Need for analgesia

Pain is the dominant symptom in arthritis. In early inflammatory arthritis pain is predominantly related to the activity of the synovitis. In late disease it is influenced by the development of joint damage and failure.

Pain can be controlled by analgesics or anti-inflammatory drugs, but equally important is the control of the underlying inflammatory disease process, replacing damaged joints and providing a range of other measures including exercise therapy, transcutaneous electrical nerve stimulation (TENS) and treatment of co-existent depression.

Practical use of analgesics

Simple analgesics can be used in all patients with inflammatory arthritis to control pain (Table 5.1); they are an adjunct to other therapy. The available drugs include paracetamol, weak and strong opioids, tramadol, and combinations of paracetamol and a weak opioid. There is some evidence from clinical trials that analgesics reduce pain in rheumatoid arthritis (RA), but the amount of data is very limited. However, almost all rheumatologists recommend using them.

Table 5.1 An analgesic ladder for arthritis

Paracetamol

Paracetamol is the most widely used analgesic. A single dose of 1000 mg paracetamol provides more than 50% pain relief over 4–6 h in moderate or severe pain compared with placebo. Its analgesic effects are comparable to those of conventional NSAIDs. Unlike other treatments, there are virtually no groups of people who should not take it. Interactions with other treatments are not a problem. At the recommended dosage there are virtually no side-effects and it is well tolerated by patients with peptic ulcers. Overdosage is a risk, as relatively small overdoses can cause hepatic failure.

Despite being used for many years, the mechanism of action of paracetamol is not well understood. It may act centrally, producing analgesia through raising the pain threshold by inhibiting prostaglandin synthetase in the hypothalamus. At therapeutic doses it does not inhibit prostaglandin synthetase in peripheral tissues, and consequently has no anti-inflammatory activity.

The drawback of paracetamol is that patients need to take 6–8 tablets daily to achieve any analgesic benefit.

Codeine and dihydrocodeine

Opioids bind to specific opioid receptors, which are found principally in the central nervous system and gastrointestinal tract. Endogenous opioid peptides are produced by the body and are essential in controlling responses to pain.

The most widely used opioids in rheumatic diseases are codeine and dihydrocodeine. These weak opioids have centrally mediated effects. They are effective after 20–30 minutes and last for about 4 hours. Dihyrocodeine has about twice the potency of codeine. These drugs show a ceiling effect for analgesia and higher doses give progressively more adverse effects, particularly nausea and vomiting. These adverse effects outweigh any additional analgesic effect. One major drawback is that they are relatively constipating. They also cause central side-effects, such as drowsiness.

Tramadol

Tramadol is effective in the relief of moderate to moderately severe pain. It is useful in some patients with inflammatory arthritis. It is a synthetic, centrally acting analgesic, with some opioid properties. Tramadol causes less constipation than opiates and dependence is not a clinically relevant problem. To be fully effective, tramadol needs to be given at a dose of 50–100 mg every 4–6 hours. A slow-release formulation can be useful if night pain is a particular problem. Common adverse effects of tramadol include headache, dizziness and somnolence, which often preclude its use in patients who need to be mentally alert in the day.

Stronger opiates

Analgesics such as oral morphine and oxycodone are virtually never used in treating inflammatory arthritis. The reason for not using such strong opiates is the belief that their addictive nature is more disadvantageous than their therapeutic benefit. They can also have significant gastrointestinal side-effects. However, such negative views reflect custom and practice rather than any rigorous scientific testing.

One new approach to pain relief is to give transdermal opioids such as fentanyl and buprenorphine. This appears both effective and relatively free of gastrointestinal side-effects, and is advantageous in patients with otherwise uncontrolled pain. There are currently very limited data for their use in arthritis.

Compound analgesics

Paracetamol is often combined with a weak opiate in a single tablet. Readily available compound analgesics are paracetamol with codeine (co-codamol) and dihydrocodeine (co-dydramol). These compound drugs have the same effects and adverse reactions as the individual drugs.

Other drugs

Many other drugs are used to treat pain in arthritis. In particular, tricyclic antidepressants, such as amitriptyline, can be used to control pain and improve sleep. Their beneficial effects on pain must be weighed against their side-effects and the drowsiness they can cause, which may be worsened by other concomitant therapy.

Neuropathic analgesics such as pregabalin and gabapentin may be required in patients with arthritis if pain is primarily due to nerve and nerve root irritation and compression.

Classification

NSAIDs are a diverse group of drugs, so named to distinguish them from steroids and non-narcotic analgesics. Although they are one of the most frequently used groups of drugs, their benefits must be set against significant risks from gastrointestinal and other toxicity. They are usually given orally, but can also be used locally as creams or gels.

Indications

NSAIDs are used to control the symptoms of arthritis including pain and inflammation; they also reduce tenderness and stiffness. Inflammatory synovitis due to RA or seronegative arthritis, inflammatory back pain due to ankylosing spondylitis, and degenerative arthritis due to osteoarthritis are all treated using NSAIDs.

In recent years there has been growing concern about the adverse risk of NSAIDs, particularly in older adults. Consequently more emphasis should be placed on simple analgesics, particularly in non-inflammatory conditions.

Mechanism of action and COX1/COX2 effects

Inflammation involves many mediators, including prostaglandins. NSAIDs inhibit cyclo-oxygenase (COX), which has a key role in prostaglandin synthesis. COX has two isoforms. COX1 is responsible for ‘housekeeping’ prostaglandins involved in normal renal, gastric and vascular function. COX2 is induced at sites of inflammation. NSAIDs are classified by their effects on COX1 and COX2.

NSAIDs have other effects, including uncoupling oxidative phosphorylation, inhibiting lysosomal enzyme release and complement activation, antagonizing kinins and inhibiting free radicals. No single mechanism fully explains how NSAIDs work.

Conventional nsaids

Although there are many NSAIDs, most specialists use only a few. Commonly used NSAIDs are shown in Table 5.2. NSAIDs reduce pain, joint tenderness and the duration of early morning stiffness. They have little impact on systemic effects of joint inflammation and do not reduce the increased ESR of active RA.

Table 5.2 Commonly used oral non-steroidal anti-inflammatory drugs

Frequent dosing provides greater flexibility for individual patients, but also means taking more tablets at frequent intervals. Giving a NSAID once daily is more convenient, but risks greater toxicity. Side-effects are minimized by giving the lowest dose compatible with symptom relief. Systematic reviews have found no major differences in efficacy between the currently available NSAIDs, although there are differences in their adverse reactions. However, individual patients often show considerable variation in their responses to different NSAIDs.

COX2 drugs (COXIBS)

Identification of the COX2 iso-enzyme provided a new therapeutic target. The aim was to achieve similar anti-inflammatory action and pain relief to conventional NSAIDs, but without the gastrointestinal toxicity associated with COX1 inhibition. Several drugs in this class are now available, including celecoxib and etoricoxib. Coxibs have the same range of efficacy as conventional NSAIDs.

Adverse reactions to NSAIDs

These are the main limiting factors to the use of NSAIDs. Overall, NSAIDs are one of the commonest classes of drugs causing adverse events. Risks increase with age and NSAIDs must be used carefully in the elderly. Minor adverse effects such as dyspepsia and headache are commonplace, and rashes also occur. Renal, gastrointestinal and cardiac side-effects cause more problems. Central nervous system side-effects, such as drowsiness and confusion, are often underestimated. Haematological side-effects are unusual. NSAIDs can exacerbate pre-existing asthma.

Renal adverse events are one area of concern. As prostaglandins regulate kidney function, NSAIDs can cause dose-dependent renal side-effects, especially in patients with pre-existing renal disease. Common problems are peripheral oedema, hypertension, and reduced effects of diuretics and anti-hypertensive drugs. When renal blood flow is reduced, for example by cardiac failure or diuretic use, the added inhibition of prostaglandin synthesis by NSAIDs further impairs blood flow, and this can cause overt renal failure, particularly in the elderly. Other renal problems seen occasionally include acute renal failure, hyperkalaemia, and interstitial nephritis and papillary necrosis.

Gastrointestinal toxicity is the main problem with NSAIDs. The range of adverse effects includes dyspepsia, gastric erosions, peptic ulceration, bleeding, perforation, haematemesis or melaena, small bowel inflammation, occult blood loss and anaemia. The most serious problems are perforations, ulcers and bleeds. Many patients who have serious gastrointestinal complications do not have prior dyspepsia. In the absence of warning signs there is no way to ascertain whether a patient is on the point of developing serious problems.

If NSAID use is unavoidable, some protective strategy is needed, particularly in those patients at greatest risk. There are several potential options. One choice is to co-prescribe a proton pump inhibitor, such as omeprazole. This is effective and acceptable to patients. H₂-receptor antagonists also help, but are less effective than proton pump inhibitors. Alternatively, the patient could be co-prescribed a prostaglandin analogue, such as misoprostol. This is also effective, but causes added side-effects, such as diarrhoea, and is less well tolerated than proton pump inhibitors. The final option is to use one of the newer COX2 drugs.

Coxibs undoubtedly have less gastrointestinal toxicity and decrease the risk of gastric ulcers. However, their overall toxicity may not be reduced compared with conventional NSAIDs as one form of toxicity may be replaced by another. The risk of NSAID-induced complications is increased particularly in patients with a previous clinical history of gastroduodenal ulcer, gastrointestinal bleeding or gastroduodenal perforation. The use of even a COX2-selective agent should, therefore, be considered especially carefully in this situation.

Cardiovascular adverse events, including myocardial infarction, cardiac failure and stroke, are an increasing concern. They are thought to be more common when NSAIDs are used continuously long-term. They are also more common in patients with pre-existing cardiac disease and associated cardiac risk factors. Some of the increased risk, particularly for cardiac failure, is due to fluid retention. However, there are other mechanisms involved. Initially these cardiovascular toxicities were thought to be a specific problem with coxibs, but it is now accepted that they can occur with most NSAIDs. Some NSAIDs, particularly naproxen, appear to have a relatively low excess risk of cardiovascular disease.

The choice between conventional NSAIDs and coxibs is complex. Coxibs are most valuable in patients most at risk of serious upper gastrointestinal side-effects, who do not have cardiac risk factors. Patients at ‘high risk’ of developing serious gastrointestinal adverse events include those of 65 years of age and over, those using concomitant medications known to increase the likelihood of upper gastrointestinal adverse events, those with serious co-morbidity, and those requiring the prolonged use of maximum recommended doses of standard NSAIDs. However, these patients are also at high risk of cardiovascular and renal adverse effects, so that the best choice may to be to avoid NSAIDs altogether.

Topical NSAIDs

NSAIDs can be used topically as creams or gels. These local NSAIDs are modestly effective and extremely safe. They are used mainly in osteoarthritis and local soft-tissue problems.