Treatment of knee osteoarthritis

Knee osteoarthritis is a common disabling condition that affects more than one-third of persons older than 65 years. Exercise, weight loss, physical therapy, intra-articular corticosteroid injections, and the use of nonsteroidal anti-inflammatory drugs and braces or heel wedges decrease pain and improve function. Acetaminophen, glucosamine, ginger, S-adenosylmethionine (SAM-e), capsaicin cream, topical nonsteroidal anti-inflammatory drugs, acupuncture, and tai chi may offer some benefit. Tramadol has a poor trade-off between risks and benefits and is not routinely recommended. Opioids are being used more often in patients with moderate to severe pain or diminished quality of life, but patients receiving these drugs must be carefully selected and monitored because of the inherent adverse effects. Intra-articular corticosteroid injections are effective, but evidence for injection of hyaluronic acid is mixed. Arthroscopic surgery has been shown to have no benefit in knee osteoarthritis. Total joint arthroplasty of the knee should be considered when conservative symptomatic management is ineffective.     

Viscosupplementation for Osteoarthritis: a Primer for Primary Care Physicians

Introduction

Osteoarthritis (OA) constitutes a growing public health burden and the most common cause of disability in the United States. Non-pharmacologic modalities and conservative pharmacologic therapies are recommended for the initial treatment of OA, including acetaminophen, and topical and oral non-steroidal anti-inflammatory drugs. However, safety concerns continue to mount regarding the use of these treatments and none have been shown to impact disease progression. Viscosupplementation with injections of hyaluronans (HAs) are indicated when non-pharmacologic and simple analgesics have failed to relieve symptoms (e.g., pain, stiffness) associated with knee OA. This review evaluates literature focusing on the efficacy and/or safety of HA injections in treating OA of the knee and in other joints, including the hip, shoulder, and ankle.

Methods

Relevant literature on intra-articular (IA) HA injections as a treatment for OA pain in the knee and other joints was identified through PubMed database searches from inception until January 2013. Search terms included “hyaluronic acid” or “hylan”, and “osteoarthritis”.

Discussion

Current evidence indicates that HA injections are beneficial and safe for patients with OA of the knee. IA injections of HAs treat the symptoms of knee OA and may also have disease-modifying properties, potentially delaying progression of OA. Although traditionally reserved for second-line treatment, evidence suggests that HAs may have value as a first-line therapy in the treatment of knee OA as they have been shown to be more effective in earlier stages and grades of disease, more recently diagnosed OA, and in less severe radiographic OA.

Conclusion

For primary care physicians who treat and care for patients with OA of the knee, IA injection with HAs constitutes a safe and effective treatment that can be routinely administered in the office setting.     

Functional outcome in knee osteoarthritis after treatment with hylan G-F 20: a prospective study

OBJECTIVE: To assess functional change in patients with knee osteoarthritis (OA) after treatment with intra-articular hyaluronic acid (Hylan G-F 20; Synvisc). DESIGN: Prospective case series with 6-month follow-up. SETTING: Outpatient community orthopedic practice. PARTICIPANTS: Eighty-four consecutive patients referred to private orthopedic group with symptoms and radiographic evidence of unilateral or bilateral knee OA who had either failed or could not tolerate the side effects of conservative treatment. Sixty-one patients completed the study. Nineteen patients were lost to follow-up. Four patients withdrew from study due to subsequent knee arthroplasty. INTERVENTION: Three weekly injections of Hylan G-F 20 into one or both (if bilaterally symptomatic) knees (110 knees total). OUTCOME MEASURE: SF-36 Health Survey was completed before treatment and 6 months after treatment. RESULTS: Statistically significant improvement (p < .001) in Physical Functioning, Role-Physical, Bodily Pain, Social Functioning, and Role-Emotional categories on 6-month follow-up survey. Age and percent above ideal body weight were not significant predictors of functional change. CONCLUSION: Efficacy of intra-articular injection of Hylan G-F 20 for knee OA 6 months after injection is demonstrated in several categories of the SF-36, indicating a measurable improvement in overall functioning in these patients.     

Potential Impact of Biologically Derived Hyaluronic Acid on Quality of Life in Patients with Knee Osteoarthritis in the United States

Introduction

Knee osteoarthritis is one of the leading causes of disability in the world. Intra-articular hyaluronic acid (IA-HA) is a treatment modality that provides a minimally invasive treatment option for the management of osteoarthritis-related symptoms. This study examined the current and potential economic impact of using a biologically derived, high molecular weight hyaluronic acid preparation (Euflexxa) on the US population for the management of knee osteoarthritis.

Methods

A model was developed to estimate the total number of patients with symptomatic knee osteoarthritis in the US in 2015, distributed by Kellgren–Lawrence (K–L) grade, and the number of people living with total knee arthroplasty (TKA). The potential utility of Euflexxa was applied to this model population to determine the current and potential impact of the treatment as the total number of quality adjusted life years (QALY) saved within the US population.

Results

There are approximately 12 million people currently suffering from symptomatic knee osteoarthritis in the US, and approximately 5 million living with TKA. It was estimated that, with a target treatment group of K–L grades 2–3, there are approximately 4 million patients eligible for treatment with a high molecular weight intra-articular hyaluronic acid injection. With current use, it is estimated that Euflexxa can save 36,730 QALY/year among the US population, and has the potential to save an additional 369,181 QALY/year if used by all eligible patients.

Conclusions

This study demonstrates that more widely used, biologically derived, high molecular weight IA-HAs, such as Euflexxa, have the potential to save a substantial number of QALYs among the US population with symptomatic knee osteoarthritis. Funding: Ferring Pharmaceuticals Inc.

     

Hyaluronic acid treatment for osteoarthritis of the knee.

Osteoarthritis of the knee is a leading cause of chronic disability in the United States. It is a heterogeneous condition that causes pathogenic changes that are presumably irreversible. In many cases, knee pain is often progressive and leads the patient to seek medical attention. Pharmacologic and nonmedicinal treatments are, in most cases, only modestly successful in relieving pain. Hyaluronic acid (HA) functions as the backbone of the proteoglycan aggregates necessary for the functional integrity of articular cartilage of the knee. Two drugs made up of HA derivatives have recently become available for patients in whom simple analgesics and conservative non-pharmacologic therapy have failed. This article reviews the epidemiology, pathogenesis, diagnosis, and medical management of osteoarthritis of the knee, with an emphasis on the physiologic and pharmacologic mechanisms of HA. Health care providers may administer HA via intra-articular injection in primary care, rheumatologic or orthopedic settings, or they may refer their patients to specialists for consultation.     

Osteoarthritis: current concepts in diagnosis and management

Most patients with osteoarthritis seek medical attention because of pain. The safest initial approach is to use a simple oral analgesic such as acetaminophen (perhaps in conjunction with topical therapy). If pain relief is inadequate, oral nonsteroidal anti-inflammatory drugs or intra-articular injections of hyaluronic acid-like products should be considered. Intra-articular corticosteroid injections may provide short-term pain relief in disease flares. Alleviation of pain does not alter the underlying disease. Attention must also be given to nonpharmacologic measures such as patient education, weight loss and exercise. Relief of pain and restoration of function can be achieved in some patients with early osteoarthritis, particularly if an integrated approach is used. Patients with advanced disease may eventually require surgery, which generally provides excellent results.     

Baker's Cyst with Knee Osteoarthritis: Clinical and Therapeutic Implications

ObjectiveSeveral symptoms are common to knee osteoarthritis and Baker''s cyst. To what extent each condition contributes to the patient''s discomfort is still a matter of debate. The aim of the present study was twofold: first, to compare the burden of symptoms in patients with isolated knee osteoarthritis and patients with knee osteoarthritis associated with Baker''s cyst; second, to assess the outcomes after conservative treatments.Subject and MethodsPatients suffering from monolateral idiopathic knee osteoarthritis were enrolled. Demographic, anthropometric and clinical data (KOOS scale) were collected. Ultrasound evaluation was performed according to standard protocols. On the basis of the clinical presentation different therapeutic options were used (fluid withdrawal, hyaluronic acid and/or steroids injections).ResultsOne-hundred and thirty patients were included in the study (97 with isolated knee osteoarthritis, 33 with knee osteoarthritis and Baker''s cyst). In basal conditions, lower scores in KOOS sub-scales were observed in patients with knee osteoarthritis associated with Baker''s cyst and in patients with effusion compared with patients without effusion. At 3 months after therapy significant higher scores were observed in both groups. At 6 months the scores were unchanged in the patients without Baker''s cyst, but worsened in those with Baker''s cyst.ConclusionsThe study shows that Baker''s cysts associated with knee osteoarthritis contribute to the burden of symptoms. The conservative treatment of both conditions allows significant improvements, but in the medium term (6 months) the efficacy of the therapy declines in patients with knee osteoarthritis associated with Baker''s cyst.     

Hyaluronic acid for the treatment of knee osteoarthritis: long-term outcomes from a naturalistic primary care experience

OBJECTIVE: Intraarticular hyaluronic acid is indicated for patients with osteoarthritis of the knee. However, clinical experience, especially efficacy and adverse events, with repeated injection series in the long term are limited. DESIGN: Patients were referred to a large primary care center for management of osteoarthritis of the knee. All were naive to intraarticular hyaluronic acid therapy and met our entry criteria, including resting visual analog scale pain of > 45 mm, radiographic confirmation of unilateral knee grade 1-3 osteoarthritis, and willingness to receive intraarticular therapy. Patients received a three-intraarticular injection series with Suplasyn (10 mg/ml, 2-ml injection) over 3 wks. Patients were instructed to return for consideration of repeat injection series based on their perception of pain restricting daily activity and a resumption of severity similar to their initial presentation. This prospective naturalistic cohort was followed for 6.7 yrs. Patients completed baseline assessment of rest and walking visual analog scale pain (primary efficacy variable), completed a 5-point categorical global satisfaction score, and recorded adverse events and concomitant therapeutic modality use at each study visit. Patients returned for consideration of a repeat injection series based on their perception of symptom severity and were eligible if their resting visual analog scale pain was > 45 mm. The three-injection series and data collection were repeated, and again, patients were given similar instructions regarding consideration of a third injection series. RESULTS: Of 897 referral patients, 537 (mean age, 68 +/- 8 yrs; mean duration of symptoms, 7.4 +/- 4.1 yrs) met our criteria, and only 21 patients did not return for a second injection series. The mean time between first and second series was 27 +/- 7 wks. The change in walking visual analog scale pain was significantly improved from baseline after the first series (81.3%, P < 0.001) and second series (86.7%, P < 0.0001). Similarly, resting visual analog scale pain was significantly decreased from baseline after the first (P < 0.001) and second (P < 0.001) series, and patient satisfaction was significantly improved with each injection series (P < 0.03 and P < 0.01). Very few adverse events were recorded and were limited to local pain and swelling. Use of concomitant therapeutic modalities at presentation for a second injection series included: nonsteroidal anti-inflammatory drugs/cyclooxygenase-2 medications (37%), acetaminophen (31%), oral nutraceuticals (12%), and physical therapy and bracing (12%). CONCLUSIONS: Intraarticular hyaluronic acid injections were highly effective in improving resting and walking pain in patients with osteoarthritis of the knee on a first and a second treatment series. Duration of symptom control was about 6 mos, and the therapy was highly satisfactory to patients and was associated with very few local adverse events and limited use of concomitant therapeutic modalities. These data support the potential role of intraarticular hyaluronic acid as an effective long-term therapeutic option for patients with osteoarthritis of the knee.     

Adhesive capsulitis: a review

Adhesive capsulitis is a common, yet poorly understood, condition causing pain and loss of range of motion in the shoulder. It can occur in isolation or concomitantly with other shoulder conditions (e.g., rotator cuff tendinopathy, bursitis) or diabetes mellitus. It is often self-limited, but can persist for years and may never fully resolve. The diagnosis is usually clinical, although imaging can help rule out other conditions. The differential diagnosis includes acromioclavicular arthropathy, autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis), biceps tendinopathy, glenohumeral osteoarthritis, neoplasm, rotator cuff tendinopathy or tear (with or without impingement), and subacromial and subdeltoid bursitis. Several treatment options are commonly used, but few have high-level evidence to support them. Because the condition is often self-limited, observation and reassurance may be considered; however, this may not be acceptable to many patients because of the painful and debilitating nature of the condition. Nonsurgical treatments include analgesics (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs), oral prednisone, and intra-articular corticosteroid injections. Home exercise regimens and physical therapy are often prescribed. Surgical treatments include manipulation of the joint under anesthesia and capsular release.     

Intra-articular injections for osteoarthritis of the knee

If usual medical measures fail to control the pain of knee osteoarthritis and allow the patient to cope with its symptoms, intra-articular injections of a corticosteroid, a hyaluronan, or both can be tried.     

Efficacy and safety of hyaluronan treatment in combination therapy with home exercise for knee osteoarthritis pain

OBJECTIVE: To assess the efficacy and safety of intra-articular injections of sodium hyaluronate combined with a home exercise program (HEP) in the management of pain associated with osteoarthritis (OA) of the knee. DESIGN: Single-blinded, parallel-design, 1-year clinical study with sequential enrollment. SETTING: University-based outpatient physiatric practice. PARTICIPANTS: Sixty patients (18 men, 42 women; age, > or =50 y) with moderate-to-severe pain associated with OA of the knee. INTERVENTIONS: (1) Five weekly intra-articular hyaluronate injections (5-HYL); (2) 3 weekly intra-articular hyaluronate injections (3-HYL); or (3) a combination of an HEP with 3 weekly intra-articular hyaluronate injections (3-HYL+HEP). MAIN OUTCOME MEASURES: The primary outcome measure was a 100-mm visual analog scale for pain after a 50-foot walk (15.24 m). Secondary measures included the Western Ontario and McMaster Universities Osteoarthritis Index subscales. RESULTS: The 3-HYL+HEP group had significantly faster onset of pain relief compared with the 3-HYL (P<.01) and 5-HYL groups (P=.01). All groups showed a mean symptomatic improvement from baseline (reduction in baseline pain at 3 mo was 59%, 49%, and 48% for the 3-HYL+HEP, 3-HYL, and 5-HYL groups, respectively) that was clinically and statistically significant. There were no between-group differences in the incidence or nature of adverse events. CONCLUSIONS: The combined use of hyaluronate injections with HEP should be considered for management of moderate-to-severe pain in patients with knee OA.     

Changes in sagittal ground reaction forces after intra-articular hyaluronate injections for knee osteoarthritis

OBJECTIVES: To examine the gait patterns and the sagittal ground reaction forces (GRFs) in persons with knee osteoarthritis (OA) after intra-articular injection of hyaluronate and to investigate the duration of its treatment effectiveness. DESIGN: Case-comparison study. SETTING: Gait laboratory in a tertiary care center. PARTICIPANTS: Fifteen subjects (30 knees) with symptomatic knee OA (stage I or II, according to the Ahlb?ck grading system), and 15 age-, mass-, and gender-matched non-OA control subjects (30 knees). INTERVENTION: After initial gait analysis, the group with knee OA received 5 weekly intra-articular injections of hyaluronate to bilateral knees. Gait analysis was performed again for the group with knee OA after the completion of hyaluronate injections. MAIN OUTCOME MEASURES: Forceplate sagittal GRFs and gait parameters of velocity, cadence, step length, and stride time. RESULTS: The distinctive 2-peak force vector GRF was lost in persons with knee OA. The first peak rise time was significantly delayed (P<.05). The group with knee OA also revealed slower walking velocity and cadence, as well as longer stride time, than the control group (P<.05). The distinctive 2-peak force vector GRF diagram could be recovered in patients with knee OA after the completion of hyaluronate injections. CONCLUSIONS: Gait patterns and GRFs improved significantly after intra-articular knee injection of hyaluronate in persons with Ahlb?ck stages I and II knee OA. The clinical treatment effect was immediate and may last for 6 months or more.     

Ultrasonographic assessment of Baker's cysts after intra-articular corticosteroid injection in knee osteoarthritis

PURPOSE: To assess sonographic changes in Baker's cysts (BCs) of patients with knee osteoarthritis after a single intra-articular corticosteroid injection. METHODS: Thirty patients with knee osteoarthritis complicated with a symptomatic BC received a single intra-articular injection of 40 mg triamcinolone acetonide. Knee pain, swelling, and range of motion were evaluated. BC area and thickness of the cyst wall were measured with sonography before and 4 weeks after local treatment. RESULTS: A significant improvement in knee pain, swelling, and range of motion after corticosteroid injection was accompanied by a decrease in size of the BCs as well as in thickness of the cyst wall as measured by sonography. Moreover, the reduction of BC area on sagittal scans after treatment was significantly correlated with the improvement in range of motion. CONCLUSIONS: In this series of osteoarthritis patients, injection of corticosteroids inside the knee joint accounted for a reduction in BC dimensions as well as cyst wall thickness. Sonography can be used not only for the diagnosis of BCs but also to monitor response to therapy.     

Intra-articular injections of hyaluronic acid in the treatment of painful shoulder

Twenty-nine patients (mean age, 61 years) received three intra-articular injections of 10 mg of hyaluronic acid in 1 ml of phosphate buffer; the injections were given at three-day intervals. Six of the patients had osteoarthritis, six had Duplay's disease, and 17 had both osteoarthritis and Duplay's disease. The patients were evaluated after each injection and 11 days after the last injection. On all measures of treatment effectiveness, including joint mobility, pain, and analgesic consumption, the patients showed rapid and significant improvement. No side effects were reported.     

Cross-sectional Analysis of Recommendations for the Treatment of Hip and Knee Osteoarthritis in Clinical Guidelines

ObjectiveTo compare guideline recommendations for hip and knee osteoarthritis (OA) and their level of evidence.Data SourcesMEDLINE, Embase, the Cochrane Library, and websites of professional societies were searched in June 2020 using keywords such as knee or hip osteoarthritis, degenerative arthritis, guideline, and practice guideline.Study SelectionGeneral treatment guidelines for OA of the hip or knee published in English. After 461 abstracts were screened, 31 publications (17 guidelines from 10 professional societies) were included for analysis.Data ExtractionThree reviewers assessed the quality of the guidelines according to the Appraisal of Guidelines for Research and Evaluation II tool. The rating of evidence and strength of recommendation was extracted and standardized into the Grading of Recommendations Assessment, Development, and Evaluation criteria.Data SynthesisOf the 17 guidelines included, 6 (35%) were of high quality, 10 (59%) of moderate quality, and 1 (6%) of low quality. Guidelines published after 2017 were of good quality. Although guidelines generally agreed on a nonsurgical multimodal concept, including patient education, exercise, and weight loss in obese, some recommendations remained vague and the level of evidence varied widely. In pharmacologic treatment, oral nonsteroidal anti-inflammatory drugs were the mainstay for pain management. Guidelines published after 2017 were more cautious in their recommendation for the use of paracetamol and strong opioids. Disagreement was observed for chondroitin sulfate, glucosamine, and intra-articular hyaluronic acid injections. Recommendations were conflicting for the use of insoles, braces, and transcutaneous electrical stimulation. The main indications for hip/knee arthroplasty were severe, persisting pain and loss of function despite nonsurgical treatment. No guideline defined a minimum time of conservative treatment before surgery.ConclusionsWe found a wide variation in evidence and strength of recommendations for OA treatment. Recommendations on when to refer patients for surgery remained unclear.     

Analgesia and the patient with osteoarthritis

Osteoarthritis is the most common form of arthritis, its prevalence increasing with age: as much as 80% of the population over 75 years show radiologic signs of the condition. Symptoms include pain, stiffness, and functional impairment; however, not all patients are symptomatic. Management starts with nonpharmacologic interventions, followed by pharmacologic means, and ultimately by surgical intervention. The management is multidisciplinary and is tailored to the needs of the individual patient. It is, therefore, a good model of collaborative care: multidisciplinary management of a chronic condition for which the patients themselves coordinate the use of the management options, with information and guidance from health care professionals and written materials, as needed. Guidelines for the management of osteoarthritis have been developed and are applied in different continents. These guidelines are based on searches of the literature and evidence-based interpretation, in combination with expert opinion. Pharmacologic management guidelines state that based on its overall efficacy, toxicity profile, and cost, paracetamol-acetaminophen should be tried first and, if successful, should be used as the preferred long-term analgesic. In patients who do not experience adequate symptomatic relief with paracetamol-acetaminophen, alternative or additional pharmacologic agents should be considered, especially nonsteroidal anti-inflammatory drugs (NSAIDs). When the combination of paracetamol-acetaminophen with NSAIDs fails, tramadol may be given. Most patients with osteoarthritis are able, after discussion with their physician, to manage their symptoms themselves. They make use of educational occupational, and physical advisers, and they use their medication on demand. The basis of this self-administered pharmacologic management is paracetamol-acetaminophen, sometimes in combination with NSAIDs. A promising option for the future is the development of symptomatic slow-acting drugs for osteoarthritis that possess structure-modifying properties.     

Using hyaluronic acid drugs in local intra-articular therapy of osteoarthrosis in the knee joint

AIM: To assess efficacy of intraarticular injection of ostenil in knee joint osteoarthrosis. MATERIAL AND METHODS: Sixty patients with gonarthrosis of x-ray stage I-III (mean age 65 years, mean duration of the disease < 7 years) on chondroprotectors and nonsteroid anti-inflammatory drugs (NAD) in a standard dose received a course (3-5 weekly intra-articular injections) of 2 ml injections of ostenil. Assessment of the arthrologic status (VAS, Leken's index, WOMAC index, HAQ index, subjective and objective evaluation of the disease symptoms, need in NAD) was made initially, 5 weeks and 12 months after the treatment. RESULTS: Significant improvement was seen in 60% patients. Pain and stiffness in the knee joint relieved 2-fold. The function improved less. OA severity by Leken's index decreased by two degrees. 20% patients stopped intake of NAD, 32% had no need in taking NAD regularly. Subjective and objective assessment (by the patient and by the doctor) of the symptoms severity improved twice. Twelve months later the arthrological status worsened but not to the baseline. CONCLUSION: Hyaluronic acid drugs act long, are effective and safe for local intra-articular therapy of gonarthrosis.     

Hyaluronic acid as a treatment for ankle osteoarthritis

Viscosupplementation refers to the concept of synovial fluid replacement with intra-articular injections of hyaluronic acid (HA) for the relief of pain associated with osteoarthritis (OA). Intra-articular viscosupplementation was approved by the Food and Drug Administration (FDA) in 1997. It is currently indicated only for the treatment of pain associated with knee OA. However, OA can occur in several of the weight-bearing joints of the foot and ankle. Ankle OA produces chronic disability that directly impacts the quality of life. There is only limited published literature relating to the use of HA in the ankle. This paper will review the authors’ experience, indications, clinical outcomes, and complications of viscosupplementation therapy in patients with ankle OA.     

Effects of intra-articular hylan G-F 20 injections on clinical and biomechanical characteristics of the knee in osteoarthritis

The objectives of this study were to investigate the effects of Hylan G-F 20 (Synvisc; Genzyme Biosurgery, Ridgefield, New Jersey, USA) injections on clinical and biomechanical gait characteristics of patients with knee osteoarthritis. The design was a before-after trial, set in the gait laboratory of the rehabilitation unit of a university hospital. Twelve patients participated with an average age (+/-SD) of 63.2+/-4.4 years, and Kellgren and Lawrence grade II or III knee osteoarthritis. The main outcome measures were the Western Ontario McMaster Universities Osteoarthritis Index, and time-distance, kinematic and kinetic parameters of gait. The intervention used was a single course of three bilateral intra-articular injections of 2 ml Hylan G-F 20. One week after the treatment, the pain subscore and total score of WOMAC decreased from 9.2+/-2.7 to 4.8+/-3.1 and from 42.1+/-15.2 to 37.9+/-13.5, respectively. There was improvement in sagittal plane excursions of the knee (from 40.2+/-8.1 to 43.3+/-8.5), in extensor and adductor moments (from 0.26+/-0.2 to 0.14+/-0.1 and from 0.45+/-0.1 to 0.41+/-0.1, respectively), and in scaled vertical forces (from 85.8+/-4.5 to 88.4+/-5.4). All these differences were statistically significant.In conclusion, intra-articular Hylan G-F 20 injections not only decrease pain in patients with knee osteoarthritis, but can alter the natural history of the disease by decreasing excessive loads in the knees.     

Management of Parkinson's disease. Strategies, pitfalls, and future directions.

In coming years Parkinson's disease will become increasingly prevalent as the baby boom generation grows older. Diagnosis often is complicated and requires careful consideration of symptoms and neurologic findings. Optimal symptomatic treatment of Parkinson's disease involves an individualized approach with each patient and ongoing evaluation of benefits versus side effects. Neurosurgical intervention is an option for some patients who are not adequately helped by medical therapy. New treatments (e.g., stem cell therapy) are currently being studied and may be available in the foreseeable future.