Pain Interventions for the Knee, Hip, and Shoulder

Indications and Mechanism of Action

Local anesthetics are often utilized in combination with corticosteroids for IA and extra-articular injections. The rationale for utilizing LAs includes providing pain relief for the needle insertion itself and diagnostic purposes, as well as diluting and distributing the steroid preparation within the joint.

Local anesthetics act by reversibly binding to sodium channels on neuronal cell membranes, thereby blocking nerve conduction. Local anesthetics also have transient anti-inflammatory effects and inhibit several leukocyte functions.

Local anesthetics commonly employed for joint injections include the short-acting LA lidocaine and the long-acting LAs bupivacaine and ropivacaine.

Adverse Effects and Complications Associated With Local Anesthetic Injection

Local anesthetics are associated with local and systemic side effects. Local effects of LAs include myotoxicity and chondrotoxicity. Myotoxicity can occur from LA administration in or around muscle tissue, although it is usually not clinically relevant and muscle regeneration occurs. Bupivacaine is more myotoxic than lidocaine and ropivacaine. Local anesthetics produce myonecrosis through the lytic degeneration of the sarcoplasmic reticulum and mitochondria. The addition of corticosteroids to LA injection amplifies the muscle damage and prolongs the recovery phase. Myonecrosis rarely presents any clinically discernible manifestations in the course of routine use of local anesthetics for IA joint injections.

Local anesthetics are also chondrotoxic. Most reported cases of chondrolysis occurred after the use of continuous IA local anesthetic infusions to manage postoperative pain rather than single IA injections. In vitro studies have demonstrated that LAs cause mitochondrial dysfunction and apoptosis in human chondrocytes. Chondrotoxic effects are influenced by the LA type and concentration. Grishko et al. demonstrated that 2% lidocaine caused massive necrosis of cultured chondrocytes after 24 hours of exposure, whereas 1% lidocaine caused a detectable but insignificant decrease in cell viability. Therefore clinically, the use of lower concentrations of local anesthetic may be advantageous. For longer acting LAs, in vitro studies indicate that 0.5% ropivacaine is significantly less chondrotoxic to cultured human articular cartilage than 0.5% bupivacaine. Similar to myotoxicity, combining LA with corticosteroids amplifies chondrotoxicity. Although the molecular mechanisms of LA chondrotoxicity are still incompletely elucidated, LAs are thought to lead to mitochondrial dysfunction by influencing sodium, calcium, and potassium channels, ultimately resulting in cell necrosis or cell apoptosis in a time- and dose-dependent manner.

When combining LA with corticosteroids, flocculation— aggregation of the particles of steroid—may occur. Indeed, dilution with either saline or LA may influence the size of corticosteroid particles. Betamethasone sodium phosphate/betamethasone acetate (Celestone Soluspan) should not be mixed with LAs that contain the excipients methylparaben, propylparaben, or phenol because of an increased risk of flocculation. Flocculation leads to larger particles that may clog smaller bore needles, preventing injection. The effect of flocculation of the injected steroid on their therapeutic effect is unclear. Theoretically, the change in the size of the microaggregates of steroids could significantly alter the bioavailability of the steroid over time and the distribution within the joint after injection, altering their therapeutic effect.

Systemic effects of LAs include allergic reactions, central nervous system, and cardiac toxicity. When appropriate steps are taken to avoid intravascular injection, including frequent aspiration and using small volumes for musculoskeletal injections, the incidence of these occurrences are low. Allergic reactions are more common with amino-ester LAs secondary to the production of metabolites related to para-aminobenzoic acid. Allergic reactions may also be because of the preservatives contained within the carrier solution (e.g. methylparaben). Cross-sensitivity does not exist between LA structural classes.

Indications and Mechanism of Action

Corticosteroids are often used for pain associated with symptomatic arthritis and soft tissue conditions, e.g. tendinitis, bursitis, and tenosynovitis. Numerous guidelines with a specific focus on osteoarthritis of the knee recommend IA corticosteroid injection for short-term pain relief. Intraarticular steroid injections should be part of a multimodal treatment plan that includes aerobic and muscle-strengthening programs. Contraindications to IA injection are shown in Table 67.1 .

The exact mechanism of action of corticosteroids in reducing arthritic joint pain has not been completely defined. Corticosteroids placed in the joint exert both local and systemic effects. ^{, ,} In individuals with RA, changes in the non-injected knee thermographic index, a quantitative measure of radiated energy from a defined area of the joint surface, have been demonstrated after IA prednisolone and triamcinolone hexacetonide (TH) injection into the symptomatic knee. ^, Intraarticular placement of methylprednisolone acetate (MPA), 40 or 80 mg, resulted in detectable systemic serum levels with peak levels occurring between 2 and 12 hours after injection. Additionally, endogenous serum cortisol levels were suppressed for up to one week after injection. The systemic effects are further confirmed by the reduction of systemic inflammatory marker levels, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).

Corticosteroids have significant anti-inflammatory and immune effects and are active at the cellular level by combining with receptors to alter the rate of messenger ribonucleic acid synthesis and specific protein production. Specifically, corticosteroids result in increased synthesis of annexin-1 (lipocortin 1). Annexin-1 has phospholipase A ₂ -inhibitory activity that reduces the production of multiple inflammatory mediators, including eicosanoids, lysosomal enzymes, interleukin-1, leukotrienes, and prostaglandins. The clinical response to IA steroids is accompanied by histologic improvement and decreased expression of genes involved in articular cartilage destruction. Additionally, corticosteroids reduce microvascular permeability and synovial perfusion and increase synovial fluid viscosity.

Corticosteroids seem to exert greater therapeutic effects with IA injection versus systemic or intramuscular (IM) administration. Injection of corticosteroid into multiple joints in RA patients resulted in greater improvement in ACR Criteria, patient disease activity, number of tender points, and reduced systemic side effects compared to equivalent IM dosing. There is moderate evidence to support the effectiveness of IA steroid injections into the knee, with studies suggesting efficacy up to three months after injection.

Corticosteroid Selection (Structure and Function)

The first steroid used for IA injection was hydrocortisone. ^, Pharmacologic developments have resulted in the advancement of steroid preparations over the past 50 years. However, substantial variation still exists for agent selection. There remains a paucity of randomized controlled trials (RCTs) comparing the efficacy of different corticosteroids for osteoarthritis. Thus evidence-based recommendations to guide steroid selection cannot be made. In 2014, a survey of ACR members indicated that agent selection for IA injections was usually determined empirically, and no consistent pattern was reported in terms of the type of corticosteroid based on anatomic site. The three most commonly utilized agents were MPA (used by 45% of respondents), triamcinolone acetonide (TA; 26.1%), and TH (22.1%).

Table 67.2 lists commonly utilized corticosteroids that are FDA-certified for IA injection. TA extended release formulation is FDA-approved only for use in the knee joint and has not been studied in other peripheral joints. Approved for commercial use in the United States in 2017, it is supplied as a crystalline powder that is mixed at point-of-care with the manufacturer-supplied diluent to deliver 32 mg of TA extended release in 5 mL of solution that is equivalent to 40 mg of immediate-release TA. The extended release formulation utilizes poly (lactic-co-glycolic acid; PLGA) microspheres that allows for the slow release of TA. This formulation allows for the prolonged presence of steroids in the joint. The only other corticosteroid approved for IA injection is dexamethasone. Dexamethasone, a highly water soluble, non-particulate steroid preparation, exerts primarily systemic effects even after IA injection and is not routinely utilized for IA injections. ^, Ultimately, the selection of a depot corticosteroid can be based on cost and multiple pharmacologic properties, including solubility, crystal, and molecular structure.

Corticosteroid solubility may influence the duration of action, although published studies are conflicting. TH is the most insoluble injectable corticosteroid. Some IA injection studies have demonstrated a prolonged duration of activity with TH compared to other corticosteroids with higher solubility. Derendorf et al. demonstrated that TH was associated with lower levels of systemic absorption and higher synovial levels than similar IA administration of TA. Comparison of TH and MPA for knee osteoarthritis did not support steroid solubility as the only factor influencing drug duration of action and therapeutic efficacy. After three weeks, TH was more effective, but only MPA resulted in continued improvement in pain and disability scores at eight weeks. Another study comparing TH and MPA for RA treatment demonstrated a longer therapeutic effect with TH. Thus available data are conflicting.

There is limited evidence to guide corticosteroid selection based on the peripheral joint target. MPA and TA seem to have similar short and intermediate term effectiveness for improving pain and function in peripheral joint targets. Most studies do not show greater pain improvement with a higher dose of steroids.

The adverse effect profile of a corticosteroid should also be considered. Methylprednisolone acetate may be utilized for both joint and soft tissue injections, whereas TH is not recommended for soft tissue injections because of the higher risk of calcification, necrosis, and atrophy of soft tissues. ^{, ,}

Corticosteroid Dosing and Post-injection Protocols

Corticosteroid dosing ranges for various joints are listed in Table 67.2 . Evidence-based recommendations for dosing and the maximum injection frequency do not exist. Cumulative doses of epidural steroid injections greater than 200 mg methylprednisolone equivalents annually have been shown to be associated with compromised bone mineral density, and practitioners should be aware of the total steroid exposure a patient receives over time from all injection sources. Standard recommendations for weight bearing joints include a maximum of three to four injections per year, typically with three to four months between injections. ^, Conflicting evidence exists regarding the long-term safety of repeated IA corticosteroid injections. Long-term corticosteroid safety was studied by Raynauld et al. in a randomized, double-blind placebo-controlled trial that compared IA knee injections of TA or saline every three months for up to two years. No detrimental effects or joint space destruction were observed on radiographs. Balch et al. found no radiographic evidence of corticosteroid-induced joint destruction after long-term repeated IA injections (from four to 15 years) on knee joints affected by RA and osteoarthritis. However, a recent RCT examining IA corticosteroid injection treatment demonstrated significantly greater cartilage volume loss with no significant difference in pain scores with triamcinolone compared to saline when administered every three months over a two-year period. Moreover, 80 mg of TA is not superior to 40 mg for IA knee injection in terms of pain relief or functional improvement.

Following IA corticosteroid injection, patients are often advised to avoid overusing the joint for two to three days post-injection. Studies investigating potential benefits of rest following corticosteroid injections have reported conflicting results. Chakravarty et al. demonstrated additional improvement in individuals that rested for 24 hours after IA injection, while Chatham et al. found no benefit in individuals that rested for 48 hours.

If an individual is going to undergo a joint replacement surgery in the near future, caution should be exercised in performing IA injections close to the surgical date (typically within three months). Retrospective comparative studies demonstrated an increased risk for deep infection in individuals that received IA corticosteroid injections shortly before the surgical replacement procedure. However, Kokubun et al. did not observe increased complications or infections IA injections within 90 days prior to total knee replacement. A meta-analysis in 2014 showed no clear association between IA injections performed prior to arthroplasty and the development of subsequent infection following joint replacement. However, this study was not limited to injections performed within 90 days of surgery and thus speaks more to the apparent safety of injections performed at any time prior to arthroplasty. Patients should be counseled on the risks of periprosthetic infections when considering the use of IA injections as temporizing pain reduction techniques prior to joint replacement surgery.

Adverse Effects and Complications Associated With Corticosteroid Injection

The adverse effects and complications of corticosteroid injections can be divided into local and systemic effects. Local adverse effects include tissue (skin or fat) atrophy, Nicolau’s syndrome, tendon rupture, cartilage damage, post-injection flare, hemarthrosis, joint destruction, avascular necrosis, and septic arthritis. ^{, , ,} Local tissue atrophy is one of the most common local adverse effects occurring in 1%–8% of cases and is often associated with superficial injection, inaccurate placement, and less soluble agents, e.g. triamcinolone compounds. Skin atrophy typically develops between one and four months after injection. ^, Methylprednisolone acetate is less frequently associated with soft tissue atrophy. Another common adverse effect is post-injection flare in pain, with a prevalence of 2%–25%. Post-injection flare typically presents within a few hours of injection and resolves within one to three days.

Concern also exists for corticosteroid-specific effects on cartilage, tendon, and bone. Current data on corticosteroid effects on cartilage are conflicting. Animal studies have been inconsistent, with some demonstrating cartilage destruction while others revealing a cartilage-protective effect during acute inflammatory events. Clinical studies suggest that cartilage loss may occur more frequently with repeated injections in large numbers. ^, Avascular necrosis has also been reported after joint injections, with the hip being the most commonly affected joint. This complication typically occurs after multiple joint injections within a short period and is seen more often in individuals who are concurrently taking oral steroids. Tendon disruption has also occurred following corticosteroid injection, and care should be taken to avoid direct injection within tendons. ^,

Hemarthrosis and septic arthritis are two infrequent complications that carry significant morbidity. No specific guidelines exist for the performance of IA steroid injections in individuals on anticoagulants, and surveys have demonstrated substantial practice variation. A small study demonstrated a low risk of hemorrhage in individuals taking warfarin sodium that received IA injections. Septic arthritis has a reported incidence ranging from one in 3,000 to one in 50,000. ^{, ,} To reduce the risk of this adverse event, it is important to understand contraindications to injection ( Table 67.1 ) and utilize a stringent aseptic technique. When performing a joint injection, if synovial fluid appears abnormal, the aspirated fluid should be sent for a complete white blood cell count (WBC) count, including differential, crystal analysis, Gram stain, and culture. Steroids should not be placed until the synovial fluid analysis ( Table 67.3 ) is reviewed and interpreted. Septic arthritis is a medical emergency and can result in cartilage destruction, septicemia, and death within a few days if untreated. When septic arthritis is suspected, orthopedic surgery and infectious disease specialists should be consulted immediately. Arthrocentesis and synovial fluid analysis ( Table 67.3 ) are mandatory for diagnosis and to guide treatment. Blood tests including a WBC, ESR, and CRP are neither sensitive nor specific in diagnosing or excluding septic arthritis. Broad-spectrum antibiotics are initially started after obtaining the synovial fluid, and antibiotic selection is further guided by culture and sensitivity results. Septic arthritis has also been reported following viscosupplementation injections.

Systemic adverse effects of IA corticosteroids include endocrine, metabolic, and vascular effects. The most common and predictable endocrine effect is the rapid suppression of endogenous cortisol production. Maximal suppression of serum cortisol levels occurs 24–48 hours after IA injection. Adrenocorticotropic hormone (ACTH) levels typically return to normal between one and four weeks, indicating recovery of normal endogenous steroid production. ^{, ,} Metabolic effects include elevation of blood glucose levels in diabetic patients. In people with diabetes with appropriate glucose control, acute hyperglycemia may persist for two to three days with peak glucose levels reaching 300 mg/dL. ^, Facial flushing is an unpleasant adverse effect seen in 15%–40% of patients. The effect occurs, on average, 19 hours after injection and is self-limiting, lasting approximately 36 hours. Triamcinolone administration is associated with a higher rate of facial flushing.

Indications and Mechanism of Action

Viscosupplementation refers to IA administration of synthetic hyaluronic acid (HA). Intraarticular HA administration (IAHA) was initially recommended by numerous specialty guidelines, including the ACR, Osteoarthritis Research Society International (OARSI), and European League Against Rheumatism (EULAR), as a treatment option for the management of knee osteoarthritis. ^{, ,} Expert consensus supported the use of IAHA as an effective treatment in mild to moderate knee OA and is a well tolerated treatment in the knee and other joints. However, the 2019 ACR and Arthritis Foundation Guideline for the management of osteoarthritis of the hand, hip, and knee continued to strongly recommend the utilization of intraarticular glucocorticoid injections but changed their position on intraarticular HA injections. The 2019 recommendations conditionally recommended against the use of intraarticular HA injections in individuals with osteoarthritis of the knee and strongly recommended against its use in patients with hip osteoarthritis. The guidelines concluded that the initial recommendation for IA HA injections did not consider the risk of bias of individual primary studies. The studies that demonstrated benefit were often restricted to studies with a higher risk of bias. When meta-analyses were limited to trials with a low risk of bias, the effect size of HA injections compared to saline was not statistically significant. Therefore careful risk-benefit assessment and patient and physician informed decision making is required before performing IA viscosupplementation for the knee

IA HA administration is approved by the United States Food and Drug Administration (FDA) only for knee osteoarthritis. Off-label application of IAHA has been reported for the shoulder, hip, and ankle. Selection criteria include failure of standard noninvasive treatment programs with clinical and radiologic signs of knee osteoarthritis. ^, Osteoarthritis severity may be an important predictor in determining the magnitude of clinical response to IAHA injection. In general, IAHA seems most beneficial in individuals with early osteoarthritis and radiographic evidence of joint space preservation. Contraindications to IAHA injection are shown in Table 67.1 .

Although the exact mechanism of action is unknown, the treatment goal is to restore the viscoelastic properties of synovial fluid. Observed treatment benefits are not entirely explained by IA residence time, which is considerably shorter than the duration of clinical benefit. Several in vitro and pre-clinical studies have proposed additional mechanisms of action for IAHA, including inhibition of inflammation and cartilage degradation, reduction of pain mediators, and induction of in vivo HA synthesis. ^, HA has been best studied in the knee; some studies show that it may provide longer lasting improvement in pain and function than intra-articular steroid (IAS).

Viscosupplementation Agent Selection (Structure and Function)

HA is a glycosaminoglycan synthesized by synoviocytes, fibroblasts, and chondrocytes that confers viscous and elastic properties to the joint. Viscosupplementation formulations differ in their origin, production method, molecular weight, treatment schedule, and physicochemical properties. At least 12 HA preparations are approved for knee osteoarthritis in the United States, initially offered as a series of injections with the first single injection option introduced in 2009. Formulations are classified as cross-linked or non-cross-linked and are further defined by chemical modifications and production method (avian- versus non-avian-derived products). Non-avian products are produced by bacterial fermentation. All available avian preparations are derived from rooster combs and are purified natural products. The avian sourced hylan G-F 20, Gel-One®, and non-avian sourced Monovisc®, Durolane® are chemically modified (cross-linked HA) to increase the molecular weight to replicate the properties of native synovial fluid more closely and to lengthen IA residence half-life. ^, No conclusive evidence exists that differences in viscosupplement physical properties translate into superior clinical efficacy.

Dosing and Post-injection Protocols

The recommended dosing regimens for specific viscosupplementation products are based on the physical properties and the manufacturers’ prescribing recommendations. Currently, there is insufficient evidence to guide the appropriate injection frequency and dosing intervals. Common recommendations are either for a single injection or a total of two to five weekly injections based on the selected product ( Table 67.4 ), but these are solely based on the manufacturer’s recommendations that arose from the pre-marketing registry trials for each product. Evidence-based recommendations do not exist for interval timing for repeating treatment, although repeated courses of IAHA are generally safe and well tolerated, with injections or series spaced at least six months apart demonstrating effectiveness in several RCTs. Insurance providers typically require a minimum of 6 months between repeated treatment courses. Pre-injection synovial fluid aspiration and avoidance of excessive weight bearing activities for 48–72 hours post-injection may yield better outcomes. ^{, ,}

Adverse Effects and Complications Associated With Viscosupplementation Injection

In general, viscosupplementation is well tolerated with more local reactions but fewer systemic side effects than other medical interventions for managing knee osteoarthritis. Frequently reported local adverse effects include injection site pain, short term erythema, and joint effusion development. These effects are typically mild and resolve within 24–48 hours.

Other infrequent local adverse effects include pseudosepsis and pseudogout. Pseudosepsis, a severe acute inflammatory reaction, is considered an extreme local adverse reaction. It is characterized by a large effusion, severe pain, and cellular infiltration occurring within 24–72 hours after the injection. Pseudosepsis often requires clinical intervention such as arthrocentesis, IA corticosteroids, and systemic analgesics. Pseudosepsis may be misdiagnosed as septic arthritis. The proposed mechanisms of pseudosepsis include an immune reaction to cross-linked products. Inappropriate injectate placement has also been suggested as a causative factor in pseudosepsis. ^, When pseudosepsis is suspected, other clinical conditions such as septic arthritis must be ruled out.

Pseudogout is a type of crystal-induced arthropathy characterized by calcium pyrophosphate crystal deposition. Individuals with pseudogout present with acute pain, joint swelling, and decreased function. The pathophysiology leading to pseudogout after IAHA is not clearly understood. Pseudogout occurs more frequently in patients with preexisting chondrocalcinosis. Therefore IAHA should be used with caution in these individuals. ^, Pseudogout may also be mislabeled as pseudosepsis. Synovial fluid analysis is helpful in making the correct diagnosis ( Table 67.3 ).

Anatomy

The shoulder is a complex anatomic structure allowing multidirectional movement. The shoulder girdle refers to several articulations associated with important muscle groups that provide a wide range of shoulder movement. Three important shoulder joints are the glenohumeral, acromioclavicular, and sternoclavicular. The glenohumeral joint is a ball and socket joint that allows abduction, adduction, flexion, extension, rotation, and circumduction. The acromioclavicular joint is situated superficially between the lateral end of the clavicle and the acromion process of the scapula. The rotator cuff muscles include the supraspinatus, infraspinatus, teres minor, and subscapularis. The subacromial bursa is positioned within the subacromial space between the overlying deltoid muscle and the underlying supraspinatus tendon and provides rotator cuff lubrication.

Injection techniques for the shoulder including palpation (anatomic landmarks) and image guided (ultrasound and fluoroscopy) approaches. We will focus the discussion on image guided techniques for the three major anatomic locations for shoulder injections: 1) subacromial/subdeltoid bursa, 2) glenohumeral joint, and 3) acromioclavicular (AC) joint. Shoulder injection using only anatomical landmarks may be inaccurate, which may adversely affect short-term clinical outcomes. ^,

Subacromial/Subdeltoid Bursa Injections