Walter F. Kean

The use of NSAIDs in rheumatic disorders 2005: a global perspective.

Population studies and World Health Organisation (WHO) statistics indicate that 10–50% of individuals suffer from musculoskeletal disorders. Up to 3% will be classified as disabled due to their bone and joint condition, and the majority will suffer from pain. Almost all will require non-steroidal anti-inflammatory drugs (NSAIDs) and other analgesics for their management. The large majority of this population is elderly and, hence, at greater risk of adverse effects to the NSAIDs. The NSAIDs are a necessary choice in pain management because of the integrated role of the cyclo-oxygenase (COX) pathway in the generation of inflammation and in the biochemical recognition of pain. For over 80 years the management of musculoskeletal pain was hampered by NSAID toxicity problems related to the traditional NSAIDs. In the early 1990s, paracetamol was recommended as the first-choice analgesic for osteoarthritis, but subsequent studies have shown that paracetamol has a significant gastrointestinal (GI) toxicity profile. In addition, it has lower analgesic efficacy than NSAIDs and is, thus, not an effective alternative to NSAIDs in any of the inflammatory arthritides. The identification of cyclo-oxygenase 2 (COX-2) and the subsequent introduction of the COX-2-selective inhibitor NSAID drugs was thought to be a major breakthrough with the expectation of a significant reduction in G/I side-effects. This has not been the case for celecoxib, and indeed for all COX-2-selective inhibitors when given with ASA. The COX-2-selective inhibitors also inhibit renal COX-2 with the potential for problems of fluid retention, oedema, hypertension and congestive heart failure. The major controversy with respect to the COX-2-selective inhibitors as a class has been the increase in myocardial infarction and other cardiovascular events observed in some studies. Thus, the initial expected global benefits of the COX-2-selective inhibitors may be outweighed by their potential for toxicity. Recent studies have shown that the use of a proton-pump inhibitor drug with traditional NSAIDs and with COX-2-selective inhibitors has been shown to significantly reduce GI symptoms and peptic ulceration. Thus, the traditional NSAIDs have been re-established as the preferred choice in the management of arthritis and musculoskeletal disorders.

Osteoarthritis: symptoms, signs and source of pain

Osteoarthritis is the most common form of arthritis. The condition is characterised by loss or failure of the functional and/or biochemical integrity of the joint. The clinical symptoms include joint stiffness, pain and dysfunction, but the principal problem for the majority of patients is the pain. Although there are no pain receptors in the cartilage, the origin of the pain is thought to be due to stimulation of the A delta mechanoreceptors and the C polymodal nerve endings in the synovium and surrounding tissues. However, some of the pain experienced in and around the joints is referred pain or sympathetic efferent pain. In addition, there is a poor correlation of clinical symptoms with radiological or imaging appearance. This lack of correlation of clinical evaluation and imaging makes attempts at treatment difficult and compromises attempts to design studies and to evaluate the outcome of osteoarthritis in clinical trials.

Chirality in antirheumatic drugs

Use of chiral molecules in clinical practice may cause problems because different chiral forms of a drug (enantiomers) may have different biological activities--yet clinicians have little awareness of these risks. After discussion of the chemical conventions used to describe chirality, examples of the influence of chirality on the efficacy and toxicity of antirheumatic drugs are given. It is recommended that single enantiomers should be used in biological experiments and clinical trials.

d-penicillamine: Chemistry and clinical use in rheumatic disease

The discovery of D-penicillamine and its uses in medicine are reviewed. Chemical-physical properties are discussed, and the molecular structure of D-penicillamine and several of its reaction products are illustrated. Examples of its three main types of biochemical reactions--sulfhydryl-disulfide exchange, thiazolidine formation, and metal chelation are included. Trials of D-penicillamine in RA patients are reviewed critically. The administration of the drug is discussed in detail, including dosages, clinical and laboratory responses, patterns of adverse side effects or toxicity, drug-induced autoimmune diseases, indications and contraindications, and the monitoring and management of patients.

Review of the pharmaceutical properties and clinical effects of the topical NSAID formulation, diclofenac epolamine

ABSTRACT Background: Topical formulations of non-steroidal anti-inflammatory drugs (NSAIDs), in particular diclofenac (DI), have become popular for treating various acute and chronic painful inflammatory conditions. Objective: To perform a literature review of (1) the use of topical NSAIDs; (2) the pharmaceutical, pharmacokinetic and pharmacodynamic properties of a medicated plaster (patch) containing diclofenac epolamine (DI-EP, Flector Tissugel, Flector patch*) compared with other formulations of topical NSAIDs; and (3) evaluation of the clinical findings from studies with this novel DI-EP patch. Outcomes: (1) Pharmacokinetic studies involved determination of DI from DI-EP and separately epolamine (EP) and the epoxide metabolite (N-oxide-EP) in laboratory animals and humans; the latter being the major metabolite in humans. About 2% of DI is absorbed by the skin in humans and is excreted in the urine. Maximum plasma concentrations of 17.4 ng/mL DI are reached at 5.4 hours (approximate steady state conditions); the plasma elimination half-time (t½) being 26.4 hours. Low systemic levels of DI and EP are produced from DI-EP. Pronounced accumulation of DI occurs in the muscle layers and in synovial fluids of arthritic patients; (2) No significant toxicity occurs from EP nor N-oxide-EP, while that of oral DI-EP was similar to that from DI; and (3) In acute musculoskeletal conditions (sprains, tendonitis and sports injuries) and osteoarthritis DI-EP patches control pain and signs of joint or physical injury compared with placebo controls by 3–5 days with almost complete pain relief at 14 days. DI-EP was shown to have equivalent therapeutic effect to another DI diethylammonium gel formulation (Voltaren Emulgel†). There were no reports of serious adverse events in the gastro-intestinal (GI) tract, kidneys or liver from DI-EP. Mild GI symptoms and skin reactions occur in 2 and10% of patients, respectively. Conclusions: The patch delivery of DI in DI-EP affords controlled delivery of the active drug in contrast to that from application of gels or ointments of NSAIDs.

Management of chronic musculoskeletal pain in the Elderly: Opinions on oral medication use

Abstract.The use of oral medication in the treatment of chronic musculoskeletal pain in the elderly requires careful selection of drugs to control pain with consideration for both the physiological state and the presence of disease(s). Recent advances have improved the understanding of biomolecular mechanisms of chronic pain. These include the production of powerful pro-inflammatory cytokines by glial and microglial cells, which then lead to activation of major pain pathways from the periphery through the dorsal horn and supra-spinal pathways to the somatosensory and other higher cortical centres. This has allowed better recognition for intervention with anti-inflammatory agents to control cytokine production (e. g. prednisolone, triamcinolone and other brain-penetrating corticosteroids). Advances in understanding of chronic pain have lead to recognition of neuronal PX2 puringergic receptors as potential sites for drugs to control pain by more selective actions. Pain control in the elderly involves extensive use of analgesics, among them the non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol (acetaminophen), and various narcotics. Each of these has its drawbacks, mostly related to potential toxicities. Attempts to reduce the serious gastro-intestinal (GI) adverse effects of the NSAIDs by the introduction of the highly selective COX-2 inhibitors (coxibs) have only had limited benefit in reducing these untoward actions. Moreover, the risks of serious cardiovascular (CV) and renal side-effects, though statistically infrequent, are none the less of major concern. Cardio-renal effects have been attributed to some (e. g. diclofenac), but not all (e. g. naproxen) conventional NSAIDs. Here we make recommendations for a selection of certain NSAIDs to be used for pain therapy in the elderly in consideration of their relative safety and pharmacokinetics. While newer formulations of narcotics have given some advance in pain control, the application of this group of drugs requires close supervision in the elderly, especially those with cognitive decline, since drug actions on the central and peripheral nervous systems (CNS, PNS) can result in significant adverse effects of these agents (e. g. constipation, drowsiness, respiratory and cardiovascular decline).Improvements in the safety and effectiveness of musculoskeletal pain therapy in the elderly can only be achieved by identification and frequent re evaluation of the cause of the chronic pain and the impact on the patient’s general medical state.

Gold induced thrombocytopenia: 12 cases and a review of the literature

Gold induced thrombocytopenia is immune mediated, with the production of platelet associated IgG leading to peripheral platelet destruction. An association with HLA-DR3 has been demonstrated. Corticosteroid therapy is effective in treatment, although other modes of therapy may be as efficacious.

Osteoarthritis of the knee and hip. Part I: aetiology and pathogenesis as a basis for pharmacotherapy

Objectives  Osteoarthritis (OA) of the knee and hip is among the most frequent and debilitating arthritic conditions. Aside from surgical intervention in severe cases, conventional treatment involves relieving painful symptoms with non‐steroidal anti‐inflammatory drugs (NSAIDs), narcotic and non‐narcotic (weak) analgesics and physical therapy. To obtain insight into the extent of pathological changes in hip and knee OA we reviewed current literature on the pathogenesis of this state as a basis for current pharmacotherapy options.

Efficacy and Toxicity of d‐Penicillamine for Rheumatoid Disease in the Elderly

The efficacy and the toxicity pattern of d‐penicillamine were studied in patients with rheumatoid disease followed up between April 1975 and March 1979. The population of patients was divided into an elderly group (≥60 years old, mean = 65 years) and a younger group (<60 years old, mean = 41 years). Patients with classic or definite rheumatoid disease not responsive to nonsteroidal drugs were eligible. The mean durations of disease prior to d‐penicillamine therapy were five years in the elderly and seven years in the younger group. Overall, the mean follow‐up time was 11 months. The average dosages of d‐penicillamine were 461 mg/day in the elderly and 520 mg/day in the younger patients. Results indicated that d‐penicillamine was efficacious in 75 per cent of the elderly during all time periods after three months, and in 75 per cent of the younger patients after three months until at least two years. Prior gold‐salt therapy did not influence efficacy. Toxicity was significantly greater in the elderly for overall skin rash (P < 0.01), severe skin rash (P < 0.01), and marked abnormalities in the ability to taste (P < 0.05). The incidence of hematologic toxicity was not increased in the elderly compared with the younger patients. Toxicity in either group was not influenced by prior gold‐salt therapy. It is concluded that d‐penicillamine was equally efficacious in both elderly and younger groups, and that the toxicity patterns were similar except for increased tendencies toward rashes and taste abnormalities in the elderly.

Osteoarthritis IV: Clinical therapeutic trials and treatment

This article discusses the potential usefulness of clinical therapeutic trials and criticises the failure of the value of guidelines in the management of osteoarthritis (OA). We have provided an overview of the benefits and side effects of non steroidal anti-inflammatory drugs (NSAIDs) in OA, including the introduction of the COX-2 selective inhibitors. In addition we have briefly reviewed the use of local NSAIDs, narcotic analgesics, injection methods, disease modifying drugs, gene therapy, surgical treatment, and non pharmacological intervention.