Arthritis and Pain Management: Pharmacological Methods of Treatment

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There are many pharmacological interventions that can be used to manage pain in arthritis. However, in selecting the appropriate approach, the clinician needs to consider the efficacy, adverse side effects, dosing frequency, patient preference, and cost in selecting medication for pain management [1].

When a patient develops the first signs of an inflammatory arthritis, the main priority is symptom relief, with pain being the cardinal sign of inflammation that patients most want help with. However, it has become increasingly clear that for inflammatory arthropathies such as RA simply treating the symptoms with non-steroidal anti-inflammatory drugs (NSAIDs) or analgesics is inadequate, because features of the disease that lead to damage to the joints, and then to disability, will carry on unchecked. In addition to symptom-relieving drugs, patients also need disease-modifying drugs that have been demonstrated to slow down or stop the damaging aspects of the disease.

There are two aims in the pharmacological treatment; firstly to reduce inflammation and/or modulate the autoimmune response and secondly to modulate the pain response. Medications can be considered in five classes:

  • simple analgesics;
  • non- steroidal anti-inflammatory drugs (NSAID);
  • Disease modifying anti-rheumatic-drugs (DMARD’s);
  • steroids;
  • biologics;
  • Adjuvant analgesics (e.g. antiepileptic and antidepressant therapy used for pain relief)
  • Others.

Simple analgesics

These include Paracetamol, Dextroproproxyphene, Codeine and Salicylates. Even though it has been in use for over 100 years, little is known of the mechanism of action of Paracetamol although it may work in part by inhibiting prostaglandin synthesis, its action seems to work via the central nervous system rather than through peripheral effects. There is little evidence from randomised controlled studies that delineate whether it is useful for arthritis pain. It is recommended for pain relief in addition to core treatment i.e. self management techniques [2], [3] and should be considered ahead of oral NSAIDs, COX-2’s inhibitors and steroids.


NSAIDs

Traditional NSAIDs act as prostaglandin synthetase inhibitors and therefore decrease the production of prostaglandins which accompanies inflammation. Whilst helpful in inflammatory conditions, NSAIDs can mask signs and symptoms of RA at presentation [4]. Although Paracetamol often gives adequate pain control in OA, NSAID’s are the most effective treatment for persons who experience the pain of RA and that the evidence suggests that it is slightly more efficacious than paracetamol, The risk of adverse events with NSAIDS however, may outweigh the benefits especially in older patients. The GI risk is well known and increased attention is now paid to the increased cardiovascular risk, in part due to the withdrawal of Rofecoxib and Valdecoxib several years ago. The latest NICE guidelines for OA [2] recommends using a topical NSAID or Paracetamol in the first instance followed by either/or a non selective NSAID or COX-2 of the lowest possible dose for the shortest possible period. If a non selective oral NSAID/COX-2 inhibitor is prescribed, then it should be co-prescribed with a proton pump inhibitor, choosing the  combination with the lowest acquisition cost.

Topical NSAIDs application demonstrates therapeutic levels of NSAID within the synovial fluid, fasciae and muscles demonstrating both intra and extra articular pharmaecological effects. Topical preparations produce a maximal blood plasma NSAID concentration of only 15% that achieved following oral administration of a similar dose resulting in far fewer side effects than oral NSAIDs.

DMARDs

The effective and early treatment of rheumatoid arthritis makes a very big impact on the subsequent course of the disease by improving quality of life and reducing joint damage. However, treatment should begin within 3 months of the onset of the disease or preferably even earlier [3], and it must be effective. We know that drugs and biologic treatments slow or even halt joint damage and improve the quality of life.

The drug management of rheumatoid arthritis is an established mode of treatment. Commonly used disease modifying drugs (DMARDs)include Sulfazalazine, Methotrexate, Hydroxychloroquine  and Leflunomide, used as monotherapy or increasingly, in combination.  More traditional DMARDs such as intramuscular gold and Penicillamine have for the most part been superceded due to their poorer evidence base and more significant toxicity concerns. They are a group of disparate drugs that can dramatically ease the pain and stiffness of RA and should be considered as a component of the first choice of pharmacotherapy for individuals with early, active RA. They also improve haematological parameters e.g. Hb, ESR, CRP and will improve grip strength and decrease tenderness and synovitis. For this reason they are said to be disease modifying.

The NICE guidelines on the management of Rheumatoid Arthritis [3] recommends

  • In people with newly diagnosed active RA, offer a combination of DMARDs (including Methotrexate and at least one other DMARD, plus short-term glucocorticoids) as first-line treatment as soon as possible, ideally within 3 months of the onset of persistent symptoms.
  • Consider offering short-term treatment with glucocorticoids (oral, intramuscular or intra-articular) to rapidly improve symptoms in people with newly diagnosed RA if they are not already receiving glucocorticoids as part of DMARD combination therapy.
  • In people with recent-onset RA receiving combination DMARD therapy and in whom sustained and satisfactory levels of disease control have been achieved, cautiously try to reduce drug doses to levels that still maintain disease control.
  • In people with newly diagnosed RA for whom combination DMARD therapy is not appropriate (for example, because of comorbidities or pregnancy, during which certain drugs would be contraindicated), start DMARD monotherapy, placing greater emphasis on fast escalation to a clinically effective dose rather than on the choice of DMARD.
  • In people with established RA whose disease is stable, cautiously reduce dosages of disease-modifying or biological drugs. Return promptly to disease-controlling dosages at the first sign of a flare.
  • When introducing new drugs to improve disease control into the treatment regimen of a person with established RA, consider decreasing or stopping their pre-existing rheumatological drugs once the disease is controlled.
  • In any person with established rheumatoid arthritis in whom disease-modifying or biological drug doses are being decreased or stopped, arrangements should be in place for prompt review.

DMARDs are slow acting, typically taking 6 - 12 weeks before any benefit is noticed. This can cause poor compliance, a feature not usually seen with more immediate-acting simple analgesics and NSAIDs. Maetzel et al [5] undertook a meta-analysis of treatment termination rates among patients with RA receiving disease modifying drugs. They found that the medial survival time for taking methotraxate was longer than that for parenteral gold or Sulphasalazine. Sulphasalazine withdrawal for lack of efficacy was higher than that for parenteral gold or methotrexate. Sulphasalazine and parenteral gold withdrawals because of toxicity were higher than that for Methotrexate. All these drugs are potentially toxic, and monitoring with regular blood tests is essential (except in the case of Hydroxychloroquine where retinal checks should be carried out). Because of the toxicity, the risk has to be weighed against benefit. The inclusion of steroid therapy in an initial combination approach can produce more rapid symptom control pending the onset of DMARD action.

DMARDS can be used concomitantly with Paracetamol and NSAIDs for pain relief.


Steroids

  • These can be delivered intra-articularly or systemically. Intra-articular steroids are very useful and are indicated if any or a few individual joints are inflamed. They are contraindicated by sepsis (either in the joint or of the skin nearby) and should not be given systemically in patients with OA. Repeated joint injection is inadvisable (maximum of 4-6 times/year). Benefit is variable, but virtually all patients gain at least some benefit. For some it lasts days whereas in others several months. However, corticosteroids should not be prescribed without an accurate diagnosis). For RA patients NICE (2009) recommends:
    • short-term treatment with glucocorticoids for managing flares in people with recent-onset or established disease to rapidly decrease inflammation.
    • In people with established RA, only continue long-term treatment with glucocorticoids when:
      • The long-term complications of glucocorticoid therapy have been fully discussed
      • All other treatment options (including biological drugs) have been offered.
      • In elderly patients, drug monitoring may be impractical on a DMARD, and a small dose of steroid, e.g. Prednisolone, will be all that is required. The doses of Prednisolone are relatively small, indeed they are rarely more than 15 mg and often 2.5-5 mg. Systemic steroids undoubtedly and predictably control the inflammation, but they should only be used judiciously because of their long list of side-effects. Patients also find that once on them if the dose is reduced, they may have an acute flare up. Very gradual reductions of dose may be necessary (e.g. 1 mg/month).

For osteoarthritis NICE [2] suggests that 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. There is no clear message from the available evidence as to whether any particular corticosteroid preparation is more effective than another, or on which dose of a given preparation is most effective. In clinical practice, the short-term pain relief may settle flares of pain and also allow time for patients to begin other interventions such as joint-related muscle strengthening.

Opioids

Although the evidence for analgesics being helpful in RA is sparse, the NICE guidelines for Rheumatoid Arthritis [3] considered that there was sufficient data to suggest that they are effective in controlling pain, andthat there should accordingly be a recommendation that these drugs should be offered where other approaches have not resulted in satisfactory pain control. In addition, bearing in mind the need to use NSAIDs and COX2 inhibitors in the lowest effective doses for the shortest periodsof time it was also felt important to emphasise that analgesics should be considered as a way to decrease reliance on these drugs.

Strong opioids also are needed in three particular situations:

  • postoperatively, RA remains the inflammatory arthritis requiring most surgical intervention;
  • sepsis, damaged joints are more likely to become infected;
  • fracture, usually fracture of osteoporotic bone requiring surgical repair in the case of fractured neck of femur, or opiate therapy with wedge compression of the thoracic spine.

The evidence supporting the use of opioid analgesia in the NICE osteoarthritis guidelines 2008 is poor, with virtually no good studies examining their effects upon peripheral joints. There is little evidence to suggest that dose escalation makes a difference and very little data on different opioid formulations or routes of administration.

Biologics

These include anti-tumour necrosis factor (anti-TNF) and anti-B-cell therapy, which act highly specifically on cells or molecules that are important in driving the disease process, and have been developed against the background of an increasing understanding of the pathogenesis of inflammatory arthritis. Infliximab and Etanercept were the first anti-TNF drugs, available for clinical use in the late 1990s (though not approved by NICE until 2002). Newer anti-TNF agents have emerged since, as well as other biological therapies that block other pathways that are important in inflammatory arthritis. Anti-TNFs can be rapidly effective in just over 60% of RA patients. They are much more expensive than conventional DMARDs, which has limited their uptake in many countries. Not all biological therapies have been deemed by NICE to be cost-effective and currently the anti-interleukin-1 (anti-IL-1) drug anakinra is therefore not available in the NHS. The anti-TNF drugs (Infliximab, Etanercept, Adalimumab and Certolizumab pegol) have been approved by NICE, together with Rituximab (an antibody directed against B-lymphocytes) for patients who fail on anti-TNF. With the exception of Certolizumab pegol, which is subject to separate guidance, NICE is now recommending (in its June 2010 draft guidelines) the use of a second anti-TNF if the first one fails, provided that patients are intolerant of, or there are contraindications to, Rituximab or Methotrexate. They are also recommending that Abatacept (a T-cell inhibitor) and Tocilizumab (anti-IL-6) be made available to the same group of patients.

Others

There are a variety of other pharmacological approaches that have or are being used in relieving pain and these include:

  • Capsaicin is derived from chilli peppers. As well as a counter irritant effect it also depletes neurotransmitters in sensory terminals, thereby reducing the transmission of painful stimuli. There is currently limited data with short term follow up for the positive effects of topical Capsaicin. Most of the data also applies to knee studies whereas much of its use is found in hand OA. Capsaicin should be considered as an adjunct to core treatment for knee or hand OA.(NICE 2008)
  • Hylan G-F 20 viscosupplementationaddresses the degradation of hyaluronic acid (HA) in the synovial fluid of patients with knee osteoarthritis by the addition of exogenous HA, or its derivatives, by intra-articular injection and is cited for the treatment of knee osteoarthritis in the guidelines of several professional societies. It has a high molecular weight (average 6000 kDa) HA product consisting of two cross-linked components. Approved in several countries for the treatment of pain associated with knee osteoarthritis, the recommended treatment regimen for the treatment of knee osteoarthritis pain is one 2 ml intra-articular injection per week for three consecutive weeks. Spitzer et al (2010) conclude that it is also useful in the treatment of hip OA. NICE guidance on OA, however, did not recoomend viscosupplementation on the grounds of lack of proven cost effectiveness.
  • Fish oil- Fish oil use has been used as a supplement in the treatment for OA.  Of particular interest are the omega 3 oils and Lyprinol a patented extract of the New Zealand Green Lipped Mussel.  The trials relating to the use of fish oils are even fewer than those relating to glucosamine and chondroitin use.
    • Cho et al(2003) researched the clinical efficacy and safety of Lyprinol by way of a multi-centre trial involving 60 patients in patients with knee and hip OA.  They concluded that Lyprinol had an overall beneficial effect with 80% of patients reporting an improvement in pain and joint function.  Cho et al also concluded that Lyprinol had no known or reported side effects in the study group.
    • Ameye et al [6] in 2006 reviewed randomised controlled trials and evaluated glucosamine and chondroitin, use of omega 3 polyunsaturated fatty acids and the use of New Zealand Green Lipped Mussel. They concluded that omega 3 oils are deemed to have anticatabolic and anti-inflammatory properties.  With regards to Green Lipped Mussel use, they reviewed a small double blind placebo controlled randomised controlled trial involving a trade marked product of the mussel called Seatone and found a small improvement in pain experienced by patients involved as did Cobb and Ernst in 2006 [7]
  • Glucosamine and Chondroitin -  Glucosamine is an amino monosaccharide. The rationale for its use in osteoarthritis (OA) is that it is a precursor for glycosaminoglycans, and glycoproteins which are a major component of joint cartilage and synovial fluid. Commonly sold forms of glucosamine are Glucosamine sulphate and glucosamine hydrochloride. It is available in the UK in over 50 different preparations (in strengths of 500mg, 750mg and 1500mg, as tablets, capsules and liquid formulations, and with or without Chondroitin). Evidence to support the efficacy of Glucosamine hydrochloride as a symptom modifier is poor. For the non-licensed product (Glucosamine Sulphate), the evidence is not strong enough to warrant recommending that it should be prescribed on the NHS. One glucosamine hydrochloride product is licensed, it would not be cost effective to prescribe glucosamine on the NHS [2].
    • Many people with osteoarthritis take over-the-counter nutriceutical products and may benefit from clear, evidence-based information. In particular, NICE [2] recommend that it would be beneficial to advise people who wanted to trial over-the-counter glucosamine that the only potential benefits identified in early research are purely related to a reduction of pain (to some people, and to only mild or modest degree with glucosamine sulphate 1500 mg daily.)

References

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