Consensus Guidelines on Interventional Therapies for Knee Pain (STEP Guidelines) from the American Society of Pain and Neuroscience

Introduction Background

Knee pain affects tens of millions of people in the United States annually – the pain can be disabling and often negatively impacts the patient’s quality of life, function and can even prevent one’s ability to simply ambulate across a room. While osteoarthritis is the most common cause of knee pain,1 there are numerous other lesser known causes that can present in a variety of ways with significant overlap between the various diagnoses. As one would expect from a condition with such a large incidence, there are a wide variety of treatments available to treat knee pain; however, there is no consensus on which treatments should be offered over others and in what order. The purpose of these guidelines is to consolidate the data into one document on the various modalities available, ranging from medication and physical therapy to interventional treatments and joint arthroplasty, thus offering practitioners a sing

These clinical guidelines are based on a systematic review of published studies examining the conservative, interventional, and surgical treatment options for the most common sources of knee pain in adults: knee osteoarthritis, post-surgical knee pain, soft tissue injury to the knee, and complex regional pain syndrome (CRPS) involving the knee joint. The intent and purpose of these guidelines is to help practitioners integrate the current evidence into clinical practice. Given the broad nature of the topic, effort was placed on reviewing recent meta-analyses and systematic reviews to summarize key findings and recommendations.

Incidence

Knee pain is a common reason for patients to present to primary care physicians and pain medicine specialists alike. An estimated 25% of Americans over the age of 55 have constant knee pain,2 and the most common underlying etiology is osteoarthritis.3 Knee osteoarthritis is more common in the geriatric population with increasing incidence with age.4 Up to one in five people over the age of 50 reports severe difficulty with physical function due to knee pain even without a formal diagnosis of osteoarthritis.4 Extrapolating this to the United States population reveals that up to 21 million Americans are suffering with reduced ability to function due to knee pain.5

As we see a rise in the aging population and obesity rates, the incidence and prevalence of knee pain is expected to rise. For the most common culprit of knee pain, knee osteoarthritis, the incidence and prevalence are difficult to accurately define, given knee osteoarthritis can exist radiographically without symptoms or clinically due to symptomatic pathology. The pooled global incidence of knee OA was 203 per 10,000 person-years in individuals aged 20 and over.6 Not all patients with knee pain suffer from symptomatic osteoarthritis, however. With the rise in access to healthcare and surgery, the incidence of persistent post-surgical knee pain after total knee arthroplasty is also a source of chronic knee pain. Despite good outcomes for most patients who undergo total knee arthroplasties, approximately 20% of the patients experience chronic pain after total knee arthroplasty (TKA).7 Among the post-arthroplasty population, the incidence of neuropathic post-surgical pain, concerning for CRPS, can be as high as 34%.8 Ultimately, the rising prevalence of chronic knee pain will present challenges within our healthcare systems as well as economic costs associated with them. These guidelines hope to provide evidenced-based decision support to physicians and other healthcare providers to improve the quality and efficiency of care.

Economic Burden of Knee Pain

Osteoarthritis is a prevalent and disabling condition currently affecting 40 to 50 million Americans, with approximately 10–30% of those afflicted having significant pain, impaired function, and decreased quality of life.1,9,10

The pain and loss of function can be debilitating; in developed countries the resultant socioeconomic burden is large, costing between 1% and 2.5% of gross domestic product.11 The socioeconomic burden of knee and hip OA alone averages more than $12,000 per patient annually in both direct and indirect costs of disease.12 In 2015, the average cost of TKA was approximately $16,000 per discharge, summing up to almost $10 billion in inpatient costs alone.13 Time lost from employment and leisure by participants and their unpaid caregivers accounted for 80% of the total cost.12 A 2017 study found that, when compared to healthy controls, knee OA patients had significantly more per-patient-per-year outpatient and pharmacy claims and costs. Knee OA patients incurred $7707 more per-patient-per-year total healthcare costs than controls.14

In a national, cross-sectional, population-based study, it was found that about one-third of the population aged 50–64 had OA and more than half were out of paid work. Only knee OA was associated with early exit from work. The estimated annual cost of early exit from work attributable to OA was €384 per capita, €1294 per OA patient and €2095 per OA patient out-of-work.15 In another study, it was estimated that mean health losses due to knee OA over people’s lifetimes are 3.44 quality-adjusted life years (QALYs) per person.16

Opioids

The United States accounts for 5% of the worldwide population yet consumes roughly 80% of opioids worldwide.17 As a nation, we have a obvious proclivity for choosing opioids to treat pain, even in cases where other treatments have been shown to be more effective and safer long term – as is the case when it comes to treating knee pain. From 2004 to 2014, 16% of the patients presenting with knee pain and osteoarthritis were prescribed opioid medications for treatment.18 Despite this, there are no data supporting the effectiveness of chronic opioids for either pain or functional improvement in patients with osteoarthritis.19 In fact, only about 35% of the patients who take opioids for osteoarthritis report pain improvement.20 This is compared to 31% of the patients who were given placebo for similar pain.20 Similar numbers are revealed when we evaluate physical functional improvements in response to opioids or placebo.20 While opioids have not demonstrated benefits, they definitely have their risks. Opioid-naïve patients who are prescribed an 8-day supply of opioids have a 13.5% probability of continuing opioid therapy at 1-year.21 If this is increased to >30 days, the probability increases to 29.9%.21 With the Centers for Disease Control (CDC) reporting 46,802 opioid overdose deaths in 2018,22 the risk of opioid therapy in this population is felt to be greater than any potential benefit, with the exception of high-risk patients with limited alternative therapies.

Despite the presence of a plethora of suitable alternatives (most of which possess high levels of evidence to support their utility), practitioners continue to recommend opioids for the treatment of knee pain – even though there is little-to-no evidence to support their use in this particular setting. One of the principal goals of these guidelines is to illustrate just how many evidence-based treatment options that are available for knee pain that go beyond a seemingly innocuous prescription for opioid pain medication.

Methods

The Consensus Guidelines on Interventional Therapies for Knee Pain (STEP) panel is composed of participants considered experts in the field and was selected by the American Society for Pain and Neuroscience (ASPN) executive board after receiving nominations. The board’s approach ensured diversity across practice locations and panelist demographics. Consideration was given to research experience, clinical experience, prior publications, work in the field, professional specialty, and speaking engagements. Invitations were sent, and upon acceptance, writing assignments were made. Database searches used replicable methods and are presented with outcomes, in each of the recommendations sections below. Multiple panelists contributed to the same topic in order to ensure consensus across experts. Panel members recused themselves from any section with actual or perceived conflict of interest. A third party was employed to edit the overall documents once panel members drafted their sections.

Literature search and summary methods were in accordance with the US Preventive Services Task Force (USPSTF) criteria for evidence level and degree of recommendation.23 In treatment areas with early or incomplete literature the expert opinion of the panel contributors was presented, expert consensus was sought to fill gaps in knowledge. USPSTF criteria for evidence levels, meaning of recommendation degrees, and strength of consensus, assuming a quorum of 80% of the participants available for vote, appear in Tables 13.23

Table 1 USPSTF Hierarchy of Studies by the Type of Design

Table 2 USPSTF Meaning of Recommendation Degrees

Table 3 USPSTF Strength of Consensus

Evidence was quality ranked according to the following methods:

Evidence Level 1 evidence is as a score of 39 or greater on the randomized controlled trial (RCT) and observation study score sheet (out of 48) on the Interventional Pain Management—Quality Appraisal of Reliability and Risk of Bias Assessment (IPM) score sheet24 and 10–12 on QAREL score sheet25 and 10–13 on Cochrane.26 Level 2 evidence is a score between 29 and 38 on the RCT and observational study score sheet (out of 48) on IPM procedure scores sheet24 and 8–9 on QAREL25 and 8–9 on Cochrane.26 Level 3 is a score between 16 and 28 on IPM procedures score sheet24 and 6–7 on QAREL25 and 6–7 on Cochrane.26 Is a score <16 on IPM score sheet24 and <6 on QAREL25 and Cochrane score sheet.26

Additionally, a qualitative modified approach to grading of evidence is in Table 4, modified from Manchikanti et al27

Table 4 Level I–V Definitions

Lastly, a guide for strength of recommendations is also available via the National Guideline Clearinghouse Extent Adherence to Trustworthy Standards (NEATS) instrument (see Table 5).28

Table 5 NEATS Recommendations

Patient Evaluation and Imaging Physical Exam

As in all areas of medicine, a thorough physical exam is a crucial step in the work-up and diagnosis of knee pain. While imaging can provide a clear answer as to what pathology may or may not present within the knee joint, it may not be able to definitively diagnose what the pain generator is. An examination of the knee should start with basic inspection to assess for swelling or skin changes. There are a number of pathologies in the knee that may cause swelling or edema in or around the joint (ie, osteoarthritis, Baker’s cyst, infection, soft tissue injury, etc) and would likely require further work up. Skin changes, such as erythema, shiny appearance, or loss of hair, may suggest CRPS or infection depending on the precipitating factors leading up to the symptoms.

Next, the provider should perform a cursory exam on the joint that includes

Muscle strength: extension (quadriceps femoris, L3, femoral nerve); flexion (hamstrings, S2, sciatic nerve) Range of motion: 0° to 135° Sensation: L3 – medial aspect, L4 – anterior aspect, L5 – lateral aspect, S1 – posterior-lateral aspect, S2 – posteriod-medial aspect Palpation: posterior tenderness is common with Baker’s cysts; medial or lateral tenderness may indicate a soft tissue injury (ie, meniscus, collateral ligament, etc)

The final, and perhaps most important, part of the exam involves performing a series of “special” maneuvers – these are a series of standardized examination techniques that specifically stress certain parts of the knee to reveal if a particular part or aspect has been injured (Table 6).29–31

Table 6 “Special” Maneuvers for Examining the Knee

X-ray, MRI, CT, Bone Scan X-ray: According to the American College of Radiology (ACR) Appropriateness Criteria, radiographs should be the initial imaging modality utilized for the evaluation of knee pain. Radiographs provide adequate evaluation of the joint space, osteophyte and subchondral cyst formation, displaced or chronic stress fractures, joint effusions, and sclerosis in the subarticular region.32,33 Magnetic resonance imaging (MRI): If radiographs are normal, or demonstrate a joint effusion, the ACR recommends an MRI without intravenous (IV) contrast as the next most appropriate study. MRI accurately demonstrates the soft tissues of the knee, without the use of ionizing radiation, and depicts tendon and ligamentous damage, tears and other abnormalities of the meniscus, the presence of synovitis, the extent of effusions, the presence and/or rupture of a popliteal cyst, the extent of cartilage loss, bone marrow lesions, subchondral insufficiency fractures, tibial stress fractures, and osteonecrosis.32,34 MRI with and without IV contrast is not usually indicated when initial radiograph is negative or a joint effusion is detected. However, the utilization of IV contrast may be beneficial to help more accurately diagnose such causes of chronic knee pain as infrapatellar bursitis, adhesive capsulitis, patellofemoral friction syndrome (“runner’s knee”), pigmented villonodular synovitis (PVNS), and Hoffa’s fat pad syndrome.32,35 Computed tomography (CT): While not a first-line imaging modality for the evaluation of knee pain, according to the ACR, under certain circumstances, a CT without IV contrast may be indicated for the evaluation of knee pain, especially in settings where MRI may be contraindicated (ie, in a patient with a non-MRI compatible pacemaker, spinal column stimulator, or deep brain stimulator). CT offers enhanced bony detail and may be useful to confirm a prior osseous injury such as a subtle acute non-displaced fracture or chronic stress fracture. In the setting of chronic knee pain related to patellofemoral syndrome, CT may be helpful in evaluating the patellofemoral anatomy.32,35 CT with IV contrast is not usually indicated but may be used to evaluate the menisci, articular cartilage, and the presence of loose bodies.32 Bone scan: Bone scan is not usually indicated to evaluate patients with knee pain. Bone scan has low specificity and decreased anatomic resolution when compared to CT or MRI. However, bone scan may help to distinguish between bone and soft-tissue origins for pain.32,33,35 Ultrasound: Ultrasound is not often useful as a diagnostic tool for the comprehensive examination of the knee. It may be appropriate to use ultrasound to confirm a suspected effusion or popliteal cyst, and can be utilized to guide in aspiration of synovial fluid which can be evaluated for crystal disease or infection.32 It also may be utilized to evaluate for synovial pathology, where the use of power Doppler ultrasound can demonstrate increased synovial blood flow that is associated with knee pain.32,36,37 Ultrasound is also useful for following patients with iliotibial (IT) band syndrome and in evaluating medial plicae.32,34 Ultrasound can also demonstrate an extrusion of the meniscus (with is suggestive of an underlying meniscal tear) and, on occasion, can detect peripheral meniscus tears, and chondrocalcinosis.32,34 Kellgren–Lawrence Scale

The Kellgren and Lawrence system is a widely used method by which osteoarthritis (OA) is graded radiographically. Originally published in 1957, and still in use today, the method classifies OA by five grades:

Grade 0 (none): nothing on X-ray Grade 1 (doubtful): suspect OA Grade 2 (minimal): OA definitely present, yet minimal Grade 3 (moderate) moderate osteophytes, joint space narrowing, may be some sclerosis or bony deformations Grade 4 (severe) severe joint space narrowing, large osteophytes, severe sclerosis and bony deformity.38

The scale has both interobserver and intra-observer validation for reliability and with diagnostic accuracy.39 The Kellgren–Lawrence scale is limited by its ability to comment on disease progression and detect changes as it assumes linear disease progression starting with osteophytes and then to joint space narrowing, ending in joint deformation, the latter not being able to be measured without the former being present.39

Common Conditions Causing Knee Pain Sprains Background: Knee sprains include injury to any of the ligamentous structures within the knee joint. Major ligaments include the anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), medial collateral ligament (MCL), and lateral collateral ligament (LCL) and will be discussed here. Additionally, there are the anterolateral ligament (ALL), transverse meniscal ligament, posterior meniscofemoral ligament, oblique popliteal ligament, arcuate ligament, popliteofibular ligament, and the ligaments that form the joint capsule. Etiology: Ligamentous knee sprains are due to trauma or sports injury, both with contact and non-contact forces. The ACL is commonly injured during plant and cut maneuvers due to increased knee abduction during hip adduction and knee valgus during hip internal rotation.40 Additionally, internal rotation of the tibia increases risk of ACL strain. These three movements are combined in landing from jump with hip extended and internally rotated, knee extended and valgus, tibia internally rotated, and foot planted.40 Hewett et al evaluated ACL injury mechanics in female athletes and found that abduction angle was 8° greater in ACL injury and those with ACL injury had 2.5 times greater abduction moments.41 PCL injuries are usually concomitant with injury to other ligaments particularly when varus or valgus stress or rotational force is involved. The PCL is injured with posterior translation of the tibia in relation to the femur. Force is required and a PCL tear is commonly known as a “dashboard injury” which occurs when the flexed knee hits a motor vehicle dashboard during a collision and is translated posteriorly, or during hyperflexion of the knee with the foot in plantar flexion, such as falling onto the flexed knee.42 MCL injuries can occur in isolation or in combination with the ACL or PCL. The MCL originates at the medial epicondyle of the tibia deep to the pes anserine and inserts 5–7 cm below the joint line. It functions as the primary medial knee stabilizer and resists valgus stress, anterior tibial translation, and internal rotation. The most common mechanism of injury to the MCL is direct lateral force to the knee or maneuvers that induce severe valgus stress to the knee, and injury most often occurs at the femoral insertion.43 The LCL is the primary stabilizer of the lateral knee, originates at the lateral epicondyle of the femur and inserts on the medial fibular head. It resists varus stress, external rotation and posterior displacement of the fibula; therefore, it can be injured by contact and non-contact forces in these planes. Common mechanism of injury is direct varus force to the medial knee or hyperextension stress across the knee.44 Diagnostic Criteria: Sprains are graded based on severity: Grade 1 – mild, painful stretching or minimal tearing of fibers, Grade 2 – moderate, painful, partial tearing of fibers, Grade 3 – severe, painful or sometimes not painful, complete rupture of ligament and may demonstrate instability. Clinical physical exam findings: ACL – knee line pain, positive Lachman’s test. PCL – dimple sign, posterior drawer test, posterior sag test, quadriceps active test, external rotation recurvatum test.42 MCL – medial joint line pain and tenderness, positive valgus stress test. LCL – lateral joint line pain and tenderness, lateral joint edema, positive varus stress test, lateral compartment laxity with figure 4 position. History and physical exam support the clinical diagnosis, and imaging should include weight—bearing knee series and stress radiographs; however, the gold standard for diagnosis of ligament injury in the knee is MRI. Treatment: Symptomatic pain emanating from knee sprains is typically managed conservatively with topical or oral non-steroidal anti-inflammatory drugs (NSAIDs) in those without contraindications as well as alternating ice and heat. From an orthopedic perspective, grade I and II sprains are treated with progressive weight bearing as tolerated, bracing, gentle active assisted range of motion, and strengthening of surrounding supportive musculature and are specific to each ligament involved. Some isolated Grade 3 sprains are treated with a longer period of immobilization and bracing, toe touch weight bearing, followed by aggressive range of motion (ROM); however, combined injury or severe Grade 3 sprains with complete ligament rupture can be treated surgically, particularly if the ACL is involved.43 Meniscal Injuries Background: The menisci function to absorb shock and transmit load forces across the femorotibial joint and protect the articular cartilage. The medial and lateral menisci are composed of layers of collagen fibers. The superficial layer is finely woven, the surface layer comprises randomly oriented fibers, and the deepest layer is a combination of circumferential and radial fibers. The menisci are located between the medial and lateral femorotibial joints. The medial meniscus is attached to the tibial plateau by the coronary ligaments and is C-shaped. The lateral meniscus is circular and more mobile with loose attachments. The outermost 3 mm is the “red zone”, is well vascularized from the peri-meniscal plexus off the genicular arteries. Most tears in the red zone will heal. Within 3–5mm from the capsular junction is the “white zone”, with reduced perfusion, some tears will heal. The remaining meniscus >5mm from the capsular junction makes up the inner two-thirds, is avascular, receives nutrients from the synovial fluid, and most tears will not heal. Meniscus tears cause knee pain by direct effect on the nociceptors in the meniscus tissue and synovium, as well as by elevated levels of intra-articular cytokines.45 Types of traumatic tears: Longitudinal vertical tear: if lesion stable then conservative management. Surgical debridement vs repair for unstable lesions. Radial tear: debridement vs surgical repair. Root tear: often associated with ACL tear, debridement vs surgical repair. Types of degenerative tears: Horizontal cleavage in young athletes: rare, due to overuse, if cessation of the activity fails then proceed to surgical intervention. Degenerative meniscal lesions in the elderly: prevalence increases with age, 60% asymptomatic, associated with osteoarthritis, conservative management.45 Diagnostic criteria: Clinical presentation includes joint line pain, knee locking, and positive special tests including McMurray, Ege, and Thessaly due to their high sensitivity and specificity.45 Radiologic evaluation with weightbearing AP, lateral, and Schuss views are first-line evaluation to assess for alternative sources of pain such as osteoarthritis. If pain persists despite conservative therapy, MRI is obtained to evaluate the menisci. Treatment: Similar to sprains, pain secondary to meniscal injuries is managed symptomatically (ie, PT and NSAIDs). If the pain fails to respond to conservative care and/or persists beyond the acute phase, intra-articular injections should be considered. Intra articular platelet-rich-plasma injection has not been identified to improve meniscus healing. If the joint is unstable and/or non-invasive treatment modalities fail, surgical intervention is usually indicated, depending on the type and severity of the tear.46 Tendinopathy Background: Tendinopathy is characterized by pain and dysfunction in a tendon, commonly due to excessive load or strain. In active patients and athletes, overuse can lead to chronicity.47 The most common tendinopathy in the knee is of the patellar tendon, is colloquially known as “jumper’s knee” since it is commonly seen in jumping athletes, and can lead to microtears at the tendon insertion at the distal pole. Diagnostic criteria: Diagnosis is based on history and physical exam. Patients with patellar tendinopathy present with anterior knee pain that is worse with activity, tenderness to palpation at the inferior pole of the patella. Other tendinopathies present with tenderness to palpation and pain at the tendon insertion site with activation of the muscle. Radiologic imaging will be normal. Ultrasound can assist in confirming diagnosis and will show loss of the normal fibrillar pattern, increased spacing between fibrillar lines, and generally reduced echogenicity.48 MRI will show increased signal at the tendon insertion. Treatment: Pain secondary to tendinopathy is treated symptomatically in the acute phase – this includes NSAIDs and physical therapy with a progressive loading program. Additional adjuncts for pain control such as cryotherapy, peritendinous injection with corticosteroids or platelet-rich plasma (PRP), and extracorporeal shockwave therapy can be considered if the pain fails to respond to NSAIDs and PT and/or the pain persists beyond the acute phase.49 Ultrasound-guided needle tenotomy, percutaneous needle scraping, and high volume injection, and stem cells are at the forefront of regenerative medicine for tendinopathy and are currently being evaluated.50 If non-invasive management fails, surgical intervention would be the next step.49 Bursitis Background: A bursa is a sac filled with synovial fluid that acts as a friction cushion between structures. There are 10 bursa within and around the knee, and the 4 major bursa are the prepatellar, suprapatellar, infrapatellar, and pes anserine bursa. When friction or trauma irritates a bursa, it can become inflamed and be a significant source of knee pain. Bursitis is clinically recognized by localized pain, point tenderness, and edema at the sight of the bursa. Septic bursitis may also present with erythema, warmth, and systemic symptoms such as fevers and leukocytosis. Etiology: Superficial to the patella is the subcutaneous prepatellar bursa, which can become inflamed with kneeling activities, and is colloquially called “housemaid’s knee or carpenter’s knee”. Inferior to the patella are two bursae, subcutaneous infrapatellar bursa which lies superficial to the patellar ligament, and the deep (subtendinous) infrapatellar bursa which lies deep to the patellar ligament. Inferomedial knee pain may be caused by anserine bursitis. The anserine bursa lies deep to the pes anserinus comprising the tendinous attachments of the semitendinosus, gracilis, and sartorius. Proximal to the anserine bursa and deep to the semimembranosus tendon is the semimembranosus bursa. There are three lateral bursae: the bursa deep to the iliotibial tract, bursa deep to the lateral collateral ligament, and the inferior subtendinous bursa deep to the biceps femoris tendon. Posteriorly, there are two subtendinous bursa, one deep to the medial and lateral heads of the gastrocnemius. A bursa can become inflamed by overuse leading to increased friction across the bursa. Septic bursitis requires bacteria to enter the bursa and is associated with trauma. Diagnostic criteria: Physical exam is significant for pain and point tenderness overlying the affected bursa and may be associated with swelling. Prepatellar bursitis will present with egg-shaped swelling superficial to the patella. Septic bursitis may present with erythema and warmth. Radiologic knee series are usually normal. Evaluation with ultrasound will show a hypoechoic fluid filled sac or discrete fluid collection at the site of pain indicating bursitis.51,52 Treatment: The treatment of bursitis-related knee pain is typically focused on reducing the inflammation of the bursa, itself – this includes ice, NSAIDs, activity modifications (such as knee pads for prepatellar bursitis), injections of corticosteroid, and therapeutic aspiration. For patients with active lifestyle or occupational demands and non-septic bursitis, intrabursal injection of corticosteroids provides acute pain relief. If septic bursitis is suspected, infectious workup includes blood sampling for evaluation of leukocytosis and aspiration of bursal fluid with gram stain and cell count. Treat septic bursitis with antibiotics. Recurrent or persistent severe bursitis may benefit from surgical interventions such as bursectomy.53,54 Osteoarthritis Background: Osteoarthritis of the knee is a common source of knee pain, increases with advancing age, and is more prevalent in women than in men. Etiology: It is a disorder that develops after macro and micro-trauma leads to maladaptive repair response, activation of the pro-inflammatory immune response, and is characterized by cell stress and extracellular matrix degradation.55 Mechanical stress, varus and valgus malalignment lead to excessive loading of bone and subsequent development of bone marrow lesions, abnormal focal remodeling, and loss of articular cartilage. Osteoarthritis can involve one or both knees and can occur in any of the three compartments of the knee, most commonly in the medial compartment. Symptom onset is gradual, can be localized or generalized joint pain that is worse with weight bearing and joint motion, and relieved with rest. Morning stiffness resolves in less than 30 minutes and the joint may stiffen briefly after inactivity. Clinical exam findings include bony enlargement, small effusions that are body temperature, and crepitus with joint motion.56 Diagnostic criteria: Diagnosis can be made based on history and physical exam. Standing radiographs may not show pathology in early OA so normal radiological findings do not exclude OA. Radiologic findings include osteophytes, subchondral cysts, subchondral sclerosis, and joint space narrowing which is graded using the Kellgren–Lawrence grading system (discussed previously).56,57 MRI is used to assess soft tissue if associated injury is suspected; however, it is rarely indicated for diagnosis of osteoarthritis. Ultrasound is an inexpensive and portable way to visualize the knee joint and assess for effusions and osteophytes; however, it is not accurate when assessing degree of joint space narrowing.56 Treatment: With the exception of joint arthroplasty and regenerative therapies, most treatments for knee pain secondary to OA are palliative in nature. Treatments are tiered depending on the stage and level of disability of the patient. Conservative management includes activity modifications, weight loss if appropriate, exercise, physical therapy, and education. NSAIDs should be considered first line for “as-needed” symptomatic pain control.19,20,58,59 Opioids have minimal benefit in OA and are associated with undesirable side effect profile and safety risks, therefore use is discouraged.60 Intra-articular injections with corticosteroid or hyaluronic acid (HA) are well-accepted treatments for temporary symptomatic relief. Biologics such as PRP or mesenchymal stem cells have been proposed to attenuate the pro-inflammatory degradation in OA and potentially remodel the joint.61 Several adjunct medications such as cathepsin K inhibitors, Wnt inhibitors, anabolic growth factors, nerve growth factor inhibitors are being studied as a means of not only reducing the pain from knee OA but potentially stopping the progression of structural damage. For patients with advanced knee osteoarthritis who failed conservative therapy and who are candidates, total joint replacement is definitive treatment.56 CRPS Background: CRPS is a chronic neurologic pain condition caused by trauma and is characterized by the presence of autonomic dysfunction, persistent regional inflammatory changes, lack of dermatomal distribution. Clinical presentation often includes allodynia, hyperalgesia, and skin temperature changes. It is formally known as “causalgia” or “reflex sympathetic dystrophy”. CRPS is divided into Type I (formerly reflex sympathetic dystrophy) due to trauma with no associated major nerve injury, and Type II (formerly causalgia) due to trauma or surgical insult in the presence of major nerve injury.62 CRPS occurs in the peripheral limbs and therefore is a source of knee pain. Etiology: CRPS is a combination of nervous system sensitization, autonomic dysfunction, and inflammatory changes in response to injury. Shortly after injury, inflammatory factors (tumor-necrosis factor alpha and prostaglandin E2) are released which leads to peripheral nociceptive sensitization and subsequent hyperalgesia. It is thought that persistent firing of Aδ and C afferent neurons fire persistently leading to engagement of the autonomic nervous system and the distinct CRPS symptomatology. Peripheral nociceptors become sensitive to catecholamines after injury. There is probable chronologic change in the peripheral nervous system leading to degradation of large somatomotor A⍺ neurons and preservation of Aδ fibers. Continuous firing of peripheral nerves also leads to increased synaptic firing in the dorsal horn. This process is mediated by neuropeptides including glutamate and Substance P, leading to allodynia and hyperpathia. Over time, the central nervous system responds by central reorganization of motor and sensation pathways. Autonomic dysregulation is thought to be due to coupling of adrenergic and nociceptive pathways. During the acute phase, studies have shown circulating catecholamines and norepinephrine, which explains vasodilation, edema, and change in limb temperature. Over time, this leads to catecholamine sensitivity, which explains the vasoconstriction, cold temperature, and clammy skin seen in chronic CRPS. The innate immune system also plays a role. Mast cells release cytokines and neuropeptide levels increase (substance P and gene-related-peptide) leading to elevated inflammatory factors (TNF, IL-1b, IL-6, nerve growth factor) and subsequent peripheral sensitization to noxious stimuli.62 Diagnostic criteria: The Budapest criteria state that patients must meet all four criteria for diagnosis of CRPS (Table 7).63 Nerve damage can be diagnosed by electromyography (EMG).64 Sudeck atrophy is a radiologic finding consistent with CRPS and includes diffuse osteopenia with juxtacortical demineralization, and subchondral cystic changes.65 Stellate ganglion block causing sympathetic blockade with associated reduction in symptoms has been shown to be efficacious for treatment and confirmation of CRPS Type 1 diagnosis.66 Treatment: As is the case for the treatment of CRPS in any body part, a proactive, multidisciplinary approach that includes pain management, psychiatric, physical therapy, primary care, and case worker/social work at time of diagnosis is important. Treatment is divided into acute and chronic phases. Acute treatment focuses on pain control with local nerve blocks and rehabilitative modalities to alleviate pain, manage edema, and prevent contractures. Pain management includes systemic steroids, tramadol, gabapentin, antidepressants, ketamine, calcium channel blockers, bisphosphonates, and baclofen. Therapeutic modalities include edema control, range of motion, mirror therapy, graded motor imagery, acupuncture, biofeedback, stress loading, and aerobic conditioning. Chronic pain that is refractory to acute treatment is managed by progressing to spinal cord stimulator, dorsal root ganglion stimulator, or botulinum toxin (Botox) injection. Palliative surgical treatment includes nerve decompression, resection of neuromas, joint contracture release, and amputation.62,64,65,67

Table 7 Budapest Criteria for CRPS Diagnosis

Chondromalacia Background: Patellar chondromalacia is softening of the patellar articular cartilage and is a common source of anterior knee pain. Patellar chondromalacia is a precursor to patellar osteoarthritis. Etiology: The patella is in the trochlear groove and friction during knee flexion causes breakdown of the patellar cartilage. Malalignment of patellar tracking within the trochlear groove can increase this friction and is often due to vastus medialis oblique (VMO) weakness. The exact etiology is unclear; however, it is proposed that friction trauma to superficial chondrocytes results in a proteolytic enzymic breakdown of cartilage matrix.68 Diagnostic criteria: Anterior knee pain that may be exacerbated by squatting, jumping, rising from sitting, or ascending/descending stairs. Retro-patellar crepitus may be present during knee range of motion, joint effusion, and >2 cm quadriceps wasting support chondromalacia. Tenderness over the medial or lateral patellar facets suggests progression to osteoarthritis. Special tests include patellar grind and patellar apprehension. Radiologic imaging with Merchant or skyline view is useful for evaluating the patellofemoral compartment.69 Sagittal-patellar tilt should be taken into consideration during evaluation if MRI is obtained. Aksahin et al70 evaluated patellar chondromalacia with MRI and found that sagittal plane malpositioning and chondral lesions might be related to chondromalacia. Tuna et al71 found that patellar tilt and trochlear dysplasia were related to the presence of chondromalacia. Treatment: Pain control for mild cases of chondromalacia is typically managed with NSAIDs, bracing, weight loss (if appropriate), activity modification, and a physical therapy regimen that focuses on stretching the VMO and strengthening the lower extremity kinetic chain.69 In a systematic review of outcomes, faster VMO reflex time was associated with improvement after exercise intervention.72 Moderate cases of chondromalacia may require intra-articular injections of corticosteroid or hyaluronic acid. If conservative management fails after 3–6 months, surgical intervention may be warranted.69 Biologic treatments including PRP and stem cell therapy are of particular interest due to their ability to potentially slow or even reverse progression of cartilage degradation. A study of autologous chondrocyte implantation (ACI) to patellar cartilage defects resulted in significant functional improvement at minimum 2 years and lasted up to 15 years.73 Surgical modalities include tubercle osteotomy to correct lateral maltracking, realignment, patellectomy, patellofemoral replacement, and total knee replacement.69 Post-Surgical Knee Pain (PSKP) Background: PSKP can be a difficult condition to diagnose, especially in the acute phase, as reports of pain after surgery are to be expected – it is not until several weeks, or even months, into the postoperative period that a practitioner will begin to suspect something is “wrong.” Even then, once any complications with the surgery (ie, infection, prosthesis malfunction, fracture, etc) have been ruled out, the usual assumptions are either malingering or drug seeking. For these reasons, PSKP tends to be underdiagnosed and its true incidence is difficult to measure as many patients reporting symptoms of PSKP are simply taken back to the operating room for subsequent surgeries. For example, many patients who undergo arthroscopic knee surgeries for knee OA eventually undergo total knee arthroplasty (TKA). A systematic review reports the overall incidence of TKA after knee arthroscopy is 2.62% and increases to 3.98% when selecting for older patients. The mean and median time from arthroscopy to TKA was 3.4 and 2.0 years, respectively.74 Annual revision rates of TKA are 0.49%, compared to revision rates of medial unicompartmental arthroscopy (1.07%), lateral unicompartmental arthroscopy (1.13%), and patellofemoral arthroscopy (1.75%).75 Nearly 20% of the patients experience suboptimal results following TKA, and residual post-TKA pain is a common complaint.76 Predictors of increased residual post-TKA pain include other pain sites, catastrophizing, and depression.77 Etiology: Post-TKA pain can be caused by intrinsic or extrinsic etiologies. Table 8 outlines the possible causes. Diagnostic criteria: Assessment of residual post-TKA pain includes detailed history, review of surgical reports, and physical exam. Acuity, onset, nature, exacerbating factors can help distinguish between intrinsic and extrinsic causes. Physical exam includes visual inspection including joint alignment, palpation, range of motion, patellar tracking and stability in coronal/sagittal planes during range of motion, gait, and exam of the hip and spine. Preoperative and postoperative radiologic images should be reviewed. Obtain weight bearing anterior-posterior, lateral, and merchant views of the knee. Additionally, weightbearing films of the entire leg, hip, and ankle will assess varus or valgus abnormalities. Diagnostic intra-articular local anesthetic injection will support diagnosis of intra-articular source if pain is relieved within a few minutes of injection.76 Treatment: Treating knee pain secondary to surgery can be extremely complicate given the fact that it may not be readily apparent what the pain is consequential to. Is it merely postsurgical discomfort that is taking longer than expected to heal, is it the result of a nerve injury (ie, CRPS Type II), a new pathology created by the surgery itself, or something else entirely? An unfortunate confounding factor that negatively impacts these situations is the presence of opioids as these patients will all inevitably be taking due to their having just had a surgical procedure. As such, multimodal analgesia is the optimal perioperative pain control regimen and reduces long-term opioid use with improved patient outcomes. This includes a combination of preemptive analgesia, neuraxial anesthesia, peripheral nerve blockade, patient controlled analgesia, local infiltration analgesia, and oral opioid/non-opioid medications.78 Yu et al report discontinuing patient-controlled analgesia and femoral nerve blocks from the multimodal regimen and replacing them with liposomal bupivacaine resulted in less overall opioid consumption, with no difference in functional recovery or reported pain control.79 In patients with centrally sensitized knee pain prior to TKA, duloxetine should be considered to minimize post-TKA pain.80 For patients with persistent post-TKA pain, physical therapy, range of motion, and transcutaneous electrical nerve stimulation (TENS) are conservative measures that are effective.81 Interventional therapies to consider include nerve blockade, peripheral nerve neuromodulation, and dorsal root ganglion neuromodulation.

Table 8 Intrinsic or Extrinsic Etiologies of Post-TKA Pain

Recommendations Regarding Conservative Care Medication NSAIDs

Twenty-one randomized control trials were included in this systematic review of oral NSAIDs for knee pain. Overall, three separate knee pain diagnostic groups had sufficient evidence to warrant inclusion. Twelve studies were included on knee osteoarthritis;82–93 eight studies were included on pain following total knee arthroplasty;82–85,94–101 and one study was included on patellofemoral pain syndrome.102 Of the studies regarding knee OA, five studies reported level 1 evidence in support of NSAID use, four studies reported level 2 evidence in support of NSAID use, and two presented level 3 evidence in support of NSAID use. Each of the supporting studies reported at least 30% reduction in knee pain with NSAID use. Of note, one study reported non-superiority of naproxen over placebo.85 Of considerable interest, cyclooxygenase-2 (COX-2) inhibitors were as effective as non-selective NSAIDs across studies, with several reporting enhanced analgesia and all describing a decreased incidence of adverse side effects, primarily GI upset, with COX-2 inhibitors. One RCT even described superiority of celecoxib 20 mg qd over tramadol 300 mg extended release, with each superior to placebo.89

Regarding pain following total knee arthroplasty, each of the eight included studies supported the use of NSAIDs, with seven reporting level 1 evidence and one study reporting level 2 evidence. Consistent with the bulk of evidence for COX-2 inhibitors in knee osteoarthritis, COX-2 inhibitors were also supported across all studies, with sustained analgesic benefit noted after from COX-2 inhibitor use in the first weeks following arthroplasty.

Lastly, one study described a significant analgesic benefit of acute NSAID use in patellofemoral syndrome versus placebo, with a 5-point reduction in visual analog scale (VAS) score in comparison to 2 point with placebo102 (see Table 9).

Table 9 Evidence Table Regarding NSAIDs

In summary, oral NSAIDs are moderately effective in controlling pain in patients with moderate-to-severe pain due to knee osteoarthritis and pain s/p total knee arthroplasty. COX-2 selective NSAIDs are similarly effective to non-selective NSAIDs in controlling pain with the advantage of a considerably improved safety profile, especially regarding gastrointestinal upset. While all NSAIDs are associated with an increased risk of acute kidney injury, patients with a history of hypertension, heart failure, or diabetes have higher chance of developing these complications.

Consensus Points for NSAIDs NSAIDs are an effective treatment for mild-to-moderate pain secondary to osteoarthritis knee pain; Level 1, Grade A, Consensus Strong Topical NSAIDs are recommended before oral treatments because of their lower systemic exposure/toxicity; Level 1, Grade A, Consensus Strong Topical diclofenac 70–81 mg/day should be considered as first-line pharmacological treatment for knee OA - can be effective and generally safer than oral NSAIDs due to reduced systemic exposure and lower dose; Level 1, Grade A, Consensus Strong NSAIDs should not be used for patients with comorbidities due to risk of adverse events; Level 1, Grade A, Consensus Strong NSAIDs should not be used on a long-term basis (>3 months) due to side effect profile (cardiovascular and gastrointestinal) and lack safety data; Level 1, Grade A, Consensus Strong Celecoxib and non-selective NSAIDs are as effective as opioid for knee OA; Level 1, Grade A, Consensus Strong Due to low effect on pain and physical function, regardless of dose, the potential clinical benefit of opioids does not outweigh the potential harm in patients with knee OA; Level 1, Grade A, Consensus Strong Topicals

Out of the 17 studies included in this study, 6 reported level 1 evidence in support of the use of topical NSAIDs for knee osteoarthritis.103–108 9 studies reported level 2 evidence in support of topical NSAIDs109–117 one reported level 3 evidence in support of topical NSAIDs;118 and one study reported level 2 evidence not in favor of topical NSAID therapy.119 Adverse events were rare in all included studies, primarily limited to minor skin irritation at the site of application. The clinical effect of topical NSAIDs was modest at best in comparison to placebo, but all studies did report statistically significant improvements in pain reduction. There was insufficient evidence to support recommendations for other topical medications (eg, capsaicin, copper). Osteoarthritis of the knee was the only diagnosis with sufficient literature to support recommendations regarding topical NSAID therapy.

Importantly, five separate studies demonstrated non-inferiority to oral NSAID therapy. Of note, one study reported inferiority of topical NSAID therapy in comparison to placebo. Indeed, the placebo effect was readily apparent in each study, which is a well-known phenomenon found in trials of topical medications (see Table 10).

Table 10 Evidence Table Regarding Topicals

To sum, topical NSAIDs have established efficacy comparable to oral NSAID therapy in the treatment of knee osteoarthritis, with a vastly improved adverse side effect profile and decreased cost. Topical NSAIDs may be preferable for patients with knee osteoarthritis older than 75, those with comorbidities or at an increased risk of renal, cardiovascular, or gastrointestinal adverse events.

Consensus Points for Topicals Topical NSAIDs are an effective treatment for symptomatic knee osteoarthritis and can be utilized as part of as an adjuvant analgesic treatment plan; Level 1, Grade A, Consensus Strong Topical NSAIDs should be utilized before oral NSAID therapy for the treatment of knee osteoarthritis; Level 1, Grade A, Consensus Strong Opioids

Due to the US opioid crisis, the use of chronic opioids for osteoarthritic, neuropathic, and non-surgical pain syndromes is currently under scrutiny.120 Prior to 2013, 15.9% of the patients with knee osteoarthritis were prescribed an opioid.18 While opioid prescribing for this condition has not been directly studied since, opioid prescribing has declined or all comers since 2013. Despite this, opioid prescribing for chronic knee pain continues to be routinely practiced.

Welch and colleagues performed a systematic review of 22 double blinded trials (8942 participants) which compared opioids for chronic osteoarthritic knee pain versus placebo.120 These authors found based on low-quality evidence that opioids provided no clinical relevant improvement in disability and no clinically relevant pain relief of 50% or greater.120 While there was no difference in serious adverse events compared to placebo, there was a relevant dropout rate for the opioid group due to side effects.120

Krebs et al conducted a randomized controlled trial comparing acetaminophen and non-steroidal anti-inflammatory medications in patients with osteoarthritis of the back, knee, and hip.121 While this study did not directly isolate knee patients, they found that there was no difference between the two groups in pain-related function and brief pain inventory interference.121 There was significant improvement in pain intensity in the non-opioid group when compared to opioids. Lastly, the opioid group had greater medication-related side effects and adverse events.121

There is limited peer-reviewed literature evaluating the benefits of opioids for chronic post-surgical knee pain specifically, but we do know that chronic opioid use has risks of opioid use disorder and overdose. Others have also detailed that chronic opioid use prior to total knee arthroscopy is an independent risk factor for persistent opioid use after surgery.122,123

There is also little peer-reviewed literature evaluating the benefits of opioids for neuropathic knee pain. Busse et al in a systematic review of opioids for non-cancer pain found that opioids, compared to placebo, were associated with small but significant improvements in pain and physical functioning in patients with neuropathic pain but also associated with side effects.124 Vergne-Salle specifically discussed opioids for neuropathic pain of the knee in an expert review and stated that opioids should only be used when other available treatments have failed.125 This is because high doses are often needed to provide the desired effect and these are associated with high morbidity and mortality.125

Consensus Points for Opioids Due to low effect on pain and physical function, regardless of dose, the potential clinical benefit of opioids does not outweigh the poten

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