Personalized Medicine: Tailored Approaches to Knee Pain Treatment in Singapore

Pain is a subjective and polymorphic experience, and knee pain in particular can stem from a diverse range of causes such as injury, osteoporosis, or rheumatoid arthritis. A study has shown that knee pain sufferers with higher catastrophizing characteristics were more likely to avoid physical therapy and receive injections. These patients are less likely to take an active role in their treatment decisions, and it is important to provide them with the most suitable treatment from the onset, in order to encourage the positive attitude and behavior required for effective treatment. Unfortunately, the wide variety of available treatments has no clear consensus for the most effective solutions for particular causes of pain. This can often lead to a trial and error approach, wrestling with treatments that have limited efficacy for sometimes significant risk or inconvenience to the patient. An informative approach to treatment decisions based on predicted responses can offer a personalized solution with favorable risk-benefit ratios. This approach is currently lacking in musculoskeletal medicine, and the perceptibility of gene-related treatments may provide an incentive for research toward personalized solutions for knee pain.

Personalized medicine is rapidly becoming an important aspect of research and treatment. The key lies in the consideration of an individual’s genetic makeup prior to their symptoms or diagnosis of a disease. This concept is diametrically opposed to the “one-size-fits-all” notion of treatment, where treatment protocols and drug dosages are generalized en masse, without taking into account individual differences between patients. However, tailoring treatment to the specific genetic predisposition of the patient can yield increased efficacy in symptom alleviation or cure, while preventing adverse side effects from treatment. This can be achieved through the identification of genetic markers which indicate a patient will respond positively to a certain treatment, or conversely, face an adverse reaction. This information can be gleaned using gene expression or SNP analysis, and provides a solid foundation on which informed decisions about treatment can be made.

Understanding Knee Pain

Beneath the patella (kneecap), there exists a small pocket of fluid known as the bursa. It functions mostly as a gliding surface to reduce friction between tissues, minimizing irritation. The result of trauma to the knee, overuse, misalignment of the knee, and physical activity, a tear can occur in the tendons located within the knee. This tear usually occurs in the quadriceps or patellar tendon. Individuals who partake in running and jumping activities are more likely to experience a knee tendon tear. Obese individuals are also prone to knee tendon tears due to added stressors on the knee. A high force impact or twisting of the knee, or a fall, is the typical cause of a knee ligament tear. These types of injuries can be partly evaded by modifying the activity to reduce stress on the knee and consistently maintaining a healthy weight. An injury to the knee affecting the articular cartilage (shock absorber of the knee) can result from those with knee alignment problems or previous injuries. It is the most likely injury for athletically active and high-skill level individuals. Patellar dislocation usually occurs when twisting the knee with a planted foot. Lastly, osteoarthritis, the most common form of arthritis, is the gradual and degenerative wearing of the articular cartilage.

Causes of Knee Pain

Normal knee anatomy The knee is formed by the following bones: The femur. A large bone in the thigh, which provides strong support for your weight. The tibia. A larger bone in the lower leg. The fibula. A smaller bone in the lower leg. The patella. The kneecap. The knee is a hinge joint; this motion is allowed by the ability of the tibia to roll and glide on the femur. The knee is one of the most important and one of the most complex joints in the human body. Your knee is made up of many important structures, any of which can be injured. The most common cause for chronic knee pain and disability is the result of arthritis. Osteoarthritis is the inflammation of the knee and it involves the degradation of the articular surface as well as the growth of extra bone, often resulting in the total loss of articular cartilage. Another common reason for knee pain is an injury, often to the anterior cruciate ligament (ACL). An injury can also cause bleeding in the joint which, if not treated correctly, can cause long-term damage.

Symptoms of Knee Pain

Buckling and Locking Weakness in the knee can cause it to buckle. Buckling is most likely to occur with damage to the collateral ligaments or the meniscus. Locking is a symptom that suggests a meniscus tear. The torn fragment of the cartilage can get in the way of joint movement, causing the knee to lock in a certain position. A locked knee will be painful, and it is usually impossible to straighten the leg from the locked position.

Inflammation Internal bleeding after an injury could cause the knee to swell and feel painful. And swelling that comes and goes may be caused by a chronic meniscus tear. The tearing of a meniscus will often trap a piece of the torn cartilage in the knee joint, and the knee may feel okay most of the time, but uncomfortable giving way and unable to support weight.

Pain Inflammation causes painful moves and activities such as walking, going up or down stairs, sitting or standing for long periods, and squatting. A swollen knee looks bulky and puffy, and it may be difficult to bend the affected knee.

Traditional Treatment Options

Physical therapy has been shown to be as effective as surgery for the treatment of osteoarthritis of the knee. It increases function, decreases pain, and reduces disability. Treatment methods may include isometric strengthening exercises for the quadriceps and hamstring muscles, range of motion exercises, aquatic therapy, and stationary cycling. Weight loss and exercise in patients with osteoarthritis and overweight have a significant effect in decreasing pain and improving function. This is because excessive weight places additional stress on the joints, further damaging the cartilage. A program of diet and exercise has the added bonus of improving overall health. High-intensity or high-impact sports and occupations involving kneeling and squatting may need to be modified as they can cause increased joint damage. The objective of physical therapy is to improve the patient’s quality of life by improving the function of the affected joint. Randomized controlled trials and meta-analyses have shown that exercise therapy is effective and have identified important factors for the prescription of exercise.

Medications for inside knee pain are often relieved by using anti-inflammatory drugs and other medications that can be used to relieve the symptoms of the disease, such as pain and restricted movement. Although these drugs should be used under the supervision of a knee pain doctor Singapore, they allow the patient to avoid pain, which prevents normal daily activities. There are a large variety of anti-inflammatory medications available, from the simple, such as paracetamol and aspirin, to the more potent non-steroidal anti-inflammatory drugs (NSAIDs) and prescription-only medicines. These medications often have side effects, so it is important to discuss the pros and cons of each with a doctor. They are typically used for 4-6 weeks. Pain relief medication may also be injected directly into the knee. Glucocorticoid or cortisone injections have a powerful anti-inflammatory effect and can reduce swelling and pain. These injections provide rapid and effective but short-term relief and are typically used as a quick fix measure. Hyaluronic acid is a naturally occurring substance in the joint which acts to lubricate and cushion the joint and can become depleted in osteoarthritis. Injections of synthetic hyaluronic acid can provide pain relief for longer than cortisone injections, over a course of several weeks, and have few side effects, but there is some controversy over their effectiveness.

Medications for Knee Pain

In general, there are three kinds of drugs which may be useful in the management of knee problems: oral analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), and intra-articular injections of corticosteroids. Paracetamol is usually the first option, as this has the fewest long-term side effects. Opioid analgesics are not recommended for treatment of chronic pain due to substantial risk of addiction and limited evidence of long-term benefit. The most widely used opioids are codeine, tramadol, dihydrocodeine, and co-codamol. All have been associated with a significant risk of adverse events in older adults (aged >65 years), with codeine being particularly risky due to its metabolism to morphine by CYP2D6. There is evidence from chronic pain conditions other than knee osteoarthritis that opioids have similar efficacy to NSAIDs on pain, but demonstrate superior tolerability due to fewer gastrointestinal adverse events. However, in osteoarthritis, there is no evidence to support their long-term use for pain relief. Due to increased risk of cardiovascular and gastrointestinal events, and kidney toxicity, it is recommended that NSAIDs are used at the lowest effective dose for the shortest necessary time. Topical NSAIDs are preferential to oral NSAIDs in seniors due to similar efficacy with fewer adverse events. However, all NSAIDs, including topical preparations, have a black box warning from the FDA regarding increased risk of heart attack and stroke. Therefore, the decision to use NSAIDs should take into account individual patient preferences and risks for cardiovascular and gastrointestinal harm.

Physical Therapy for Knee Pain

“Patients may not realize that the way they walk is contributing to their knee pain. Simple things like walking with the knee pointed inwards can cause knee pain. Gait re-education is important to re-teach the normal walking pattern.” This is just one example of a form of therapy provided in Singapore that can be tailored to a patient’s condition.

Another form of exercise commonly used in Singapore for knee pain is gait re-education. This is highly applicable for patients who have had a knee injury or surgery. A recent study showed that for patients following an ACL reconstruction, there was altered knee and hip mechanics during a simple walking task. This abnormal gait pattern is likely to contribute to the onset of knee OA and specific exercises can prevent this. A current physiotherapy student from Nanyang Polytechnic, Nur Aqilah binte Mazlan believes in the importance of this therapeutic modality.

Physical therapy is a form of treatment that focuses on the rehabilitation and prevention of knee pain. In Singapore, there are numerous facilities that cater to physical therapy and many will captivate the idea of personalized medicine and integrate the two. The aim is to tailor a program specific to the patient’s knee pain condition so as to optimize the benefits. Usually, an assessment is done to identify the muscle groups that are weak or shortened and these will be contributing to the knee pain. Specific exercises will then be prescribed to target these areas. For instance, a patient with knee OA may have weakness in their quadriceps muscle group. A recent systematic review revealed that for these patients with medial knee OA, the most effective exercise was quadriceps strengthening. This has been further supported by another study which showed that for knee OA, strong quadriceps predicted a reduced risk of developing symptomatic and worsening radiographic knee OA.

Injections for Knee Pain

Hyaluronic acid is a natural substance in joint fluid that acts as a lubricant and shock absorber. Injections of hyaluronic acid are intended to act as a lubricant and slow the progression of osteoarthritis. It is only approved for treatment of osteoarthritis in the knee. The effectiveness of this procedure is still a somewhat controversial issue, as the relief in pain provided is similar to that of corticosteroid injections. It may be most beneficial if used in earlier stages of osteoarthritis. The brand of hyaluronic acid that will be used and the source it is extracted from can vary. Some studies have shown that hyaluronic acid injections can have prolonged benefits, lasting for several months up to one year. It is typically given in a series of weekly injections, usually 3-5 in total.

Several types of injections may be recommended, depending on the severity and nature of the patient’s knee pain. Corticosteroid injections are commonly used to treat all forms of knee pain. The benefit will only be temporary if the pain results from pressure on the kneecap due to misalignment. The injection is usually not given in these cases as it has little effect on the underlying malalignment and the pain is likely to recur. Corticosteroid injections are most effective if there is an inflammatory component to the pain. The physician may not inject directly into the painful area if he or she believes it is too inflamed. If a patient has diabetes, the physician will need to monitor the blood sugar as corticosteroids can cause a temporary increase.

Personalized Medicine for Knee Pain

Medicine is moving into an era of personalization in which prediction, diagnosis, and treatment of disease will be tailored to the individual patient. Personalized medicine will have an impact on knee pain, where the underlying pathomechanisms are diverse and the clinical presentations may look similar. In the current paradigm, decision-making about treatment is often unsystematic and the results unpredictable. Patients may undergo a number of different treatments, including knee surgery, with no real way of predicting beforehand which treatment will be best for the individual. The transition to an evidence-based approach in which treatment decisions are based on predicted response is an essential step forward from the current trial-and-error method. This will first require the identification of clinical phenotypes and underlying mechanisms that predict who will respond to a particular treatment. A recent example of phenotype identification is the Kellgren and Lawrence (KL) scheme (radiographic OA) and the prediction that patients with little knee pain and KL changes are less likely to respond to treatment. This could be taken one step further, in that a particular patient with little knee pain and KL changes could be identified as having certain subtle gait abnormalities and muscle weakness pattern which are causing his early OA. If these abnormalities are known to be the cause of his OA, treatment to correct the biomechanical abnormality might be more successful than the traditional treatment for OA of that severity. In this way, identification of clinical phenotypes can lead to targeted treatment.

Diagnostic Techniques in Personalized Medicine

In current medical practice, the diagnostic process is often informed by the patient’s self-reported description of symptoms, which may be inaccurate or misleading, and followed by a physical examination that is largely non-specific for the underlying pathology. Frequently, the diagnostic pathway will also include a trial of treatment, which may be both diagnostic and therapeutic in nature. For example, an analgesic injection into a knee joint may be given to a patient with unclear pain localization. If the symptoms fail to respond to this treatment, the patient may be referred to an orthopedic surgeon for consideration of surgery. The decision-making process for both the patient and surgeon is then swayed by the severity of symptoms and functional disability, rather than the underlying pathology. An accurate diagnosis is a prerequisite for effective treatment, but it is an unrecognized shortcoming of the current knee pain management pathway. Because treatments are rarely targeted at specific knee pain phenotypes, there is no requirement in the current knee pain pathway for a precise diagnosis. This contrasts with the highly refined diagnostic process employed in other disease areas, such as cancer and connective tissue diseases, with targeted treatments. The situation is ripe for the development of a more sophisticated diagnostic approach. One of the advantages of personalized medicine in knee pain is that it offers the prospect of a more precise diagnosis, which is a prerequisite for targeted treatment. This diagnostic approach will be different from that in the current pathway and will involve the classification of patients into smaller, well-defined knee pain phenotypes, which can then be targeted with specific treatments. To understand how this might be achieved, it is helpful to first consider the classification criteria and diagnostic algorithm employed in an area of medicine and disease with well-defined phenotypes, such as rheumatoid arthritis.

Tailored Treatment Plans

Medications are the mainstay of treatment of OA. Paracetamol is usually the first-line analgesia. Recent reports have questioned its efficacy in OA; however, it is still widely used, especially in the elderly, due to its very low side effect profile. Anti-inflammatory medications are effective at providing pain relief, especially in patients with inflammatory arthritis; however, the risk of cardiothrombotic events and gastrointestinal side effects will limit its usage in certain patients. Topical NSAIDs are effective for symptom relief with lower systemic bioavailability. Intra-articular steroid injections are safe and effective at providing temporary pain relief and are useful in patients in whom NSAIDs are contraindicated. There is ongoing development of disease-modifying drugs. Glucosamine and chondroitin supplements have been used by patients with variable results. There is still no strong evidence to support the use of DMARDs. Hydroxychloroquine has a good safety profile, is inexpensive, and has some benefit in controlling pain and disability in OA; it may be a viable option in certain patients. Low-dose methotrexate has also been used with some efficacy, especially in patients with inflammatory OA, but the risk of hepatotoxicity and bone marrow suppression will limit its use. The balance of risks usually outweighs the benefits when it comes to the usage of biological agents. A recent systematic review has recommended further study to evaluate the efficacy of bisphosphonates and calcitonin.

The way in which pain varies from one person to another implies that treatment should also be individualized. The final goal in the treatment of OA is to relieve pain and improve or at least maintain the current level of activities of daily living. One method to achieve this will be by slowing down disease progression.

Advantages of Personalized Medicine for Knee Pain

From a treatment perspective, providing tailored interventions to defined groups of individuals is more efficient than previous attempts to address a myriad of knee pain symptoms with a single treatment (i.e. nonsteroidal anti-inflammatory drugs). It is also likely that tailored treatments will have the advantage of aligning with patient preferences, because our previous work has shown that individuals hold identifiable beliefs about the causes of their knee pain and expectations for treatment. In some cases, it may be possible to enhance adherence to tailored interventions for knee pain by addressing psychosocial factors. For example, individuals with co-morbid depression and knee pain are unlikely to adhere to an exercise regimen for knee osteoarthritis, but targeted depression treatment may lead to greater adherence and improved knee pain outcomes. Finally, a significant advantage of tailored treatments within the context of knee pain management is that using treatments with known efficacy and safety profiles in the groups for which they are intended will maximize benefit and minimize risk.

The potential advantages of personalized medicine for knee pain management are wide-ranging. From a public health perspective, injured group participants reported significantly fewer days of missed work and less impairment in activity 6 months following treatment than patients in the usual care group. Indirect cost analyses for total joint arthroplasty indicate that early interventions that prevent the progression of OA have the potential to decrease costs related to knee pain by billions of dollars. Indeed, long-term research shows that patients with chronic diseases (including knee pain) most desire interventions that will allow them to continue their daily routines.

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