What are the side effects of Meloxicam. How does Meloxicam affect blood pressure. What is the recommended dosage for Meloxicam. What are the primary uses of Meloxicam. How does Meloxicam interact with other medications.

Understanding Meloxicam: An Overview of the Medication

Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammation caused by various arthritic conditions. It’s available as a generic medication and under the brand name Mobic. Meloxicam comes in three forms: oral tablets, injections, and oral capsules.

How does Meloxicam work? This medication belongs to the NSAID class, which helps reduce pain, inflammation, and fever. While its exact mechanism of action isn’t fully understood, it’s believed to decrease swelling by lowering levels of prostaglandin, a hormone-like substance that typically causes inflammation.

Primary Uses of Meloxicam

• Osteoarthritis
• Rheumatoid arthritis
• Juvenile idiopathic arthritis (JIA) in children ages 2 years and older

Meloxicam and Its Impact on Blood Pressure

One of the significant concerns associated with Meloxicam use is its potential impact on blood pressure. Can Meloxicam cause high blood pressure? Yes, increased blood pressure is a known side effect of this medication.

Symptoms of extreme high blood pressure can include:

• Dull headaches
• Dizzy spells
• Nosebleeds

Is Meloxicam safe for individuals with hypertension? Patients with existing high blood pressure should consult their healthcare provider before starting Meloxicam. Regular blood pressure monitoring may be necessary during treatment.

Common Side Effects of Meloxicam

While Meloxicam can be effective in treating arthritic pain and inflammation, it may cause various side effects. What are the most common side effects of Meloxicam?

• Abdominal pain
• Diarrhea
• Indigestion or heartburn
• Nausea
• Dizziness
• Headache
• Itching or rash

These side effects are generally mild and may subside within a few days or weeks. However, if they persist or worsen, it’s crucial to consult a healthcare provider.

Serious Side Effects and Risks Associated with Meloxicam

While less common, Meloxicam can potentially cause serious side effects that require immediate medical attention. What are the severe side effects of Meloxicam?

• Heart attack
• Stroke
• Gastrointestinal problems (bleeding, ulcers, or tearing)
• Liver damage
• Kidney damage
• Skin problems (blistering, peeling, or red skin rash)
• Anemia

Patients should be aware of the symptoms associated with these serious side effects and seek immediate medical help if they occur.

Meloxicam Dosage and Administration

The appropriate dosage of Meloxicam varies depending on the condition being treated and the patient’s age. What is the typical dosage for Meloxicam?

• For osteoarthritis: 7.5 mg once daily, which may be increased to 15 mg if necessary
• For rheumatoid arthritis: 7.5 mg once daily, which may be increased to 15 mg if necessary
• For juvenile rheumatoid arthritis (in children 2 years and older): 0.125 mg/kg once daily, up to a maximum of 7.5 mg per day

It’s essential to follow the prescribed dosage and not exceed the recommended amount without consulting a healthcare provider.

Drug Interactions with Meloxicam

Meloxicam can interact with various medications, potentially altering their effectiveness or increasing the risk of side effects. Which medications interact with Meloxicam?

• Antidepressants and anxiety drugs (e.g., SSRIs, SNRIs)
• Blood thinners (e.g., warfarin)
• Other NSAIDs (e.g., aspirin, ibuprofen)
• ACE inhibitors and ARBs (blood pressure medications)
• Diuretics
• Lithium
• Methotrexate

Patients should inform their healthcare provider about all medications, supplements, and herbal products they are taking before starting Meloxicam.

Precautions and Considerations When Taking Meloxicam

Certain individuals may need to exercise caution or avoid using Meloxicam altogether. Who should be cautious about taking Meloxicam?

• Patients with a history of heart disease or stroke
• Individuals with gastrointestinal problems
• People with liver or kidney disease
• Pregnant women, especially in the third trimester
• Breastfeeding mothers
• Individuals with a history of asthma or allergic reactions to aspirin or other NSAIDs

It’s crucial to discuss any existing health conditions or concerns with a healthcare provider before starting Meloxicam treatment.

Monitoring and Managing Meloxicam Treatment

Regular monitoring is essential when taking Meloxicam to ensure its effectiveness and minimize potential risks. How should patients be monitored while on Meloxicam?

• Regular blood pressure checks
• Periodic liver and kidney function tests
• Monitoring for signs of gastrointestinal bleeding
• Assessment of cardiovascular risk factors

Patients should report any unusual symptoms or side effects to their healthcare provider promptly. Additionally, it’s important to attend all scheduled follow-up appointments to ensure proper management of the treatment.

Lifestyle Modifications to Support Meloxicam Treatment

While taking Meloxicam, certain lifestyle changes may help maximize its benefits and minimize potential risks. What lifestyle modifications can support Meloxicam treatment?

• Maintaining a healthy diet rich in fruits, vegetables, and whole grains
• Staying well-hydrated to support kidney function
• Engaging in regular, low-impact exercise as recommended by a healthcare provider
• Managing stress through relaxation techniques or mindfulness practices
• Avoiding or limiting alcohol consumption
• Quitting smoking, if applicable

These lifestyle changes, combined with proper medication use, can contribute to better overall health outcomes and potentially reduce the risk of side effects associated with Meloxicam.

Alternatives to Meloxicam for Pain Management

While Meloxicam can be effective for many patients, some individuals may need to explore alternative options due to side effects or contraindications. What are some alternatives to Meloxicam for pain management?

• Other NSAIDs (e.g., ibuprofen, naproxen)
• Acetaminophen
• Topical pain relievers
• Physical therapy
• Acupuncture
• Cognitive-behavioral therapy for pain management
• Disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis

The choice of alternative treatment depends on the individual’s specific condition, overall health, and personal preferences. A healthcare provider can help determine the most appropriate alternative if Meloxicam is not suitable.

Comparing Meloxicam to Other NSAIDs

How does Meloxicam compare to other NSAIDs in terms of effectiveness and side effects? Meloxicam is often considered to have a lower risk of gastrointestinal side effects compared to some other NSAIDs, such as ibuprofen or naproxen. However, it may carry a higher risk of cardiovascular side effects.

The choice between Meloxicam and other NSAIDs often depends on individual factors such as:

• The specific condition being treated
• The patient’s medical history and risk factors
• Potential drug interactions with other medications
• The patient’s response to previous NSAID treatments

A healthcare provider can help determine which NSAID is most appropriate based on these factors.

Long-term Use of Meloxicam: Benefits and Risks

For some patients, long-term use of Meloxicam may be necessary to manage chronic conditions such as osteoarthritis or rheumatoid arthritis. What are the potential benefits and risks of long-term Meloxicam use?

Benefits of Long-term Meloxicam Use

• Consistent pain relief
• Improved joint function and mobility
• Enhanced quality of life for those with chronic arthritis
• Potentially slowed progression of joint damage in some forms of arthritis

Risks of Long-term Meloxicam Use

• Increased risk of cardiovascular events
• Potential for gastrointestinal complications
• Possible kidney function impairment
• Risk of liver damage
• Potential for developing tolerance, requiring higher doses over time

Patients on long-term Meloxicam therapy should be closely monitored by their healthcare provider. Regular check-ups and periodic assessments of the medication’s benefits versus risks are essential to ensure safe and effective long-term use.

Special Considerations for Meloxicam Use in Different Populations

The use of Meloxicam may require special considerations in certain populations. How should Meloxicam be used in different patient groups?

Elderly Patients

Older adults may be at higher risk for side effects, particularly gastrointestinal bleeding and kidney problems. Lower starting doses and close monitoring are often recommended for this population.

Children and Adolescents

Meloxicam is approved for use in children 2 years and older with juvenile idiopathic arthritis. Dosing is based on weight, and close monitoring for side effects is crucial.

Pregnant Women

Meloxicam should be avoided during pregnancy, especially in the third trimester, due to potential risks to the fetus. Alternative pain management strategies should be discussed with a healthcare provider.

Patients with Cardiovascular Risk Factors

Individuals with a history of heart disease, high blood pressure, or stroke may need to avoid Meloxicam or use it with extreme caution under close medical supervision.

Patients with Gastrointestinal Risk Factors

Those with a history of ulcers, gastrointestinal bleeding, or inflammatory bowel disease may need to avoid Meloxicam or use it in conjunction with stomach-protecting medications.

In all cases, the decision to use Meloxicam should be made on an individual basis, weighing the potential benefits against the risks for each patient.

Side effects, dosage, uses, and more

1. Meloxicam oral tablet is available as both a generic and brand-name drug. Brand name: Mobic.
2. Meloxicam comes in three forms: an oral tablet, an injection, and an oral capsule.
3. Meloxicam oral tablets are nonsteroidal anti-inflammatory drugs (NSAIDs). They’re used to treat pain and inflammation caused by osteoarthritis, rheumatoid arthritis, and juvenile rheumatoid arthritis.

Meloxicam is a prescription drug. It comes in three forms: an oral tablet, an injection, and an oral capsule.

Meloxicam oral tablet is available as the brand-name drug Mobic.

Meloxicam oral tablet is also available as a generic drug. Generic drugs usually cost less than the brand-name version. In some cases, they may not be available in all strengths or forms as the brand-name drug.

Why it’s used

Meloxicam decreases inflammation and pain. It’s approved to treat:

• osteoarthritis
• rheumatoid arthritis
• juvenile idiopathic arthritis (JIA) in children ages 2 years and older

How it works

Meloxicam belongs to a class of drugs called nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs help reduce pain, inflammation, and fever.

It isn’t known how this medication works to decrease pain. It may help reduce swelling by lowering levels of prostaglandin, a hormone-like substance that usually causes inflammation.

Meloxicam can cause mild or serious side effects. The following list contains some of the key side effects that may occur while taking meloxicam. This list does not include all possible side effects.

For more information on the possible side effects of meloxicam, or tips on how to deal with a troubling side effect, talk with your doctor or pharmacist.

More common side effects

The more common side effects that can occur with meloxicam include:

• abdominal pain
• diarrhea
• indigestion or heartburn
• nausea
• dizziness
• headache
• itching or rash

If these effects are mild, they may go away within a few days or a couple of weeks. If they’re more severe or don’t go away, talk to your doctor or pharmacist.

Serious side effects

Call your doctor right away if you have serious side effects. Call 911 if your symptoms feel life threatening or if you think you’re having a medical emergency. Serious side effects and their symptoms can include the following:

• Heart attack. Symptoms can include:
  • chest pain or discomfort
  • trouble breathing
  • cold sweat
  • pain or discomfort in one or both arms, your back, shoulders, neck, jaw, or area above your belly button
• Stroke. Symptoms can include:
  • numbness or weakness of your face, arm, or leg on one side of your body
  • sudden confusion
  • trouble speaking or understanding speech
  • vision problems in one or both eyes
  • trouble walking or loss of balance or coordination
  • dizziness
  • severe headache with no other cause
• Stomach and intestinal problems, such as bleeding, ulcers, or tearing. Symptoms can include:
  • severe stomach pain
  • vomiting blood
  • bloody stools
  • black, sticky stools
• Liver damage. Symptoms can include:
  • dark urine or pale stools
  • nausea
  • vomiting
  • not wanting to eat
  • pain in your stomach area
  • yellowing of your skin or whites of your eyes
• Increased blood pressure: Symptoms of extreme high blood pressure can include:
  • dull headache
  • dizzy spells
  • nosebleeds
• Water retention or swelling. Symptoms can include:
  • rapid weight gain
  • swelling in your hands, ankles, or feet
• Skin problems, such as blistering, peeling, or red skin rash
• Kidney damage. Symptoms can include:
  • changes in how much or how often you urinate
  • pain with urination
  • Decreased red blood cells (anemia)

GASTROINTESTINAL SIDE EFFECTS
Abdominal pain, diarrhea, upset stomach, and nausea occur very often with this drug. Pain, vomiting, and diarrhea may occur more often in children than adults. Sometimes these side effects can cause more serious stomach problems.

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If you or your child has these side effects and they bother you or don’t go away, talk to your doctor.

Meloxicam oral tablet can interact with several other medications. Different interactions can cause different effects. For instance, some can interfere with how well a drug works, while others can cause increased side effects.

Below is a list of medications that can interact with meloxicam. This list does not contain all drugs that may interact with meloxicam.

Before taking meloxicam, be sure to tell your doctor and pharmacist about all prescription, over-the-counter, and other drugs you take. Also tell them about any vitamins, herbs, and supplements you use. Sharing this information can help you avoid potential interactions.

If you have questions about drug interactions that may affect you, ask your doctor or pharmacist.

Antidepressants and anxiety drugs

Taking meloxicam with certain antidepressant and anxiety medications raises your risk of bleeding. Examples of these drugs include:

• selective serotonin reuptake inhibitors, such as citalopram
• selective serotonin and norepinephrine reuptake inhibitors, such as venlafaxine

Corticosteroids

Taking meloxicam with corticosteroids can increase your risk of stomach ulcers or bleeding. Examples of these drugs include:

• prednisone
• dexamethasone

Cancer drug

Taking pemetrexed with meloxicam can increase your risk for infection, kidney problems, and stomach issues.

Transplant drug

Taking cyclosporine with meloxicam can increase the levels of cyclosporine in your body, causing kidney problems. If you take these drugs together, your doctor should monitor your kidney function.

Disease-modifying antirheumatic drug

Taking methotrexate with meloxicam can increase the levels of methotrexate in your body. This can result in kidney problems and an increased risk of infection.

Anticoagulant/blood thinner

Taking warfarin with meloxicam increases your risk of stomach bleeding.

Bipolar disorder medication

Taking lithium with meloxicam can cause amounts of lithium in your blood to increase to dangerous levels. Symptoms of lithium toxicity may include tremors, excessive thirst, or confusion. If you take these drugs together, your doctor may monitor your lithium levels.

Blood pressure drugs

Taking these medications with meloxicam may reduce the blood pressure-lowering effects of these drugs. Examples of these drugs include:

• angiotensin receptor blockers (ARBs), such as candesartan and valsartan
• angiotensin-converting enzyme (ACE) inhibitors, such as benazepril and captopril
• beta blockers, such as propranolol and atenolol

Diuretics (water pills)

Taking certain diuretics with meloxicam can decrease the effect of these drugs. Examples of these diuretics include:

• hydrochlorothiazide
• furosemide

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Meloxicam is an NSAID. Combining it with other NSAIDs may increase your risk of side effects, such as stomach bleeding or ulcers. Examples of NSAIDs include:

• aspirin
• ibuprofen
• naproxen
• etodolac
• diclofenac
• fenoprofen
• ketoprofen
• tolmetin
• indomethacin

The meloxicam dosage your doctor prescribes will depend on several factors. These include:

• the type and severity of the condition you’re using meloxicam to treat
• your age
• the form of meloxicam you take
• other medical conditions you may have, such as kidney damage

Typically, your doctor will start you on a low dosage and adjust it over time to reach the dosage that’s right for you. They’ll ultimately prescribe the smallest dosage that provides the desired effect.

The following information describes dosages that are commonly used or recommended. However, be sure to take the dosage your doctor prescribes for you. Your doctor will determine the best dosage to suit your needs.

Forms and strengths

Generic: Meloxicam

• Form: oral tablet
• Strengths: 7.5 mg, 15 mg

Brand: Mobic

• Form: oral tablet
• Strengths: 7.5 mg, 15 mg

Dosage for osteoarthritis

Adult dosage (ages 18 years and older)

• Typical starting dosage: 7.5 mg taken once per day.
• Maximum dosage: 15 mg per day.

Child dosage (ages 0–17 years)

Dosage for people younger than 18 years hasn’t been established. This drug has not been found to be safe and effective in this age group for this condition.

Dosage for rheumatoid arthritis

Adult dosage (ages 18 years and older)

• Typical starting dosage: 7.5 mg taken once per day.
• Maximum dosage: 15 mg per day.

Child dosage (ages 0–17 years)

Dosage for people younger than 18 years hasn’t been established. This drug has not been found to be safe and effective in this age group for this condition.

Dosage for juvenile idiopathic arthritis (JIA)

Child dosage (ages 2–17 years)

• Typical starting dosage (130 lbs/60 kg): 7.5 mg once daily.
• Maximum dosage: 7.5 mg per day.

Child dosage (ages 0–1 years)

Dosage for children younger than 2 years hasn’t been established. This drug has not been found to be safe and effective in this age group.

Special dosage considerations

For people receiving hemodialysis: This drug isn’t removed in dialysis. Taking a typical dosage of meloxicam while receiving hemodialysis may cause a buildup of the drug in your blood. This could cause worsened side effects. The maximum daily dose for people ages 18 years and older and receiving hemodialysis is 7. 5 mg per day.

FDA warnings

• This drug has a black box warning. This is the most serious warning from the Food and Drug Administration (FDA). A black box warning alerts doctors and patients about drug effects that may be dangerous.
• Heart risk warning: This drug may increase your risk of developing a blood clot, heart attack, or stroke, which can be fatal. Your risk may be higher if you’re taking it long term, at high doses, or if you already have heart problems or risk factors for heart disease, such as high blood pressure. You shouldn’t take meloxicam for pain before, during, or after coronary artery bypass graft surgery. This can increase your risk for a heart attack or stroke.
• Stomach problems warning: This medication may increase your risk of developing stomach and intestinal problems. These include bleeding, ulcers, and holes in your stomach or intestines, which can be fatal. These effects can occur any time while you’re taking this drug. They may happen without any signs or symptoms. Adults ages 65 years and older are at higher risk of these stomach or intestinal problems.

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Allergy warning

Don’t take meloxicam if you’ve had itchy skin, symptoms of asthma, or an allergic reaction to aspirin or other NSAIDs. A second reaction could be much more severe.

Liver damage warning

This drug may affect your liver. Symptoms may include yellowing of your skin or whites of your eyes and liver inflammation, damage, or failure. Your doctor may check your liver function while you take this drug.

Blood pressure warning

This medication may increase or worsen your blood pressure. This can increase your risk of heart attack or stroke. Your doctor may check your blood pressure while you’re taking meloxicam. Some medicines for high blood pressure may not work as well as they should when you’re taking meloxicam.

Allergy warning

Meloxicam can cause a severe allergic reaction. Symptoms may include:

• trouble breathing
• swelling of your throat or tongue
• hives

Don’t take meloxicam if you have asthma, runny nose, and nasal polyps (aspirin triad). Don’t take it if you’ve had itching, trouble breathing, or an allergic reaction to aspirin or other NSAIDs.

Don’t take this drug again if you’ve ever had an allergic reaction to it. Taking it again could be fatal (cause death).

Multiorgan hypersensitivity/DRESS warning

This medication can cause multiorgan hypersensitivity. This is also known as a drug reaction with eosinophilia and systemic symptoms (DRESS). This syndrome can be life threatening. Call your doctor right away if you have symptoms, such as a rash, a fever, or swollen lymph nodes.

Harm to developing fetus warning

You shouldn’t take meloxicam if you’re pregnant or planning to become pregnant. Meloxicam can cause harm to a developing fetus if taken at 20 weeks or later in pregnancy. If you are between 20 to 30 weeks of pregnancy, only take this drug if your doctor has told you to. Do not take this drug if you are more than 30 weeks pregnant.

Warnings for people with certain health conditions

For people with heart or blood vessel diseases: This medication increases your risk of blood clots, which can cause a heart attack or stroke. It may also cause fluid retention, which is common with heart failure.

For people with high blood pressure: This medication may make your blood pressure worse, which can increase your risk of having a heart attack or stroke.

For people with stomach ulcer or bleeding: Meloxicam can make these conditions worse. If you have a history of these conditions, you have a higher chance of having them again if you take this medicine.

For people with liver damage: Meloxicam can cause liver disease and changes in your liver function. It may make your liver damage worse.

For people with kidney disease: If you take meloxicam for a long time, it may decrease your kidney function, making your kidney disease worse. Stopping this drug could reverse kidney damage caused by the drug.

For people with asthma: Meloxicam can cause bronchial spasm and difficulty breathing, especially if your asthma gets worse if you take aspirin.

Warnings for other groups

For pregnant women: Using meloxicam during your third trimester of pregnancy increases the risk of negative effects to your pregnancy. You should not take meloxicam after 30 weeks of pregnancy. If you’re pregnant, talk to your doctor. Meloxicam should be used during pregnancy only if the potential benefit justifies the potential risk.

You should also talk to your doctor if you’re trying to get pregnant. Meloxicam can cause a reversible delay in ovulation. If you’re having a hard time getting pregnant or are getting tested for infertility, don’t take meloxicam.

For women who are breastfeeding: It isn’t known if meloxicam passes into breast milk. If it does, it could cause side effects in your child if you breastfeed and take meloxicam. You and your doctor may decide whether you’ll take meloxicam or breastfeed.

For seniors: If you’re age 65 years or older, you may have a higher risk of side effects from meloxicam.

For children: For the treatment of JIA, this drug has been found to be safe and effective for use in children 2 years and older. It should not be used in children younger than 2 years.

For the treatment of other conditions, this drug has not been found to be safe and effective for children of any age. It should not be used in people younger than 18 years.

Meloxicam oral tablet may be used for short-term or long-term treatment. It comes with risks if you don’t take it as prescribed by your doctor.

If you stop taking the drug or don’t take it at all: Your symptoms will remain and may worsen.

If you miss doses or don’t take the drug on schedule: Your medication may not work as well or may stop working completely. For this drug to work well, a certain amount needs to be in your body at all times.

If you take too much: You could have dangerous levels of the drug in your body. Symptoms of an overdose of this drug can include:

• nausea
• vomiting
• stomach pain
• stomach bleeding

Overdosing on meloxicam can cause organ failure or serious heart problems. If you think you’ve taken too much of this drug, call your doctor or seek guidance from the American Association of Poison Control Centers at 800-222-1222 or through their online tool. But if your symptoms are severe, call 911 or go to the nearest emergency room right away.

What to do if you miss a dose: If you miss a dose, take it as soon as you can, However, if it’s just a few hours until your next dose, skip the missed dose and take the next one on time.

Never try to catch up by taking two doses at once. This could result in serious side effects.

How to tell if the drug is working: You should have less pain and inflammation.

Keep these considerations in mind if your doctor prescribes meloxicam oral tablet for you.

General

• You can take meloxicam with or without food. If it upsets your stomach, take it with food or milk.
• You can cut or crush the oral tablet.

Storage

• Store this medication at room temperature, 77°F (25°C). If needed, you can keep it for short periods at temperatures between 59°F and 86°F (15°C and 30°C).
• Keep this medication away from high temperatures.
• Keep your medications away from areas where they could get damp, such as bathrooms.

Refills

A prescription for this medication is refillable.You should not need a new prescription for this medication to be refilled. Your doctor will write the number of refills authorized on your prescription.

Travel

When traveling with your medication:

• Always carry your medication with you. When flying, never put it into a checked bag. Keep it in your carry-on bag.
• Don’t worry about airport X-ray machines. They won’t damage your medication.
• You may need to show airport staff the pharmacy label for your medication. Always carry the original prescription-labeled container with you.
• Don’t put this medication in your car’s glove compartment or leave it in the car. Be sure to avoid doing this when the weather is very hot or very cold.

Clinical monitoring

During your treatment with this drug, your doctor may check your:

• blood pressure
• liver function
• kidney function
• red blood cell count to check for anemia

Insurance

Many insurance companies require a prior authorization for this drug. This means your doctor will need to get approval from your insurance company before your insurance company will pay for the prescription.

There are other drugs available to treat your condition. Some may be better suited for you than others. Talk with your doctor about other drug options that may work for you.

Disclaimer: Medical News Today has made every effort to make certain that all information is factually correct, comprehensive, and up to date. However, this article should not be used as a substitute for the knowledge and expertise of a licensed healthcare professional. You should always consult your doctor or another healthcare professional before taking any medication. The drug information contained herein is subject to change and is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. The absence of warnings or other information for a given drug does not indicate that the drug or drug combination is safe, effective, or appropriate for all patients or all specific uses.

Meloxicam Raised Blood Pressure Through the Roof!

Tens of millions of people take oral NSAIDs (nonsteroidal anti-inflammatory drugs) every day. We are talking about celecoxib, diclofenac, ibuprofen, meloxicam and naproxen. Most people realize that such drugs can be irritating to the digestive tract. Indigestion or stomach ulcers are not uncommon. What is less well realized is that these drugs can raise blood pressure. Many doctors and pharmacists may assume that this only occurs in people with existing hypertension. But even people with normal blood pressure can be affected. This reader discovered that meloxicam raised blood pressure way too high!

A Scary Situation!

Q. I was prescribed meloxicam for pain and inflammation. After just one day, my blood pressure went from my typical reading of 120/75 up to 210/131.

I discontinued the prescription immediately. The same thing had happened to my mother when she was prescribed Celebrex.

Anyone prescribed NSAID-type arthritis medicines ought to be very careful. You should self-monitor your blood pressure closely in the first few days, because by the time you get back in to see your provider you could have already had a stroke or heart attack.

A. You describe a well-known but often overlooked adverse drug reaction. Nonsteroidal anti-inflammatory drugs (NSAIDs) can raise blood pressure. This includes OTC pain relievers such as ibuprofen or naproxen as well as prescription medications like celecoxib (Celebrex), diclofenac (Voltaren) and meloxicam (Mobic). Your suggestion to measure blood pressure when taking NSAIDs is really important!

An article in JAMA Internal Medicine (Nov. 22, 2021) noted that people taking antidepressants, NSAIDs, steroids or estrogens are more likely to have uncontrolled hypertension or need extra BP medicines. Here are the conclusions of this study:

“In this nationally representative survey study, 18% of US adults with hypertension reported taking medications that may cause elevated BP. The use of these medications was associated with increased odds of uncontrolled hypertension among individuals not taking antihypertensives and greater use of antihypertensives among both patients with controlled and uncontrolled hypertension.”

This reader is not the only person to discover that meloxicam raised blood pressure.

From Normal to Hypertension on Meloxicam

Q. After diagnosing my arthritis, my doctor prescribed meloxicam. During the three years I took it, my blood pressure went from 120/80 to 190/144. Unfortunately, he wasn’t monitoring it.

When I found I had such high blood pressure, I got off the meloxicam and was put on lisinopril. Six months later, my BP is stable at 130/86. I do want it lower, so the fight is still on. Please monitor your blood pressure while you are on meloxicam.

A. Great advice to anyone taking an NSAID (nonsteroidal anti-inflammatory drug). That includes OTC pain relievers like ibuprofen and naproxen as well as prescription arthritis drugs like celecoxib, diclofenac or meloxicam.

The Black Box Warning with Meloxicam

The FDA mandates the following warning with meloxicam and other NSAIDs.

“NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.”

Meloxicam Raised Blood Pressure:

The FDA also requires this caution in the official prescribing information:

“NSAIDs, including meloxicam, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV [cardiovascular] events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including meloxicam, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. ”

We are not sure whether most prescribers share this information with their patients. And we fear that people taking over-the-counter drugs like ibuprofen or naproxen may not take such a warning to heart. After all, OTC drugs are supposed to be safe.

Readers Report Meloxicam Raised Blood Pressure:

Jane has RA (rheumatoid arthritis) and is in pain:

“I took NSAIDS (meloxicam or ibuprofen) for RA pain for a year. These drugs gave me high blood pressure. As soon as I got off these NSAIDs, my blood pressure went back to normal. However, there are so few drugs that doctors will prescribe for pain. I feel abandoned.”

Ralph also developed blood pressure problems with ibuprofen:

“I was suffering from shingles and took a lot of ibuprofen for several months. On a visit to the doctor for the condition, my blood pressure was 179/100.

“I am 73 years old, and have consistently had blood pressure in the range of 120/70 my entire adult life. I researched The People’s Pharmacy website and a man my age reported his sudden rise in blood pressure, saying when he quit taking ibuprofen, his blood pressure quickly dropped to normal.

“I bought a blood pressure cuff so I could test, quit taking Ibuprofen, and my blood pressure was back to normal in two days.”

Judi had a scary encounter with naproxen:

“Last year my surgeon put me on naproxen before it became necessary for him to do neck surgery on me. On day 21 of taking naproxen my blood pressure spiked to 234/180 and I went to the ER. I will never take NSAIDS again.”

Pat also got into trouble with naproxen:

“I haven’t been prescribed meloxicam, but I have been prescribed naproxen for arthritis pain. I have also noticed elevated blood pressure since taking this. So, what does the doctor do? Prescribe a diuretic-type drug to lower blood pressure. I decided to stop NSAIDs altogether, even the OTC type. ”

What’s a Person To Do if NSAIDs Raise Blood Pressure?

Most people take NSAIDs because they are in pain. But if such drugs raise blood pressure, they are inappropriate. Taking another medication to treat hypertension brought on by a pain reliever is not the answer.

Anyone caught in this situation may wish to consult our eGuides to Alternatives for Arthritis and Blood Pressure Treatment.

Tough Time of Year:

This is the time of year people start sniffling and sneezing because of colds and influenza. Oral decongestants such as phenylephrine or pseudoephedrine can also raise blood pressure. Here is a link to our article on other medications that can increase blood pressure. You will be surprised that hemorrhoid remedies can also do this!

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Tolerability and safety of meloxicam | Badokin V.V.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in clinical practice. In Europe, this class of pharmacological agents in polyclinic practice is prescribed by 82% of general practitioners and 84% of rheumatologists, and in the hospital they are used in 20% of patients. The main property of NSAIDs is to suppress the inflammatory process or significantly reduce its intensity. In addition, they have a distinct analgesic and antipyretic effect.

NSAIDs are most widely used in the treatment of inflammatory and degenerative diseases of the joints and spine, diffuse connective tissue diseases, microcrystalline arthropathies, extra-articular soft tissue diseases, a large group of diseases accompanied by pain in the lower back, osteoporosis and other bone diseases accompanied by pain. They are also used in cardiology for inflammatory cardiopathy and as a means of preventing thrombosis, in preoperative preparation and management of patients after “small” operations, with headaches, oligomenorrhea, and many other inflammatory processes accompanied by fever and pain. Their positive effect in oncology as a means of preventing colonorectal cancer or metastasis of malignant tumors, in neurology in the treatment of Alzheimer’s dementia, as well as their preventive effect on the development of atherosclerosis, especially in patients with immunoinflammatory diseases, are discussed.
In rheumatology, NSAIDs are the main symptom-modifying drugs for short-term and long-term therapy of a large number of diseases, as well as drugs of choice for the initial therapy of arthritis of various origins. Recently, there have been isolated reports that NSAIDs have not only a symptomatic effect. It is believed that they are able to slow down the progression of certain diseases, such as ankylosing spondylitis and osteoarthritis. In one of the papers published at 1999, it was indicated that among the direct costs of treatment in patients with rheumatoid arthritis, 75% are accounted for by NSAIDs [1]. The generally accepted point of view on the need for basic anti-inflammatory therapy at an early stage of rheumatoid arthritis and the introduction of high technologies in the complex therapy of this disease have, of course, reduced this percentage, but it remains quite significant in the structure of the cost of treating this inflammatory joint disease, like many other diseases.
The main mechanism of action of NSAIDs is the suppression of prostaglandin biosynthesis. As is known, prostaglandins are characterized by a wide range of biological effects (Table 1). [2,3].
The pharmacological activity of NSAIDs is not limited to the suppression of prostaglandin production. In addition, they inhibit the synthesis of leukotrienes, the formation of superoxide radicals and the release of lysosomal enzymes, affect the activation of cell membranes, the aggregation and adhesion of neutrophils, the functions of lymphocytes, and the synthesis of leukotrienes. Hence it is clear why NSAIDs have not only a positive (therapeutic) effect, but also have a fairly large range of adverse events (Table 2). The most frequently observed gastrointestinal disorders of varying severity – from mild to incompatible with life. NSAIDs have nephro- and hepatotoxicity, contribute to fluid retention, the development of heart failure, arterial hypertension, and have a dystrophogenic effect on the myocardium. They affect the metabolism of brain cells and cause severe headaches and other manifestations of cerebral toxicity. Hematological disorders are possible, up to the development of severe cytopenias, hypo- and aplastic anemia, inhibition of platelet aggregation, impaired hemostasis with massive bleeding. NSAIDs often cause a variety of allergic reactions and broncho-obstructive syndrome (“aspirin” asthma), which is associated with their effect on the synthesis and release of leukotrienes.
When choosing an NSAID and its daily dose, one should take into account their anti-inflammatory activity and tolerability, the possibility of combination with other types of therapy, the presence of concomitant diseases, metabolic features in the body, pharmacokinetics, COX (cyclooxygenase) – selectivity. Of great importance is the identification of risk factors for adverse events of NSAIDs, which include older age, a history of gastrointestinal pathology, concomitant diseases (arterial hypertension, heart failure, liver and kidney disease), taking high doses of NSAIDs, combined therapy of NSAIDs with glucocorticoids, low doses of acetylsalicylic acid or indirect anticoagulants. It is generally accepted that selective COX-2 inhibitors, which include meloxicam (Movasin et al.), have a higher safety.
Meloxicam is a derivative of enoliconic acid. It, like all other NSAIDs, has anti-inflammatory, analgesic and antipyretic activity. More than 99.5% of meloxicam is protein bound. In the synovial fluid, its concentration is 2 times less than in the blood plasma, but still high enough to suppress the inflammatory process in the tissues of the joint. Its half-life is 20 hours, and this gives rise to a single dose during the day. It is excreted from the body in urine and feces. The drug has a cumulative property, while its maximum concentration occurs on the 3-5th day of admission. For a faster therapeutic effect, it is advisable to carry out the so-called “stepwise” therapy, which consists in intramuscular administration of 15 mg of meloxicam in the first three days of treatment, followed by transfer of the patient to oral administration of the drug [4]. The daily dose of meloxicam is 15 mg. A lower dose is indicated for patients with erosive gastritis, gastric ulcer or decreased glomerular filtration rate, as well as for elderly patients who have a decrease in the excretion of many drugs. Meloxicam in the body does not interact with other drugs, including cytostatics, diuretics, cardiac glycosides, b-blockers, and others, which is of great importance for the rational treatment of patients with concomitant (comorbid) diseases.
High clinical efficacy of meloxicam has been demonstrated in patients with rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, pain in the lower back and many other diseases. The evidence base for meloxicam is based on numerous randomized, placebo-controlled trials in which its efficacy and tolerability were compared with placebo and the main NSAIDs – COX-selective and COX-non-selective [5-7]. The duration of therapy in these studies ranged from 4 weeks. up to 18 months Significant improvement, which occurred after 2 weeks. from the start of therapy with meloxicam, lasted for 18 months, i. e. the entire observation period. In terms of its effectiveness, meloxicam was not inferior to diclofenac, naproxen and piroxicam. Good results of treatment with meloxicam were obtained not only in patients with rheumatoid arthritis, but also with ankylosing spondylitis in its 12 months. application. According to its therapeutic activity, 15 mg of meloxicam had the same effect as 20 mg of piroxicam, and a further increase in the daily dose (up to 22.5 mg/day) was not accompanied by an increase in its anti-inflammatory and analgesic effect.
The greatest number of studies on the clinical efficacy and safety of meloxicam has been carried out in osteoarthritis. The expediency of prescribing meloxicam in osteoarthritis is dictated by its positive effect on the metabolism of hyaline cartilage, the main springboard for the development of the pathological process in this disease [8,9]. Meloxicam has an anabolic effect, inhibits interleukin-1, expresses growth factors, including transforming growth factor-1, inhibits the degradation of aggrecan, neutralizes the action of metalloproteinases and inhibits chondrocyte apoptosis, i. e. actively intervenes in the development of the pathological process in this disease [10,11].
Most of the studies evaluating meloxicam in osteoarthritis met the current requirements for approbation of drug preparations. They were multicenter, prospective, double-blind and performed according to a single protocol [12–14]. Meloxicam led to a significant decrease in the subjective manifestations of the disease with a decrease in the intensity of pain when walking and at rest. In some cases, there was complete relief of pain, a significant decrease in the intensity of morning stiffness or its cessation, resolution of manifestations of secondary (reactive) synovitis, and improvement in the function of the affected joints.
The efficacy of meloxicam in patients with osteoarthritis was studied in the MELISSA (Meloхicam Large Scale International Study Safety Assessment) and SELECT (Safety and Efficacy Large scale Evaluation of COX inhibiting Therapies) studies, in which the therapeutic activity of meloxicam (7. 5 mg/day) was compared with diclofenac (100 mg/day) or piroxicam (20 mg/day) [12,13]. Nearly 20,000 patients participated in these two trials. Meloxicam was found to be equivalent in clinical efficacy to diclofenac and piroxicam. Cancellation of the drug due to its low efficiency in the groups of diclofenac, piroxicam and meloxicam did not exceed 1.7%.
In the treatment of NSAIDs, a wide range of adverse events are observed. Prevention and treatment of these complications is one of the most important iatrogenic problems of modern medicine. The most common is gastrotoxicity. Every year, 100,000 patients develop adverse events associated with taking NSAIDs, which can have serious consequences due to the possible development of profuse bleeding, perforation of the wall of the stomach or intestines [15]. NSAID gastropathy is largely due to the half-life of individual drugs, differences in their systemic absorption, the basic pH of gastric juice, but above all, the degree of suppression of prostaglandin synthesis. Adverse events that develop when taking COX-non-selective drugs in 30% of patients are manifested by gastric and intestinal dyspepsia, 15% – endoscopically confirmed gastric ulcers, 1.7% – perforations or hemorrhages. Such severe prognostic gastroenterological complications as bleeding, perforation and ulcers in most cases occur without pain, which makes their timely diagnosis difficult, and in some patients lead to death.
NSAID-induced lesions of the gastrointestinal tract extend to all its departments and are characterized by polymorphism of manifestations. The mechanisms underlying such damage to the gastrointestinal tract are diverse and are associated with a decrease in blood flow in the mucosa and a violation of its trophism, the basic pH of gastric juice, the difference in systemic absorption of NSAIDs and adhesion of neutrophils. The direct toxic effect of NSAIDs on the digestive tract is an important component only at the beginning of treatment. The importance of genetic factors in the genesis of gastrointestinal bleeding caused by NSAIDs is discussed. Apoptosis of cells, especially the gastric mucosa, is also important. But the main cause of gastrointestinal complications of NSAIDs is associated with suppression of prostaglandin synthesis.
However, selective COX-2 inhibitors can also lead to severe complications. Interestingly, the relative risk of gastrointestinal bleeding in the appointment of specific COX-2 inhibitors is more pronounced than in the treatment of standard NSAIDs. Thus, this indicator in patients over 65 years of age treated with lumiracoxib is 3.18, and with non-selective COX – 2.3, in males – 2.6 and 1.7, respectively. A high risk of bleeding was noted in patients who take combination therapy with lumiracoxib and aspirin (2.89) [16]. The presented data are the key to the prevention of gastropathy, possible bleeding and other serious complications in the treatment of NSAIDs. These measures should be carried out in all patients with risk factors and should include the appointment of selective NSAIDs and proton pump inhibitors, as well as monitoring for possible adverse events.
NSAID-gastropathy is significantly less common when taking meloxicam. The European pharmacoepidemiological multicentre prospective study evaluated the tolerance of meloxicam and other NSAIDs in patients with rheumatic diseases [10]. The duration of therapy was 6 months. Groups of patients in individual centers were randomized according to the main parameters of the pathological process. In the treatment with meloxicam, adverse events such as abdominal pain, gastritis, dyspepsia were significantly less common, and gastrointestinal bleeding was registered only in two out of 2530 patients, while other NSAIDs led to such a complication in 10 out of 1996 patients.
Interesting data were obtained in the MELISSA study, in which the tolerability of meloxicam 7.5 mg / day was studied in a comparative aspect. and diclofenac 100 mg/day. in 9323 patients with osteoarthritis. The duration of therapy was 4 weeks. This study involved 27 countries, including Russia [4,13]. The overall frequency of gastrointestinal adverse events in the appointment of diclofenac was significantly higher than in the treatment of meloxicam (19 and 13%, respectively), and according to E. S. Tsvetkova – in 22.2 and 6.8%, respectively [9]. Gastric dyspepsia, abdominal pain, nausea and vomiting, and diarrhea were significantly less common. Due to the development of adverse events, 2 times more patients stopped treatment with diclofenac than with meloxicam. The overall tolerability of meloxicam, according to doctors, was good in 91% and satisfactory in 9%, and the tolerability of diclofenac was good (84%), satisfactory (9%) and unsatisfactory (7%). Similar results were obtained in the SELECT study, in which meloxicam 7.5 mg/day. compared with piroxicam 20 mg/day. in 8227 patients with osteoarthritis.
It is interesting to note that when using meloxicam, the risk of developing gastrointestinal complications was also lower in individuals who simultaneously took acetylsalicylic acid to prevent thromboembolic complications (10.3% and 15.4%). A meta-analysis of a large number of studies showed that meloxicam compared with traditional NSAIDs (diclofenac, piroxicam and naproxen) reduces the risk of drug withdrawal due to the development of gastrointestinal complications by 41%, the risk of serious adverse reactions (perforation, ulceration, bleeding) – by 48% and the risk of intestinal dyspepsia – by 27%.
When taking NSAIDs, damage to the small intestine is more common than damage to the stomach. Enteropathy can develop rapidly, for example, after 14 days from the start of NSAID therapy. It is manifested by nonspecific edema, diaphragmatitis, ulcers, penetration, strictures, intestinal dyspepsia, bleeding, and iron deficiency anemia [17]. Selective COX-2 inhibitors reduce the risk of enteropathy by 50% compared with standard NSAIDs. Intestinal endoscopy using special capsules or double balloon endoscopy allows a detailed analysis of pathological changes in the small intestine when prescribing this group of drugs.
Recently began to pay close attention to NSAID-colonopathy, which occurs relatively often. Morphologically, the lesion of the large intestine is manifested by ischemic or collagenous colitis. The clinical stigmata of such colonopathy are ulcers, perforations, strictures of ischemic origin, obstructions, and recurrent irritable bowel syndrome [18]. In rare cases, massive intestinal bleeding is observed. Standard NSAIDs are 2 times more likely to lead to NSAID colonopathy compared to selective COX-2 inhibitors.
One of the complications of NSAID therapy is hepatotoxicity [19]. An increase in aminotransferases by 3 times or more is detected both with the appointment of standard and selective COX-2 inhibitors. Genetic factors, in particular the expression of cytochrome P450, are also involved in the induction of hepatotoxicity. Meloxicam has less hepatotoxicity than the widely used diclofenac. So, when taking meloxicam, an increase in AST was registered in 3%, and diclofenac – in 9% [9,12].
Much attention is paid to the cardiovascular adverse events of NSAIDs, in particular myocardial infarction and cerebrovascular accident [20, 21]. It should be noted that all traditional and selective NSAIDs are COX-2 inhibitors, although, of course, to varying degrees, and all of them dose-dependently increase the risk of thromboembolic complications [22]. On the other hand, almost all NSAIDs, both non-selective and selective, contribute to an increase in blood pressure, which, in turn, can also lead to thrombosis. However, there is no doubt that the higher the COX-2 selectivity, the more likely the development of cardiovascular and cerebral thrombotic complications. This primarily applies to specific COX-2 inhibitors – coxibs. According to Layton (2003), cardiovascular thrombotic complications during long-term treatment with meloxicam are observed in 0.1% of patients, celecoxib – in 0.16% and rofecoxib – in 0.14%, and cerebrovascular – in 0.27%, 0.39% and 0.48%, respectively. According to the FDA and the European Medical Agency, a contraindication to the use of specific COX-2 inhibitors is coronary heart disease or a history of stroke. With great caution, they should be used in individuals with risk factors for coronary heart disease and in elderly people.
Meloxicam differs from other selective COX-2 inhibitors in its effect on platelet aggregation, which is explained by the peculiarities of its structure. In particular, it binds to the upper part of the COX-2 channel, and highly selective coxibs – to the side pocket of the COX-2 channel, while they inhibit thromboxane to a lesser extent, and this explains the increased risk of thromboembolic complications in their use, t. to. thromboxane is actively involved in platelet aggregation.
NSAID prostaglandin inhibition leads to cardiorenal effects, which include impaired water and salt metabolism, arterial hypertension, congestive heart failure, nephrotic syndrome, acute renal failure. Some of these effects are associated with impaired cerebral circulation, and above all with arterial hypertension. Cerebral strokes against the background of long-term use of NSAIDs are associated not so much with an increase in diastolic blood pressure as systolic and, even more so, with the value of pulse pressure. Individual NSAIDs that increase systolic blood pressure include ibuprofen, rofecoxib, and etoricoxib. These three drugs are considered risk factors for ischemic stroke. Meloxicam is the least likely to increase blood pressure, both systolic and diastolic. In this regard, it is close to diclofenac, which also does not lead to an increase in blood pressure [23].
G. Singh et al. conducted a large study involving 3. 1 million people [data presented at the EULAR congress in Barcelona in 2007]. The vast majority of individuals included in this study were taking NSAIDs for various diseases. In this work, 15659 cases of cerebrovascular accident were identified. The relative risk of ischemic stroke for rofecoxib and indomethacin was 1.26, piroxicam -1.25, naproxen – 1.24, ibuprofen – 1.19, diclofenac – 0.98, celecoxib – 0.97. The value of this risk for meloxicam was 0.88, and it was the same as in the control group, not taking NSAIDs. Thus, meloxicam is not a risk factor for stroke. A positive feature of this drug is the lack of interaction with antihypertensive drugs when they are used together.
Often, NSAIDs contribute to the development of skin reactions, which are among the most common adverse events in the appointment of this group of drugs. Skin reactions are characterized by polymorphism of their manifestations and are divided into characteristic and uncharacteristic. The former include allergic contact dermatitis, photoallergic contact dermatitis, acute urticaria or angioedema, recurrent chronic urticaria, contact urticaria, fixed drug rash, and the atypical ones include bullous vasculitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS– syndrome (drug rash with eosinophilia and systemic manifestations).
Most often, skin rashes are caused by standard NSAIDs – acetylsalicylic acid, ketoprofen, ibuprofen, piroxicam, but reactions to selective COX-2 inhibitors are also possible. These reactions are based on an immunological mechanism. In Stevens-Johnson syndrome and toxic epidermal necrolysis, massive apoptosis of epidermal cells is observed, caused by cytotoxic T cells that release perforin and grancime B. The development of acute urticaria on NSAIDs is a consequence of immunoglobulin E (IgE)-dependent reaction. In such cases, they act as a hapten. Repeated exposure of the drug leads to an immune-dependent reaction with the formation of antibodies directed to a specific NSAID.
With the appointment of COX-1 inhibitors, an increased production of leukotrienes (LTA4) is observed. Therapy with leukotriene receptor antagonists can block NSAID-induced urticaria or significantly reduce their severity. COX-2 selective drugs show good tolerance in patients with chronic urticarial rash and aspirin-induced asthma, which fully applies to meloxicam [24].
Thus, meloxicam not only has a pronounced anti-inflammatory and analgesic effect, but is also characterized by good tolerability and high safety. The spectrum of adverse events is much lower than that of non-selective and selective COX inhibitors. These properties, along with its high clinical efficacy, have contributed to its widespread introduction into the complex therapy of not only inflammatory and degenerative rheumatic diseases, but also many other pathological conditions.

Literature
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4. Tsvetkova E.C. Evaluation of the effectiveness of Movalis in osteoarthritis and rheumatoid arthritis (data from a multicenter Russian study). Scientific and practical. rheumatol. 2005; 2:29–31.
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6. Huskinsson E.C., Ghozlan R., Kurthen R. et al. A long-term study to evaluate the safety and efficacy of meloxicam therapy in patients with rheumatoid arthritis. Br J Rheumatol 1996; 35 (suppl 1): 29–34.
7. Wojtulewsky J.A., Schattenkirchner M., Barselo P. et al. A six-month double-blend trial to compare the efficacy and safety of meloxicam 7.5 and naproxen 750 mg daily in patients with rheumatoid arthritis. Br J Rheumatol 1996; 35 (suppl 1): 22–8.
8. Nasonova V.A. Meloxicam (Movalis) is a selective COX-2 inhibitor in clinical practice. Scientific and practical. rheumatol. 2000; 4:16–21.
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10. Degner F., Lanes S., van Ryn J., Sigmund R. Pharmacological and clinical profile meloxicam. Therapeutic roles of selective COX-2 inhibitors. Eds Vane JR, Botting RM. William Harvey Press, London, 2001.
11. Henrotin Y., Reginster T.. In vitro difference among non-steroidal antiinflammatory drug in their activities related to osteoarthritis pathophysiology. Osteoarthritis Cartilage 1999; 7:355–7.
12. Dequeker J., Hawkey C., Kahan A. et al. Improvement in gastrointestinal tolerability on the selective cyclooxygenase (COX)–2 inhibitor meloxicam, compared with piroxicam: results of the Safety and Efficacy Large scale Evaluation of COX inhibiting Therapies (SELECT) trial in osteoarthritis. Br J Rheumatol 1998; 37:946–51.
13. Hawkey C., Kahan A., Steinbruck K. et al. Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. International MELISSA Study Group. Meloxicam Large Scale International Study Safety Assessment. Br J Rheumatol 1988; 37:937–45.
14. Hosie J., Distel M. , Bluhmki E. Melochicam in osteoarthritis: a 6-month, double-blind comparison with diclofenac sodium. Br J Rheumatol 1996; 35 (suppl): 39–43.
15. Hawkey C.J. Non-steroidal anti-inflammatory drugs: who should receiv prophylaxis? Aliment Pharmacol Ther 2004; 20, Supple 2:59-64.
16. Rostom A., Muir K., Dube C. et al. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane collaboration systematic review. Clin Gastroenterol Hepatol 2007; 5:818–828.
17. Avebayo D., Bjarnason C. Is non-steroidal anti-inflammatory drugs NSAID enteropathy clinically more important than NSAID gastropathy? Postgrad Med J 2006; 82:186–191.
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“golden mean” of non-steroidal anti-inflammatory drugs

Rapid and most complete pain relief is one of the 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 confidence, which is important when it comes to the onset of a chronic disease requiring 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 most cases of chronic non-cancer pain [1-3].

From the point of view of medical science, chronic pain is a serious and independent threat to the patient’s life. Persistent severe pain determines the negative changes in homeostasis, mediated by the reaction of the sympathetic-adrenal system – an increase in blood pressure and heart rate, as well as procoagulative changes in the blood coagulation system. These changes lead to a significant increase in the risk of developing dangerous cardiovascular complications (CVS) [1, 2].

In such nosological forms as OA and chronic LBP, 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 CVCs is significantly increased [1, 2].

This statement is confirmed by a study by Swiss scientists E. Nüesch et al. [4], who assessed the frequency of deaths in 1163 patients with OA with a follow-up period of about 5 years. According to the data obtained, the risk of death due to CVD in patients suffering from this “non-fatal” disease is 1.7 times higher than in the general population. In the course of the subsequent analysis, the scientists identified the only factor that was clearly associated with the development of fatal CVCs in patients with OA – a pronounced dysfunction of the joints, preventing normal movement. Among the dead, such disorders were observed in 35%, while among the survivors – only 17% ( p <0.001) [4].

Similar results are presented by Japanese researchers M. Tsuboi et al. [5], who observed the dynamics of the state in 944 patients with various rheumatic diseases for 10 years. It was found that in patients with gonarthrosis the risk of death from CVE is more than 2 times higher than in the population (odds ratio – OR – 2.32).

The work of Australian scientists K. Zhu et al. [6], who followed a group of 1484 elderly women (over 70 years of age) with chronic LBP for 5 years. Among them, 21.7% initially and 26.9% at the end of the observation period experienced pain daily. In this subgroup, the risk of death from CVE was more than 2 times higher (relative risk – RR 2.13 at 95% confidence interval – CI – from 1.35 to 3.34) than in the group of patients who had less pain .

It is impossible not to note one more, purely practical aspect of the problem of adequate anesthesia. Patients come to the doctor’s office primarily for relief of suffering; “understanding” the situation, finding out the exact diagnosis is a secondary, although undoubtedly important, goal of seeking medical help. Excessive enthusiasm for diagnostic measures and “basic” means 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, the effective elimination of the most painful symptoms will be the most effective way to win the patient’s trust and achieve strict adherence to a complex scheme of long-term pathogenetic therapy [1, 2].

However, effective control of chronic pain is not easy. An illustration of this is the work of the 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 the respondents were dissatisfied with the effect of prescribed drugs, and only 1 patient out of 6 considered himself completely satisfied with the result of analgesic therapy.

In this regard, the data of British researchers M. Gore et al. [8], who evaluated the practice of prescribing analgesics (paracetamol, NSAIDs, tramadol, “weak” and “strong” opioids) in patients with OA and LBP. For various reasons – due to inefficiency, adverse events, etc., during the 1st month of treatment, prescribed drugs were canceled in almost 90% of patients (from 30 to 60% were cases of replacement therapy, up to 15% – its increase – the use of various combinations). It can be seen that in most cases (not less than ⅔), the analgesic drug initially recommended by the doctor did not justify hopes 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. Its development involves local inflammation, muscle spasm, damage to the elements of the ligamentous apparatus, biomechanical disorders, dysfunction of the pain system (peripheral and central sensitization, “exhaustion” of antinociceptive mechanisms, etc.) [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 OPS organs [1-3].

The main mechanism of the pharmacological action of NSAIDs is associated with the blockade of cyclooxygenase-2 (COX-2), which is formed in the foci of tissue damage and is responsible for the active synthesis of prostaglandins (PG) – 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 effect 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 occur in response to persistent and powerful pain stimulation 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 the data of 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 in his arsenal. This creates difficulties for practitioners, because even experts cannot always determine the criteria for the merit of drugs that should be used to decide on the choice of one or another 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 the drug has an advantage in any parameter, it is likely that it will also have certain disadvantages.

The analgesic effect of all NSAIDs when used in therapeutic doses is practically the same. At least there is no conclusive 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, two polar groups are distinguished, differing in their selectivity for COX-2 (their main pharmacological “target”): non-selective (n-NSAIDs) and highly selective – “coxibs”. The selectivity of NSAIDs avoids the 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 (CO) of the gastrointestinal tract (GIT). The blockade of COX-1 (characteristic of n-NSAIDs) leads to a significant increase in the risk of developing severe, life-threatening gastrointestinal pathology (gastropathy and enteropathy associated with NSAIDs – 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 CV events – myocardial infarction (MI) and ischemic stroke [3]. As can be seen, 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 CVS pathology.

n-NSAIDs (except for ketorolac, suitable only for short-term use) are more acceptable for patients of the older age group with a moderate risk of developing CVC, 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).

A position between n-NSAIDs and “coxibs” should be assigned to drugs with moderate selectivity for COX-2. Their use should lead to a smaller number of pronounced 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 CVS. This is a kind of “golden mean”, which is acceptable for most patients and is especially interesting now, when the medical community, after the bad memory of the “coxibs crisis”, is very wary of highly selective COX-2 inhibitors. At the same time, the problem of NSAID gastropathy, which is so characteristic of n-NSAIDs, will never lose its relevance.

In the mid-1990s, this position was occupied by diclofenac. However, at present, this drug no longer meets the high requirements of safe pharmacotherapy. In our country, primarily due to the widespread use of cheap generics of this drug, it is with diclofenac that the greatest number of complications in the form of organic and functional disorders of the gastrointestinal tract are associated [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 CVD and 21 cohort studies, a total of > 2.7 million individuals), the risk of MI increases with the use of diclofenac by approximately 40% (OR 1.4). In a population study by Danish scientists E. Fosbøl et al. [13], taking diclofenac was accompanied by the highest risk of developing myocardial infarction, stroke, and death from CVD among NSAIDs, higher than that of coxibs.

Significantly more interest is attracted by another representative of the “golden mean” – a moderately selective COX-2 inhibitor meloxicam, which appeared in 1995 g. 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 of the world.

Meloxicam has been extensively tested in a large number of clinical trials; its effectiveness has been studied in a wide range of diseases and pathological conditions, ranging from anesthetic practice to chronic joint diseases. These studies clearly confirmed that meloxicam is in no way inferior in its therapeutic potential to the “traditional” NSAIDs in 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 is its good tolerability. In a series of large randomized clinical trials (RCTs), a significantly lower number of complications in the form of organic and functional disorders of the gastrointestinal tract was unambiguously confirmed when using this drug compared to n-NSAIDs.

The 4-week MELISSA study ( n =9323) compared meloxicam 7.5 mg with diclofenac 100 mg/day. The total number of side effects in the form of organic and functional disorders of the gastrointestinal tract 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 treated with meloxicam was 2 times less: 3 and 6.1%, respectively ( p <0.001). Dangerous complications - clinically pronounced ulcers, gastrointestinal bleeding (GI) and perforation while taking meloxicam were also less common (but not significant) - 5 and 7 cases, respectively [23].

A SELECT RCT ( n = 8656) was conducted in a similar manner, but piroxicam 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 RCT MELISSA, dyspepsia and associated episodes of discontinuation of therapy were significantly more common in patients treated with the comparator drug: 10.3 and 3.8% versus 15.4 and 5.3%, respectively ( p <0.001) [ 24].

D. Yocum et al. [25] 774 patients with OA received meloxicam at a dose 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 – 19and 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 2155 German doctors who observed 13,307 rheumatological patients who received meloxicam at a dose of 7.5 mg (65%) or 15 mg (33%) for 1-3 months. The efficacy and tolerability of the drug was assessed by analyzing the data provided by the attending physicians in the relevant questionnaires. Although the majority of patients were over 60 years old, 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 – only in 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, comparing meloxicam 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 disorders of the gastrointestinal tract (RR 0.64 at 95% CI from 0.59 to 0.69), the incidence of dyspepsia (OR 0.73 at 95% CI from 0.64 to 0.84), symptomatic ulcers, GI and perforations (OR 0.52 at 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 of the gastrointestinal tract (OR 0. 59 at 95% CI from 0.52 to 0.67).

A later meta-analysis by G. Singh [25], which included data from 28 RCTs (24,196 patients), also confirms the higher safety of meloxicam at a dose of 7.5 mg compared to traditional NSAIDs in relation to the gastrointestinal tract. Thus, the frequency of gastrointestinal bleeding when using this dose of meloxicam was only 0.03% (when taking 15 mg 0.2%), while in those receiving diclofenac at a dose of 100-150 mg / day – 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 who were in 2002-2005. on inpatient treatment at the clinic of the FGBU NIIR RAMS. The studied groups consisted of persons who underwent esophagogastroduodenoscopy during this period for various reasons: 425 patients who received meloxicam, and 2428 – diclofenac (Fig. 1) . Figure 1. Detection of ulcers and multiple (> 10) erosions of the stomach and / or duodenal ulcer in patients who regularly received meloxicam or diclofenac [29]. In patients taking meloxicam, ulcers occurred almost 2 times less often, including patients with such a risk factor as an ulcer history [29].

In recent years, the problem of the negative effects of NSAIDs on the distal gastrointestinal tract has attracted much attention of researchers and practitioners. First of all, we are talking about NSAID enteropathy – a pathology of the small intestine (TC), 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 GI bleeding, perforation and strictures of the TC; 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 high, 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 IDA 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 CVD.

This is confirmed by the work of G. Sands et al., published in 2012. [32]. The researchers conducted a meta-analysis of 51 RCTs comparing the safety of celecoxib and n-NSAIDs ( n = 50,116) to determine the relationship between reduced hemoglobin levels and the incidence of life-threatening systemic complications. It turned out that anemia dramatically increased the risk of developing severe CVD. 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 did not have signs of anemia, it was only 0.2%. Similarly, the progression of coronary heart disease (CHD) was observed in 1.2 and 0.3% of patients [32].

NSAID enteropathy is a problem characteristic of “traditional” NSAIDs. There is strong evidence that c-NSAIDs (“coxibs”) are significantly safer than “traditional” NSAIDs in terms of the risk of developing this pathology [3].

The most modern technique for accurately diagnosing pathology of the mucous membrane of the jejunum and ileum, which occurs while taking NSAIDs, is video capsule endoscopy (VCE). It was she who was used in a number of studies that compared the effect of “coxibs” and n-NSAIDs on the state of TC [3, 33].

In recent years, the first reports of a relatively low incidence of NSAID enteropathy with the use of meloxicam have appeared, confirmed by TBEV data. Thus, we recently conducted a study on the effect of meloxicam (Movalis) and diclofenac on the state of TC in 15 patients with AS. The choice of this nosological form for studying 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 SO TC – the presence of inflammation, hemorrhages, erosions or ulcers were detected equally often while taking meloxicam 15 mg / day or diclofenac 100-200 mg / day: 71.4 and 75%, respectively. However, the average number of erosions was significantly less in those who received movalis: 6.2±4.7 and 9.4±7.3, respectively [34].

Our data are consistent with those of Y. Maehata et al. [35]. They performed VCE in 29 volunteers with initially normal SO TC who received meloxicam 10 mg/day or celecoxib 200 mg/day for 2 weeks. The number of persons who, after a course of NSAIDs, had a pathology of the TC, when using meloxicam, was less than when taking “coxib” – 26.7 and 42.9% respectively.

It can be stated that, in relation to CVR, meloxicam is at least no worse than “traditional” NSAIDs. So, in a series of RCTs conducted in the late 90s of the XX century, it was shown that the risk of developing severe CV events when using meloxicam does not exceed that against placebo.

According to the results of the meta-analysis of 28 RCTs conducted by G. Singh [28], the incidence of myocardial infarction with the use of 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 above work by P. McGettigan and D. Henry [12], meloxicam showed a mild (not exceeding the average level for all NSAIDs), inherent in the entire class of NSAIDs, the ability to increase the risk of developing MI – by about 20% (OR 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. 40% increased risk).

Comparable results presented by Finnish scientists A. Helin-Salmivaara et al. [36]. They conducted a large population-based study in which the RR for the development of NSAID-related CV events was assessed in 33,309 patients with MI (138,949 – corresponding control; Fig. 2 ). data from a population study conducted in Finland: 33,309 patients with MI, 138,949 – controls) [36]. The risk level for those taking meloxicam was at the average level – OR 1.25. This is somewhat higher than in those taking naproxen (OR 1.19), but clearly less compared to diclofenac (OR 1.35) and especially nimesulide (OR 1.69).

There is a very curious fact: meloxicam was once studied as a component of IHD therapy (!). During 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 who underwent similar antithrombotic therapy constituted the control – they were assigned a placebo. Treatment outcomes in the meloxicam group were clearly better. So, among the patients who received this drug, no one developed MI and no patient died; at the same time, there were 2 cases of MI and one coronary death in the control group. In the 1st group, revascularization was required in 6 (10%) patients, and in the 2nd – 15 (25%; р <0. 05) [37].

Nowadays, such a study seems rather like medical casuistry; nevertheless, it can serve as a good illustration of the favorable tolerability of meloxicam in patients with risk factors for CVD.

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 the analysis of the California Database of Patients with MI ( n =15 343). In patients treated with meloxicam in combination with aspirin, the risk of MI was significantly lower than in patients who received this 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 treated with these drugs together, the risk of MI was even slightly higher than in patients who took ibuprofen alone: ​​OR 1.2 and 1. 08, respectively [38].

When discussing the benefits of meloxicam, attention should be paid to the low risk of allergic skin reactions. Although these complications are rare with the use of NSAIDs, in some cases they can be a serious problem. Meloxicam in this regard is quite safe. Thus, according to American authors, during the first 2 years of using 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 frequency 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 that have shown the possibility of using meloxicam in patients who have 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, the assessment of the risk of 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 17,289of participants in an 18-month MEDAL RCT (comparison of etoricoxib and diclofenac) who received diclofenac, a three-fold increase in alanine aminotransferase activity was noted in 3.1%, and a ten-fold increase in 0.5% [43]. Although not a single episode of liver failure or jaundice was recorded, such a clear negative dynamics of biochemical parameters is of concern and is the reason for interrupting therapy.

Fortunately, these problems are not typical for meloxicam.

In the available literature, against the background of treatment with this drug, only isolated cases of asymptomatic, but a significant increase in the level of transaminases or clinically pronounced liver dysfunctions were not noted [44, 45].

Comparative hepatotoxicity of various NSAIDs was studied by 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 showed the best tolerance. The frequency of hepatotoxic reactions during its use was 23.6 episodes per 100,000 person-years. A similar indicator 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 physicians, the “reputation” of the drug is of great importance, which is acquired over the 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 tolerance and actively use it in their work.