Fast-acting drugs for the treatment of osteoarthritis

Non-narcotic analgesics (for example, paracetamol) are more often used in the washout period when testing NSAIDs. However, the results of comparative studies conducted in the 80-90s of the last century indicate that paracetamol can be an alternative to other NSAIDs, the analgesic and anti-inflammatory effect of which is indisputable, as a symptomatic therapy for osteoarthritis in patients with mild to moderate pain syndrome.

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Paracetamol

The mechanism of action of paracetamol is associated with a decrease in the activity of oxidized forms of cyclooxygenase (COX)-1 and -2 in the central nervous system and spinal cord.

The main clinical symptom of osteoarthrosis - pain - weakly correlates with histological changes in the synovial membrane and articular cartilage. In addition, pain in osteoarthrosis can be caused not only by synovitis, but also by stretching of the joint capsule, ligaments, and nerve endings in the periosteum above the OF, microfractures of trabeculae, intraosseous hypertension, and muscle spasm. Based on the above, it can be concluded that in osteoarthrosis there is not always a need for the anti-inflammatory effect of a symptomatic agent.

The results of comparative studies of the efficacy and tolerability of NSAIDs in patients with osteoarthrosis in the overwhelming majority of cases demonstrate moderate positive dynamics of the joint syndrome. For example, according to VCH Tyson and A. Glynne (1980), before treatment with ibuprofen or benoxaprofen, patients noted perceived pain on 100 mm VAS at an average level of 55 mm, and after 4 weeks of treatment - at a level of 34 mm, i.e. the dynamics was only 21%. Other studies noted that against the background of NSAID treatment, the dynamics of joint syndrome indicators fluctuated between 10-20% and the same difference (i.e. 10-20%) was recorded between the results in the main group and in the placebo group. Typically, patients with osteoarthritis on 100 mm VAS note the initial pain value at the level of 40-60 mm, which decreases to 25-45 mm against the background of a course of NSAID therapy. Therefore, it is not surprising that "simple" analgesics are no less effective than NSAIDs in many patients.

Treatment of patients with osteoarthritis of the knee joint of varying severity with paracetamol was effective in 30% of them, including patients who took NSAIDs before the study.

JD Bradley et al (1991) compared the efficacy of paracetamol and ibuprofen in a double-blind, placebo-controlled study in patients with overt gonarthrosis with moderate joint changes on radiographs. The authors found that the efficacy of the "anti-inflammatory" dose of ibuprofen (2400 mg/day) did not differ from the "pain-relieving" dose of ibuprofen (1200 mg/day), as well as paracetamol at a dose of 4000 mg/day. In addition, in patients with clinical signs of synovitis (swelling, effusion), the dynamics of the studied parameters under the influence of the "anti-inflammatory" dose of ibuprofen did not differ from that during treatment with paracetamol. Similar results were obtained by J. Stamp et al (1989), who compared the efficacy and tolerability of paracetamol and flurbiprofen in patients with osteoarthritis.

JH Williams et al (1993) conducted a two-year, double-blind, placebo-controlled comparative study of the efficacy of paracetamol 0.65 g 4 times daily and naproxen 375 mg 2 times daily. Of 178 randomized patients, only 62 completed the study, with the number of dropouts in the paracetamol group being slightly higher than in the naproxen group. The high percentage of withdrawals of informed consent for participation in the study is probably due to suboptimal doses of both drugs. Paracetamol and naproxen did not differ in efficacy and tolerability.

A comparative study of the efficacy of paracetamol 3 g/day and a combination of paracetamol 3 g/day and codeine 180 mg/day was terminated despite a more pronounced analgesic effect. The reason for the early termination of the study was the high frequency of side effects in patients taking paracetamol/codeine.

According to P. Seidemann et al. (1993), the analgesic effect was more pronounced when naproxen at a dose of 0.5 or 1 g/day was added to paracetamol (4 g/day), and this combination was not inferior in effectiveness to monotherapy with naproxen at a dose of 1.5 g/day. Although these data require confirmation, they indicate the advisability of combining paracetamol at a therapeutic dose with naproxen at a low dose.

According to KD Brandt (2000), in 40-50% of patients with osteoarthritis, effective control of joint pain can be achieved with paracetamol, but it is not possible to predict the analgesic effect of simple analgesics in a particular patient.

The main advantage of paracetamol compared with other NSAIDs is its lower toxicity to the gastrointestinal tract. However, drug overdose (above 10 g/day) is associated with hepatotoxicity. A population study conducted in Sweden found that the incidence of hospitalizations associated with paracetamol hepatotoxicity was 2 cases per 100,000 population per year. In patients with liver disease, hepatotoxicity is observed when taking paracetamol in normal therapeutic doses (up to 4 g/day). The results of clinical observations indicate that in patients with chronic alcoholism, hepatotoxicity occurs during treatment with paracetamol at a dose of < 10 g/day. To avoid side effects, paracetamol should be prescribed in the minimum dose that allows achieving a therapeutic effect, and it should not be recommended to people with alcoholism.

Paracetamol does not inhibit prostaglandin synthesis in the renal epithelium, but an experiment demonstrated its tropism for the renal papillae with excessive accumulation of its metabolites in the papillary tissue, which is associated with the development of papillary necrosis characteristic of paracetamol. Literature data indicate the development of side effects from the kidneys with an overdose of paracetamol. TG Murray et al. (1983) did not find a connection between chronic renal failure (CRF) and the use of analgesics. TV Perneger et al. (1994) reported the results of a study of the risk of developing chronic renal failure when taking over-the-counter painkillers. According to their data, a cumulative dose of paracetamol over 1000 tablets doubles the risk of developing chronic renal failure. At the same time, the authors of the study claim that these results indicate the absence of a connection between the use of acetylsalicylic acid and the development of chronic renal failure. The data of T. V. Perneger and co-authors are questionable and require confirmation. The National Kidney Foundation recommends paracetamol as a painkiller of choice in patients with impaired renal function.

At the same time, the results of the study by CM Fored et al. (2001) of the Swedish Population Register for 1996-1998 showed that regular use of paracetamol, acetylsalicylic acid, or both drugs increases the risk of developing chronic renal failure. The authors emphasize that previous kidney disease or systemic pathology are predisposing factors. A total of 926 patients with a newly diagnosed renal failure and 998 control group individuals were examined, of whom 918 and 980, respectively, had the necessary documentation. Among patients with renal failure, 37% and 25%, respectively, regularly took acetylsalicylic acid and paracetamol, while in the control group, the figures were 19% and 12%. The relative risk of developing renal failure increased with increasing duration of use and increasing dose of drugs, which was more constant in those taking paracetamol than acetylsalicylic acid, but the authors could not exclude the role of predisposing factors.

Paracetamol does not affect platelet function and can therefore be recommended as the drug of choice for patients with osteoarthritis taking anticoagulants.

Paracetamol can prolong the half-life of warfarin, mainly in patients taking the latter at a dose higher than 10 mg/day. Therefore, in patients taking warfarin with paracetamol, it is necessary to carefully monitor the prothrombin time.

Narcotic analgesics are not recommended for patients with osteoarthritis. Due to the high risk of side effects (nausea, vomiting, constipation, urinary retention, confusion, drowsiness, mental and physical dependence, etc.), opium derivatives are used for osteoarthritis only in special clinical situations.

Tramadol

Tramadol is a relatively new analgesic, a synthetic opioid drug, which has two mechanisms of action:

• interacts with c-opioid receptors,
• inhibits the uptake of norepinephrine and serotonin.

As a painkiller, tramadol 100 mg is more effective than codeine 60 mg and is comparable to combinations of codeine with acetylsalicylic acid or paracetamol. In a two-week comparative study of tramadol (300 mg/day) and dextropropoxyphene (300 mg/day) in 264 patients with osteoarthritis, a decrease in the severity of pain in the affected joints was noted in 70% of patients treated with tramadol and in 50% with dextropropoxyphene. However, the former caused more side effects (mainly nausea/vomiting, dizziness). According to a double-blind, randomized comparative study of the efficacy of tramadol (300 mg/day) and diclofenac (150 mg/day) in 60 patients with osteoarthritis, at the end of the 1st and 4th weeks of treatment, the reduction in pain in the affected joints was the same in both groups; this study also reported a greater number of side effects with tramadol treatment (23 cases) compared with diclofenac (2 cases). SF Roth (1995) published the results of a placebo-controlled study of tramadol in 50 patients with osteoarthritis who still had pain despite NSAIDs. Tramadol treatment was more effective than placebo, but was accompanied by a greater number of side effects, mainly nausea, constipation, and drowsiness.

When tramadol is prescribed in recommended doses, severe side effects (respiratory depression) have not been recorded. To reduce the risk of dyspepsia, it is advisable to titrate the tramadol dose to the target over 4-5 days, starting with 50 mg/day. D. Choquette et al. (1999) recommend prescribing tramadol to patients with osteoarthritis only in the case of ineffectiveness or intolerance to NSAIDs and paracetamol.

Codeine and dextropropoxyphene

Codeine and dextropropoxyphene are synthetic opioids that are often used in the treatment of osteoarthritis in combination with NSAIDs and/or paracetamol, despite their potential to cause addiction. In a comparative study, a combination of paracetamol at a dose of 2 g/day and dextropropoxyphene at a dose of 180 mg/day in patients with osteoarthritis was more effective than paracetamol (3 g/day) and codeine (180 mg/day). Another study found that dextropropoxyphene and paracetamol were better tolerated by patients than dihydrocodeine. However, according to RI Shorr et al. (1992), the risk of femoral fractures in elderly patients receiving codeine or dextropropoxyphene was 1.6 (95% confidence intervals (CI) = 1.4-1.9), and the combination of codeine or dextropropoxyphene with psychotropic drugs (sedatives, antidepressants, etc.) increased the risk of fractures to 2.6 (95% CI = 2.0-3.4).

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