Osteoarthritis of the knee, in Chicago and elsewhere - II. DRUG THERAPY

Simple analgesia and topical non-steroid anti-inflammatory drugs (NSAID) for pain control, over the counter (OTC drugs). The core treatments (physiotherapy) in Chapter I. can improve pain long term. However, pharmacological agents for pain control are necessary.

Paracetamol (acetaminophen) is an antipyretic analgesic with a central, although ill defined, mechanism of action. The effect size for paracetamol in OA is only small. The main reason that paracetamol has been previously recommended so strongly is its perceived safety in addition to its low cost and ready availability. There is growing evidence to associate paracetamol with many of the side effects recognised to occur with NSAIDs, especially gastrointestinal bleeding. The combination of paracetamol and NSAID particularly appears to increase the risk of GI events. Furthermore, it can cause severe life-threatening hepatic failure, particularly in combination with alcohol intake. Thus, paracetamol recommendations have recently changed.

Topical NSAIDs are extremely popular with patients and associated with good adherence. It makes eminent sense to patients to apply a medicine directly to the painful site, and given that patients with OA usually have only one or two symptomatic joints at any one time, such an approach is feasible and well be suited to OA. Topical NSAIDs are strongly recommended for pain relief for hand and knee OA, it should be considered as a first line drug option.

When directly compared, topical NSAIDs have been shown to be almost as effective as the oral equivalent NSAIDs or coxibs, but are associated with a lower incidence of GI and systemic side effects. Topical NSAIDs vary greatly with respect to the active drug, carrier base and physical state (creams, gels, sprays). They usually require application three times daily, when they are smeared onto the skin and do not need to be ‘rubbed in’.

Pharmacological agents for pain control by prescriptionTopical capsaicin is an alkaloid derived from chilli peppers. Capsaicin selectively binds to a protein which is a heat-activated calcium channel on the surface of peripheral nociceptor fibres. Capsaicin activates the channel at lower than body temperature, giving a burning sensation. Prolonged activation of these neurons by repeated application of capsaicin gradually depletes a key neurotransmitter for pain and heat, thus reducing the transmission of painful stimuli. Topical capsaicin applied three times daily can reduce pain associated with hand or knee OA  It shows a progressive effect that is usually maximal between 1 and 2 weeks. An initial burning sensation which wears off after the initial few days of application is very common, Patients should be warned to wash their hands carefully after application and to avoid contact with their eyes and mucosal membranes. Unfortunately, capsaicin is only licensed in some countries for OA and for neuropathic pain (eg, post-herpetic neuralgia).

Oral NSAIDs (including selective COX-2 inhibitors)Oral NSAIDs may be considered in patients who are unresponsive to acetaminophens. There is clear evidence to show superior efficacy of NSAIDs compared to paracetamol, but no consistent data exist supporting superior efficacy of one NSAID over another. In general terms, however, NSAIDs are not very potent analgesics for OA. Withdrawal of chronic NSAIDs from patients with OA, replaced by simple analgesia and lifestyle advice resulted no worsening of OA symptoms.

The main concern with NSAIDs, of course, is life-threatening toxicity. NSAIDs can cause serious GI complications such as ulcers, bleeds, perforations. This risk increases especially with age and concurrent use of other medications. Current European recommendations for prescribing NSAIDs in patients at increased risk of GI toxicity are to use COX-2 selective agents, or non-selective NSAIDs plus proton pump inhibitors (PPI) for gastroprotection. Unfortunately, the reduced GI risk associated with the use of COX-2 selective agents is largely lost when low-dose aspirin is co-administered. It is important to note that non-selective NSAIDs cannot substitute for low-dose aspirin treatment for cardiovascular indications.

As a group, patients with OA are predominantly in the category of increased GI risk as they are over 65 years of age and/or have comorbidities, including cardiovascular disease, justifying prophylaxis with gastroprotection. Because of this, and for cost effectiveness reasons,  guidelines recommend co- prescription of a PPI with both non-selective and COX-2 selective agents for any patient with OA. In any case, NSAIDs should be administered at the lowest effective dose for the shortest time necessary.

In addition to GI toxicity, there is considerable concern over cardio-renal safety. There is growing evidence that this risk is common to both unselective NSAIDs and COX-2 selective agents, although the degree of risk may vary between individual drugs. For example, the estimated increase in risk of serious cardiovascular events seems to be the lowest from naproxen. The current advice from the European Agency (EMA) is that COX-2 selective NSAIDs are contraindicated in patients with ischaemic heart disease or stroke Caution should be applied for patients with risk factors for heart disease, such as hypertension, hyperlipidaemia, diabetes and smoking, as well as for patients with peripheral arterial disease. This again includes a high proportion of older patients with OA.

Direct renal toxicity, especially in the elderly, and multiple drug interactions (especially with diuretics and antihypertensive medication) are further major safety concerns in the OA population. There are animal data that suggest that NSAIDs can inhibit bone repair and may have adverse effects on cartilage metabolism, especially OA cartilage.

Opioids are widely recommended and used, there are only a very few trials in patients with knee, hip or hand OA, and little data to suggest that dose escalation is effective. Side effects largely limit their use and are more common in the elderly, the most troublesome being nausea, constipation, dizziness, confusion, somnolence and itching. Dependence and possible addiction from long-term use for non-cancer pain are further limiting factors.

Nevertheless, the use of opioids increased dramatically in the USA and some other countries following the withdrawal of rofecoxib and the growing concerns about the safety of NSAIDs. Most guidelines recommend that if paracetamol and topical agents are ineffective, then the addition of ‘weak’ opioids (eg, codeine, tramadol) should be considered. Stronger opioids (eg, oxycodone, fentanyl, morphine sulfate) should only be used for severe OA pain in exceptional circumstances, predominantly as a short-term interim measure before surgical intervention.

Neuroactive agents and antidepressants Duloxetine, an SNRI, has recently been recommended for patients with knee OA and patients with multisite OA, following trial evidence demonstrating that it has beneficial effects on pain. Side effects include nausea, dry mouth, somnolence and fatigue among others, but it is usually reasonably well tolerated. It has an ‘uncertain’ recommendation for patients with knee only OA.  

There are a few data to support the use of low-dose tricyclic antidepressants (Melipramin) as analgesics in OA. However, they may be considered for refractory pain in patients with OA who also have depression and non-restorative sleep. As depression is a common comorbidity patients with OA, successful treatment of their depression can improve OA pain and disability.

‘Nutraceuticals’ is a term used to cover a wide range of natural products and foods that are thought to have health benefits. For OA there are numerous nutraceuticals that claim either pain relieving benefits and/or retardation of joint damage. They are available for self-purchase in pharmacies, health food stores and supermarkets. Being food products there are no strict regulations and no compulsory quality control. Nevertheless, such products are extremely popular and have huge sales worldwide.

The rationale for the use of glucosamine and chondroitin is that they are basic components of cartilage glycosaminoglycans and that dietary supplementation will improve the integrity of the hyaline cartilage matrix. There is no clear rationale, however, for any mechanism of pain relief in OA. The mode of action and the in vivo/in vitro effects of these compounds remain highly controversial, but their safety is rarely disputed. Overall, trial evidence for slow onset symptom benefit is the best for glucosamine sulfate at a single dose of 1500 mg/day.

Intra-articular glucocorticoid

There is good evidence to justify IA injection of long-acting glucocorticoid for pain relief in knee and hip OA. This intervention is quick and simple to do and has a large effect size. It produces relatively rapid relief of severe pain within a few hours to a few days or even weeks. In knee OA, there are no clear clinical predictors of response such as presence of effusion, synovitis or degree of structural damage. This treatment is recommended in all guidelines, being well supported by expert opinion. Other joints affected by OA that are commonly injected include the trapeziometacarpal, acromioclavicular and first metatarsophalangeal joint.

Although sepsis is a theoretical concern, as long as sensible sterile precautions are observed, IA steroid injection is a very safe, easily undertaken and well tolerated procedure. The main side effects encountered in practice in a minority of patients are: a temporary exacerbation of pain, post-injection facial flushing for 24–72 hs post-injection, worsening of blood sugar values in diabetic patients.

IA steroid injection is a very useful treatment to instil confidence and optimism in a patient. It helps them realise that their pain can be helped and may encourage a more positive approach to other elements of their management plan. It is particularly helpful at providing a temporary respite to allow the patient to commence physical interventions such as neuromuscular training, or to tide the patient over an important event such as a family wedding or holiday.

Intraarticular hyaluronan (see Blog 4). Hyaluronic acid (HA), also known as hyaluronan or hyaluronate, is a large molecular weight glycosaminoglycan that is a constituent of many tissues including both the synovial and cartilage extracellular matrix. The viscoelastic properties of HA aid joint lubrication and maintain tissue hydration.

Synovial lining cells are the main source of articular HA. The initial rationale to use HA in OA was to correct the reduced HA molecular weight and concentration observed in OA synovial fluid and to improve joint lubrication—so-called ‘viscosupplementation’. A range of HA preparations is now available, varying in terms of molecular weight, degrees of cross linkage and polymerisation, and source of manufacture.

Most preparations require a course of three weekly injections to demonstrate symptom benefit, which poses logistical and cost disadvantages. A single injection preparation is available but has limited clinical trial data at present. Post-injection flares are infrequent but can be more florid than those seen with steroid or saline injections. Most guidelines give guarded recommendation for consideration of HA in OA.