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New Frontiers in Knee Pain Research: Insights from Singaporean Experts

The World Health Organization declared that by 2020 the burden of musculoskeletal conditions would be most costly to society, with low back and neck pain being the leading cause of years lived with disability followed by severe osteoarthritis. However, despite the remarkable progress in cell and molecular biology, research in the past two decades has failed to produce major breakthroughs in the management and treatment of knee pain which is the most frequent and debilitating symptom for lower limb osteoarthritis and injury. It is evident that a new approach is needed and communicating with leaders in the field on their perspective of the current state of knee pain research and potential research directions may be the stimulant at which change begins. In an effort to ameliorate the global impact of knee pain, it is still crucial to individualize country specific research. Epidemiological work done in various countries has shown that factors influencing the presence and or intensity of knee pain may be different and most likely multi factorial across different societies. Hence an international understanding of knee pain is essential when attempting to correlate biological changes with clinical symptoms and thereby guide clinical decision making. As the biological and structural changes of knee pain can be better understood in the confines of clinical context, linking basic science with clinical research is seemingly the most efficient way to improving management and treatment knee pain. An accumulation knowledge from experts worldwide is more the justification for this study on Singapore. With the current absence of research on knee pain Singapore, insight from leaders in the field will be a part of a fundamental process in understanding and managing knee pain for our current and future generations.

Overview of Knee Pain Research

Knee research is crucial as there are still many issues and discrepancies in some of the conditions. It is essential for improving the quality of life in the people who are affected by the conditions. Research could also lead to better methods of treatments and prevention, and may provide a potential solution for certain conditions. Therefore, it is clear that research is most significant in patients and helps advance understanding for the conditions and treatments available.

Long-term knee pain is usually associated with arthritis, which gradually destroys the knee joint over time. All of the aforementioned conditions are irreversible and would implicate much discomfort in the patient. Therefore, effective measures for pain or symptom relief are highly sought after.

Knee pain is a common ailment of senior citizens, and that also includes those who are physically active. It is often caused by various injuries from overuse, sudden activity that moves or twists the knee, to the damages caused by the degeneration of the articular cartilage. As such, many knee damage cases require surgical intervention. A surgical procedure would most usually lead to arthroplasty and knee replacement therapy.

Knee joint is a hinge that connects two largest muscle groups in the legs, the quadriceps and the hamstrings, to the thigh bone and the shin. Essentially, its primary functions are to allow movement of the legs and provide stability in bearing the weight of the body. This said, the knee is more predisposed to injury due to its intricate parts.

Importance of Singaporean Experts’ Insights

This may be achieved by using the results of qualitative research, information from which has been used to develop belief-based questionnaires to identify unhelpful beliefs about OA and its treatments. Singaporean experts currently have active tertiary and research practices in the area of knee OA and are interested in preventing the disease and its progression. Their insights, if integrated with current research, may be able to guide the future development of prevention strategies specific to the nature and populations of knee OA and to identify individuals and groups most likely to benefit from them.

Primary prevention of OA is currently not possible as the cause of the disease is not fully understood and its preclinical phases have not been identified. Secondary prevention strategies, in the form of identifying and treating high-risk individuals early in the disease process, may be more feasible. By better understanding the nature of OA and identifying individuals with strongly held negative beliefs about its nature and evidence-based treatments, preventative measures can be targeted at groups most likely to benefit from them.

Understanding the attitudes and beliefs about knee osteoarthritis (OA) and its treatment is important for the design and success of primary and secondary prevention strategies. Patient perceptions about the nature of OA, its cause, and the value of evidence-based treatments influence decisions to implement prevention strategies and undertake evidence-based treatments.

Current Understanding of Knee Pain

It is clear which people with knee pain will benefit from total joint replacement, but difficult to determine the best treatment for the rest. Total joint replacement is not suitable for many patients because they are too young, have medical or mental comorbidities, or it has an unacceptable risk-to-benefit ratio for their lifestyle. Today, it is these people who are increasingly seeking alternative treatments. However, most of the current evidence about the effectiveness of treatments for chronic knee pain is for joint replacement and pharmaceutical prescription. There has been very little research on the non-operative management of knee pain. Far too many treatment modalities are advertised and practiced without scientific evidence of their effectiveness. Development of new effective treatments and refining the indications for current treatments are a priority. New treatments need to be directly compared with one another and with placebo. The outcome measures used should include pain, physical function, and joint structure. The natural history of the structural and symptomatic changes of the disorders that cause knee pain should be elucidated. This will enable identification of risk factors for rapid progression or those patients prone to recurrent symptoms. All of these are aims of these guidelines.

Knee pain, especially from osteoarthritis, is a common and disabling problem. The knee can be affected by almost any joint disorder, and the pain varies in intensity from mild to severe. The distal and proximal tibiofibular joints can be a source of pain, as can the patellofemoral and superior tibiofibular joints. Pain in the knee may be the result of inflammation, infection, or a tumor affecting any of the anatomical structures around the knee. These guidelines are mostly concerned with pain because of a degenerative joint disorder. They do not cover the management of pain associated with acute injury or the operative treatment of specific structural abnormalities. It is hoped that more research will help identify strategies for managing the many types of knee pain. This should result in the development of a new classification system for disorders of the knee and evidence-based treatment guidelines.

Causes and Risk Factors

Risk factors that are associated with the onset and progression of knee pain are impairments that affect the mechanical integrity of the knee joints. These impairments can be due to developmental factors, direct acute trauma, or a disease process. Control events that affect tissue integrity and impair mechanical function may lead to knee pain. These include muscle weakness, obesity, joint malalignment, and an acute overload to a particular tissue that leads to tissue damage.

Knee pain is a common symptom that can be directly related to the degeneration of joint tissues due to fibrosis or to the biochemical changes in the nerve or in the CNS. It is often associated with an increase in activity or weight. The progression of knee pain is also related to the inflammatory phase of the arthritic diseases. However, there are a vast number of conditions, both acute and degenerative, that can lead to symptoms. Identification of the etiological factors involved in knee pain in individual patients is often difficult and frequently the exact cause is never determined. This is further complicated by the fact that a patient may have more than one condition causing symptoms in the same knee or different conditions in both knees.

Diagnosis and Assessment Techniques

Plain film x-rays have been the traditional investigation for knee pain and are useful in the diagnosis of OA, fractures, some systemic causes of pain about the knee, and in certain cases of malignancy. Magnetic resonance imaging (MRI) is more specific in the identification of soft tissue abnormalities and is superior for the diagnosis of many painful knee conditions. Vast improvements in MRI technology and the development of specific sequences for certain pathologies have further enhanced the utility of this tool. MRI can be particularly useful in research settings for the diagnosis of pre-osteoarthritic conditions and early OA. However, it should be noted that the identification of structural abnormalities on imaging in the absence of clinical symptoms is common. This has led to the definition of ‘clinical OA’ as symptoms and/or signs of OA (such as pain or reduced movement) in conjunction with radiographic changes. This is an important distinction to make when discussing the natural history of knee pain and could have implications for the diagnosis of treatment efficacy. Computed tomography, ultrasound, and diagnostic arthroscopy also have specific indications for the diagnosis of certain knee conditions but are generally surpassed by MRI in most instances. An excess of imaging in cases of uncomplicated OA is known to be unhelpful and could serve to identify conditions requiring surgical intervention. However, access to certain types of imaging can vary greatly between geographic regions and healthcare settings.

Diagnosis, surveillance, and assessment are important in understanding knee pain and knowing whether current treatment techniques have affected the natural history of a condition. Gaining knowledge of intrinsic risk factors for knee pain in the absence of traumatic injury is important in understanding progression to specific knee pain disorders and in the development of preventive interventions. Although it has been understood for some time that knee pain and OA are not synonymous, the ability to diagnose all potential causes of knee pain has been more elusive. The largely clinical identification of patellofemoral pain and lack of definitive diagnostic criteria for many non-traumatic knee conditions has hindered progress in this area. With increased understanding of tissue-specific pathology for many knee conditions, advances in imaging, and a move towards more specific clinical phenotyping for certain disorders, the ability to diagnose knee pain conditions should increase.

Treatment Options and Challenges

When conservative treatment fails, an increasing number of younger patients are considered candidates for partial meniscectomy or chondroplasty. However, the efficacy of these operations may only be minor, and arthroscopic debridement as a treatment for OA knee has been found to have no added benefit over placebo. Recent findings question the current practice of arthroscopic partial meniscectomy for degenerative tears, showing that it is no better than sham surgery.

Various conservative and surgical methods aim to reduce pain and improve function, with the most common treatment being non-steroidal anti-inflammatory drugs and simple analgesics. Other ways to reduce pain, for example, is the use of intra-articular corticosteroid injections and opioid analgesics. These ways to reduce pain are clinically effective. However, the use of corticosteroids has well-known detrimental effects on articular cartilage.

Treatment of knee pain: A recent review concluded that the management of knee osteoarthritis (OA) is well below the current standards, and one issue is the lack of consensus on the best method of managing knee OA. This can largely be due to there being no cure for knee OA, and the pain can be attributed to a variety of causes, including inflammation and biomechanical factors such as meniscal tears.

Emerging Trends in Knee Pain Research

The past two decades of knee pain research have witnessed an explosion of interest in therapeutic interventions. This is in no small part due to the increasing economic burden that knee pain places on healthcare resources and worldwide activity limitations. Unfortunately, many practical and surgical therapies have proved largely ineffective, while others demonstrate only moderate success. This brings us to the long-term goals of developing more effective interventions for the prevention and treatment of knee pain and its related symptoms. What researchers have begun to realize is that the pursuit of effective interventions first requires a clear understanding of the conditions and mechanisms underlying knee pain. Essentially, the success of any intervention is predicated on an accurate diagnosis and clear understanding of the target condition. With this in mind, we could postulate that current knee pain research trends are gradually shifting from interventional studies to investigations of etiology and pathophysiology. In basic terms, this means that more researchers are trying to figure out exactly what causes knee pain, what happens in the joint when pain develops, and what are the best ways to alleviate or halt this process. This trend is reflected by some of the interesting and diverse work presented at OARSI this year, and could potentially signal a new era of more successful interventions for knee pain.

Novel Therapies and Interventions

Patients with knee osteoarthritis, a major cause of chronic and disabling pain, often are inadequately or suboptimally managed in treatment, in part because the joint has inherently limited regenerative potential. Current interventions, both non-surgical and surgical, often are not fully effective or are only temporarily so. Thus, there is a pressing need for developing new therapies that are more regenerative in intent, in order to prevent, retard, or reverse the degenerative cascade in joint tissues and thereby affect a more permanent cure. Durability of therapeutic effect is an important, but often neglected, outcome measure in clinical trials of knee OA therapies. Randomized, placebo-controlled, long-term trials should be more the norm than has been the case in the past. They should compare both symptom- and structure-modifying effects of interventions and involve larger numbers of patients. It is hoped that these will become more feasible as therapies improve to have disease-modifying effects.

Advances in Imaging and Diagnostic Tools

Other important advancements come in the area of detecting biomarkers for the disease. Biomarkers are biological markers that indicate the presence and severity of a disease. Although there are no validated biomarkers for osteoarthritis, recent research has identified key biomarkers with the use of various methods, most notably proteomics. A reliable biomarker for osteoarthritis would bring a steady and cost-effective form of diagnosis and could also be used to monitor disease progression and the success of different treatments. This still has a long way to go but is a very promising area for the future.

Magnetic resonance imaging (MRI) has been cited as the most suitable technique for the assessment of the structure and composition of articular tissues, as it is non-invasive and has multi-planar capabilities. High-resolution MRI has been found to be the most accurate non-invasive method for the assessment of cartilage volume. It has also proven to be valuable in the assessment of bone marrow lesions and synovitis, both of which are predictors of pain and progression of the disease.

The current techniques for diagnosing osteoarthritis may be much too simplistic. Recent research has shown that osteoarthritis is a much more complex disease. Researchers have found that there is a wide array of abnormalities in the joint, many of which are not visible on an x-ray. It is these unseen abnormalities which are likely to be the source of the patient’s pain. Knowing this, it is time for a more sophisticated approach to diagnosing the disease.

Integrative Approaches for Holistic Management

The section “New Frontiers in Knee Pain Research: Insights from Singaporean Experts” highlights the key components of integrative medicine, reviews the current state of integrative medicine research, and discusses the future of integrative knee pain management. “Integrative medicine is concerned with treating the patient in the most thorough manner possible. In the case of knee pain, often times patients will simply take pain medication and not deal with the issue that is causing the pain,” says Dr. Wayne Jonas, President and CEO of Samueli Institute and a retired lieutenant colonel in the Medical Corps of the U.S. Army. “In such cases, the pain medication may simply mask the pain and not solve the original issue. We want to address both the issue and the pain with the most efficient methods available.” This involves taking into account conventional treatments, lifestyle modification, behavior and psychological strategies, and various complementary and alternative options when approaching knee pain and its causes. Little study has been done on integrative knee pain management, but recent trials have shown promise in using acupuncture for joint pain caused by aromatase inhibitors in breast cancer treatment. On a larger scale, a recent study has shown that alternating glucosamine and chondroitin with Celecoxib is more effective than Celecoxib alone in treating knee osteoarthritis. This suggests that using simple, yet more complex integrative management strategies can be safe, feasible, and more effective than conventional treatment options. With further study of more complex and individualized protocols, integrative medicine may prove to be one of the most effective options for knee pain management in the near future.

Future Directions and Potential Breakthroughs

Synovial is an incredibly complex tissue involved in nutrient exchange, cartilage lubrication, and metabolic waste removal. Its dysfunction has been implicated in a plethora of arthridites, ranging from osteoarthritis to ankylosing spondylitis. Development of reliable in vitro models that mimic its genetic and functional properties would be a substantial advancement in the knee pain field, culminating in a better understanding of disease pathogenesis and potential identification of novel therapeutic targets and agents. This would enable early diagnosis of pre-osteoarthritic states and tracking of disease progression, which would be invaluable in testing the aforementioned potential novel therapies and interventions. New MRI techniques to assess cartilage and meniscal quality would also be a valuable research direction.

Collaborative Efforts and Knowledge Exchange

On the international front, Singapore has garnered much attention for her success in biomedical sciences research and development. This is attributed to the heavy investment into research and development by the government in a bid to establish Singapore as the Biopolis of Asia. The various research institutes have taken part in multiple collaborations and sharing exercises with research groups from other countries. Notably, the Institute of Medical Biology (IMB) has established the IMB-McGill Alliance with the Faculty of Medicine at McGill University, Canada. This initiative allows for an exchange of ideas and expertise that would ultimately elevate the standards of both establishments. Another local institute, the Singapore Institute for Clinical Sciences (SICS), a research institute under the A*STAR banner, signed a Memorandum of Understanding with the Swiss Institute of Bioinformatics to promote joint research in fields like epigenetics and bioinformatics, using the study of the Asian populations as a reference to world populations. These various collaborations no doubt provide an opportunity for local researchers to gain further knowledge from their foreign counterparts and keep abreast with the latest developments in their fields of research. A telling sign of Singapore’s influence in the global research arena would be the hosting of the OARSI World Congress in 2010. The OARSI congress is an annual event that showcases the latest clinical and basic research in knee osteoarthritis and serves as a platform for professionals from various health disciplines to discuss and share ideas in order to improve patient care and further the prevention and treatment of musculoskeletal disorders. The hosting of this prestigious event marks the first time it will be held in Asia. This is an indicator of the growing recognition of Singapore’s efforts and contribution towards knee pain research on an international level.

International Collaborations in Knee Pain Research

An example of this is the ongoing collaboration between Singapore and Otago University in New Zealand. The exchange of research methodology and ideas between these two countries is expected to result in multiple high-quality research studies and has the potential to influence health policy in the future. A second example is the use of large-scale multi-center observational studies and clinical trials involving many countries. By understanding the differences between various countries in risk factors, natural history, and treatment effects for knee pain, research can be targeted at specific areas and designed to have a global impact in the future.

International collaborations in knee pain research have proven to be beneficial and essential in advancing knowledge and understanding of the many complexities of knee pain. The sharing of ideas and methodology across different cultures and between clinicians, researchers, and academics has the potential to provide new and innovative ways of looking at problems in knee pain. By learning from the methods and mistakes from other countries and from research on other musculoskeletal conditions, we in Singapore can build on and design high-quality studies that could significantly improve the understanding and management of knee pain in the future. This can, in turn, reduce the prevalence and burden of this condition on society.

Sharing Best Practices and Expertise

Through sharing best practices and expertise, Singapore orthopedics and researchers are producing a collaborative legacy of effort to progress knee treatment and care on an international scale. This paves the way for future research and opens doors for potential collaborations to improve the understanding of knee conditions and the development of best non-surgical and surgical practices.

Globally, high tibial osteotomy (HTO) is a surgery used to correct specific knee joint deformities and to delay the onset of knee arthritis in the younger, more active patient. It is an alternative to arthroplasty and joint replacement. While short-term success clinical findings were favorable, long-term joint survival rates were unknown. An international expert panel led by Associate Professor Kevin Lim was funded by the ISAKOS with an aim to set best practice guidelines and a prospective study on HTO to determine indications and contraindications, optimal techniques, and long-term clinical and joint survival outcomes. The collaborative effort involved knee surgeons, a variety of medical and orthopedic specialists, and even a health economist from 5 different continents. This would be one of the first few initiatives in Asia to bring together global expertise to standardize an Asian practice, and it has the potential to change the course of HTO management both in Asia and internationally.

Two of the experts also shared insights and findings from Singapore in knee pain research work in best practices and expertise. According to Khoo, in clinical research practice, the most important research trials were those that tested treatments that were widely used but were unproven scientifically. This conundrum faced his anecdote of the use of inexpensive antibiotics to prevent infection in knee joint replacement. With a mission to improve standards of such trials, he co-founded the International Society of Arthroplasty Registries, where registries are set as a standard for comparative data analysis on arthroplasty procedures and joint sparing treatments. This is particularly important to Asia, where joint replacements are still under practiced and knee arthritis treatment can still be relatively conservative with a higher preference for traditional medicine.

Translating Research Findings into Clinical Practice

When conducting randomized controlled trials (RCT), there is a need for the best treatment to be tested upon. Often the current best treatment is not available and it is necessary to develop the new treatment or compare it with existing treatments. This occurred when Dr. Jianhua An was comparing the short-term efficacy of hyaluronic acid (HA) treatment with naproxen and adaptive NSAID therapy on patients with knee OA. He had to access the best available HA and was provided with a new drug-free preparation and a new processed form of HA from Seikagaku Corporation Japan. On comparison with the available HA in Singapore, the 2 Japanese preparations are not yet available here, but it is hoped that they will be the standard HA for comparison with other new knee OA treatments in the near future. All these trials proved the success of translation as the knowledge gained has led to improved treatments for knee OA.

The most effective way to ensure that research is directly translated to clinical practice is to perform the research in a clinical setting. This way, the research never loses sight of its overall goal and researchers can constantly compare new knowledge with practical results. Associate Professor of the National University of Singapore, Lumbar Kyphosis and Competing Interest Dr. Lau Tang Chuan states that much of his work involving identifying risk factors for the development and progression of osteoarthritis (OA) “is pursued with the intention of applying the tools or knowledge in selected groups of patients so as to prevent the occurrence or slow the progression of disease”. An example of successful translation is Professor Chitranjan Ranawat’s decade-long patellofemoral study, which has since become an internationally recognized method for classifying knee osteoarthritis. His years of painstaking work led to the development of a classification system for the disease, which has since proven to be “valid and reliable” in determining osteoarthritis severity and choice of treatment options. Based on data obtained from MRI and x-rays, 250 patients were classified and monitored over a 3-year period, with excellent results.

Translating research findings into clinical practice is the ultimate goal in all medical research studies. In order to close the gap between discovery and application, researchers – the content generators – need to find ways to transfer their newly acquired knowledge to a practical setting, which in the case of medical research is the clinical environment. This is a field which is now being recognized as a sub-discipline to medical research and is termed health research. This article identifies the strategies used by some of Singapore’s top medical researchers to achieve translation of their research findings to improved clinical practice for patients with knee pain.

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