Cymbalta®

Cymbalta (duloxetine) is a representative of the newest generation of antidepressants. This drug can be classified as the fifth generation of antidepressants. Antidepressants “come from” tuberculosis, because in the 1940s. The euphoric effect of isonicotinic acid hydroxide was noted in severe tuberculosis patients with bleeding. It was later shown that this effect is due to the irreversible blockade of monoamine oxidase (MAO), an enzyme that destroys biogenic amines (including serotonin) in the synaptic cleft. The next step was the discovery of tricyclic antidepressants (TCAs), which can only be considered accidental to a certain extent. Subsequently, new generations of antidepressants were created thanks to knowledge of the stages of life of the mediator [2]:

• synthesis;
• secretion;
• accumulation;
• release into the synaptic cleft;
• reception;
• destruction in the synaptic cleft;
• reverse capture.

It should be taken into account that biogenic amines - dopamine, norepinephrine, serotonin - have much in common both in the above-described stages of the life of mediators (including common enzyme systems of destruction), and from the point of view of their importance in the pathogenesis of many neurological and psychiatric diseases.

TCAs have been shown to be serotonin, dopamine, and norepinephrine reuptake inhibitors. They have proven to be much more effective and safer in the treatment of depression than irreversible MAO blockers, and for many decades they were the “gold standard” for antidepressants. The advent of TCAs led to MAO blockers leaving clinical practice and returning only with the discovery of reversible MAO blockers such as moclobemide. Moreover, these drugs began to be considered as selective inhibitors of MAO type A, mainly involved in the destruction of serotonin.

The TCA ideology was further developed in selective serotonin reuptake inhibitors (SSRIs). These drugs have undoubted advantages, such as high efficiency, sufficient safety, and the absence of the need for dose titration and withdrawal syndrome. All this has made them very popular not only in psychiatric, but also in general therapeutic practice. SSRIs have also been shown to be highly effective in the treatment of anxiety disorders and this has led to their use in the treatment of generalized anxiety and panic disorders.

Another group of drugs are antidepressants that affect reception by blocking postsynaptic or presynaptic receptors. These include, in particular, mianserin, an antagonist

a2-adrenergic receptors and serotonin receptors (5HT1A and 5HT2C), and trazodone is a 5HT2 receptor blocker.

Thus, until the mid-1990s. The main trend in the development of antidepressants was their selectivity towards monoamine mediators. However, it was subsequently shown that additional therapeutic possibilities lie in the combination of inhibition of serotonin and norepinephrine reuptake, which allows accelerating the onset of the antidepressant effect and affecting pain [8]. All this led to the creation of dual-action antidepressants that selectively block the reuptake of serotonin and norepinephrine. The first representative of this class was venlafaxine. Cymbalta (duloxetine) is a new representative of the class of dual-acting antidepressants.

According to the mechanism of action, Cymbalta is a balanced and powerful inhibitor of the reuptake of serotonin and norepinephrine [12]. The drug is one of the antidepressants with the strongest affinity (affinity) for the transport subunits of serotonin and norepinephrine. Balance means approximately equal binding of transport subunits that perform the reuptake of these mediators.

The affinity coefficient K is estimated in vitro as the drug concentration required to inhibit 50% of the maximum binding sites determined by the radioligand method. The lower the K coefficient, the smaller the amount of drug needed to inhibit binding sites and the stronger the affinity of the drug for transport subunits. According to this indicator, Cymbalta is 3 times superior to venlafaxine [12].

Restoring the balance between serotonergic and noradrenergic mediation with Cymbalta plays a critical role in the treatment of depression and pain, given the role of imbalance of these mediators in the formation of emotional and pain disorders.

Cymbalta has virtually no effect on dopamine reuptake blockade and does not interact with cholinergic and histaminergic receptors.

The pharmacokinetics of Cymbalta is linear and dose dependent. The maximum concentration in plasma is reached after 6 hours, and after food intake - after 10 hours [11]. The half-life of the drug in plasma is 12 hours. Cymbalta is metabolized in the liver through isoenzymes 2D6 (primary metabolic pathway) and 1A2 of the cytochrome P450 system. Cymbalta is classified as a moderate inhibitor of the 2D6 isoenzyme. More than 90% of the drug is protein bound, and this should be taken into account when co-prescribing Cymbalta with substances that may compete with it for this binding. Cymbalta should be combined with caution with TCAs (2D6 inhibition) and antiarrhythmic drugs. Cymbalta does not inhibit isoenzymes 1A2 and 3A4, which mediate the metabolism of most drugs. Therefore, in neurological practice, the use of Cymbalta practically does not limit the use of other drugs. Cymbalta metabolites are inactive and 70% are excreted in the urine. Age and gender have little effect on the pharmacokinetics of the drug, which is why dosage adjustment is not required depending on these indicators.

The clinical effectiveness of Cymbalta against depression can be considered fully studied, since placebo-controlled and comparative studies have been conducted on the use of this drug in adult patients diagnosed with major depressive disorder (in accordance with DSM-IV criteria) [9]. Already in the first week of treatment with Cymbalta at a dose of 60 mg, a significant improvement in the well-being of patients on the Clinical Global Impression (CGI) scale was observed in comparison with the placebo group [3, 4]. The level of depression on the Hamilton scale under the influence of Cymbalta began to significantly decrease from the second week of treatment. At the end of therapy, the effect of Cymbalta was 1.5 times greater than the effect of placebo.

Undoubtedly, the most important indicator for any drug is its safety. As part of the studies, more than 11,500 patients received Cymbalta. The initial dose of Cymbalta is usually equal to the therapeutic dose and is 60 mg/day (single dose) [4, 5]. To reduce the severity of side effects in the first week of use, you can take the drug at a dose of 30 mg/day. Cymbalta is prescribed to patients over 18 years of age. Currently available data indicate that there are no differences in the effectiveness or tolerability of Cymbalta in older and younger patients. It is not recommended to use the drug in patients with severe renal and hepatic pathology [11].

In general, Cymbalta is well tolerated, and the spectrum of its side effects is close to the safety profile of other modern antidepressants. In clinical studies, the following side effects were most often observed [3, 10]:

• nausea (20%);
• dry mouth (15%);
• constipation (11%);
• decreased appetite (8%);
• increased fatigue (8%);
• drowsiness (7%);
• increased sweating (6%).

As a rule, nausea was the reason for discontinuation of the drug, which occurred in 1% of cases. Using Cymbalta 30 mg during the first week reduces the likelihood of developing this side effect.

Taking into account the noradrenergic activity of Cymbalta, the most serious attention in its study was paid to the activity of the cardiovascular system. The drug was shown to not cause negative cardiovascular effects: heart rate increased by two beats per minute compared to placebo, and there was no connection between the increase in blood pressure and the dose of Cymbalta. However, it is recommended to monitor blood pressure at the beginning of treatment. There were no significant changes in the ECG.

Undoubtedly, depression plays a very important role in neurology and occurs in a wide variety of diseases. Depression accompanying somatic or neurological diseases further worsens the quality of life of patients and is more difficult to treat [1, 6]. Moreover, depression can significantly modify the course of the underlying disease, and the use of antidepressants seems to “clear” its clinical picture.

In stroke patients, depression increases the risk of disability and mortality [1]. Patients with chronic neurological diseases are generally more susceptible to depression than patients with somatic pathology. Neurological diseases in which depression can occur are very numerous [1, 2]:

• cerebrovascular diseases;
• chronic pain syndromes of various origins;
• extrapyramidal diseases - Parkinson's disease, Huntington's chorea, etc.;
• Alzheimer's disease and other dementias;
• multiple sclerosis;
• brain tumors;
• epilepsy;
• consequences of traumatic brain injury;
• encephalopathy of endocrine origin (with hypothyroidism, thyrotoxicosis).

The list goes on, and there is an undeniable pattern: the longer and more severe the neurological disease, the greater the degree of disability of the patient, the higher the risk of depression and its severity.

It should also be emphasized that a number of drugs have prodepressant activity:

• neuroleptics;
• barbiturates;
• sleeping pills and sedatives;
• chemotherapeutic agents;
• interferons;
• H2 blockers;
• non-steroidal anti-inflammatory drugs;
• muscle relaxants;
• sulfonamides;
• corticosteroids;
• drugs that change sex hormone levels;
• antihypertensive drugs;
• calcium antagonists;
• benzodiazepines.

Based on the foregoing, it is quite obvious that Cymbalta, as a drug with a proven rapid-onset effect and the possibility of combination with other drugs used in neurological practice, will become widespread. It is important to emphasize that Cymbalta has a pronounced therapeutic effect against pain syndromes associated with depression, which has been shown in a large number of clinical studies. Many of them tested the dynamics of pain intensity using a visual analogue scale (VAS) and a somatic symptom questionnaire (Somatic Symptom Inventory - SSI). Cymbalta demonstrated high efficacy for pain on both scales (VAS and SSI). For example, the intensity of back pain under the influence of Cymbalta significantly decreased already in the first week of treatment and significantly regressed in the 2-3rd week of therapy [3]. Upon completion of treatment, the severity of almost all pain syndromes decreased, with the exception of headache [6]. The analgesic effect was independent of the reduction in emotional disorders and was 50% a direct effect of Cymbalta.

Cymbalta has been surprisingly effective for neuropathic pain. The mechanism of this phenomenon is not completely clear, but it can be assumed that the analgesic effect of the drug is associated with an increase in the activity of antinociceptive (anti-pain) systems, as a result of which the perception of pain is weakened. To date, two studies have been completed to study the analgesic effectiveness of Cymbalta in diabetic neuropathy [6]. The persistence of pain in diabetes mellitus is explained by the development of “central sensitization” due to the trigger activity of affected peripheral sensory neurons. Central sensitization involves changes in the nociceptive pathways of the central nervous system, resulting in hyperalgesia (increased sensitivity to painful stimuli), allodynia (the experience of non-painful stimuli as painful), and the sensation of pain when unstimulated.

In these studies, Cymbalta was used for 12 weeks at a dose of 60 mg/day. Compared with placebo, while taking Cymbalta, pain significantly regressed, and the improvement was observed already in the first week of treatment and persisted throughout the entire period of taking the drug. At the same time, no significant differences were identified between Cymbalta and placebo in terms of glucose metabolism.

Thus, Cymbalta is a new highly effective and fairly safe antidepressant, which will undoubtedly occupy an important place in neurological practice, having not only antidepressant, but also analgesic activity, especially in situations of intractable neuropathic pain.

Cymbalta, 14 pcs., 30 mg, enteric capsules

Inside.

Capsules should be swallowed whole, without chewing or crushing. Do not add the drug to food or mix it with liquids, because this may damage the enteric coating of the pellets.

Depression.

The initial and recommended maintenance dose is 60 mg 1 time per day, regardless of food intake.

In clinical studies, the safety of doses ranging from 60 to a maximum dose of 120 mg/day was assessed. However, there was no clinical evidence that patients who did not respond to the initial recommended dose experienced any improvement with increasing dose. Response to therapy is usually observed 2-4 weeks after the start of treatment. To avoid relapse, after achieving a response to antidepressant therapy, it is recommended to continue treatment for several months. In patients who respond positively to duloxetine therapy with a history of recurrent episodes of depression, further long-term therapy at a dose of 60 to 120 mg/day is possible.

Generalized anxiety disorder.

The recommended starting dose in patients with generalized anxiety disorder is 30 mg/day, regardless of food intake. In patients with insufficient response to therapy, the dose may be increased to 60 mg/day, the usual maintenance dose in most patients. In patients with concomitant depression, the initial and maintenance dose is 60 mg/day (see also recommendations above). In clinical studies, the effectiveness of doses up to 120 mg/day was shown, in addition, such dosages were assessed from a safety point of view. Therefore, in patients with insufficient response to the 60 mg dose, increasing the dose to 90 or 120 mg/day may be appropriate. Dose increases should be based on clinical response and tolerability.

To avoid relapse after achieving a response to therapy, it is recommended to continue treatment for several months.

A painful form of peripheral diabetic neuropathy.

The initial and recommended maintenance dose is 60 mg 1 time per day, regardless of meals. During clinical studies, the safety of doses ranging from 60 to a maximum dose of 120 mg/day, divided into equal doses, was also assessed.

Plasma concentrations of duloxetine show significant interindividual variability. Therefore, some patients with an insufficient response to a dose of 60 mg/day may experience improvement with a higher dose. Response to therapy should be assessed after 2 months. In patients with an insufficient initial response, it is unlikely that the response will improve after this period of time. The therapeutic effect should be assessed regularly (at least once every 3 months).

Chronic pain syndrome of the musculoskeletal system (including those caused by fibromyalgia, chronic pain syndrome in the lower back and osteoarthritis of the knee joint)

Initial treatment.

The recommended dose of Cymbalta® is 60 mg once a day. Therapy can be started with a dose of 30 mg for 1 week to allow patients to adapt to the drug before increasing the dose to 60 mg once daily. There is no evidence that higher doses provide additional benefit, even in patients who do not respond to 60 mg/day. Higher doses are associated with a higher incidence of adverse reactions.

Continue treatment.

The effectiveness of Cymbalta® in the treatment of fibromyalgia has been demonstrated in placebo-controlled studies lasting up to 3 months. The effectiveness of Cymbalta has not been established in longer studies, but the decision to continue treatment should be based on the individual patient's response.

In patients with renal failure:

when creatinine Cl is 30–80 ml/min, no dose adjustment is required; when creatinine Cl is <30 ml/min, the use of the drug is contraindicated.

In patients with liver dysfunction:

the drug should not be prescribed to patients with liver diseases leading to liver failure.

Age.

For elderly patients, an initial dose of 30 mg for 2 weeks is recommended for the treatment of generalized anxiety disorder before starting duloxetine at a target dose of 60 mg/day. In the future, it is possible to use the drug at a dose of over 60 mg/day to achieve a good result. A systematic evaluation of drug intake at doses above 120 mg/day has not been carried out. When using duloxetine for other indications, no dose adjustment is required depending on age.

It is recommended to use the drug in patients ≥18 years of age. Duloxetine is not recommended for use in children under 18 years of age due to insufficient data on its safety and effectiveness in this age category of patients.

Abrupt discontinuation of therapy

should be avoided. When discontinuing duloxetine treatment, the dose should be gradually reduced over 1–2 weeks in order to reduce the risk of withdrawal syndrome. If significant withdrawal symptoms occur after dose reduction or discontinuation of treatment, continuation of the previously prescribed dose may be considered. Subsequently, the doctor may continue to reduce the dose, but even more gradually.