatively preserved joint function and quality of life. (See 'Definitions' above.)
●In all patients with moderate to severe knee OA, we suggest exercise for pain relief, functional improvements, and joint protection (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.)
●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.)
●We refer patients for psychological interventions for 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 'Psychological interventions' above.)
●In patients with moderate to severe knee OA or who have symptomatic OA in multiple joints (eg, hip and spine), we suggest oral nonsteroidal antiinflammatory drugs (NSAIDs), preferably 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.)
●For patients with OA in multiple joints and concomitant comorbidities that may contraindicate oral NSAIDs and/or those 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.)
●We suggest not routinely using intraarticular glucocorticoid injections for patients with knee OA (Grade 2C). We limit the use of intraarticular 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 intraarticular glucocorticoid injections' above.)
●We refer patients to surgery when significant joint-related symptoms persist despite the use of nonsurgical interventions. (See 'Surgery' above.)
●There are several approaches that have been used to treat patients with knee OA that we generally do not recommend due to lack of data demonstrating efficacy. These include insoles and footwear, opioids, hyaluronans, platelet-rich plasma, acetaminophen, glucosamine and chondroitin, other nutritional supplements, transcutaneous electrical nerve stimulation, and acupuncture. (See "Management of knee osteoarthritis", section on 'Therapies lacking efficacy or of uncertain benefit'.)
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