Modern management of mild-to-moderate joint pain due to osteoarthritis: a holistic approach.

Osteoarthritis (OA) is the most common form of arthritis and it is often associated with significant disability and impaired quality of life. Once thought to be caused by an age-related 'wearing out' of articular cartilage, it is now recognized to be a dynamic process in which cartilage degradation alternates with repair. Several expert guidelines for the management of OA exist, which concur in their recommendations for a stepwise approach to the employment of pharmacological agents and the introduction of suggestions to extend the use of agents such as topical non-steroidal anti-inflammatory drugs, especially for mild-to-moderate forms of the disease. They also emphasize the importance of non-pharmacological measures, such as nutraceuticals, education, diet, exercise and the use of aids in improving signs and symptoms and slowing progression. In many countries, effective medicinal and nutraceutical agents are available 'over-the-counter'. This review explains the modern approach to the management of mild-to-moderate osteoarthritic pain.

Glucosamine and chondroitin for osteoarthritis.

Osteoarthritis (OA) is a common, chronic disease that most frequently affects the knees and is a major cause of disability in the elderly. It is characterized by progressive cartilage loss, accompanied by secondary changes such as osteophyte formation and calcium deposition. Inflammatory processes are also involved, leading to stiffness and pain, for which patients seek treatment. Conventional treatment includes analgesics or non-steroidal anti-inflammatory drugs, however life-style changes should also be recommended, such as weight reduction and specific exercises. Glucosamine and chondroitin, classed as over-the-counter supplements or nutraceuticals, are regularly self-administered by patients with OA. Both agents are produced endogenously in the human body and are essential components of cartilage. This review discusses the evidence that supports the use of these agents either alone or in combination for pain relief and as disease-modifying agents in OA.

A rational approach to the prevention and treatment of postmenopausal osteoporosis.

Postmenopausal osteoporosis is a common disorder. Its importance is measured by the mortality and morbidity associated with increasing numbers of fractures and the enormous social and economic cost to the community. Although the precise aetiology of postmenopausal osteoporosis remains unclear, prevention is now possible and treatment may be effective if commenced early enough in the course of the disease. Combination therapy with oestrogens and progestogens is currently the treatment of choice for prevention, in conjunction with calcium supplementation and changes in lifestyle. Prophylaxis should be offered to women at 'high risk', although the identification of this group is difficult at present. Treatment of existing disease is less effective, although oestrogens should be tried first, with calcitonin as a second choice. There is no place at present for vitamin D, anabolic steroids or parathyroid hormone. The use of fluoride or diphosphonates cannot be recommended outside research centres until further long term studies are completed, which will enable a comparison of the relative risks and benefits. Postmenopausal osteoporosis is now a preventable disease; however, further knowledge of risk factors and the identification of those at risk is essential. Treatment can then be directed at women who need it and healthy women can be spared a lifetime of unnecessary medication.

Non-steroidal anti-inflammatory drugs. Current status and rational therapeutic use.

Aspirin (acetylsalicylic acid), the first of the NSAIDs (introduced in 1899), was initially never referred to as an anti-inflammatory agent. It was the advent of cortisone in 1949 that demonstrated dramatically that corticosteroids had anti-inflammatory properties and the term 'non-steroidal anti-inflammatory drug' was first used when phenylbutazone was introduced 3 years later. Since then, the NSAIDs have proliferated. There is to date no good evidence that they halt progression of rheumatoid disease, but by easing pain and diminishing swelling they make life much easier in osteoarthrosis, rheumatoid arthritis and many other types of arthritis, and are the drugs of first choice in acute gout. Their mode (or modes) of action are obscure and though inhibition of cyclo-oxygenase (prostaglandin synthetase) is clearly important, other mechanisms are also involved. The assessment of the anti-inflammatory action of these agents has received considerable attention in clinical trials because, whatever their action may be in experimental animal models, their action in inflamed joints in human patients must be ascertained, since there may be little parallel between the two. Different experimental animal models give different results with various agents and often bear little relation to their therapeutic action in man. No attempt has been made here to review in depth all the NSAIDs that have appeared since 1952. All have anti-inflammatory and analgesic activity and all can cause gastrointestinal side effects, though effectiveness and toxicity vary from drug to drug and patient to patient, there being very great interpatient variability. Non-reactors, patients who apparently fail to respond to certain agents, need further study, for it seems that these subjects may metabolise these agents differently from others. Considerable ingenuity has been shown not only in evolving new NSAIDs but in finding new ways of administering them. The number and variety of NSAIDs in their various forms varies greatly from country to country, depending largely on the regulatory bodies of those countries. In the meantime, the search for a better, less toxic compound continues with the hope that one may be found which has a deeper and more basic action on the underlying disease process.

Glucose-6-phosphate dehydrogenase deficiency and chronic haemolysis in an English family.

Three male members of an English family with chronic haemolytic anaemia due to glucose-6-phosphate dehydrogenase deficiency are reported. The disease was symptomless in one adult, but crises, caused either by increased haemolysis or failure of marrow compensation, occurred in two children. They were typically precipitated by trivial infection. Two normal female members of the family were obligatory heterozygotes. A hitherto undescribed ;slow' variant of the enzyme was identified electrophoretically.

Diclofenac sodium in the treatment of painful stiff shoulder.

A double-blind controlled, between-patient trial was carried out in 40 patients with painful stiff shoulder to compare the effect of treatment with either 50 mg diclofenac sodium or 400 mg ibuprofen given 3-times daily for 2 weeks. The results of assessments made before and after treatment showed that although both drugs produced some improvement no statistically significant differences between the two groups in terms of pain relief or the range of movement were evident. The incidence of side-effects was also similar.

A single-dose analgesic study of naproxen sodium and soluble aspirin in patients with rheumatoid arthritis.

Nineteen patients with moderate or severe pain due to rheumatoid arthritis were entered into a double-blind, crossover comparison of single doses of 550 mg naproxen sodium and 900 mg soluble aspirin. Pain relief, measured on a visual analogue scale, showed a rapid onset of action of both drugs. Pain relief reached 50% of its maximum within 1 hour on both drugs. There were no significant differences in the pain relief/time curves. Five patients found no relief of pain with either drug but of the remaining 14 patients 10 reported an onset of action of both drugs within half an hour. Nine patient on naproxen sodium and 7 on soluble aspirin rated pain relief as good or very good. At the end of the study, 7 patients preferred soluble aspirin, 4 preferred naproxen sodium and the remainder gave no preference. There were no side-effects on eigher drug.

Clinical experience with tolmetin sodium.

Two studies are reported with tolmetin sodium. The first compared tolmetin sodium, phenylbutazone and placebo in rheumatoid arthritis. The second compared tolmetin sodium and aloxiprin in osteoarthritis and soft tissue rheumatism. In the first study, a double-blind crossover trial involving 12 patients, tolmetin sodium (1600 mg daily) was shown to be superior to placebo and comparable to phenylbutazone (400 mg daily). The reductions in morning stiffness and pain were statistically significant when compared to placebo. Tolmetin sodium and aloxiprin were compared in the treatment of osteoarthritis in a single-blind study which investigated efficacy and safety over a 3-month period. Initial dosages were 1600 mg tolmetin sodium and 6 g aloxiprin (equivalent to 5 g aspirin) daily. Thirty-four patients were enrolled in the study. Both drugs produced an improvement over the 3-months treatment period. The reduction in pain was statistically significant. The dosage of tolmetin sodium remained at 1600 mg daily for the 3-month duration of the study but side-effects necessitated the reduction of the dosage of aloxiprin in many patients and after 3-months' treatment the mean dosage was 4 g daily. Five patients withdrew from the tolmetin sodium group and 11 from the aloxiprin group. Adverse reactions including limiting side-effects, were about twice as common with aloxiprin compared to tolmetin sodium.

Flurbiprofen at night.

Three double-blind crossover trials were used to study the effects of single doses of flurbiprofen at night on pain at night, duration of morning stiffness and sleep disturbance in patients with active rheumatoid arthritis. Flurbiprofen (150 mg) was shown to be superior to placebo and 150 mg was no more effective than 100 mg. Serum levels of the drug were significantly higher with 150 mg but did not correlate with clinical effects.

Difunisal in general practice.

A large-scale, double-blind comparative study was carried out in general practice to assess the relative efficacy and tolerance of difunisal and aspirin in patients suffering from acute painful conditions such as sprains and trains, osteoarthritis, etc. Patients received either 250 mg or 500 mg difunisal twice daily, or 600 mg aspirin 4-times daily for 5 days. The results of subjective assessments of pain relief from the daily records of 1902 patients (967 on diflunisal, 935 on aspirin), and the overall assessment of response by both doctors and patients, showed that diflunisal was significantly better than aspirin. Gastric side-effects were more common and more severe in patients receiving aspirin, and more often led to withdrawal of treatment.

Short-term efficacy and tolerance of tiaprofenic acid ('Surgam') in rheumatoid arthritis and osteoarthritis: multi-centre, placebo-controlled trials.

Two multi-centre, placebo-controlled, crossover trials of tiaprofenic acid were conducted to an identical design: one in 80 patients suffering from rheumatoid arthritis, the other in 60 patients suffering from osteoarthritis. After a washout period, each patient received 600 mg tiaprofenic acid daily and placebo each for 1 week. The results were similar for both trials. Tiaprofenic acid was more effective than placebo in both rheumatoid arthritis and osteoarthritis and differences in all the assessments of efficacy used were statistically significant. This significance was attained from the first day in rheumatoid arthritis and from the second day in osteoarthritis. Tiaprofenic acid was as well tolerated as placebo. Routine laboratory tests revealed no adverse effects. Possible side-effects, which were predominantly mild and related to the gastro-intestinal system, were reported by 23% patients with tiaprofenic acid and 21% patients with placebo. The 2 patients withdrawn for possible side-effects were both receiving placebo.

Nimesulide, a balanced drug for the treatment of osteoarthritis.

World-wide experience with nimesulide confirms that it is an effective anti-inflammatory drug in the treatment of osteoarthritis. A review of several studies in this condition confirms that nimesulide is at least as efficacious as other commonly used compounds. The safety profile of nimesulide, compared to reference drugs such as naproxen, etodolac and diclofenac, demonstrates superior gastrointestinal tolerability. Nimesulide is therefore a good choice for the long-term treatment of OA.

An in vitro system for studying cartilage degradation by macrophages.

Cartilage damage in inflammatory arthritis may be mediated by a number of cell types; the macrophage is one of them. To examine their role we developed a new macrophage-cartilage co-culture system on a microscale. This used macrophages derived from the peritoneal cavity of Balb/c mice together with cartilage slices from bovine nasal septa. We examined the effects of macrophages on cartilage proteoglycan loss measured colorimetrically. When chondrocytes were dead, cartilage released proteoglycan; macrophages increase the amount of proteoglycan loss; stimulating macrophages with zymosan further increased proteoglycan loss. With live chondrocytes the situation was different. Macrophages only gave a major increase in cartilage proteoglycan loss when stimulated by zymosan. These results show it is possible to establish a simple model of macrophage-induced cartilage degradation. In this a variety of effects given by macrophages can be demonstrated depending on the presence or absence of live chondrocytes.

The response of 99Tcm-methylene diphosphonate and 99Tcm-hexametazime-labelled neutrophils to intra-articular steroid injection in rheumatoid arthritis.

The synovial and bone uptake of tracer in the knees of patients with rheumatoid arthritis (RA) was quantified using 99Tcm-hexamethyl propylene amine oxime-labelled leucocytes and 99Tcm-methylene diphosphonate (MDP), respectively. Significant neutrophil migration and MDP uptake occurred in the knees of patients with RA irrespective of the disease duration. In all but one patient neutrophil migration was reduced after intra-articular steroid injection. The change in MDP uptake after steroid injection was variable. There was a significant correlation between the percentage reduction in neutrophil migration and pain score, while the latter correlated poorly with the change in MDP uptake. The quantification of the neutrophil component of the inflammatory process is a sensitive index for monitoring RA activity and response to pharmacological interventions, while quantitative bone scintigraphy should not be employed to monitor changes in joint inflammation in patients with RA.

Radioleucoscintigraphy in osteoarthritis. Is there an inflammatory component?

The possible contribution of an inflammatory component in osteoarthritis was investigated. There was no correlation between the percentage uptakes of 99Tcm-hexamethylpropyleneamine oxime (HMPAO)-labelled white blood cells and 99Tcm-methylene diphosphonate (MDP) and between the former and pain scores. A significant correlation was found between the percentage uptake of 99Tcm-MDP and pain scores (0.002 > P > 0.01). In osteoarthritis, 99Tcm-HMPAO-labelled white cell imaging may or may not show a positive localization in the synovial membrane. Positive white cell localization appears to be limited to the area that corresponds to the radiological evidence of the condition and the positive uptake of the skeletal imaging agent.

99Tcm-labelled leucocyte imaging in active rheumatoid arthritis.

A simplified technique of labelling leucocytes with technetium-99m is described and applied to patients with active rheumatoid arthritis. The clinically active and less active knees in seven patients were imaged and the uptake of labelled leucocytes was measured. The measurements were repeated after local steroid injection into nine painful knees. A 50-80% reduction in leucocyte uptake localized to the region of the synovium was demonstrated in the eight knees which showed clinical responses and a rise of 8% in the non-responder. There was a variable response in the knees that were not injected. 99Tcm leucocyte imaging in rheumatoid arthritis is able to assess objectively joint inflammation and its response to treatment.

The clinical value of measuring immunoglobulins when assessing penicillamine therapy in rheumatoid arthritis.

Immunoglobulins are often high in active rheumatoid arthritis and fall when treatment with a slow-acting anti-rheumatic drug is instituted. We assessed the value of monitoring immunoglobulins during penicillamine therapy; 145 patients were followed for up to 5 years, IgA, IgM and IgG levels were compared to 12 other clinical and laboratory variables on 903 occasions. Mean levels of IgA and IgG fell by 10-30%. These changes were less than with ESR or clinical measures such as articular index and duration of morning stiffness. Immunoglobulin levels showed weak correlations with other variables. Only a small number of patients had hypogammaglobulinemia. Initially, 5 cases had low IgA with subsequent falls in 3 more. Initially, 2 cases had low IgG with subsequent falls in 5 more. No patients had low IgM levels. These changes seemed clinically irrelevant. Radiological progression was related to IgA levels. Patients with persistently high rates of radiological progression had persistently higher serum IgA. We conclude that IgM gives the most "acute phase" pattern of response. IgA gives more theoretically interesting information, especially concerning radiological progression. There is only a limited amount of clinically valuable information gained from measuring immunoglobulins.

Rheumatoid nodules do not predict response to treatment with slow-acting anti-rheumatic drugs.

Rheumatoid nodules have been associated with a poor long-term prognosis. We investigated whether they predict a poor response to treatment with slow-acting anti-rheumatic drugs (SAARDs). Two hundred and twenty-eight patients with rheumatoid arthritis (RA) were treated for six months with a SAARD. Clinical and laboratory assessments of disease activity were made initially and after 6 months' treatment. Patients were divided into two groups according to the presence or absence of nodules at entry. Twenty-one % had nodules before treatment but their response was no different to patients without nodules (79%), both groups showing improvements in all variables. Males were more likely to develop nodules and had a relative risk of 1.7. High titres of rheumatoid factor correlated with nodules and no sero-negative patients had nodules. We conclude that nodules are not predictive of poor response to treatment with a SAARD, despite their presence being associated with a poor long-term prognosis. One possible implication is that SAARDs themselves, despite an early response, may not effect long-term outcome.

Osteoarthritis. Changing concepts in pathogenesis and treatment.

The clinical features of osteoarthritis provide little support for the traditional view of the disease as a wear-and-tear phenomenon of aging. In many cases osteoarthritis consists of a polyarthritis with mildly inflammatory features, such as stiffness, effusions, and hot Heberden's nodes. The finding of biochemical abnormalities of cartilage throws new light on this enormously important disease and suggests the possibility of more effective therapy.

Four new anti-inflammatory drugs responses and variations.

No abstract available.