Side effects of duloxetine – NHS

Like all medicines, duloxetine can cause side effects in some people. But most people have no side effects or only minor ones.

Some of the common side effects of duloxetine will gradually improve as your body gets used to it.

Common side effects

These common side effects of duloxetine can happen in up to 1 in 10 people. There are things you can do to help cope with them:

Difficulty sleeping

Try taking duloxetine first thing in the morning.

Headaches

Make sure you rest and drink plenty of fluids. Try not to drink too much alcohol. Ask your pharmacist to recommend a painkiller. Talk to your doctor if the headaches last longer than a week or are severe.

Feeling dizzy

If duloxetine makes you feel dizzy when you stand up, try getting up very slowly or stay sitting down until you feel better. If you begin to feel dizzy, lie down so you do not faint, then sit until you feel better. Do not drive, cycle or use tools or machinery if you feel dizzy.

Blurred vision

Avoid driving, cycling or using tools or machinery while this is happening. If it lasts for more than a day or two, your doctor may need to change your treatment.

Constipation

Try to get more fibre into your diet, such as fresh fruit and vegetables and cereals, and drink plenty of water. Try to exercise more regularly, for example by going for a daily walk or run.

Diarrhoea

Drink lots of fluids, such as water or squash, to avoid dehydration. Signs of dehydration include peeing less than usual or having dark, strong-smelling pee.

Do not take any other medicines to treat diarrhoea without speaking to a pharmacist or doctor.

If you take contraceptive pills and you have severe diarrhoea for more than 24 hours, your contraception may not protect you from pregnancy. Check the pill packet for advice.

Feeling or being sick (nausea or vomiting)

Stick to simple meals and do not eat rich or spicy food. Make sure you take duloxetine in the morning with some food. Try small, frequent sips of water if you’re being sick to avoid dehydration. Signs of dehydration include peeing less than usual or having dark, strong-smelling pee.

If you take contraceptive pills and you’re being sick, your contraception may not protect you from pregnancy. Check the pill packet for advice.

Dry mouth

Chew sugar-free gum or suck sugar-free sweets.

Sweating

Try wearing loose clothing, use a strong anti-perspirant, and keep cool using a fan if possible. If this does not help, you may need to try a different type of antidepressant.

Tiredness

Do not drive, cycle or use tools or machinery if you’re feeling this way. Try taking duloxetine 1 hour before bedtime. Cut down the amount of alcohol you drink as alcohol will make you feel more tired.

If the tiredness does not go away after 2 weeks, ask your doctor for advice.

Less appetite than usual and weight loss

This side effect should get better as your body gets used to the medicine. It may also help to eat smaller meals more often and eat foods you really enjoy. If your appetite does not improve or you lose a lot of weight, ask your doctor for advice.

Feeling less interested in sex, or having problems keeping an erection or reaching orgasm

Speak to your doctor if you get this side effect and it does not go away.

Speak to a doctor or pharmacist if the advice on how to cope does not help and a side effect is still bothering you or does not go away.

Serious side effects

Serious side effects are rare and happen in less than 1 in 100 people.

Book an appointment with your doctor if you get changes in your periods, such as heavy bleeding, spotting or bleeding between periods.

Call a doctor or call 111 straight away if you have:

• hallucinations (seeing or hearing things that are not real), or you become aggressive and angry
• feelings of euphoria, excessive enthusiasm or excitement, or feeling restless so that you cannot sit or stand still
• constant headaches, long-lasting confusion or weakness, or frequent muscle cramps – these can be signs of low sodium levels in your blood
• yellowing of the whites of your eyes, or your skin although this may be less obvious on brown or black skin – these can be signs of a liver problem
• eye pain or blurred vision
• black or red poo or blood in your vomit – these can be signs of bleeding from your gut
• coughed up blood or have blood in your pee
• bleeding from your gums, or bruises that appear without a reason or get bigger

Immediate action required: Call 999 or go to A&E now if you get:

• tightness in your chest or shortness of breath
• any heavy bleeding that you cannot stop, such as cuts or nosebleeds that do not stop within 10 to 15 minutes
• painful erections that last longer than 2 hours – this may happen even when you’re not having sex
• thoughts about harming yourself or ending your life

Find your nearest A&E

Serious allergic reaction

In rare cases, it’s possible to have a serious allergic reaction (anaphylaxis) to duloxetine.

Immediate action required: Call 999 now if:

• your lips, mouth, throat or tongue suddenly become swollen
• you’re breathing very fast or struggling to breathe (you may become very wheezy or feel like you’re choking or gasping for air)
• your throat feels tight or you’re struggling to swallow
• your skin, tongue or lips turn blue, grey or pale (if you have black or brown skin, this may be easier to see on the palms of your hands or soles of your feet)
• you suddenly become very confused, drowsy or dizzy
• someone faints and cannot be woken up
• a child is limp, floppy or not responding like they normally do (their head may fall to the side, backwards or forwards, or they may find it difficult to lift their head or focus on your face)

You or the person who’s unwell may also have a rash that’s swollen, raised, itchy, blistered or peeling.

These can be signs of a serious allergic reaction and may need immediate treatment in hospital.

Other side effects

These are not all the side effects of duloxetine. For a full list, see the leaflet inside your medicines packet.

Information:

You can report any suspected side effect using the Yellow Card safety scheme.

Visit Yellow Card for further information.

Page last reviewed: 14 February 2022

Next review due: 14 February 2025

Cymbalta Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing

Warnings:

Antidepressant medications are used to treat a variety of conditions, including depression and other mental/mood disorders. These medications can help prevent suicidal thoughts/attempts and provide other important benefits. However, a small number of people (especially people younger than 25) who take antidepressants for any condition may experience worsening depression, other mental/mood symptoms, or suicidal thoughts/attempts. It is very important to talk with the doctor about the risks and benefits of antidepressant medication (especially for people younger than 25), even if treatment is not for a mental/mood condition.

Tell the doctor right away if you notice worsening depression/other psychiatric conditions, unusual behavior changes (including possible suicidal thoughts/attempts), or other mental/mood changes (including new/worsening anxiety, panic attacks, trouble sleeping, irritability, hostile/angry feelings, impulsive actions, severe restlessness, very rapid speech). Be especially watchful for these symptoms when a new antidepressant is started or when the dose is changed.

Warnings:

Antidepressant medications are used to treat a variety of conditions, including depression and other mental/mood disorders. These medications can help prevent suicidal thoughts/attempts and provide other important benefits. However, a small number of people (especially people younger than 25) who take antidepressants for any condition may experience worsening depression, other mental/mood symptoms, or suicidal thoughts/attempts. It is very important to talk with the doctor about the risks and benefits of antidepressant medication (especially for people younger than 25), even if treatment is not for a mental/mood condition.

Tell the doctor right away if you notice worsening depression/other psychiatric conditions, unusual behavior changes (including possible suicidal thoughts/attempts), or other mental/mood changes (including new/worsening anxiety, panic attacks, trouble sleeping, irritability, hostile/angry feelings, impulsive actions, severe restlessness, very rapid speech). Be especially watchful for these symptoms when a new antidepressant is started or when the dose is changed.

… Show More

Uses

Duloxetine is used to treat depression and anxiety. In addition, duloxetine is used to help relieve nerve pain (peripheral neuropathy) in people with diabetes or ongoing pain due to medical conditions such as arthritis, chronic back pain, or fibromyalgia (a condition that causes widespread pain).Duloxetine may improve your mood, sleep, appetite, and energy level, and decrease nervousness. It can also decrease pain due to certain medical conditions. Duloxetine is known as a serotonin-norepinephrine reuptake inhibitor (SNRI). This medication works by helping to restore the balance of certain natural substances (serotonin and norepinephrine) in the brain.

How to use Cymbalta

Read the Medication Guide and, if available, the Patient Information Leaflet provided by your pharmacist before you start using duloxetine and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth as directed by your doctor, usually 1 or 2 times a day with or without food. If you have nausea, it may help to take this drug with food. Swallow the capsule whole. Do not crush or chew the capsule or mix the contents with food or liquid. Doing so can release all of the drug at once, increasing the risk of side effects.

The dosage is based on your age, medical condition and response to treatment. To reduce your risk of side effects, your doctor may direct you to start this medication at a low dose and gradually increase your dose. Follow your doctor’s instructions carefully. Take this medication regularly to get the most benefit from it. To help you remember, take it at the same time(s) each day.

Keep taking this medication even if you feel well. Do not stop taking this medication without consulting your doctor. Some conditions may become worse when this drug is suddenly stopped. Also, you may experience symptoms such as dizziness, confusion, mood swings, headache, tiredness, diarrhea, sleep changes, and brief feelings similar to electric shock. Your dose may need to be gradually decreased to reduce side effects. Report any new or worsening symptoms right away.

Tell your doctor if your condition lasts or gets worse.

Side Effects

See also Warning section.

Nausea, dry mouth, constipation, loss of appetite, tiredness, drowsiness, or increased sweating may occur. If any of these effects last or get worse, tell your doctor promptly.

Dizziness or lightheadedness may occur, especially when you first start or increase your dose of this drug. To reduce the risk of dizziness, lightheadedness, or falling, get up slowly when rising from a sitting or lying position.

Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

This medication may raise your blood pressure. Check your blood pressure regularly and tell your doctor if the results are high.

Tell your doctor right away if you have any serious side effects, including: confusion, easy bleeding/bruising, decreased interest in sex, changes in sexual ability, muscle cramps/weakness, shaking (tremor), difficulty urinating, signs of liver problems (such as nausea that doesn’t stop, stomach/abdominal pain, vomiting, yellowing eyes/skin, dark urine).

Get medical help right away if you have any very serious side effects, including: black stools, vomit that looks like coffee grounds, seizure, eye pain/swelling/redness, widened pupils, vision changes (such as seeing rainbows around lights at night, blurred vision).

This medication may increase serotonin and rarely cause a very serious condition called serotonin syndrome/toxicity. The risk increases if you are also taking other drugs that increase serotonin, so tell your doctor or pharmacist of all the drugs you take (see Drug Interactions section). Get medical help right away if you develop some of the following symptoms: fast heartbeat, hallucinations, loss of coordination, severe dizziness, severe nausea/vomiting/diarrhea, twitching muscles, unexplained fever, unusual agitation/restlessness.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing, skin blisters, mouth sores.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US – Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada – Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Precautions

Before taking duloxetine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: personal or family history of psychiatric disorders (such as bipolar/manic-depressive disorder), personal or family history of suicide attempts, bleeding problems, personal or family history of glaucoma (angle-closure type), high blood pressure, kidney disease, liver disease, seizure disorder, stomach problems (such as slow emptying of the stomach), use/abuse of alcohol.

This drug may make you dizzy or drowsy. Alcohol or marijuana (cannabis) can make you more dizzy or drowsy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Avoid alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).

If you have diabetes, duloxetine may affect your blood sugar. Check your blood sugar regularly as directed and share the results with your doctor. Your doctor may need to adjust your diabetes medication, exercise program, or diet.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Older adults may be more sensitive to the side effects of this drug, especially bleeding, dizziness, lightheadedness, or loss of coordination. Older adults may also be more likely to develop a type of salt imbalance (hyponatremia), especially if they are taking “water pills” (diuretics). Dizziness, lightheadedness, or loss of coordination can increase the risk of falling.

Children may be more sensitive to the side effects of this drug, especially loss of appetite and weight loss. Monitor weight and height in children who are taking this drug. See also Warning.

During pregnancy, this medication should be used only when clearly needed. When this medication is taken during the last 30 days of pregnancy, the mother may be at an increased risk of bleeding at birth. This medication may also harm an unborn baby. Babies born to mothers who have used this drug during the last 3 months of pregnancy may rarely develop withdrawal symptoms such as feeding/breathing difficulties, seizures, muscle stiffness, or constant crying. If you notice any of these symptoms in your newborn, tell the doctor promptly.

Since untreated mental/mood problems (such as depression, anxiety) can be a serious condition, do not stop taking this medication unless directed by your doctor. If you are planning pregnancy, become pregnant, or think you may be pregnant, immediately discuss the benefits and risks of using this medication during pregnancy with your doctor.

This drug passes into breast milk and may have undesirable effects on a nursing infant. Consult your doctor before breast-feeding.

Interactions

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.

Some products that may interact with this drug are: other drugs that can cause bleeding/bruising (including antiplatelet drugs such as clopidogrel, NSAIDs such as ibuprofen/naproxen, “blood thinners” such as dabigatran/warfarin).

Other medications can affect the removal of duloxetine from your body, which may affect how duloxetine works. Examples include cimetidine, viloxazine, certain quinolone antibiotics (such as ciprofloxacin, enoxacin), among others.

This medication can slow down the removal of other medications from your body, which may affect how they work. Examples of affected drugs include antiarrhythmic drugs (such as propafenone, flecainide, quinidine), antipsychotics (such as thioridazine), tricyclic antidepressants (such as desipramine, imipramine), among others.

Taking MAO inhibitors with this medication may cause a serious (possibly fatal) drug interaction. Avoid taking MAO inhibitors (isocarboxazid, linezolid, metaxalone, methylene blue, moclobemide, phenelzine, procarbazine, rasagiline, safinamide, selegiline, tranylcypromine) during treatment with this medication. Most MAO inhibitors should also not be taken for two weeks before and at least 5 days after treatment with this medication. Ask your doctor when to start or stop taking this medication.

The risk of serotonin syndrome/toxicity increases if you are also taking other drugs that increase serotonin. Examples include street drugs such as MDMA/”ecstasy,” St. John’s wort, certain antidepressants (including SSRIs such as fluoxetine/paroxetine, other SNRIs such as desvenlafaxine/venlafaxine), tryptophan, among others. The risk of serotonin syndrome/toxicity may be more likely when you start or increase the dose of these drugs.

Tell your doctor or pharmacist if you are taking other products that cause drowsiness including alcohol, marijuana (cannabis), antihistamines (such as cetirizine, diphenhydramine), drugs for sleep or anxiety (such as alprazolam, diazepam, zolpidem), muscle relaxants, and opioid pain relievers (such as codeine). Check the labels on all your medicines (such as allergy or cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely.

Aspirin can increase the risk of bleeding when used with this medication. However, if your doctor has directed you to take low-dose aspirin for heart attack or stroke prevention (usually 81-162 milligrams a day), you should continue taking it unless your doctor instructs you otherwise.

Does Cymbalta interact with other drugs you are taking?

Enter your medication into the WebMD interaction checker

Overdose

If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe drowsiness, fainting.

Do not share this medication with others.

Lab and/or medical tests (such as blood pressure, liver function) should be done while you are taking this medication. Keep all medical and lab appointments.

If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.

Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

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CONDITIONS OF USE: The information in this database is intended to supplement, not substitute for, the expertise and judgment of healthcare professionals. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for you or anyone else. A healthcare professional should be consulted before taking any drug, changing any diet or commencing or discontinuing any course of treatment.

Simbalta: instruction, price, analogues | hard capsules, enteric Lilly S.A.

• Pharmacological properties
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duloxetine ((S)-(+)-N-Methyl-g-(1-naphthalenyloxy)-2-thiophenepropanamine) is a serotonin and norepinephrine reuptake inhibitor. It slightly inhibits dopamine uptake, has no significant affinity for histamine and dopamine, cholinergic and adrenergic receptors. The mechanism of the therapeutic action of duloxetine in depression is due to inhibition of serotonin and norepinephrine reuptake and, as a result, increased serotonergic and noradrenergic neurotransmission in the CNS. Duloxetine also normalizes pain threshold in some experimental models of neuropathic and inflammatory pain and reduces pain in a model of chronic pain. The analgesic effect of duloxetine is probably due to a slowdown in the transmission of nociceptive impulses in the CNS.

Duloxetine is well absorbed after oral administration. The maximum plasma concentration is reached 6 hours after taking the drug. Simultaneous ingestion of food slows down absorption, while the period of reaching the maximum concentration in the blood is lengthened from 6 to 10 hours, and absorption decreases (approximately 11%).

Duloxetine is highly bound to plasma proteins (greater than 90%).

Duloxetine is extensively metabolized in the body, metabolites are excreted primarily in the urine. Isoenzymes CYP 2D6 and CYP 1A2 catalyze the formation of the two main metabolites of duloxetine (glucuronide coupled to 4-hydroxy duloxetine, sulfate coupled to 5-hydroxy, methoxy duloxetine). The resulting metabolites do not have pharmacological activity.

The half-life of duloxetine is 12 hours. The mean plasma clearance of duloxetine is 101 l/h.

In patients with end-stage renal disease who are constantly on dialysis, there is a doubling of the concentration of duloxetine in the blood plasma and an increase in AUC compared with healthy individuals. Therefore, in patients with chronic renal failure, the drug is prescribed at a lower initial dose.

depression; diabetic neuropathy.

for depression and diabetic neuropathy is prescribed orally at a dose of 60 mg 1 time per day daily, regardless of food intake. Some patients may be recommended to prescribe the drug at a higher dose (up to a maximum of -120 mg / day in 2 divided doses). The possibility of prescribing at doses exceeding 120 mg / day has not been studied.

Initial dosage for patients with end-stage renal disease (creatinine clearance <30 mL/min) is 30 mg once daily.

Patients with cirrhosis of the liver are prescribed at a lower initial dose or with longer intervals between doses.

No dose adjustment is required in elderly or elderly patients. Duloxetine has not been studied in patients under 18 years of age.

hypersensitivity to duloxetine, concomitant therapy with MAO inhibitors.

during clinical trials, side effects such as constipation, nausea, dry mouth, dizziness, fatigue, insomnia and headache (≥10%) were observed. Less commonly (with a frequency of <10%, but ≥1%), tachycardia, dyspepsia, vomiting, decreased appetite, drowsiness, tremor, lethargy, sweating, feeling hot, yawning were observed. On the part of the reproductive system, ejaculation and erection disorders were observed (with a frequency of <10%, but ≥1%), decreased libido and anorgasmia. Rarely (<1%, but ≥0.1%), gastroenteritis, stomatitis, increased blood pressure, weight gain, muscle tension, taste and visual disturbances, agitation, urinary retention were observed.

Treatment with duloxetine in placebo-controlled clinical trials was associated with non-significant increases in ALT, AsAT, and CPK compared to placebo.

In clinical trials of duloxetine for the treatment of diabetic neuropathy, the mean duration of diabetes mellitus was approximately 11 years, mean initial fasting serum glucose was up to 163 mg/dl, and mean initial glycated hemoglobin was 7.80%. These studies noted a slight increase in initial fasting blood glucose after 12 weeks in patients treated with duloxetine, compared with placebo, at the usual regimen for 52 weeks. There were no changes in the rate of glycated hemoglobin, body weight of patients, lipid concentrations (Cholesterol, LDL, HDL, TG) or any side effects associated with diabetes mellitus.

The following side effects have been reported from post-marketing studies:

on the part of the organ of vision: very rarely (<0.01%) - glaucoma;

from the hepatobiliary system: very rarely (<0.01%) - hepatitis, jaundice;

from the immune system: very rarely (<0.01%) - anaphylactic reactions;

on the part of laboratory parameters: very rarely (<0. 01%) – increased activity of ALT, AST, alkaline phosphatase, bilirubin levels in the blood;

from the side of metabolism: very rarely (<0.01%) - hyponatremia;

on the part of the skin: rarely (0.01-0.1%) – rash; very rarely (<0.01%) - angioedema, Stevens-Johnson syndrome, urticaria;

from the side of the cardiovascular system: very rarely (<0.01%) - orthostatic hypotension and syncope (especially at the beginning of treatment).

patients at high risk of suicide during the treatment period should be under strict observation, since the possibility of suicidal attempts is not excluded before the onset of a pronounced remission.

Duloxetine hydrochloride has not been studied in patients under 18 years of age and should therefore not be used in this age group.

As with other CNS-active drugs, duloxetine should be used with caution in patients with a history of mania.

As with other CNS-active drugs, duloxetine should be used with caution in patients with a history of seizures.

Mydriasis has been reported in association with duloxetine, so duloxetine should be used with caution in patients with elevated intraocular pressure or at risk of developing acute narrow-angle glaucoma.

Increased plasma concentrations of duloxetine have been reported in patients with severe renal insufficiency (creatinine clearance <30 ml/min) or severe hepatic insufficiency. Such patients are advised to prescribe the drug at a lower initial dose.

In some patients, duloxetine leads to an increase in blood pressure. In patients with hypertension and / or other diseases of the cardiovascular system, monitoring of blood pressure is recommended.

In clinical studies, there was an increase in the activity of liver enzymes in the blood. In most patients treated with duloxetine, this increase was transient and resolved upon discontinuation of duloxetine treatment. A significant increase in liver enzyme activity (greater than 10 times normal) or liver damage with cholestasis, or a significant increase in enzyme activity in combination with liver damage, has rarely occurred, in some cases it has been associated with alcohol abuse.

Duloxetine was not mutagenic in experiments in vitro and in vivo .

In experiments, duloxetine at a dose of 45 mg/kg/day did not affect the reproductive function of male rats. In female rats, the use of duloxetine at a dose of 45 mg / kg / day was accompanied by such manifestations of reproductive toxicity as menstrual irregularities, a decrease in the birth rate index, survival rate, and slow growth of pups.

Adequate and well-controlled studies of the effect of the drug in pregnant women have not been conducted, so the use of the drug during pregnancy is not recommended.

Duloxetine is excreted in breast milk. The approximate daily dose in an infant is 0.14% of the dose for a nursing woman (in mg / kg). The safety of duloxetine use in a nursing infant has not been established, so breast-feeding while taking duloxetine is not recommended.

During the period of treatment with the drug, patients should refrain from potentially hazardous activities that require increased attention and speed of psychomotor reactions.

duloxetine should not be given concomitantly with MAO inhibitors or within at least 14 days after stopping treatment with MAO inhibitors. Due to the half-life of duloxetine, MAO inhibitors should also not be administered for at least 5 days after discontinuation of duloxetine treatment.

In clinical studies with the simultaneous administration of theophylline, a CYP1A2 substrate, with duloxetine at a dose of 60 mg 2 times a day, no significant changes in their pharmacokinetics were noted. These results indicate that duloxetine is unlikely to have a clinically significant effect on the metabolism of CYP1A2 substrates.

Since CYP1A2 is involved in the metabolism of duloxetine, concomitant use of duloxetine with active inhibitors of CYP1A2 may result in increased plasma concentrations of duloxetine. Fluvoxamine (at a dose of 100 mg 1 time per day), being an active inhibitor of CYP1A2, reduces the clearance of duloxetine from blood plasma by approximately 77%. In this regard, when prescribing duloxetine with CYP1A2 inhibitors (some quinolone antibacterial agents), it is advisable to prescribe duloxetine at a lower dose.

Duloxetine is a moderate inhibitor of CYP2D6. When prescribing duloxetine at a dose of 60 mg 2 times a day with a single dose of desipramine, which is a substrate of CYP2D6, the AUC of desipramine increases 3 times. Co-administration of duloxetine (at a dose of 40 mg 2 times a day) increases the stationary AUC of tolterodine (2 mg 2 times a day) by 71%, but does not affect the pharmacokinetics of the 5-hydroxyl metabolite. In this regard, when prescribing duloxetine with CYP2D6 inhibitors, which have a narrow therapeutic index, care must be taken.

Since CYP2D6 is involved in the metabolism of duloxetine, concomitant use of duloxetine with active inhibitors of CYP2D6 can lead to an increase in the concentration of duloxetine in the blood. Paroxetine (at a dose of 20 mg 1 time per day) reduces the clearance of duloxetine from blood plasma by approximately 37%. In this regard, caution should be exercised when prescribing duloxetine with CYP2D6 inhibitors.

When prescribing duloxetine in combination with other drugs that affect the central nervous system, especially with a similar mechanism of action, care should be taken.

Duloxetine binds to plasma proteins (>90%), so the administration of duloxetine to a patient who is taking other drugs that are highly bound to plasma proteins may lead to an increase in the free concentration of any of these drugs.

Clinical data on duloxetine overdose are limited. No cases of fatal overdose of duloxetine have been reported in pre-marketing clinical trials. There have been cases of overdose of the drug (up to 1400 mg), including in combination with other drugs, but they did not lead to death.

In animal experiments, the main manifestations of toxicity in case of overdose were noted from the side of the central nervous system and gastrointestinal tract. These included symptoms such as tremor, clonic convulsions, ataxia, vomiting, and anorexia.

No specific antidote known. Immediately after an overdose, gastric lavage and the appointment of activated charcoal are indicated. The airway should be secured. It is recommended to monitor the main vital signs, primarily cardiac activity, if necessary, symptomatic and supportive therapy. Duloxetine has a large volume of distribution, and therefore forced diuresis, hemoperfusion and exchange perfusion are ineffective in overdose.

at temperatures up to 30 °C in original packaging.

The use of duloxetine, a dual reuptake inhibitor, in the treatment of painful diabetic neuropathy | Guryeva

Diabetic neuropathy is known to be a common complication of diabetes mellitus and is registered in 30% of patients on the basis of the hospital registry, in 25% of patients during large-scale population studies [1]. The incidence is 2% per year. Symmetrical distal polyneuropathy (DSN) is the most common type of diabetic disorder, accounting for about 80% of all cases of diabetic neuropathy. The main etiological factors associated with DPN are the duration of the disease, poor glycemic control, age, smoking, and dyslipidemia [2, 3]. Pain is the most common disturbing symptom, forcing the patient to seek medical attention [4]. Not only diabetic polyneuropathy, but focal and multifocal diabetic neuropathies, such as isolated cranial nerve palsy or proximal motor neuropathy of the lower extremities, can be accompanied by pain. The incidence of painful diabetic neuropathy according to studies varies from 8 to 26% among diabetic patients, depending on the criteria for assessing pain [5]. Distal symmetric polyneuropathy is combined with autonomic disorders.

The onset of DPN is usually sudden and, in the absence of early intervention, the course is chronic and progressive. A decrease or loss of function of thin nerve fibers leads to a violation of pain perception (pain from hot touch and injection), as well as temperature perception – cold (Aδ) and heat (C-fibers). When thick (Aα and Aβ) nerve fibers are involved, nerve conduction velocity slows down and sensitivity to touch, pressure, and vibration decreases, which in severe cases can lead to sensory ataxia (ataxic gait).

Involvement of sensory fibers in the process causes “positive symptoms”, which include paresthesia, dysesthesia and pain, and may also be accompanied by “negative” symptoms – a decrease in sensitivity.

Persistent or episodic pain is usually localized in the feet, increases at night and decreases during walking. Patients describe the pain as deep aching, but also as a stabbing or burning sensation in the legs. Pain caused by stimuli that are not usually accompanied by pain—allodynia and hyperalgesia —significant pain caused by stimuli that are usually accompanied by mild pain—may also be present. The pain may at the same time be accompanied by a decrease in sensitivity. Neuropathic pain in diabetes mellitus persists for several years in a number of patients, causing both physical and emotional suffering, while in others it disappears completely or partially, despite a progressive decrease in the function of fine nerve fibers. Pain remission is associated with sudden metabolic changes, short duration of pain, prior weight loss, and less severe sensory loss [6].

Chronic pain is a common condition, accompanied by a decrease in quality of life and is associated with disability, however, one third of patients do not receive any treatment, 40% of patients receive inadequate therapy, and only 2% are treated by pain specialists [7].

Although the pathogenesis of pain has not yet been sufficiently elucidated, it is clear that chronic neuropathic pain arises as a result of damage and impaired adaptation mechanisms in both the peripheral and central nervous systems.

Primary pain receptors (nociceptors) are sensory endings of nerves located in various tissues and organs. The transmission and perception of pain is a two-way process and is carried out through ascending and descending neuronal pathways. Following tissue damage, there is a massive release of inflammatory mediators – histamine, prostaglandins and bradykinin, which activate and sensitize nociceptors. Further, the pain impulse through the primary afferent neurons enters the synapses of the posterior horns of the spinal cord, where the impulse passes into second-order neurons, while substance P is released into the intersynaptic gap. Through the second-order neurons of the posterior horns, the pain impulse ascends along the anterolateral spinothalamic tract, affecting the synapses in thalamus, and then goes to the somatosensory cortex for interpretation. In turn, the brain modulates ascending impulses through descending neuronal mechanisms that exercise their control through descending spinothalamic pathways [8]. Among various modulators and neurotransmitters, serotonin (5-hydroxytryptophan, 5-HT) and norepinephrine (NA) are especially important [9]. Experimental animal studies have demonstrated the involvement of the serotonergic and noradrenergic systems in pain modulation [10]. The descending pathways are designed to suppress incoming stimuli from the gastrointestinal tract and the musculoskeletal systems. Dysfunction of these pathways is accompanied by increased sensitivity to pain and even painful responses to normal non-painful stimuli. Thus, an increase in the content of 5-HT and NA is accompanied by an endogenous analgesic effect, acting through a descending inhibitory neuronal pathway at the level of the brain and spinal cord [11].

Painful diabetic neuropathy is the result of both metabolic and microcirculatory disturbances in neurons caused by chronic hyperglycemia, which lead to pathological impulses from peripheral nociceptors recognized by the brain as pain. Over time, “central sensitization” occurs, leading to further intensification and chronicization of pain. Central sensitization leads to neuronal plasticity and changes in pain conduction, which eventually transform into states where a small painful stimulus can be recognized as very strong, or pain can persist even in the absence of any stimuli [12].

Recent studies have shown that diabetes affects all levels of the nervous system, from the peripheral nerve to the brain [13]. Magnetic resonance imaging confirmed a lesion of the type of demyelination at the level of the spinal cord already in the early stages of neuropathy, identical to the consequences observed in spinal cord injury 145]. Magnetic resonance spectroscopy studies show the presence of thalamic dysfunction in diabetic sensorimotor polyneuropathy [15]. Thus, diabetes has a much more generalized effect on the nervous system than previously thought.

Dysfunction of the noradrenergic and/or serotonergic systems of the brain and spinal cord has common psychopharmacological mechanisms involved in the development of both pain and depression. The use of antidepressants has been shown in animal experiments to cause the growth of hippocampal neurons and thus induce neurogenesis. This property of antidepressants promotes neuroplasticity, and thus helps to influence the main symptoms of depression associated with mood and motivation. Studies show that “dual action” drugs that act on both the serotonin and norepinephrine systems have the most significant effect on both depression and chronic pain [11].

Chronic pain associated with diabetic neuropathy ranks second in the structure of neuropathic pain after back pain. Treatment of pain involves the impact on the pathophysiological mechanisms of its formation. The main goal of this approach is to ensure the analgesic activity of the drug or drug combinations while reducing the number of side effects, which improves the patient’s adherence to treatment.

The management of pain associated with diabetic peripheral nervous system disease is a difficult task. The progression of DPN largely depends on the severity of diabetes and the degree to which glycemic control is maintained over time. In the treatment of pain, various non-drug methods of treatment are used (acupuncture, magnetotherapy, transcutaneous electrical nerve stimulation, massage, etc.), the effectiveness of which remains unproven [13]. Currently, drug therapy is the most effective in the treatment of neuropathic pain [14, 15]. It should immediately be emphasized that simple analgesics and non-steroidal anti-inflammatory drugs in the treatment of pain in DPN are not recommended due to their inefficiency and the high frequency of adverse events with long-term use (complications from the gastrointestinal tract, liver and blood).

The main groups of drugs for the treatment of neuropathic pain in DPN are: antidepressants, anticonvulsants, opioid analgesics (Table 1).

Currently, the possibility of pathogenetic treatment of painful neuropathy is being discussed. The results obtained in multicenter placebo-controlled studies on the use of alpha-lipoic (thioctic) acid show the possibility of short-term relief of pain symptoms accompanying mild or moderate neuropathy, which recovers 3-6 months after discontinuation of the drug [16, 17]. Long-term treatment of severe persistent pain generally requires the administration of systemic or topical pharmacological agents with analgesic activity alone or in combination.

Tricyclic antidepressants (TCAs) have long existed as first-line therapy for the treatment of painful diabetic neuropathy. Amitriptyline given in gradually increasing doses of 10 to 150 mg per day. (see Table 1), provides an analgesic effect, regardless of the antidepressant effect in 7-58% of patients, which may not occur immediately, but after 2-3 weeks from the start of treatment.

TCAs inhibit the reuptake of serotonin and norepinephrine, reduce sympathetic activity, and act on receptors of the central nervous system. The use of TCAs is limited by known intolerable side effects such as sedation, blurred vision, dry mouth, orthostatic hypertension, and cardiac arrhythmias.

Currently, there is ample evidence of the effectiveness and validity of antidepressant treatment of neuropathic pain syndrome. Tricyclic antidepressants inhibit the reuptake of 5-HT and NA, but they have additional effects on muscarinic, histamine, and a-adrenergic receptors, thereby exhibiting side effects that limit their use [18]. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine and citalopram, have no clear evidence of analgesic effect, although preclinical studies have shown their effect on pain [8].

Recently, interest has been shown in the so-called “dual-acting inhibitors”, which simultaneously reduce the reuptake of both serotonin and norepinephrine, which include duloxetine and milnacipram. The results obtained in numerous animal studies in experimental models of chronic pain have convincingly shown that the effect on the serotonergic and noradrenergic systems is more effective than on the serotonergic system alone. At the same time, the perception of pain is inhibited both at the level of the posterior horns of the spinal cord and at the level of supraspinal mechanisms (transmission of central pain).

A particularly effective and well-studied selective and balanced inhibitor of dual action is duloxetine (Cymbalta), the effect of which, apparently, is mediated by effects on a1-adrenergic receptors and 5-HT2 receptors [31]. The effect of duloxetine on neuropathic pain has been studied in animal models (rat models) [11]. It has been shown to be similar to paroxetine in its effect on 5-HT and to desipramine in its ability to maintain NA levels. Compared to other dual-acting inhibitors (venflaxin and milnacipran), it was superior in efficacy. This effect was dose-dependent, did not cause neurological deficit, and had a positive effect on mechanical allodynia. Thus, the potential use of duloxetine in the treatment of persistent neuropathic pain conditions in humans has been substantiated.

The effectiveness of duloxetine for the treatment of painful diabetic peripheral neuropathy has been proven in three double-blind, placebo-controlled studies [21-24]. These studies included 1139 patients with type 1 and type 2 diabetes mellitus and pain diabetic neuropathy lasting more than 6 months; all had a 12-week duloxetine fixed-dose phase.

In the first study (Goldstein et al 2005) [21], patients received 20 mg, 60 mg once and 60 mg twice daily, and placebo for 12 weeks. The second (Raskin et al. 2006) [22] and the third (Wernicke et al. 2006) studies compared doses of duloxetine 60 and 120 mg daily with placebo, also given for 12 weeks. The second and third studies had an extended open-label phase comparing duloxetine with conventional treatment. The main objective of this phase of the study was to assess the safety and satisfaction of patients with treatment, as well as assess the quality of life (EQ-5D).

The mean age of the patients included in the studies was 60 years, the duration of diabetes was 11.7 years, and the duration of neuropathy was 3.9 years (Table 2). All patients had symptoms of painful diabetic neuropathy of a typical symmetrical nature, which lasted at least 6 months. Pain intensity was ≥4 on the mean pain intensity scale over 24 hours (maximum 10). The level of glycated hemoglobin at inclusion was ≤12%, i.e. patients were mostly in a state of poor glycemic control. In order to avoid an indirect effect of duloxetine by acting on the depressive component of pain, patients with depressive symptoms, as well as other mental and somatic diseases that could affect the outcome of treatment, were excluded from the study. The study assessed the primary criteria for effectiveness – the scale of average pain intensity within 24 hours Likert; Secondary efficacy measures included Most Intensive Pain Scale and Nocturnal Pain Intensity, Brief Description of Pain (BPI), Clinical Global Impression of Severity (CGI), Patient Global Impression of Improvement (PGI-Improvement), McGill Brief Pain Inventory, dynamic allodynia, short health questionnaire (SF-36). In all three studies, patients with symptomatic episodes of depression were excluded from the study.

The result of treatment in studies was a reduction of more than 30% in the average daily pain intensity. If duloxetine at a dose of 60 mg and 120 mg per day was superior to the placebo effect, then at a dose of 20 mg it did not differ from placebo (Fig. 2 and 3). After the analysis, it turned out that the change in the results of some psychological tests may also indicate the influence of depression on the result of pain reduction. However, this indirect component of the effect of duloxetine on pain is small and amounted to no more than 20%.

The results of the studies showed that the analgesic effect of duloxetine develops quickly – after a week of treatment with both 60 mg and 120 mg duloxetine. The reduction in pain was statistically significant and remained significant throughout the 12 weeks of treatment. The magnitude of pain reduction was 65% for 60 mg, 64% for 120 mg in the first study, 63% and 69%, respectively, in the second study and significantly exceeded the placebo response rate (42%). It was found that changes in the Beck Anxiety Scale did not affect the outcome, but analysis of the Beck Depression Scale showed a moderate effect on the pain score. Thus, it was concluded that the direct effect of duloxetine on the daily average pain scale is 88.6%, and the indirect effect reaches 11.4%.

As a result of the studies, both primary: pain intensity (average, strongest and weakest), assessed on a 24-hour intensity scale, and secondary criteria were significantly different compared to placebo. Patients also noted an improvement in health status in certain domains of the SF-36 scale, as well as in quality of life (EQ-5D).

The safety and tolerability of duloxetine was assessed in three studies, as well as in three extended (52 weeks) open-label comparative studies [23, 25, 26]. The study was not completed due to side effects in 20% of patients in the placebo group, 20.9% of patients receiving 60 mg and 25.8% of patients receiving 120 mg of duloxetine. A study of the safety and tolerability of duloxetine (Cymbalty) showed a dose-related dependence of side effects of the drug, the most typical of which is at a dose of 60 mg per day. were nausea (22%), dizziness (13%), drowsiness (18%), constipation (11%) and weakness (7%) [23, 25, 26]. These side effects were observed slightly more often when taking 120 mg of duloxetine per day. However, in most patients, side effects were moderate to mild, regardless of the type of treatment.

When compared with standard therapy in open-label 52-week studies (amitriptyline, carbamazepine, gabapentin and venlaflaxine), duloxetine showed sufficient safety and tolerability. The most common (more than 10%) side effects when taking duloxetine were nausea, and with standard therapy – peripheral edema, pain in the extremities, drowsiness and dizziness [27].

During the studies, insignificant changes in the level of glycated hemoglobin and lipids were noted, but only the change in high density lipoproteins was statistically significant in all three studies [12].

The impact of duloxetine on quality of life was evaluated in an extended 52-week phase of the study. In the domains of bodily pain, physical condition and physical functions, a positive effect of the drug was noted. For other SF-36 domains, the changes were negative, but to a lesser extent compared to the changes in the standard treatment groups [12]. On a quality-of-life scale, duloxetine significantly outperformed standard treatment.

Duloxetine is metabolized in the liver under the influence of the cytochrome P450 enzyme with the appearance of two active metabolites, its half-life is 12 hours [28]. Excretion of the drug occurs mainly through the kidneys (70%). The use of duloxetine in patients with renal insufficiency requires caution. After taking 60 mg of simbalta, the maximum plasma concentration of the drug and the distribution of the drug are approximately 2 times higher in patients with end-stage renal disease on hemodialysis than in patients with normal renal function. However, the elimination half-life is the same in both groups. Population pharmacokinetic analysis has shown that in mild to moderate renal insufficiency (creatinine clearance 30-80 ml/min. ), there is no significant effect on the pharmacokinetics of duloxetine. Cymbalta is not recommended for patients with end-stage renal disease and creatinine clearance less than 30 ml/min.

The effectiveness of duloxetine, as well as the incidence of side effects in the treatment of diabetic neuropathy, does not differ significantly with increasing age of patients. However, when prescribing the drug to elderly patients, caution is required when increasing the dose of the drug [11]. During pregnancy, especially in the third trimester, it is desirable to reduce the dose as much as possible [29].

With a sharp withdrawal of the drug, phenomena such as dizziness, nausea, headache, paresthesia may occur. The frequency of these symptoms is small and is about 2%, and therefore it is recommended to gradually reduce the dose of the drug.

Thus, neuropathic pain in diabetes mellitus is complex and, unlike nociceptive pain, is caused by disorders in both the peripheral and central nervous systems. More and more data is accumulating, indicating a whole range of disorders, including changes in the structure and function of the spinal cord, thalamic neuronal dysfunction, and a decrease in the inhibitory effect of descending neuronal pathways. Progress in the study of the pathogenesis of neuropathy opens up new ways to search for drugs that have a direct effect on the pathophysiological mechanisms of pain. The use of duloxetine (Cymbalty), a balanced selective double serotonin and norepinephrine reuptake inhibitor, in patients with diabetes mellitus occupies an important place in the complex treatment of painful diabetic neuropathy.

1. Ziegler D., Rathmann W. Dickhause T., Meisinger C., MielckA., KORA Study Group. Prevalence of polyneuropathy in prediabetes and diabetes is associated with abdominal obesity and macroangiopathy: the MONIKA/KORA Augsburg Surveys S2 and S3.Diabetes Care 2008; 31:464-469.

2. J.Show. P.Z.Zimmet, F.A.Gries and D.Ziegler. Epidemiology of Diabetic Neuropathy. In: Gries FA, Cameron NE, Low PA, Ziegler D (eds) Textbook of diabetic neuropathy. 2003; Thieme, Stuttgart, pp. 64-82.

3. Tesfaye S, Kempler P. Diabetologia 2005; 48:805-807.

4. Sindrup S.H., Jensen T.S. Efficacy of pharmacological treatment of neuropathic pain: an update and effect related to mecanosm of drug action. Pain 1999; 83:389-400.

5. Davies M., Brophy S., Williams R., Taylor A. The prevalence, severity, and impact of painful diabetic neuropathy in type 2 diabetes. Diabetes care 2006: 29; 1580-1522.

6. Ziegler D. Painful diabetic neuropathy:treatment and future aspects. Diabetes Metab Res Rev 2008:24(supple 1): 52-57.

7. Breivik H, Collett B., Ventafridda V., Cohen R. and Callacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006 May;10(4): 287-333.

8. Moshizucki D. Serotonin and noradrenalin reuptake inhibitors in animal models of pain. Hum Psychopharmacol Clin Exp 2004; 19:S15-S19.

9. Kranzler J.D., Gendreau JR, Rao SG.2002 The psychopharmacology of fybromyalgia: a drug development perspective. Psychopharmacol Bull 36; 165-213.

10. Fishbain D.2000 Evidence-based data on pain relief with antidepressants. Ann Med 32:305-316.

11. Delgado P.L. Common pathways of depression and pain. J Clin Psychiatry 2004;65(suppl 12):16-20.

12. Smith T and Nicholson RA . Review of duloxetine in the management of diabetic peripheral neuropathic pain. Vasc Health and Risk Management 2007: 3(6) 833-844.

13. Kapur D.,Neuropathic pain and diabetes. Diabetes Metab Res Rev 2003; 19:9-15.

14. Dejong RN. CNS manifestation of diabetes mellitus Postgrad Med 1977; 61:101-107.

15. Tesfay S, Selvarajah D, Emery CJ et al. Thalamic sensory neuronal dysfunction in distal symmetrical polyneuropathy. Diabetologia 47 (Suppl 1): A365.

16. Ziegler D, Ametov A, Barinov A, et al. Oral Treatment With A-Lipoic Acid Improves Symptomatic Diabetic Polyneuropathy The SYDNEY 2 trial. Diabetes Care 2006; 29:2365-70.

17. Ziegler D. Treatment of neuropathic pain. In: Gries FA, Cameron NE, Low PA, Ziegler D (eds) Textbook of diabetic neuropathy. Thieme, Stuttgart, p. 211-224.

18. MacFarlane BV, Wright A, O’Callaghan J, Benson HA.1997. Chronic neuropathic pain and its control by drugs. Pharmacology and Theraputics 75, 1-19.

19. Yokogawa F, Kiuchi Y, ishikawa Y et al. 2002. An investigation of monoamine receptors involved in aminoceptive effects of antidepressants. Anesth Analg 95:163-168.

20. Iyengar S, Webster AA, Hemrick-Luecke SK, et al. 2004. Efficacy of Duloxetine, a potent and balanced serotonon-norepinephrine reuptake inhibitor in persistent pain models in rats. J Parm Experim Therap, 311:576-584.

21. Golstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. 2005. Duloxetine vs placebo in patients with painful diabetic neuropathy. Pain 116, S. 109-118.

22. Raskin J., Smith T.R., Wong K.et al. 2006 Duloxetine versus routine care in the long term Management of diabetic peripheral neuropathic pain. J. Palliat Med, 9:29-40.

23. Wernicke JF, Pritchett YL, D’SousaDN, et al. 2006a A randomized controlled trial of doloxetine in diabetic peripheral neuropathic pain. Neurology, 67: 1411-20.

24. Wernike J, Lu Y, D’Souza DN, Waninger A, Tran P. Antidepressants: Duloxetine at doses of 60 mg QD and 60 mg BID is effective in treatment of diabetic neuropathic pain (DNP). In: Abstracts of the 2d Joint scientific meeting of the American pain society. May 2004. J. Pain 2004;5(3 suppl 1), S 48.

25. Duloxetine (Cymbalta) for diabetic neuropathic pain. The medical letter. On drugs and theraputics. Published by the medical letter inc/ NY. Vol.47 (issue 1215|1216), 2005. 67-68.

26. Wernicke JF, Raskin J., Rosen A., et al. 2006b Duloxetin in long term management of diabetic peripheral neuropathic pain: an open label, 52 week extention of a randomized controlled clinical trial. Curr the Res Clin Exp, 67;283-304.

27. Raskin J, Smith TR, Wong K. et al. Duloxetine versus Routine Care in the long-Term management of diabetic peripheral neuropathic pain, J Palliative Med , Vol.