Pharmacological management

The American College of Rheumatology (ACR) has issued guidelines for pharmacologic treatment of osteoarthritis of the knee which include using one or a combination of the following:

Acetaminophen, oral Non-Steroid anti-inflammatory drugs (NSAIDS), topical NSAIDS, opioids and intra-articular corticosteroid injection.⁷⁰ The ACR conditionally recommends against using chondroitin sulfate, glucosamine, or topical capsaicin for knee osteoarthritis.⁷⁰

The choice of pharmacological intervention should be guided by severity of symptoms, their impact on function and risk assessment. Pharmacotherapy can be tailored according to disease

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severity and symptom response. Simple analgesia is the basis of pharmacotherapy; if indicated by symptoms, other agents should be added to the regimen, with follow up to assess for effectiveness.

Aiming for the fewest agents possible to achieve the desired symptom control will reduce potential risks.⁷⁸

2.7.1.1 Paracetamol and Non-steroidal anti-inflammatory drugs (NSAIDS)

Acetaminophen or paracetamol is the first line treatment for OA.For mild to moderate symptoms, its effectiveness is similar to non-steroidal anti-inflammatory drugs (NSAIDs), though for more severe symptoms NSAIDs may be more effective.⁷⁹ Healthcare professionals should consider offering paracetamol for pain relief in addition to core treatment. Paracetamol and/or topical NSAIDs should be considered ahead of oral NSAIDs, cyclo-oxygenase 2 (COX-2) inhibitors or opioids.⁴⁰

NSAIDs act primarily through inhibition of cyclo-oxygenases (COX) responsible for prostaglandin biosynthesis at the site of pain and inflammation, but might also work through peripheral and central desensitisation.⁸⁰ NSAIDS can be in topical or oral preparations.

Direct application of topical NSAIDs in the region of a painful joint is a common and recommended treatment in mild to moderate OA. This treatment is particularly useful in the management of a single painful osteoarthritic joint (especially the knee). It can provide a safe and effective alternative to systemic anti-inflammatory therapy.^{40, 77}

To be effective, a topical NSAIDs needs to penetrate the skin and enter the circulation or additionally be absorbed into the underlying tissue. The formulation with respect to its lipid and aqueous solubility (requirements for passing through the stratum corneum and epidermal layer respectively) determines the degree of dermal penetration.⁸⁰ Formulations of gels and sprays are more effective than creams. Studies show that penetration of the topical NSAIDs into the intra- and peri-articular structures via the local bloodstream gives rise to therapeutic concentrations within these tissues without significant systemic absorption. This accounts for their superior safety

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profile over oral therapy with respect to systemic renal, cardiovascular and gastrointestinal toxicity. Compared to oral NSAIDs, topical therapy is associated with fewer systemic adverse events and gastro-intestinal side effects.⁸¹ Topical NSAIDs should be considered with paracetamol as first line treatment ahead of oral NSAIDs, COX-2 inhibitors or opioids in view of their efficacy and relative safety.⁷⁰

Although oral NSAIDs and COX-2 inhibitors may be regarded as a single drug class of

‘NSAIDs’, the recommendations continue to use the two terms for clarity, and also because of the differences in side-effect profile.⁴⁰ Where paracetamol or topical NSAIDs are ineffective for pain relief for people with osteoarthritis, then substitution with an oral NSAID/COX-2 inhibitor should be considered. Oral NSAIDs/COX-2 inhibitors should be used at the lowest effective dose for the shortest possible period of time.⁴⁰

All oral NSAIDs/COX-2 inhibitors have analgesic effects of similar magnitude but vary in their potential gastrointestinal, liver and cardio-renal toxicity; therefore, when choosing the agent and dose, healthcare professionals should take into account individual patient risk factors, including age. When prescribing these drugs, consideration should be given to appropriate assessment and/or ongoing monitoring of these risk factors.^{40, 70}

NSAIDs are associated with gastric problems, dyspepsia, thrombus formation and renal failure.

Risks are lower with topical gels than oral preparations.⁸² The development of Cox-2 selective anti-inflammatory drugs reduced the incidence of gastric side-effects, but highlighted another problem of NSAID use; the increased risk of thrombus formation, particularly with long-term use, in older people and in those with other prothrombotic risk factors. This increases the risk of myocardial infarction and stroke.⁸² The Agency for Healthcare Research and Quality (AHRQ) comparison found that acetaminophen was modestly inferior to NSAIDs in reducing osteoarthritic

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pain but was associated with a lower risk of Gastrointestinal (GI) adverse effects. On the other hand, acetaminophen poses a higher risk of liver injury.⁸³

2.7.1.2 Topical analgesics

Topical counter-irritants are agents that are frequently applied locally to relieve musculoskeletal pain in the extremities.⁸⁴ The most commonly used rubefacient is

salicylate, but this class of agent also includes nicotinate esters.

The principal action of rubefacients is to act as a skin irritant. This results in reddening from vasodilatation and increased blood flow, but also leads to a soothing sensation of warmth i.e.

counter-irritation.⁸⁵ This is consistent with the fact that no benefit is found using a rubefacient applied distal to the site of pain. Pain may also be offset or altered in the underlying muscle, joint and tendon by irritation of the sensory nerve endings. More recently there is evidence to suggest that salicylates and other rubefacients may act via the transient receptor potential (TRP) ion channels involved in thermal and pain sensation.⁸⁵

Topical capsaicin is a lipophilic alkaloid extracted from chilli peppers that has an extremely potent irritant effect. It works by initially selectively activating and sensitising c-nociceptors in the skin by binding the transient receptor vanilloid type 1 (TRPV1) cation channel. Substance P is released which causes local irritation; however with repeated applications, levels are depleted leading to reversible desensitization of pain fibres and eventual degeneration of epidermal nerve fibres resulting in hypoalgesia.⁸⁶

2.7.1.3 Opioid analgesics.

Opioids or opiates are also used in the management of osteoarthritis of the knee. They are usually reserved for treatment of moderate to severe pain in osteoarthritic patients for whom acetaminophen, NSAIDs, exercise, and physical therapy have not worked or when there are contradictions to their use.⁷¹ Opiates are superior in pain control when compared to NSAIDS but

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can lead to dependence and addiction.⁸⁷ The commonly used opiates are codeine, hydrocodone, oxycodone and tramadol. They are available in pills, liquids, or suckers to take by mouth, and in shot, skin patch, and suppository form.

Opiates relieve pain by suppressing perception of pain and emotional response to pain. They reduce not only the number of pain signals sent by the nervous system but also the brain's reaction to those pain signals. Opioids can be extremely effective in the management of pain. However, their benefits can be outweighed by side-effects such as nausea, vomiting, dizziness and constipation, which affect a lot of people who use these drugs.⁷⁷ Long-term use of opioids is associated with tolerance, where sensitivity to the analgesic effects of opioids decreases over time, and hyperalgesia, where sensitivity to painful stimuli increases.⁷⁷

2.7.1.4 Intra-articular injections

Intra-articular pharmacologic therapy includes injection of a corticosteroid or sodium hyaluronate (ie, hyaluronic acid [HA] or hyaluronan), which may provide pain relief and have an anti-inflammatory effect on the affected joint. Ultrasound guidance can facilitate arthrocentesis and injection and is increasingly being adopted by physicians such as rheumatologists and physiatrists for this purpose.⁸⁸

Intra-articular steroid injections: Intra-articular (IA) corticosteroid injections have been widely used to treat symptomatic peripheral joint OA for many years. The corticosteroid exerts its anti-inflammatory effect by interrupting the immune and anti-inflammatory cascade at several levels. Local delivery of high doses of corticosteroid minimises systemic toxicity and can result in rapid improvement in symptoms during acute or severe symptom flares, especially in knee and hand OA.⁸⁸

Corticosteroid preparations differ in solubility and potency: more soluble preparations have a shorter duration of action, e.g. hydrocortisone acetate, compared to longer acting emulsion based

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preparations, which are only slightly soluble, e.g. methlyprednisolone acetate (MPA) or relatively insoluble, e.g.triamcinolone acetonide (TCA). Longer acting preparations are more effective for intra-articular injections as they remain in the joint longer, though in practice the choice of agent is usually based on local availability and cost.⁸⁸

Most manufacturers advise against corticosteroid dilution with local anaesthetic (e.g. lignocaine) because of the risk of clumping and precipitation of steroid crystals. However this remains common practice and provides additional benefits. There is early temporary relief of symptoms. It verifies delivery of steroid to site of pain; and dilutes the suspension, enabling even distribution within the joint and hence avoids placement of highly concentrated fluid into a single area.⁸⁸ Intra-articular corticosteroid injections should be considered as an adjunct to core treatment for the relief of moderate to severe pain in people with osteoarthritis.

Intra-articular sodium hyaluronate: Endogenous hyaluronan, previously known as hyaluronic acid (HA), is a large linear glycosamino-glycan. It is a major non-structural component of both the synovial and cartilage extracellular matrix and of synovial fluid. Key functions in the joint are to confer viscoelasticity and lubrication, and to help maintain tissue hydration and protein homeostasis by preventing large fluid movements.⁴⁰ The therapeutic goal of intra-articular viscosupplementation with HA is therefore to restore the natural protective function of hyaluronan in the joint.⁴⁰

The mechanism by which HA exerts its therapeutic effect is not certain. Possible mechanisms include direct binding to receptors (CD44 in particular) in the synovium and cartilage that can lead to several biologic activation pathways.⁸⁹ Intraarticular residency is short (hours), but the reported benefit is long (months). The short-term mode of action might be based on the pain relieving effect of the viscoelastic fluid in the affected joint. In the long term a sequence of events might be triggered which restores the trans-synovial flow and subsequently the metabolic and rheological

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homeostasis of the joint.⁹⁰ However there is minimal evidence for a role in long term disease modification. Intra-articular injection of sodium hyaluronate, also referred to as viscosupplementation, has been shown to be safe and possibly effective for symptomatic relief of knee osteoarthritis.⁹⁰ The evidence for HA efficacy is mostly in knee OA, with a slower onset of action but more durable response than IA corticosteroid injection.

Tricyclic antidepressants

Tricyclic antidepressants (TCAs) work by blocking the uptake of serotonin and noradrenaline from synapses in the brain and spinal cord. These neurotransmitters are involved in inhibiting pain signals, and blocking their removal from synapses improves the body’s inhibition of pain signals.

Theoretically, TCAs should be helpful in OA pain, but only one study has explored this. The study was inconclusive in terms of pain relief, but support is emerging for the benefits of TCAs in OA pain.⁴⁰