Pharmacological properties of the drug Meloxicam-ratiopharm
Meloxicam is an NSAID of the oxicam group with anti-inflammatory, analgesic and antipyretic properties that are associated with selective inhibition of the COX-2 isoenzyme. The selectivity coefficient IC50 for meloxicam is 2. Meloxicam is almost completely absorbed from the gastrointestinal tract. Absolute bioavailability after oral administration is about 89%. After a single oral dose, the maximum concentration in the blood plasma is reached after 5–6 hours. With repeated administration, an equilibrium state is achieved after 3–5 days from the start of use. When taken orally at a dose of 7.5 or 15 mg of meloxicam 1 time per day, the concentration in the blood plasma (Cmin–Cmax) at steady state reaches 0.4–1.0 mg/l (7.5 mg) or 0.8– 2.0 mg/l (15 mg), respectively. With long-term use, the concentration in the blood plasma at steady state does not change. Absorption does not change when taken simultaneously with food. The bioavailability of meloxicam after intramuscular administration is 89%. The maximum concentration in the blood is achieved 1 hour after administration. Meloxicam has a high degree of binding to blood proteins, mainly albumin (99%). Meloxicam enters the synovial fluid, the concentration in it is equal to the concentration in the blood plasma. The volume of distribution is on average 11 liters. Individual variations are approximately 30–40%. Meloxicam is metabolized by liver enzymes. Four different pharmacologically inactive metabolites of meloxicam have been identified in urine. The main metabolite, 5'-carboxymeloxicam (60%), is formed by oxidation of intermediate metabolites 5'-hydroxymethylmeloxicam. The amount of 5'-hydroxymethylmeloxicam released unchanged is 9%. In vitro , it was found that the initial stage of this transformation is carried out mainly through CYP 2C9 with minor participation of CYP 3A4. The formation of two other metabolites (16 and 4% of the dose taken, respectively) is associated with the action of peroxidase. Meloxicam is excreted mainly in the form of metabolites, in equal parts with urine and feces. Meloxicam is detected in urine in insignificant (trace) quantities. The average half-life is about 20 hours. The total plasma clearance averages 8 ml/min. When administered orally in therapeutic doses (7.5 and 15 mg), meloxicam exhibits linear pharmacokinetics.
Meloxicam tablets: main characteristics
Meloxicam is a non-steroidal drug that has anti-inflammatory and antipyretic effects. It helps in eliminating pain and works as an analgesic. Available in 3 forms:
- Pills.
- Solution (in glass ampoules).
- Suppositories.
The active ingredient is meloxicam, a derivative of enolic acid. Dispensed only with a doctor's prescription. The drug is stored at room temperature (no more than 25 degrees) within the general shelf life (no more than 2 years).
Use of the drug Meloxicam-ratiopharm
The solution for injection is administered only intramuscularly (iv administration is contraindicated). It is advisable to prescribe parenteral administration only during the first days of treatment. For further therapy, it is recommended to use tablets. Arthrosis in the acute phase: dose 7.5 mg/day. If the condition does not improve, you can increase to 15 mg/day. Rheumatoid arthritis, ankylosing spondylitis: dose 15 mg/day. Depending on the therapeutic effect, the dose can be reduced to 7.5 mg/day. The daily dose of meloxicam should not exceed 15 mg. Take the daily dose 1 time during meals with a glass of water or other liquid. Special groups of patients Elderly patients with an increased risk of side effects In elderly patients, the recommended dose for long-term therapy of rheumatoid arthritis or ankylosing spondylitis is 7.5 mg / day. In patients with an increased risk of side effects, therapy should be started with a dose of 7.5 mg/day. Impaired renal function In dialysis patients with severe renal impairment, the daily dose of meloxicam should not exceed 7.5 mg. In patients with mild or moderate renal impairment (creatinine clearance more than 25 ml/min), there is no need to reduce the dose. Impaired liver function In patients with mild or moderately severe liver dysfunction, there is no need to reduce the dose of the drug.
Meloxicam - a broad view of the problem of use
Table 1. Associations between acute renal failure and NSAID use
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of drugs that perhaps no doctor can do without. Diseases of the musculoskeletal system, inflammatory and traumatic lesions are the range of diseases in the treatment of which NSAIDs are used, because they have an analgesic and anti-inflammatory effect.
NSAIDs, according to international and national guidelines, are prescribed either as a first-choice analgesic or as a second-choice analgesic when paracetamol fails to provide sufficient pain relief for various musculoskeletal complaints such as back pain, shoulder pain, osteoarthritis [1–3].
The use of traditional non-selective NSAIDs is known to be associated with frequent adverse events from the gastrointestinal tract (GIT), primarily in its upper parts [4]. The need to reduce the number of such complications has led to the development of new classes of NSAIDs, mainly selective cyclooxygenase (COX)-2 inhibitors and specific (highly selective) COX-2 inhibitors [5].
According to the mechanism of action, all existing NSAIDs can be divided into four groups (and the division into “predominant” and “specific” COX-2 inhibitors is largely arbitrary) [6]:
selective COX-1 inhibitors (low doses of acetylsalicylic acid);
non-selective COX inhibitors (most “standard” NSAIDs);
predominantly selective COX-2 inhibitors (nimesulide, meloxicam);
specific (highly selective) COX-2 inhibitors (coxibs).
The last two groups of NSAIDs were developed in connection with the assumption that the anti-inflammatory, analgesic and antipyretic effects of NSAIDs are due to inhibition of COX-2, and the most common side effects are associated with inhibition of COX-1 activity. This became the basis for the synthesis of new NSAIDs - selective COX-2 inhibitors (nimesulide, meloxicam), and then even more selective, specific COX-2 inhibitors (coxibs).
The desire to achieve selectivity regarding COX-2 was dictated primarily by the desire to obtain drugs that are no less effective than “standard” NSAIDs, but less dangerous in terms of undesirable effects, primarily in terms of their effect on the gastrointestinal mucosa. The comparable therapeutic efficacy of COX-2 selective and traditional NSAIDs has been repeatedly confirmed in animal and clinical studies [7].
The selectivity of NSAIDs for COX inhibition is quite conditional and relative. This is because selective COX-2 inhibitors have a high degree of blockade of COX-2, while at the same time they slightly block COX-1. In addition, the selectivity of COX inhibition may be dose dependent and vary depending on the assay used to assess COX activity. For example, in the United States, etodolac and meloxicam are considered “conventional” (i.e., non-COX-2 specific) NSAIDs. In Canada and most European countries, meloxicam in particular is considered a COX-2 selective NSAID based on William Harvey's modified whole blood assessment methods [8].
Low back pain (LBP) is a very common clinical syndrome. It is estimated that approximately 84% of adults may experience at least one episode of LBP during their lifetime, and relapses occur in 5–60% of patients [9].
LBP is the most common condition for which patients seek medical help [10]. In the United States, back pain, which is associated with lost work time among employees aged 40 to 65 years, is estimated by employers at $7.4 billion per year [11], and, according to some estimates, $50 billion is spent annually on the treatment of LBP [ 12]. In Australia, direct medical costs associated with the treatment of LBP are estimated to be more than $1 billion per year, with an additional $8 billion in indirect costs [13]. Although the treatment prognosis for most patients with the first attack of LBP is positive, in 20% of cases it is possible to transform LBP into chronic LBP, which lasts 3 months or more [14]. Three-quarters of the total direct and indirect health care costs and lost productivity associated with LBP are attributable to chronic pain [15]. Therefore, it is important to effectively treat acute LBP to prevent it from developing into a chronic form.
A systemic analysis using the Cochrane database of the use of NSAIDs in LBP revealed the same effectiveness of various NSAIDs, including selective COX-2 inhibitors, but with the best tolerability of the latter [16], and therefore this group of drugs can be recommended to a patient with LBP - for example, the drug Liberum (meloxicam), which is available in the form for intramuscular injection 15 mg in an ampoule. The advantages of the drug include the fact that it is produced in accordance with GMP standards, as well as the optimal price/quality ratio. Liberum belongs to the class of oxicams (enolic acid derivative). The drug predominantly selectively inhibits the enzymatic activity of COX-2. Meloxicam is structurally different from other COX-2 inhibitors, such as coxibs, and binds to the top of the COX-2 channel, rather than to the side of this enzyme, like celecoxib [17]. Liberum does not have a damaging effect on the gastrointestinal tract, cardiovascular system, or kidneys.
For example, acute renal failure (ARF) may develop. A thorough analysis of the risk of developing acute renal failure in elderly patients was carried out in the USA [18]. According to the program for assessing the effectiveness and safety of drugs prescribed between 1999 and 2004. in persons over 65 years of age, the side effects of NSAIDs were assessed when taken for 6 months or more. Patients receiving two NSAIDs simultaneously were excluded from the study. Of 183,446 patients with a mean age of 78 years, AKI leading to hospitalization occurred in 870 patients. The most common NSAID prescribed to this group of patients was celecoxib, which was taken by every third patient. Table 1 shows the relative risk and 95% confidence interval of developing AKI when taking various NSAIDs in comparison with celecoxib.
A significant increase in the risk of developing acute renal failure by 50% and 100% was obtained for ibuprofen and indomethacin, respectively. The table shows that meloxicam has the lowest risk of developing acute renal failure among the selective and non-selective NSAIDs analyzed, i.e. Liberum has a better tolerability profile compared to non-selective NSAIDs (for example, diclofenac) due to the selective suppression of COX-2.
The pharmacokinetic features include the following: binding to plasma proteins is 99%. Passes through histohematic barriers and penetrates into the synovial fluid. Concentration in synovial fluid reaches 50% of Cmax in plasma. It is excreted equally in feces and urine, mainly in the form of metabolites. 1/2 of meloxicam is excreted unchanged through the intestines in 15–20 hours. Plasma clearance averages 8 ml/min.
In case of LBP, NSAIDs and B vitamins are often combined, since neurotropic vitamins enhance the analgesic effectiveness of NSAIDs and themselves have analgesic activity. Taking this into account, a combination of Vitaxon and Liberum can be proposed. Vitaxon contains thiamine hydrochloride 100 mg, pyridoxine hydrochloride 100 mg, cyanocobalamin 1 mg and lidocaine hydrochloride 20 mg, release form - 2 ml in an ampoule. By combining Liberum and Vitaxon, it is possible to reduce the duration of treatment, reduce the dosage of NSAIDs, and increase patient compliance. With such synergy, complex and safe effects of these two drugs, this combination can be recommended in the practice of both neurologists and therapists. Liberum is prescribed 1 ampoule IM 1 time per day, the course of treatment is usually 3–5 days, Vitaxon is prescribed in parallel 1 ampoule IM 1 time per day daily for 5–10 days, subsequently switching to more infrequent injections (2-3 times a week for 2-3 weeks).
It is interesting to note that the parenteral form of meloxicam for intramuscular administration has its own characteristics. Thus, due to the significant half-life of meloxicam, its concentration when taking the tablet form stabilizes in the patient’s blood only on the 3rd–4th day. Therefore, to quickly relieve severe or acute pain, it is necessary to use a parenteral form, which is also important in the treatment of acute LBP. Pharmacokinetic studies have shown that intramuscular use of meloxicam leads to faster absorption of the drug than its oral administration; maximum plasma concentration is achieved within 1.5 hours after IM administration compared to 5–7 hours after oral administration [19]. In this case, 90% of Cmax is achieved within 30–50 minutes after injection. This increase in absorption determines the faster onset of action of meloxicam administered intramuscularly compared to oral administration.
In order for IM administration to be considered as an alternative to the oral route of administration, very good local tolerability is required. However, many NSAIDs are poorly tolerated when administered intramuscularly, causing local tissue irritation and necrosis, often in combination with systemic adverse events [20]. Studies in animal models (rabbits) have shown that the local tolerability of meloxicam is better than that of other NSAIDs. After its intramuscular administration, no histopathological changes were detected, while when using piroxicam or diclofenac, a large area of necrosis developed. In addition, if we talk about the drug Liberum, it has a very convenient packaging - 5 ampoules per package, which is usually enough for acute pain syndrome to regress.
The effectiveness of meloxicam in the form for intramuscular administration and for oral administration at a dose of 15 mg was compared in 113 patients with acute sciatica. It was found that both dosage forms of the drug significantly reduced pain. The average time of onset of the analgesic effect did not differ significantly in patients receiving meloxicam intramuscularly or orally and was 80 and 89 minutes. In both treatment groups, the severity of spontaneous pain significantly decreased (compared to the initial level); no significant differences were found. But IM administration of meloxicam was superior to oral administration of the drug in terms of maximum reduction in induced pain, assessed when raising a straight leg (p
Another study examined the effectiveness of a single IV dose of meloxicam 15 mg and IM diclofenac 75 mg followed by 7 days of oral meloxicam 15 mg and diclofenac 100 mg, respectively, in 183 patients with acute lumbago. IV meloxicam demonstrated a significantly faster mean time to analgesic effect (30 min) compared with diclofenac (60 min). The reduction in pain within 30 minutes after injection was also statistically significantly higher in the meloxicam group (p=0.048). Overall efficacy scores in the meloxicam group were significantly better than in the diclofenac group, both as assessed by investigators (p=0.02) and by patients (p=0.01). In addition, in the meloxicam group, as assessed by investigators and patients, general and local tolerability was significantly higher (p
Osteoarthritis (OA) is a disease that is usually classified as degenerative joint disease, characterized by the development of synovitis and is an indication for the use of drugs that relieve the inflammatory process.
It has been shown that the effectiveness of meloxicam in the treatment of patients with OA is equal to the effectiveness of non-selective NSAIDs (diclofenac, piroxicam) [23], and tolerability is much better [24].
The drug has demonstrated equivalent effectiveness to that of non-selective NSAIDs in other rheumatological diseases: rheumatoid arthritis, ankylosing spondylitis [25].
A systematic review was conducted of the clinical effectiveness and cost-effectiveness of selective COX-2 inhibitor NSAIDs (etodolac, meloxicam, celecoxib, rofecoxib, valdecoxib and lumiracoxib) compared with non-selective NSAIDs in the treatment of OA and rheumatoid arthritis [26]. Results from 16 randomized controlled trials that compared meloxicam with placebo or non-selective NSAIDs (naproxen, diclofenac, nabumetone or piroxicam) indicate that there is a low risk of adverse effects with meloxicam at a daily dose of 7.5–22.5 mg. sides of the gastrointestinal tract.
Diabetic retinopathy (DR) is the most common cause of blindness in people over 50 years of age. There is a body of evidence suggesting that DR is an inflammatory disease. Animal models with DR show that at the onset of the disease, vascular permeability increases, leukostasis appears, resulting in the formation of vascular dysfunction and the death of the capillary endothelium. Therefore, a number of anti-inflammatory drugs, such as etanercept, aspirin or meloxicam, reduce the level of leukostasis and reduce the possibility of death of the endothelium of the retinal capillaries [27].
Thus, based on the results of randomized clinical trials and post-registration studies of meloxicam, it can be stated that the drug [28]:
clear analgesic and anti-inflammatory activity was revealed in chronic diseases of the joints and spine, as well as in acute pain syndromes (lumboischialgia);
high gastrointestinal tolerance has been confirmed;
large-scale pharmacoepidemiological studies confirm the low risk of severe side effects from the gastrointestinal tract, previously established in controlled clinical trials and in the process of meta-analysis;
no increase in the incidence of cardiovascular toxicity was noted.
Therefore, meloxicam, and in particular Liberum, can be recommended for widespread use in patients with various diseases that are accompanied by pain syndromes.
Contraindications to the use of the drug Meloxicam-ratiopharm
Hypersensitivity to meloxicam or other NSAIDs, including acetylsalicylic acid (contraindicated in patients who experience symptoms of asthma, nasal polyps, angioedema or urticaria after taking acetylsalicylic acid or other NSAIDs); During pregnancy and breastfeeding; gastrointestinal ulcers (both in history and in the acute phase); severe liver or kidney failure; gastrointestinal and cerebrovascular bleeding or bleeding of other localization; severe uncorrectable heart failure; age up to 15 years.
Side effects of the drug Meloxicam-ratiopharm
When assessing the frequency of side effects, the following statistics are used as a basis:
Often | ≥1/10 patients |
often | ≤1/10 but ≥1/100 patients |
Sometimes | ≤1/100 but ≥1/1000 patients |
rarely | ≤1/1000 but ≥1/10,000 patients |
very rarely | ≤1/10,000 patients |
From the peripheral blood: often - anemia; sometimes - changes in the blood picture - thrombocytopenia, leukopenia, agranulocytosis. From the immune system: rarely - allergic reactions. From the side of the central nervous system: often - loss of consciousness, headache; sometimes - dizziness, tinnitus; rarely - mood swings, drowsiness and nightmares, confusion. From the side of the organ of vision: rarely - impaired visual acuity. From the cardiovascular system: sometimes - tachycardia, increased blood pressure, skin flushing with a feeling of heat. From the respiratory system: rarely - patients with a history of allergic reactions to acetylsalicylic acid or other NSAIDs may experience asthma attacks. From the gastrointestinal tract: often - pain in the epigastric region, nausea and vomiting, gastralgia, flatulence, constipation or diarrhea; sometimes - gastrointestinal bleeding, gastric ulcer, esophagitis, stomatitis; rarely - gastrointestinal perforation, gastritis, colitis. In elderly patients, peptic ulcers, perforations, or gastrointestinal bleeding may be particularly severe. From the liver and biliary tract: sometimes - impaired liver function; rarely - hepatitis. From the skin: often - itching, skin rash; sometimes - urticaria; rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis/Lyell's syndrome, angioedema of the skin and/or mucous membrane, erythema multiforme, photosensitivity. From the urinary system: sometimes - renal dysfunction (increased concentrations of urea and creatinine in the blood serum); rarely - renal failure. General disorders: often - swelling.
Side effects
When using Meloxicam in different forms, the following side effects may be observed:
- allergies (itching, rash, blistering);
- anemia, leukopenia;
- headache, dizziness;
- high drowsiness;
- swelling;
- increased urea content;
- increased heart rate;
- rush of blood to the chest, neck and face;
- increase in pressure.
In rare cases, other side effects were observed: nephrotic syndrome, kidney necrosis, and tinnitus.
Special instructions for the use of Meloxicam-ratiopharm
Given the risks associated with the use of meloxicam, the duration of its use should be as short as possible, and the daily dose should be the minimum effective. Before starting treatment with meloxicam, it is necessary to undergo a course of treatment for esophagitis, gastritis, peptic ulcers of the stomach and duodenum (such patients may have a history of relapses during treatment with meloxicam). In patients with a history of gastrointestinal pathology, it is necessary to assess the condition of the digestive tract in order to detect gastrointestinal bleeding. As with the use of other NSAIDs, asymptomatic gastrointestinal bleeding or perforation, sometimes resulting in death, has been reported during treatment with meloxicam. In elderly people, gastrointestinal bleeding or gastrointestinal perforation is more severe. In such cases, treatment with meloxicam is discontinued. Severe life-threatening allergic reactions (such as anaphylactic reactions) may occur when using NSAIDs, including meloxicam. In this case, the use of meloxicam should be stopped immediately and appropriate treatment should be carried out. In isolated cases, NSAIDs can cause interstitial nephritis, glomerulonephritis, necrosis of the hepatic papillae, or nephrotic syndrome. A transient increase in liver function tests is noted. In most cases, these disorders are temporary. In case of persistent violation of these indicators, the use of meloxicam should be discontinued. By causing potassium, sodium and water retention, as well as interacting with diuretics, NSAIDs can worsen the condition of patients with heart failure or hypertension (arterial hypertension). The use of NSAIDs may cause decompensation of latent renal failure. Kidney function returns to normal after discontinuation of therapy. Use with caution in the elderly, with heart failure, liver cirrhosis or renal failure, as well as in patients using diuretics. When treating such patients, it is necessary to monitor diuresis and renal function. The effect of treatment should be regularly monitored, assessing the need for its continuation. Like other drugs that inhibit COX or prostaglandin synthesis, meloxicam may mask the symptoms of infectious diseases (such as fever). In some cases, the drug has a negative effect on reproductive function, so it is not recommended for women planning pregnancy. The tablets contain lactose, so the drug should not be prescribed to patients with hereditary lactose deficiency, galactosemia or glucose/galactose malabsorption syndrome. There is no data on the negative effect of meloxicam on the ability to drive vehicles or operate machinery. If there are disorders of the central nervous system (decreased visual acuity, increased fatigue, dizziness or other disorders), these types of activities are contraindicated.
Quick and complete pain relief is one of the top priorities of medical care. Pain is the most unpleasant manifestation of the main pathological conditions, so its effective suppression can significantly improve the quality of life of patients and gain their trust, which is important when it comes to the onset of a chronic disease that requires long-term pathogenetic therapy.
Pain therapy is of fundamental importance in musculoskeletal diseases, such as osteoarthritis (OA) and low back pain (LBP), which are currently associated with the majority of cases of chronic non-cancer pain [1-3].
From the point of view of medical science, chronic pain appears to be a serious and independent threat to the patient’s life. Persistent severe pain determines negative changes in homeostasis, mediated by the reaction of the sympathetic-adrenal system - increased blood pressure and heart rate, as well as pro-coagulative changes in the blood coagulation system. These changes lead to a significant increase in the risk of developing dangerous cardiovascular complications (CVD) [1, 2].
In such nosological forms as OA and chronic low back pain, which are not accompanied by visceral pathology, but are characterized by severe pain that often persists for months and years, the risk of developing fatal cardiovascular complications is significantly increased [1, 2].
This position is confirmed by a study by Swiss scientists E. Nüesch et al. [4], who assessed the incidence of deaths in 1163 patients with OA during a follow-up period of about 5 years. According to the data obtained, the risk of death due to cardiovascular disease in patients suffering from this “non-fatal” disease is 1.7 times higher than in the general population. In a subsequent analysis, scientists identified the only factor that was clearly associated with the development of fatal cardiovascular events in patients with OA—severe joint dysfunction that interferes with normal movement. Among those who died, such disorders were observed in 35%, while among survivors - only 17% ( p
<0,001) [4].
Similar results were presented by Japanese researchers M. Tsuboi et al. [5], who observed the dynamics of the condition in 944 patients with various rheumatic diseases for 10 years. It was revealed that in patients with gonarthrosis, the risk of death from cardiovascular complications is more than 2 times higher than in the population (odds ratio - OR - 2.32).
A striking illustration of the relationship between pain and the risk of developing cardiovascular complications was the work of Australian scientists K. Zhu et al. [6], who observed a group of 1484 elderly women (over 70 years old) suffering from chronic LBP for 5 years. Among them, 21.7% initially and 26.9% at the end of the observation period experienced pain every day. In this subgroup, the risk of death from cardiovascular complications was more than 2 times higher (relative risk - RR 2.13 with 95% confidence interval - CI - from 1.35 to 3.34) than in the group of patients in whom pain was noted less frequently .
One cannot fail to note one more, purely practical aspect of the problem of adequate pain relief. Patients come to see a doctor primarily for relief from suffering; “to understand” the situation, to find out an accurate diagnosis is a secondary, although undoubtedly important, goal of seeking medical help. Excessive focus on diagnostic measures and “basic” remedies to the detriment of simple and effective methods of pain control can cause a negative attitude of the patient towards the attending physician and turn him away from the methods of classical medicine. On the contrary, effective elimination of the most painful symptoms will be the most effective way to gain the patient’s trust and achieve strict compliance with a complex regimen of long-term pathogenetic therapy [1, 2].
However, achieving effective control of chronic pain is not easy. An illustration of this is the work of Spanish scientists L. Arboleya et al. [7], who assessed the opinion on the results of treatment of 897 patients with OA who received analgesics for at least 6 months, most often non-steroidal anti-inflammatory drugs (NSAIDs): diclofenac, aceclofenac and piroxicam. 46% of respondents were dissatisfied with the effect of the prescribed medications, and only 1 patient out of 6 considered themselves completely satisfied with the result of pain therapy.
In this regard, the data of British researchers M. Gore et al. are very interesting. [8], who assessed the practice of prescribing analgesics (paracetamol, NSAIDs, tramadol, “weak” and “strong” opioids) in patients with OA and LBP. For various reasons - due to ineffectiveness, adverse events, etc., during the 1st month of treatment, prescribed drugs were discontinued in almost 90% of patients (from 30 to 60% were cases of replacement of therapy, up to 15% - its intensification - the use of various combinations). It can be seen that in the majority of cases (at least ⅔), the analgesic drug initially recommended by the doctor did not live up to expectations and did not become a solution to the pain problem [8].
It should be remembered that the development of pain, especially chronic pain, is a complex, multicomponent pathological process. Local inflammation, muscle spasm, damage to elements of the ligamentous apparatus, biomechanical disorders, dysfunction of the pain system (peripheral and central sensitization, “exhaustion” of antinociceptive mechanisms, etc.) take part in its development [1, 2, 9, 10]. It is obvious that monotherapy, even with the most effective means, cannot always ensure therapeutic success. Only an integrated approach, based on the combined use of drugs with different mechanisms of action, can achieve effective control of chronic pain (Table 1)
.
First-line pharmacotherapy for musculoskeletal pain is undoubtedly NSAIDs. They have a unique combination of analgesic, anti-inflammatory and antipyretic effects, providing effective relief of the main symptoms associated with the pathology of the organs of the organs of the respiratory system [1-3].
The main mechanism of pharmacological action of NSAIDs is associated with the blockade of cyclooxygenase-2 (COX-2), which is formed in areas of tissue damage and is responsible for the active synthesis of prostaglandins (PGs), the most important mediators of pain and inflammation. It is important to note that the analgesic effect of NSAIDs is realized not only by reducing the excitability of peripheral pain receptors. Probably no less important is the influence of NSAIDs on the central mechanisms of pain formation - the phenomenon of central sensitization, which is also mediated by hyperproduction of PG (aseptic neuronal inflammation) and activation of glial cells that arise in response to persistent and powerful pain irritation of the structures of the nociceptive system [1-3 ].
Obviously, if inflammation plays an important role in the pathogenesis of acute or chronic pain (even subclinical, as in OA and dorsalgia), accompanied by active synthesis of biologically active substances such as interleukins 1 and 6, tumor necrosis factor, the use of NSAIDs will be appropriate and necessary. Moreover, in this situation, as data from many clinical studies show, in terms of their therapeutic activity, NSAIDs have a clear advantage over other analgesics - paracetamol and opioids, which do not have anti-inflammatory properties [1-3].
The therapist has an exceptional variety of NSAIDs at his disposal. This creates difficulties for practicing physicians, because even experts cannot always determine the criteria for the merits of drugs that should be used to decide on the choice of a particular NSAID. The situation is further complicated by the active advertising activities of some manufacturing companies, promoting their product as “the most effective and safe among all possible.” However, real practice clearly shows that none of the NSAIDs can be considered the best, and if a drug has an advantage in any parameter, most likely, it will also have certain disadvantages.
The analgesic effect of all NSAIDs when used in therapeutic doses is practically the same. At the very least, there is no indisputable data obtained in the course of a series of methodically correctly organized clinical trials that any drug from this group is significantly superior to others in analgesic action. The main difference between NSAIDs (sometimes very significant) is determined by their safety [3].
Among NSAIDs, there are two polar groups that differ in their selectivity for COX-2 (their main pharmacological “target”): non-selective (n-NSAIDs) and highly selective - “coxibs”. The selectivity of NSAIDs makes it possible to avoid suppression of the activity of the biochemical “brother” of COX-2 - the COX-1 enzyme, the work of which is extremely important for maintaining many vital functions, such as the protective properties of the mucous membrane (M) of the gastrointestinal tract (GIT). Blockade of COX-1 (inherent in n-NSAIDs) leads to a significant increase in the risk of developing severe, life-threatening gastrointestinal pathology (gastropathy and enteropathy associated with NSAID use - NSAID gastropathy and NSAID enteropathy. In this regard, “coxibs” are much less dangerous [3 ].
However, selective suppression of COX-2 (without affecting COX-1) can lead to an imbalance in the synthesis of thromboxane A2 and prostacyclin, which increases the risk of vascular thrombosis. In patients with cardiovascular diseases, this is fraught with an increased risk of developing severe cardiovascular events—myocardial infarction (MI) and ischemic stroke [3]. As you can see, the use of n-NSAIDs and “coxibs” has serious limitations: they are not suitable for all patients (Table 2)
.
Accordingly, two main scenarios can be presented in which the use of representatives of these drug groups is most appropriate.
Thus, “coxibs” are more suitable for relatively young patients who need short-term analgesic therapy and have a moderate risk of developing complications in the form of organic and functional disorders of the gastrointestinal tract in the absence of severe concomitant CV pathology.
n-NSAIDs (except for ketorolac, which is suitable only for short-term use) are more acceptable for patients in the older age group with a moderate risk of developing cardiovascular complications, but without significant risk factors for developing NSAID gastropathy. In most cases, these drugs can only be used in combination with a gastroprotector (proton pump inhibitor).
The position between n-NSAIDs and coxibs should be reserved for drugs with moderate selectivity for COX-2. Their use should lead to fewer significant complications in the form of organic and functional disorders of the gastrointestinal tract, but not be accompanied by a significant increase in the risk of developing cardiovascular complications. This is a kind of “golden mean” that is acceptable for most patients and is especially interesting now, when the medical community, after the bad memory of the “Coxib crisis,” is very wary of highly selective COX-2 inhibitors. At the same time, the problem of NSAID gastropathy, so characteristic of n-NSAIDs, will never lose its relevance.
In the mid-90s of the last century, diclofenac occupied this position. However, at present, this drug no longer meets the high requirements for safe pharmacotherapy. In our country, primarily due to the widespread use of cheap generic versions of this drug, diclofenac is associated with the largest number of complications in the form of organic and functional disorders of the gastrointestinal tract [11]. The situation with the MTR is even worse. Thus, according to a meta-analysis conducted by P. McGettigan and D. Henry [12], (30 case-control studies, including 184,946 patients with cardiovascular events and 21 cohort studies, a total of >2.7 million people), the risk of developing MI when using diclofenac increases by approximately 40% (OR 1.4). In a population-based study by Danish scientists E. Fosbøl et al. [13] taking diclofenac was accompanied by the highest risk among NSAIDs of developing myocardial infarction, stroke, and death from cardiovascular events, which was higher than that of coxibs.
Another representative of the “golden mean” is of much greater interest - the moderately selective COX-2 inhibitor meloxicam, which appeared in 1995. Since then, this effective and fairly safe drug remains one of the most popular representatives of the NSAID group, which is actively used in almost all countries peace.
Meloxicam has been thoroughly tested in a large number of clinical trials; its effectiveness has been studied in a wide range of diseases and pathological conditions, ranging from anesthesiological practice to chronic joint diseases. These works clearly confirmed that meloxicam is in no way inferior in its therapeutic potential to “traditional” NSAIDs for the most common diseases characterized by musculoskeletal pain (OA, LBP, rheumatoid arthritis - RA and ankylosing spondylitis - AS) [14-22].
However, the main advantage of meloxicam should be considered its good tolerability. A series of large randomized clinical trials (RCTs) clearly confirmed a significantly lower number of complications in the form of organic and functional gastrointestinal disorders when using this drug compared to n-NSAIDs.
During the 4-week MELISSA study ( n
=9323) meloxicam at a dose of 7.5 mg was compared with diclofenac at a dose of 100 mg/day.
The total number of side effects in the form of organic and functional gastrointestinal disorders when using meloxicam was significantly less - 13.3% versus 18.7% in the diclofenac group. At the same time, the number of episodes of discontinuation of therapy due to complications in patients receiving meloxicam was 2 times less: 3 and 6.1%, respectively ( p
<0.001). Dangerous complications - clinically pronounced ulcers, gastrointestinal bleeding (GIB) and perforation while taking meloxicam were also observed less frequently (but unreliably) - 5 and 7 cases, respectively [23].
According to a similar plan, the RCT SELECT ( n
=8656), however, piroxicam at a dose of 20 mg was used as a comparison.
This study showed a significant advantage of meloxicam in relation to the risk of developing severe complications in the form of organic and functional disorders of the gastrointestinal tract, which occurred in 7 and 16 patients, respectively ( p
<0.05).
As in the MELISSA RCT, dyspepsia and associated episodes of therapy withdrawal were significantly more common in patients receiving the comparator drug: 10.3 and 3.8% versus 15.4 and 5.3%, respectively ( p
<0.001) [24] .
In the work of D. Yocum et al. [25] 774 patients with OA received meloxicam at doses of 3.75, 7.5 and 15 mg, diclofenac 100 mg or placebo for 3 months. The results of the study showed that the total number of complications in the form of organic and functional disorders of the gastrointestinal tract while taking meloxicam was significantly less than when using diclofenac - 19 and 28%, respectively ( p
<0,05).
The safety of meloxicam has also been confirmed in a number of cohort studies, such as H. Zeidler et al. [26]. This study involved 2,155 German doctors who observed 13,307 rheumatology patients who received meloxicam at a dose of 7.5 mg (65%) or 15 mg (33%) for 1-3 months. The effectiveness and tolerability of the drug were assessed by analyzing the data provided by the attending physicians in the corresponding questionnaires. Although the majority of patients were over 60 years of age, and 12% had a history of ulcers, undesirable effects in the form of organic and functional disorders of the gastrointestinal tract were noted in 0.8%, and pronounced ones in only 5 patients (4 uncomplicated gastric ulcers and 1 perforation) [26 ].
Somewhat earlier, P. Schoenfeld et al. [27] conducted a meta-analysis of 12 RCTs lasting from 1 to 24 weeks, in which meloxicam was compared with diclofenac, piroxicam and naproxen in patients with OA, RA and dorsalgia. It was shown that taking meloxicam was associated with a significantly lower total number of complications in the form of organic and functional gastrointestinal disorders (OR 0.64 with 95% CI from 0.59 to 0.69), the incidence of dyspepsia (OR 0.73 with 95% CI from 0.64 to 0.84), symptomatic ulcers, gastrointestinal tract and perforations (OR 0.52 with 95% CI from 0.28 to 0.96), as well as the risk of discontinuation of therapy due to complications in the form of organic and functional disorders Gastrointestinal tract (OR 0.59 with 95% CI 0.52 to 0.67).
A more recent meta-analysis by G. Singh [25], which included data from 28 RCTs (24,196 patients), also confirms the greater safety of meloxicam at a dose of 7.5 mg compared to traditional NSAIDs in the gastrointestinal tract. Thus, the incidence of gastrointestinal tract when using this dose of meloxicam was only 0.03% (0.2% when taking 15 mg), while in those receiving diclofenac at a dose of 100-150 mg/day it was 0.15% [28].
In order to study the effect of meloxicam on the upper gastrointestinal tract, several years ago we conducted a retrospective analysis of the development of gastric and/or duodenal ulcers in rheumatological patients treated in 2002-2005. on inpatient treatment at the clinic of the Federal State Budgetary Institution NIIR RAMS. The study groups consisted of individuals who underwent esophagogastroduodenoscopy during this period for various reasons: 425 patients receiving meloxicam and 2428 receiving diclofenac (Fig. 1)
.
Figure 1. Detection of ulcers and multiple (>10) erosions of the stomach and/or duodenum in patients regularly receiving meloxicam or diclofenac [29].
In patients taking meloxicam, ulcers occurred almost 2 times less often, including in patients with such a risk factor as a history of ulcers [29]. In recent years, the problem of the negative effects of NSAIDs on the distal gastrointestinal tract has attracted much attention from researchers and practitioners. We are talking, first of all, about NSAID enteropathy - a pathology of the small intestine (SI), which is accompanied by an increase in its permeability and the development of chronic inflammation associated with the penetration of bacteria or their components contained in the chyme into the intestinal wall. This complication can manifest itself as severe gastrointestinal tract complications, perforation and strictures of the colon; however, its most characteristic symptom is subclinical blood loss, leading to the development of chronic iron deficiency anemia (IDA) [3, 30, 31]. Recently, interest in this pathology has been very great, since even in the absence of life-threatening complications, NSAID enteropathy can have a significant negative impact on the patient’s health. After all, chronic iron deficiency anemia determines a significant decrease in the oxygen capacity of the blood, a decrease in resistance to stress and, ultimately, an increase in the risk of developing severe cardiovascular complications.
This is confirmed by the work published in 2012 by G. Sands et al. [32]. The researchers conducted a meta-analysis of 51 RCTs that compared the safety of celecoxib and n-NSAIDs ( n
=50,116), in order to determine the relationship between a decrease in hemoglobin levels and the incidence of life-threatening systemic complications. It turned out that anemia sharply increased the risk of developing severe cardiovascular events. Thus, in 932 patients who developed a clinically significant decrease in hemoglobin levels (more than 20 g/l), the incidence of MI was 0.6%, while in patients who had no signs of anemia it was only 0.2%. Similarly, progression of coronary heart disease (CHD) was noted in 1.2 and 0.3% of patients [32].
NSAID enteropathy is a problem characteristic of “traditional” NSAIDs. There is strong evidence that s-NSAIDs (“coxibs”) are significantly safer than “traditional” NSAIDs with regard to the risk of developing this pathology [3].
The most modern technique that allows you to accurately diagnose the pathology of the jejunum and ileum that occurs while taking NSAIDs is video capsule endoscopy (VCE). It was this method that was used in a number of studies that compared the effects of “coxibs” and n-NSAIDs on the state of MC [3, 33].
In recent years, the first reports of a relatively low incidence of NSAID enteropathy with the use of meloxicam, confirmed by VCE data, have appeared. Thus, we recently carried out work to study the effect of meloxicam (Movalis) and diclofenac on the state of TC in 15 patients with AS. The choice of this nosological form to study the development of NSAID enteropathy was not accidental. Patients with AS have an increased risk of developing TC pathology; there is a known association between chronic inflammatory bowel diseases and seronegative spondylitis. In addition, patients with AS often take NSAIDs, often for a long time and in high doses [34].
According to the results obtained, certain changes in the TC CO - the presence of inflammation, hemorrhages, erosions or ulcers - were detected equally often when taking meloxicam 15 mg/day or diclofenac 100-200 mg/day: 71.4 and 75%, respectively. However, the average number of erosions was not significantly lower in those receiving Movalis: 6.2±4.7 and 9.4±7.3, respectively [34].
Our data are consistent with the data of Y. Maehata et al. [35]. They performed VCE in 29 volunteers with initially normal TC status who received meloxicam 10 mg/day or celecoxib 200 mg/day for 2 weeks. The number of people in whom TC pathology was identified after a course of NSAIDs was less when using meloxicam than when taking coxib - 26.7 and 42.9%, respectively.
It can be stated that in relation to cardiovascular complications, meloxicam is at least no worse than “traditional” NSAIDs. Thus, in a series of RCTs conducted in the late 90s of the 20th century, it was shown that the risk of developing severe cardiovascular events when using meloxicam does not exceed that when using placebo.
According to the results of the meta-analysis of 28 RCTs conducted by G. Singh [28], the incidence of MI with meloxicam was lower than with diclofenac: 0.09% for a dose of 7.5 mg/day, 0.19% for 15 mg /day and 0.22% for diclofenac 100-150 mg/day.
It should be noted that according to the results of the work presented above by P. McGettigan and D. Henry [12], meloxicam has a weak (not exceeding the average level for all NSAIDs), inherent in the entire class of NSAIDs, ability to increase the risk of developing myocardial infarction by approximately 20% ( OS 1.2). According to these data, meloxicam is inferior to naproxen, but is at the level of celecoxib and ibuprofen and superior to diclofenac (OR 1.4, i.e., a 40% increased risk).
Comparable results were presented by Finnish scientists A. Helin-Salmivaara et al. [36]. They conducted a large population-based study in which the RR of CV events associated with NSAIDs was assessed in 33,309 patients with MI (138,949 matched controls; Fig. 2
).
Figure 2. Risk of developing MI while taking various NSAIDs (data from a population-based study conducted in Finland: 33,309 patients with MI, 138,949 controls) [36].
The risk level for those taking meloxicam was at an average level - OR 1.25. This is slightly more than among those taking naproxen (OR 1.19), but clearly less compared with diclofenac (OR 1.35) and especially nimesulide (OR 1.69). There is a very interesting fact: meloxicam was once studied as a component of the treatment of coronary artery disease (!). In the NUT-2 study, 60 patients with acute coronary syndrome who received aspirin and heparin as antithrombotic therapy for 1 month were additionally prescribed meloxicam 15 mg/day. Another 60 patients undergoing similar antithrombotic therapy formed a control group and were assigned a placebo. Treatment results in the meloxicam group were clearly better. Thus, among the patients receiving this drug, no one developed an MI and not a single patient died; at the same time, in the control group there were 2 cases of MI and one coronary death. In group 1, revascularization was required in 6 (10%) patients, and in group 2 - 15 (25%; p
<0,05) [37].
Nowadays, such research seems rather like medical casuistry; however, it may serve as a good illustration of the favorable tolerability of meloxicam in patients with risk factors for developing cardiovascular disease.
Meloxicam has another important advantage: unlike “traditional” NSAIDs, it does not interact adversely with low doses of aspirin and does not reduce the antiplatelet potential of the latter. This was confirmed by an epidemiological study by G. Singh et al. [38], based on an analysis of the California database of patients who had suffered a myocardial infarction ( n
=15,343). Patients receiving meloxicam in combination with aspirin had a significantly lower risk of MI than those receiving the drug without aspirin: OR 0.53 and 1.56, respectively. At the same time, the popular analgesic ibuprofen clearly worsened the effect of aspirin. In patients receiving these drugs together, the risk of developing MI was even slightly higher than in those taking ibuprofen alone: OR 1.2 and 1.08, respectively [38].
When discussing the benefits of meloxicam, you should pay attention to the low risk of allergic skin reactions. Although these complications are rare with the use of NSAIDs, they can nevertheless be a serious problem in some cases. Meloxicam is quite safe in this regard. Thus, according to American authors, during the first 2 years of use of this drug in the United States, not a single episode of Stevens-Johnson syndrome or toxic epidermal necrolysis was recorded (for example, 47 episodes while taking celecoxib) [39]. The low incidence of skin reactions when using meloxicam was also noted by K. Ward et al. [40], who published a methodological review in 2010.
Moreover, there are a number of studies showing the possibility of using meloxicam in patients who previously experienced skin allergic or bronchospastic reactions when using aspirin or other “traditional” NSAIDs [41, 42].
Severe hepatotoxic reactions are also rare side effects of NSAIDs. Nevertheless, assessing the risk of developing complications in the form of liver dysfunction is relevant for a number of representatives of this drug group, such as diclofenac and nimesulide [3]. For example, among 17,289 participants in the 18-month RCT MEDAL (comparing etoricoxib with diclofenac) who received diclofenac, a three-fold increase in alanine aminotransferase activity was observed in 3.1%, and a ten-fold increase in 0.5% [43]. Although not a single episode of the development of liver failure or jaundice was recorded, such an obvious negative dynamics of biochemical parameters is cause for concern and is the reason for interruption of therapy.
These problems, fortunately, are not typical for meloxicam.
In the available literature, during treatment with this drug, only isolated cases of asymptomatic cases are described, but no significant increase in transaminase levels or clinically significant liver dysfunction was noted [44, 45].
The comparative hepatotoxicity of various NSAIDs was studied in the work of Italian authors G. Traversa et al. [46]. They compared the incidence of liver dysfunction in 397,537 patients treated with NSAIDs in 1997-2001. According to the data obtained, meloxicam demonstrated the best tolerability. The incidence of hepatotoxic reactions with its use was 23.6 episodes per 100,000 person-years. The similar rate for nimesulide, diclofenac and ibuprofen was significant - 35.2, 39.2 and 44 episodes per 100,000 person-years [46].
Concluding the review, it should be noted that the benefits of any drug are determined not only by successful pharmacological properties and favorable results of clinical trials. For practicing doctors, the “reputation” of a drug is of great importance, which is acquired over years of its successful use in real clinical practice.
Meloxicam is a representative of NSAIDs, whose good “reputation” is beyond doubt. This drug is well known to doctors all over the world; they trust its effectiveness and good tolerability and actively use it in their work. It should be noted that the good “reputation” of meloxicam is due to a specific original drug, known abroad as Mobic, and in Russia as Movalis. It was he who was tested in numerous clinical trials, ultimately proving its therapeutic potential and favorable tolerability profile. The presence of similar benefits in numerous generic meloxicam products still requires significant evidence.
The position of meloxicam (Movalis) among other NSAIDs seems to be the most successful. Of course, this drug cannot be considered completely safe, like any other representative of this drug group. However, it is well tolerated and has a relatively low risk of developing serious complications, such as dysfunction of both the gastrointestinal tract and the cardiovascular system; it is quite effective and easy to use. In general, meloxicam today is a first-line drug for many patients suffering from acute and chronic diseases of the joints and spine.
Drug interactions Meloxicam-ratiopharm
Pharmacodynamics: Concomitant use of several NSAIDs (including salicylates) may increase the risk of developing erosive and ulcerative lesions of the gastrointestinal tract due to a synergistic effect, therefore the use of meloxicam with other NSAIDs is not recommended. When using meloxicam with diuretics, the patient must drink sufficient fluids, and regular medical monitoring of renal function is required before and during treatment. Oral anticoagulants: combined use increases the risk of bleeding due to inhibition of platelet function and damage to the mucous membrane of the stomach and intestines. Therefore, combined use with NSAIDs and oral anticoagulants is not recommended. Thrombolytic and antithrombotic drugs: when used in combination with meloxicam, an increased risk of bleeding is possible (periodic monitoring of blood coagulation parameters is necessary). ACE inhibitors and other antihypertensive drugs: simultaneous use in elderly patients with symptoms of dehydration may provoke the development of acute renal failure. In addition, combined use with meloxicam may reduce their hypotensive effect. Cyclosporine: the nephrotoxic effect of cyclosporine is enhanced. Contraception: The effectiveness of birth control may be reduced. Pharmacokinetic Lithium: NSAIDs may increase serum lithium concentrations to toxic levels (decreased renal excretion of lithium). Therefore, the simultaneous use of NSAIDs with lithium preparations is not recommended. If their combined use is necessary, the level of lithium in the blood serum should be carefully monitored before, during and after the end of the course of therapy with meloxicam and lithium preparations. Methotrexate: increases the negative effect on the blood system (threat of anemia and leukopenia). Periodic monitoring of the hemogram is necessary. Cholestyramine accelerates the elimination of meloxicam, increasing the clearance of meloxicam by 50%, reducing its half-life by 13±3 hours. This interaction is of clinical significance. When taken simultaneously with antacids, cimetidine and digoxin, no significant clinical interaction is observed. NSAIDs reduce the effectiveness of contraceptive intrauterine devices.
Meloxicam-ratiopharm overdose, symptoms and treatment
Symptoms of acute NSAID overdose are often accompanied by drowsiness, nausea, vomiting and gastralgia, which usually resolve with symptomatic therapy. Gastrointestinal bleeding may also occur. Severe poisoning can lead to increased blood pressure, acute renal failure, liver dysfunction, respiratory depression, coma, convulsions, collapse and cardiac arrest. Anaphylactoid reactions have been reported during therapeutic doses of NSAIDs in cases of overdose. After an overdose of NSAIDs, patients are given supportive and symptomatic therapy in accordance with the severity of the overdose and intoxication. Clinical studies have found that three doses of 4 g of cholestyramine orally accelerates the elimination of meloxicam.
Overdose and interaction with other drugs
If the dosage is violated, the side effects described above are observed. In this case, gastric lavage is indicated. An antidote and antagonist for Meloxicam has not been developed.
If taken together with myelotoxic medications, this may lead to increased hematotoxicity. It is not advisable to take it together with non-steroidal anti-inflammatory drugs - this can lead to ulcerative lesions and bleeding in the digestive organs.
When taken together with anticoagulants and blood pressure lowering agents, the risk of bleeding increases. When taken together with Cyclosporine, toxic effects on the kidneys are possible.