Pharmacodynamics
Naltrexone VW is a specific opioid receptor antagonist. Competitively binds to opioid receptors of all types and prevents or eliminates the effect of both endogenous opioids and exogenous opioid drugs - narcotic analgesics and their surrogates. By administering opioids in increased doses, the effect of this antagonist can be weakened or eliminated.
Apart from the properties of blocking the action of opioids, Naltrexone VF does not have significant pharmacological properties of its own, with the exception of some constriction of the pupil. At a dose of 50 mg, Naltrexone VF blocks the pharmacological effects caused by intravenous administration of 25 mg of heroin for 24 hours; at a dose of 100 mg, its effect is extended to 48 hours, and at a dose of 150 mg, up to 72 hours.
The drug does not cause addiction or drug dependence.
Pharmacokinetics
It is well absorbed after oral administration and is 95% metabolized in the liver to form pharmacologically active metabolites. The main metabolite, 6-β-naltrexone, also has the properties of a competitive opioid antagonist. In addition, 2-hydroxy-3-methoxy-6-β-naltrexone is formed. The peak content of naltrexone and 6-β-naltrexone in the blood plasma is observed one hour after taking the drug. The drug penetrates well through histohematic barriers - Vd is 1350 l; the half-life in blood plasma is 4 hours, for its metabolite 6-β-naltrexone is 13 hours, which explains its ability to cumulate.
Metabolites undergo intrahepatic recirculation. The drug is excreted through the kidneys unchanged (about 1%) and metabolized (38% as free and bound 6-β-naltrexone).
Contraindications
history of hypersensitivity to naltrexone drugs;
use of narcotic analgesics or a positive urine test for opioids;
lack of data on conducting a provocative test with naloxone (see “Method of administration and dosage”);
acute hepatitis or liver failure.
With caution: impaired liver and/or kidney function; pregnancy; lactation period; age up to 18 years (safety of use in patients under 18 years of age, during pregnancy and breastfeeding has not been established).
Spitomin 10 mg 60 pcs. pills
pharmachologic effect
Anxiolytic drug (tranquilizer) of the non-benzodiazepine series, also has an antidepressant effect.
Unlike classical anxiolytics, it does not have antiepileptic, sedative, hypnotic or muscle relaxant effects. The mechanism of action is associated with the effect of buspirone on the serotonergic and dopaminergic systems. Selectively blocks presynaptic dopamine receptors and increases the rate of excitation of midbrain dopamine neurons. In addition, buspirone is a selective partial agonist of 5-HT1A serotonin receptors. Buspirone does not have a significant effect on benzodiazepine receptors and does not affect the binding of GABA, does not have a negative effect on psychomotor functions, does not cause tolerance, drug dependence and the “oE152” syndrome on one side and with risk on the other; odorless or with a weak characteristic odor.
Directions for use and doses
The drug should always be taken at the same time of day, before or after meals, to avoid significant fluctuations in the concentration of the active substance in the blood plasma throughout the day.
The drug should not be taken occasionally for the treatment of anxiety, since the therapeutic effect of Spitomin® develops only after repeated doses and appears no earlier than after 7-14 days of treatment.
The dose should be selected individually.
The recommended starting dose is 15 mg, which can be increased by 5 mg/day every 2-3 days. The daily dose should be divided into 2-3 doses. The usual daily dose is 20-30 mg. The maximum single dose is 30 mg. The maximum daily dose is 60 mg.
In elderly patients, dose adjustment is not required, because The pharmacokinetics of buspirone do not depend on age.
If renal function is impaired, the drug should be used with caution and in reduced doses.
If liver function is impaired, the drug should be used with caution and in reduced doses; for this purpose, reduce single doses or increase the interval between doses.
Pharmacokinetics
Suction
After oral administration, buspirone is quickly and almost completely absorbed from the gastrointestinal tract. Buspirone undergoes extensive first-pass metabolism in the liver. Therefore, the unchanged substance is found in the systemic circulation in a small concentration, which has significant individual differences. Bioavailability is 4%. Cmax in blood plasma is achieved 60-90 minutes after taking the drug. In healthy volunteers, buspirone had linear (dose proportional) pharmacokinetics after administration of 10-40 mg. Similar pharmacokinetic parameters were found in elderly patients. After a single oral dose of 20 mg of the drug, its concentration in the blood plasma ranged from 1 to 6 ng/ml.
Concomitant food intake slows down the absorption of buspirone, but due to a decrease in pre-systemic clearance (the “first pass” effect), the bioavailability of buspirone is significantly increased. After administration with food, the AUC value of buspirone increases by 84%, and its Cmax increases by 16%.
Distribution
The binding of buspirone to plasma proteins is approximately 95% (86% to plasma albumin, the rest to α1 acid glycoprotein).
Css in blood plasma can be achieved approximately 2 days after the start of regular use. The apparent Vd is 5.3 l/kg.
Buspirone is excreted in breast milk. There are no data on the penetration of the drug through the placental barrier.
Metabolism
Buspirone undergoes oxidative metabolism mainly with the participation of CYP3A4 isoenzymes. Various hydroxylated metabolites are formed. The main metabolite (5-OH-buspirone) is not active. The dealkylated metabolite (1-(2-pyrimidinyl)-piperazine, 1-PP) is active. Its anxiolytic activity is 4-5 times lower than that of the parent substance, but its level in the blood plasma is higher and T1/2 is approximately 2 times longer than that of buspirone.
Removal
After a single administration of 14C-labeled buspirone, 29-63% of the radioactivity is excreted in the urine within 24 hours, mainly in the form of metabolites. Approximately 18-38% of the administered dose is excreted in the feces. After a single dose of 10-40 mg, T1/2 of the original substance is approximately 2-3 hours, and T1/2 of the active metabolite is 4.8 hours.
Pharmacokinetics in special clinical situations
If liver function is impaired, an increase in plasma concentrations of buspirone and AUC values, as well as a prolongation of T1/2, are possible. Due to the release of unchanged substance into the bile, a second peak in the concentration of buspirone in the blood plasma is possible. The drug is contraindicated in patients with severe liver failure. Patients with liver cirrhosis should be prescribed the drug at lower doses or at the same doses at extended intervals.
In renal failure, buspirone clearance may be reduced by 50%. The drug is contraindicated in patients with severe renal failure. In case of renal failure, buspirone should be prescribed with caution and in reduced doses.
The pharmacokinetics of buspirone in elderly patients is not changed.
Indications for use Spitomin 10 mg 60 pcs. pills
- Generalized anxiety disorder (GAD);
- panic disorder;
- autonomic dysfunction syndrome;
- alcohol withdrawal syndrome (as an auxiliary therapy);
- auxiliary therapy for depressive disorders (the drug is not prescribed for monotherapy of depression).
Contraindications
- Hypersensitivity to the components of the drug;
- severe renal failure (GFR
- severe liver failure (prothrombin time >18 seconds);
- glaucoma;
- myasthenia gravis;
- children and adolescents under 18 years of age (the safety and effectiveness of buspirone for this age group has not been proven);
- simultaneous use of MAO inhibitors or a 14-day period after discontinuation of an irreversible MAO inhibitor or 1 day after discontinuation of a reversible MAO inhibitor;
- lactation period (breastfeeding);
- pregnancy or suspicion of pregnancy.
With caution: liver cirrhosis, renal failure.
Application of Spitomin 10 mg 60 pcs. pills during pregnancy and breastfeeding
Due to the lack of properly controlled clinical trial data, the use of buspirone during pregnancy is only possible if the expected benefit of therapy for the mother justifies the possible risk to the fetus.
Women of childbearing potential should use adequate contraception during treatment with buspirone, since the safety of buspirone during pregnancy has not been proven.
Buspirone is excreted in breast milk. There is insufficient data from clinical studies of the use of buspirone during breastfeeding, so the drug should not be prescribed to nursing mothers.
Use in children
The use of the drug is contraindicated in children and adolescents under 18 years of age (the safety and effectiveness of buspirone for this age group has not been proven).
special instructions
Buspirone undergoes extensive metabolism in the liver. With a single dose of 30 mg in patients with liver cirrhosis, the concentration of buspirone in the blood plasma increases and the AUC increases with prolongation of T1/2 of the drug. Due to the release of unchanged substance into the bile, a second peak in the concentration of buspirone in the blood plasma is possible. The drug is contraindicated in patients with severe liver failure. Patients with liver cirrhosis should be prescribed the drug at lower doses or at the same doses at extended intervals.
In moderate to severe renal impairment, buspirone clearance may be reduced by up to 50%. The drug is contraindicated in patients with severe renal failure and GFR less than 10 ml/min. In case of mild (GFR more than 30 ml/min) and moderate (GFR 10-30 ml/min) renal failure, buspirone can be given, but care should be taken and the drug should be taken in reduced doses.
In elderly patients, no dose adjustment is required, but the drug should be used with caution, for example, due to a possible decrease in renal and/or liver function and an increased likelihood of side effects. For these patients, the drug should be prescribed in the minimum effective doses, and if the dose is increased, the patient should be closely monitored.
The drug should be used with extreme caution in patients with angle-closure glaucoma and myasthenia gravis.
Patients should be advised not to eat grapefruits or drink grapefruit juice in significant quantities, because these products may increase buspirone plasma concentrations and result in an increase in the frequency or severity of side effects.
Switching patients from benzodiazepines to buspirone: Buspirone does not relieve benzodiazepine withdrawal symptoms. If a patient is switched to buspirone after long-term benzodiazepine therapy, buspirone should be given only after the benzodiazepine taper period has been completed.
Buspirone does not cause addiction to the drug, but its administration to patients with an established or suspected predisposition to drug dependence requires careful medical supervision.
Since the anxiolytic effect appears after 7-14 days of taking the drug, and the full therapeutic effect develops in approximately 4 weeks, patients with severe anxiety require careful medical supervision during the initial period of therapy.
Patients should avoid drinking alcohol throughout the course of treatment with buspirone.
In case of lactose intolerance, when preparing a diet, the lactose content in the tablets should be taken into account (55.7 mg in 5 mg tablets and 111.4 mg in 10 mg tablets).
Impact on the ability to drive vehicles and operate machinery
The results of clinical studies showed that buspirone monotherapy does not affect the psychomotor performance of patients. Despite this, at the beginning of the course of treatment, transient undesirable effects are possible, and therefore patients should be warned that driving vehicles and operating machinery is possible only if the patient is fully confident in his psychomotor functions. The patient's ability to drive vehicles and operate machinery should be determined individually depending on the patient's response to treatment and the use of concomitant therapy.
Overdose
Symptoms: gastrointestinal disorders, nausea, vomiting, dizziness and drowsiness (also in severe forms), depression of varying degrees of severity.
Treatment: gastric lavage and symptomatic therapy. A specific antidote is unknown, dialysis is ineffective. Experience to date suggests that even extremely high doses (single oral administration of 375 mg) do not necessarily cause severe symptoms.
Side effects Spitomin 10 mg 60 pcs. pills
Buspirone is usually well tolerated. Side effects, if observed, usually occur early in the course of treatment and then disappear despite continued use of the drug. In some cases, a dose reduction is necessary.
Determination of the frequency of side effects: often (1/100), infrequently (1/100 to 1/1000), rarely (
From the cardiovascular system: often - chest pain; infrequently - fainting, arterial hypotension, arterial hypertension; rarely - cerebrovascular accidents, decompensation of heart failure, myocardial infarction, myocardiopathy, bradycardia.
From the nervous system: often - dizziness, headache, increased nervous excitability, sleep disturbances; uncommon - dysphoric reactions, depersonalization, dysphoria, increased sensitivity to noise, euphoria, hyperkinesis, fear, apathy, hallucinations, confusion, prolonged reaction time, suicidal thoughts, epileptic seizures, paresthesia, impaired coordination of movements, tremor; rarely - claustrophobia, cold intolerance, stupor, stuttering, extrapyramidal disorders, psychotic disorders.
From the senses: often - tinnitus; infrequently - blurred vision, itching in the eyes, redness of the eyes, conjunctivitis, impaired taste and olfactory sensations; rarely - inner ear disorders, eye pain, photophobia, increased intraocular pressure.
From the respiratory system: often - laryngitis, swelling of the nasal mucosa; infrequently - hyperventilation, lack of air, feeling of heaviness in the chest; rarely - nosebleeds.
From the endocrine system: rarely - galactorrhea, damage to the thyroid gland.
From the digestive system: infrequently - nausea, flatulence, anorexia, increased appetite, salivation, intestinal bleeding; rarely - diarrhea, burning sensation in the tongue.
From the urinary system: infrequently - dysuria (including frequent urination, urinary retention); rarely - bedwetting.
From the reproductive system: infrequently - menstrual irregularities, decreased libido; rarely - amenorrhea, pelvic inflammation, delayed ejaculation, impotence.
From the musculoskeletal system: infrequently - muscle spasms, muscle rigidity, arthralgia; rarely - muscle weakness, pain in muscles and bones.
From the skin and subcutaneous tissues: uncommon - swelling, itching, hot flashes, hair loss, dry skin, facial swelling, skin tenderness, rash.
Changes in laboratory parameters: infrequently - increased activity of ALT and AST in the serum; rarely - eosinophilia, leukopenia, thrombocytopenia.
Other: weight gain, fever, weight loss; rarely - alcohol abuse, loss of voice, tinnitus, hiccups.
Drug interactions
Considering the pharmacokinetic properties of the drug (low bioavailability, intensive metabolism in the liver, high protein binding), there is a high probability of interaction between buspirone and drugs when used simultaneously. However, because buspirone has a significant therapeutic breadth, pharmacokinetic interactions do not result in clinically significant pharmacodynamic changes.
MAO inhibitors: an increase in blood pressure and the occurrence of hypertensive crises have been described after the simultaneous administration of buspirone and drugs acting on MAO (moclobemide, selegiline); therefore, buspirone cannot be combined with MAO inhibitors. After discontinuation of an irreversible MAO inhibitor (for example, selegiline), at least 14 days must pass before starting administration of Spitomin® (and vice versa). Likewise, at least 14 days must pass after discontinuation of the drug Spitomin® before starting the administration of moclobemide (a reversible MAO inhibitor). However, Spitomin® can be taken 1 day after discontinuation of moclobemide.
CYP3A4 inhibitors and inducers: In vitro studies have shown that buspirone is primarily metabolized by CYP3A4 isoenzymes. Concomitant administration of buspirone and CYP3A4 inhibitors (erythromycin, itraconazole, nefazodone, diltiazem, verapamil and grapefruit juice) may lead to drug interactions, and with the administration of a strong inhibitor may also increase the plasma concentration of buspirone; therefore, it is necessary to reduce the dose of buspirone (for example, to 2.5 mg 2 times / day). Strong inducers of CYP3A4 (eg, rifampicin) may significantly reduce buspirone plasma concentrations and reduce its pharmacodynamic effects.
Highly protein bound drugs: Since buspirone is highly bound to plasma proteins (95%), there is always the possibility of interaction with other active substances characterized by high plasma protein binding. In vitro studies have shown that buspirone is not able to displace highly binding drugs (warfarin, phenytoin, propranolol) from protein binding sites, but can replace drugs with low binding, such as digoxin.
When cimetidine and buspirone are used together, the Cmax of buspirone increases by 40%, but its AUC does not change. Coadministration of these drugs requires close medical supervision.
When diazepam and buspirone are used together, the concentration of nordiazepam increases slightly, and side effects may occur: systemic dizziness, headache, nausea.
CNS depressants and alcohol: Coadministration of buspirone with triazolam or flurazepam does not increase the duration or strength of the effect of these benzodiazepines. After a single dose of 20 mg of buspirone, its effects on the central nervous system are not enhanced. There is insufficient experience with the combined use of buspirone and other anxiolytics or other drugs acting on the central nervous system (for example, antipsychotics and antidepressants). Therefore, in such cases, careful medical supervision is necessary.
Other medicinal products: Due to the lack of relevant clinical data, the combined use of buspirone with antihypertensive drugs, cardiac glycosides, oral contraceptives and hypoglycemic agents is possible only under conditions of careful medical supervision.
Side effects
At therapeutic doses in patients whose bodies do not contain opioids, naltrexone usually does not cause serious side effects. At doses exceeding 200 mg/day, naltrexone can have hepatotoxic effects.
From the digestive system: more often - nausea and/or vomiting, abdominal pain; rarely - decreased or increased appetite, anorexia, diarrhea or constipation, dry mouth, flatulence, worsening symptoms of hemorrhoids, erosive and ulcerative lesions of the gastrointestinal tract, abdominal pain, increased activity of liver enzymes.
From the nervous system and sensory organs: more often - anxiety, nervousness, unusual fatigue, general weakness, restless sleep, nightmares, headache; rarely - dizziness, blurred vision, confusion, hallucinations, central nervous system depression, ringing and a feeling of fullness in the ears, pain and burning sensation in the eyes, photophobia, irritability, drowsiness, disorientation in time and space.
From the respiratory system: rarely - cough, hoarseness, nasal congestion (hyperemia of the vessels of the nasal cavity), rhinorrhea, sneezing, broncho-obstruction, difficulty breathing, shortness of breath, nosebleeds, dry throat, increased secretion of mucous sputum, sinusitis.
From the cardiovascular system: rarely - chest pain, increased blood pressure, tachycardia, palpitations, nonspecific ECG changes, phlebitis.
From the genitourinary system: discomfort during urination, increased frequency of urination, edema syndrome (swelling of the face, fingers, feet, legs), sexual disorders in men (delayed ejaculation, decreased potency).
Allergic reactions: less often - skin rash, skin flushing (including facial flushing); rarely - hyperthermia, itching, increased secretion of the sebaceous glands, chills.
Other: more often - arthralgia, myalgia; rarely - thirst, weight gain or loss, pain in the groin area, acne, alopecia, swollen lymph nodes, lymphocytosis; in one case, the development of idiopathic thrombocytopenic purpura was described against the background of preliminary sensitization to the drug.
Opioid withdrawal syndrome: abdominal pain, epigastric cramps, anxiety, nervousness, fatigue, irritability, diarrhea, tachycardia, hyperthermia, rhinorrhea, sneezing, goose bumps, sweating, yawning, arthralgia, myalgia, anorexia, nausea and/or vomiting, tremor, general weakness.
Buspirone (pitomin) is a non-benzodiazepine anxiolytic that is a derivative of azapirone. Azapyrones are a class of drugs with high affinity for serotonin 5-HT1A receptors located on the body and in the endings of serotonergic neurons, as well as in the dendrites of postsynaptic neurons with which the serotonergic endings contact. The anti-anxiety effect of buspirone is not associated with an effect on GABA-benzodiazepine receptors. However, in terms of anxiolytic activity, buspirone is comparable to benzodiazepines such as diazepam, lorazepam or alprazolam, but unlike them, it does not cause drug dependence, cognitive and psychomotor impairment, or pronounced sedative and muscle relaxant effects [1].
Mechanism of action of buspirone
The mechanism of the anxiolytic action of buspirone, which determines its characteristics, is explained mainly by its effect on serotonin receptors. Buspirone has a high affinity for presynaptic serotonin (5-HT1A) receptors, of which it is an agonist, as well as for postsynaptic serotonin receptors, for which it can be considered a partial agonist [1].
Partial agonists are ligands that bind to receptors, but are able to cause only partial activation. If a partial agonist interacts with free receptors, it causes incomplete (50%) activation of the cell. If a partial agonist acts on a tissue whose receptors are already activated by a full agonist, then due to the displacement of the latter from communication with the receptor, the cell response decreases and, therefore, it has a blocking effect.
Thus, due to its receptor action, buspirone reduces the synthesis and release of serotonin, reduces the activity of serotonergic neurons of the raphe nuclei (“serotonin stabilizer”). Buspirone is also able to interact with postsynaptic 5-HT2 receptors, but has low affinity for them. Being a partial agonist, due to its postsynaptic action it can theoretically reduce serotonergic activity and cause an anxiolytic effect, and due to its action on somatodendritic serotonin presynaptic autoreceptors, it can theoretically enhance serotonergic activity and cause an antidepressant effect.
To a lesser extent, the drug selectively blocks pre- and postsynaptic D2-dopamine receptors. Moreover, it was originally developed as an antipsychotic drug, but it was later discovered that it has low affinity for dopamine receptors, and its presynaptic action predominates over the postsynaptic one, which prevents the neuroleptic effect.
Experimental studies have indicated a decrease in serotonin turnover with low doses of buspirone, reflecting stimulation of presynaptic autoreceptors. However, repeated administration of buspirone reduced the response of somatodendritic 5-HT1A receptors, since the decrease in 5-HT metabolism was less pronounced.
Buspirone may act as a partial agonist at postsynaptic serotonin 5-HT1A receptors in the hippocampus and prefrontal cortex, as well as at presynaptic autoreceptors on the cell bodies of serotonergic neurons. Since the effect of azapirones develops over several days, it does not appear to be due to their direct effect on the receptors. Animal studies suggest that the anxiolytic effect of these drugs is related to their action on presynaptic receptors, and the antidepressant effect is related to their action on postsynaptic receptors.
A decrease in serotonin turnover also occurs in the striatum, which may be accompanied by an inhibitory effect on dopaminergic transmission. This effect is reflected in the fact that coadministration of buspirone may attenuate apomorphine sensitization. Thus, buspirone at a relatively low dose may counteract the side effects of apomorphine. However, administration of buspirone at a higher dose caused sensitization of motor behavior [2].
This effect may be explained by blockade of presynaptic dopamine autoreceptors. The experimental administration of a relatively high dose of buspirone caused a sharp increase in the synthesis and metabolism of dopamine in the striatum.
The experiment showed that the administration of buspirone in brain dialysate reduces the level of serotonin by 50%, but increases the level of dopamine by 100% and norepinephrine by 140%, which indicates a complex effect of buspirone on monoaminergic neuromediation [3].
However, in addition to the effect on autoreceptors, buspirone also has another point of application, since the administration of haloperidol, which blocks D1- and D2-postsynaptic mesolimbic and striatal receptors, did not block the dopaminomimetic effect of buspirone. It has been shown that the antagonistic effect of the drug on D2 receptors is 15 times weaker than the effect on 5-HT1A receptors. Buspirone blocks postsynaptic dopamine receptors relatively weakly, even at high doses. It binds with higher affinity to D3 and D4 receptors than to D2 receptors. The effect on presynaptic dopamine receptors is stronger than blockade of postsynaptic receptors. Only in extremely large doses are postsynaptic striatal D1 and D2 receptors blocked quite actively. However, weak postsynaptic dopaminergic antagonism weakens the presynaptic dopaminomimetic effect of the drug, avoiding stereotypy [2, 3].
Use of buspirone for generalized anxiety and other affective disorders
The greatest experience with the use of buspirone has been accumulated in generalized anxiety disorder (GAD). Clinical research over the past 30 years has been accompanied by constant improvement of the nosological structure of anxiety disorders. At the beginning of the 20th century, understanding of anxiety disorders was rather vague, but over time their place among other mental disorders was more clearly defined, partly under the influence of pharmacological research.
Symptoms of GAD are chronic and often observed in patients visiting general practitioners. Typically, such patients present vague somatic complaints of fatigue, muscle pain or tension, and sleep disturbances.
Buspirone is the first nonbenzodiazepine anxiolytic to be approved by the FDA for the treatment of GAD based on studies showing it to be as effective as benzodiazepines.
According to DSM-V criteria [4], GAD is characterized by:
A. Excessive anxiety and worry (anxious expectations), occurring most days for at least 6 months and manifesting itself in a variety of events or actions (for example, when performing professional duties or while studying at school).
B. Difficulty controlling anxiety.
B. The presence of at least 3 of the following symptoms most days for 6 months: motor restlessness or a feeling of restlessness; fast fatiguability; difficulty concentrating and distractibility; irritability; muscle tension; sleep disturbance.
D. Clinically significant distress or impairment in social, occupational and other activities caused by anxiety, restlessness or physical (psychomotor) symptoms.
D. These disorders that cannot be explained by the physiological effect of a psychoactive substance or a somatic disease.
E. These disorders that cannot be explained by another mental illness.
Buspirone has also been successfully used for the prophylactic treatment of migraine and alcoholism in individuals with comorbid anxiety disorders, as well as for the treatment of anxious depression, anxiety, and agitation in patients with traumatic brain injury [5, 6].
The direct antidepressant effect of buspirone, independent of its anxiolytic effect, has also been demonstrated. It may be due to the fact that the sensitivity of 5-HT1A autoreceptors is increased in depression, while the properties of postsynaptic 5-HT1A and 5-HT2A receptors do not change in untreated patients with depression.
Data on the effectiveness of buspirone in obsessive-compulsive disorder are contradictory, but some studies show a positive effect of the drug, especially when combined with other psychopharmacological drugs, primarily antidepressants. An open-label study showed that adding buspirone (at a dose of 30-90 mg/day) to selective serotonin reuptake inhibitors (SSRIs) increased the effectiveness of treatment of body dysmorphic disorder in almost half of patients, mainly in those who had partial response to serotonergic antidepressants [ 7, 8].
Buspirone can be considered as an alternative to antidepressants in the treatment of social phobia. The effect of buspirone on social phobia was demonstrated in a placebo-controlled study. When added to SSRIs, buspirone can correct some of their side effects. For example, it has been shown that at a dose of 15-60 mg/day it can reduce sexual dysfunction and bruxism [8].
Anti-aggressive effect of buspirone
Special mention should be made of the anti-aggressive effect of buspirone in cases of agitation and aggressive actions in patients with dementia, attention deficit hyperactivity disorder, and traumatic brain injury [8]. At the same time, the effect of buspirone at a dose of 15-60 mg/day was noted in relation to both verbal (60%) and physical (90%) aggression [9-12].
Effect of buspirone on cognitive function
Data on the effect of buspirone on cognitive functions are contradictory; some studies showed a moderate positive effect on regulatory functions, while others showed no obvious effect [13]. In any case, unlike benzodiazepines and sedatives, buspirone does not have a negative effect on cognitive function, which distinguishes it from other drugs used to correct anxiety disorders [14].
Use of buspirone for the treatment of dependence syndrome
Due to its dopaminergic action, buspirone can be used to treat addiction syndrome. This quality was originally discovered in relation to cocaine addiction. It has been experimentally shown that intramuscular administration of buspirone blocks D2 and D3 receptors, while when administered orally, buspirone more selectively blocks D3 receptors, occupying more than 80% of the receptors. Thus, higher doses may be required to treat addiction—2 to 3 times higher than to treat anxiety (up to a maximum of 60 mg). Previous studies indicate that these doses are safe and well tolerated [15]. Correction of withdrawal anxiety under the influence of buspirone can also contribute to the treatment of alcohol and tobacco addiction [16–18].
Use of buspirone for extrapyramidal disorders
Experimental and clinical studies suggest that buspirone may be effective in treating tardive dyskinesia. Tardive dyskinesia is characterized by involuntary movements involving the muscles of the head, limbs, or trunk. It usually occurs during long-term therapy with antipsychotics, often manifesting itself or intensifying after their withdrawal. Tardive dyskinesia is usually resistant to various treatments. Although the evidence base for buspirone for tardive dyskinesia is weak, it may be an alternative to other drugs (particularly dopaminergic drugs) with dangerous side effects. The mechanism of action of buspirone in tardive dyskinesia is unclear [19, 20].
Buspirone may also be effective in patients with Parkinson's disease suffering from dyskinesias during long-term levodopa therapy. The mechanism of action of the drug is not clear enough in this case either, but the therapeutic effect depends on the dose. In recent years, it has been shown using pathomorphological and imaging methods that the serotonergic system is involved in the pathological process in Parkinson's disease, in particular in the pathogenesis of a number of non-motor symptoms, as well as drug-induced dyskinesias. Because of this, drugs acting on the serotonergic system can be effective against dyskinesias and non-motor symptoms such as depression, chronic fatigue, and psychotic disorders [21].
It has already been mentioned that 5-HT1A receptor agonists regulate the striatal concentration of dopamine formed from exogenous levodopa, due to which buspirone can attenuate drug-induced dyskinesias (“peak dose”) in Parkinson’s disease.
A clinical study [22] showed that sequential use of the drug for 3 days (at a dose of 15-30 mg/day), but not a single dose of the drug at a dose of 10 and 20 mg, led to a 20% decrease in dyskinesias (without an increase in parkinsonism symptoms ). In another study, 3 weeks of buspirone 20 mg/day reduced the severity of drug-induced dyskinesias by 71% without any negative effect on parkinsonian symptoms. Thus, buspirone can be considered as a potentially effective strategy in the correction of drug-induced dyskinesias.
These clinical data were confirmed experimentally - at a dose of 2 mg/kg, buspirone weakened violent movements by 45% in mice with an experimental model of dopaminergic dyskinesia. Administration of buspirone to rats at a dose of 0.25-2.5 mg/kg 30 minutes before levodopa reduced dyskinesias and improved locomotor activity. In an experiment, buspirone reduced catalepsy in rats induced by 6-OHDA and haloperidol.
The effectiveness of buspirone has also been shown for dyskinesias that occur after transplantation of fetal midbrain tissue. It is assumed that transplantation dyskinesias are associated with serotonergic neuromediation [23]. Correction of dyskinesias is more effective with the administration of a high dose of 5-HT1A agonist, which more completely blocks the release of the transmitter. Dopaminergic reinnervation after transplantation causes persistent dyskinesias due to the uncontrolled release of dopamine caused by serotonin. The release of dopamine occurs with less intensity than with “peak dose” dyskinesia. Accordingly, the effect in this situation is more pronounced with systemic administration of lower doses of 5-HT1A agonists [22, 23].
Buspirone may be effective in hereditary spinocerebellar ataxias, which is explained by the pronounced serotonergic innervation of the cerebellum [24]. It is believed that this effect may also be associated with an effect on noradrenergic pathways. This assumption has been supported by several studies showing that buspirone reduces mild to moderate cerebellar ataxia by 37%. The positive effect of buspirone on the severity of ataxia was confirmed in a small placebo-controlled study [25, 26].
Practical aspects of the use of buspirone (spitomin)
The main indications for the use of buspirone (spitomin) registered in the Russian Federation are generalized anxiety disorder (GAD), panic disorder, autonomic dysfunction syndrome, alcohol withdrawal syndrome (as an auxiliary therapy), depressive disorders (as an auxiliary therapy, but not prescribed for monotherapy of depression ). The literature describes the use of buspirone for various anxiety conditions, tobacco withdrawal, depression, as well as autism, obsessive-compulsive and premenstrual syndromes (in which the drug acts as an adjuvant). The mechanism of action allows its use for the treatment of resistant depression (in combination with an antidepressant) [27].
The therapeutic (anxiolytic) effect develops gradually, manifests itself after 7-14 days and reaches a maximum after 4 weeks.
The goal of treatment for mood disorders may be to achieve complete remission or, at a minimum, a reduction in symptoms, and, if possible, to prevent possible relapses. For chronic anxiety disorders, long-term maintenance therapy with buspirone may be required for long-term symptom control.
An important advantage of buspirone is that, unlike such classical anxiolytics as benzodiazepines, it does not have a negative effect on psychomotor functions, does not cause tolerance, drug dependence and withdrawal symptoms, and does not potentiate the effect of alcohol. However, alcohol consumption should be avoided during treatment with buspirone [28].
The absence of a therapeutic effect within 6-8 weeks requires an increase in the dose, but in some cases indicates resistance to the drug. If there is no effect, the drug is usually replaced with another drug (benzodiazepine or antidepressant). If the effect is partial, an antidepressant, sedative or hypnotic (for insomnia) can be added to enhance its effect. Buspirone is especially often used in combination with an SSRI or a selective serotonin norepinephrine reuptake inhibitor (SNRI) [29].
Use in persons under 18 years of age is contraindicated, according to the instructions for buspirone in force in the Russian Federation. No efficacy studies have been conducted in children and adolescents aged 6 to 18 years for anxiety disorders. Pregnancy and breastfeeding are also contraindications, although there is no direct evidence of danger.
Buspirone is usually well tolerated. Side effects, if observed, usually occur early in the course of treatment and then disappear despite continued use of the drug. In some cases, a dose reduction is necessary. As a side effect, the drug can cause dizziness, headache, weakness, sleep disturbance, decreased attention, extrapyramidal disorders (very rare), confusion, nausea, dry mouth, diarrhea, vomiting, constipation, weight loss, weight gain, myalgia, muscle spasms, rash, sweating, paresthesia. In case of overdose, vomiting, dizziness, miosis, and depression of consciousness are possible. The drug is combined with caution with antipsychotics, cardiac glycosides, antihypertensive and antidiabetic drugs, and oral contraceptives. Interaction with MAO inhibitors can lead to serotonin syndrome or hypertensive crisis with more limited symptoms; therefore, the simultaneous use of buspirone and MAO inhibitors is contraindicated in the instructions for medical use.
In the Russian Federation, the drug is presented in the form of divisible tablets of 10 mg. The initial dose is 5 mg/day, if necessary, it is increased by 5 mg every 5 days. The average daily dose is 15 mg. The maximum single dose is 30 mg, the maximum daily dose is 60 mg. The daily dose is usually divided into 2-3 doses. The advantages of the drug include safety, absence of dependence and withdrawal syndrome, sexual dysfunction and weight gain. Moreover, buspirone is able to attenuate sexual dysfunction caused by generalized anxiety and serotonergic antidepressants [28, 30].
The peculiarities of the drug include the gradual onset of the full clinical effect (within 4 weeks), while benzodiazepines act more quickly.
Buspirone is metabolized primarily by the microsomal enzyme CYP450 3A4. T½ is approximately 2-3 hours. Particular caution should be observed when combined with CYP450 3A4 inhibitors (for example, diltiazem, verapamil, itraconazole, erythromycin), which can reduce the clearance of buspirone and increase its level in the blood. You should also avoid drinking large amounts of grapefruit and grapefruit juice at the same time. The dose of buspirone should also be reduced when using HIV protease inhibitors or ketoconazole. Inducers of CYP450 3A4 (eg carbamazepine and rifampicin), on the contrary, may increase the clearance of buspirone. Buspirone increases blood levels of nordiazepam, the active metabolite of diazepam, which can cause dizziness, headache, and nausea.
For renal and liver failure of mild to moderate severity, liver cirrhosis, heart failure, and in the elderly, the drug is prescribed in lower doses. When discontinuing the drug, a gradual dose reduction is usually not necessary. In case of severe renal and liver failure, uncontrolled epilepsy, glaucoma, myasthenia gravis, the drug is contraindicated.
Thus, buspirone, with its unique neurotransmitter effects, significantly expands treatment options for a wide range of mental and neurological disorders - from anxiety disorders to dyskinesia in Parkinson's disease and ataxia. The relative safety of the drug makes its use in clinical practice very promising.
Interaction
Some drugs containing opioids (including antitussives, anti-inflammatory drugs, narcotic analgesics) may not cause the desired effect in those taking Naltrexone VF. In these cases, alternative medications that do not contain opioids should be used.
Hepatotoxic drugs mutually increase the risk of liver damage.
Lethargy or increased drowsiness is possible when combined with thioridazine.
Accelerates the appearance of symptoms of withdrawal syndrome due to drug addiction (symptoms can appear within 5 minutes after drug administration, last for 48 hours, and are characterized by persistence and difficulty in eliminating them).
Cases of incompatibility with drugs from other pharmacological groups have not been described.
Directions for use and doses
Inside.
Treatment of heroin addiction. Application begins in specialized drug addiction treatment departments.
Treatment can be started no earlier than 7–10 days after the last use of an opioid drug and provided there is no withdrawal syndrome. Abstinence from drug use is determined by urine testing for opioids. Treatment is not started until a provocative test with 0.5 mg naloxone administered intravenously becomes negative. The naloxone test is not performed in patients with signs of withdrawal syndrome or when opioids are detected in the urine. The naloxone test can be repeated after 24 hours. In the future, the patient should be under strict medical supervision. The patient must have a positive attitude toward drug addiction treatment.
Maintenance therapy. After the end of the introductory phase, 50 mg of the drug is prescribed every 24 hours (this dose is sufficient to prevent the effect of 25 mg of heroin administered intravenously).
Other treatment regimens can be used:
1. 50 mg daily for the first 5 days of the week and 100 mg on Saturday.
2. 100 mg once every 2 days or 150 mg once every 3 days.
3. 100 mg on Monday and Tuesday and 150 mg on Friday. This regimen is convenient for patients with long-term opioid deprivation.
The minimum course is 3 months, standard - 6 months.
Treatment of alcoholism. Daily intake - 50 mg, minimum course - 3 months.
Treatment is not started until a naloxone test has been performed to rule out the presence of opioids in the body.
Material and methods
The purpose of the study was implemented within the framework of an observational (statistical) program conducted in the department of treatment of borderline states and psychotherapy of the St. Petersburg Research Psychoneurological Institute named after. V.M. Bekhterev. The study was open-label.
The study included 36 outpatients who sought help in the specified department.
Inclusion criteria
patients had a verified diagnosis of panic disorder (F 41.0) in accordance with ICD-10, age from 18 to 65 years, signed informed consent, the possibility of treatment on an outpatient basis.
Exclusion criteria
were acute and chronic somatic diseases in the stage of decompensation, pregnancy and lactation; metabolic disorders or cancer, epilepsy, organic diseases of the central nervous system, drug and alcohol addiction, psychotic conditions and severe personality disorders.
The patients included in the study constituted a nosologically and syndromatically homogeneous group. According to ICD-10 criteria, a diagnosis of panic disorder was made on admission to all 30 patients.
The period of active therapy was 6 weeks. For patients who were taking other psychotropic drugs at the start of the study, an additional one-week wash-out period was prescribed.
All patients of the 1st (main) group (30 people) were prescribed combination therapy: spitomin (buspirone) as a monopharmacotherapy at a dose of 30 mg/day (10 mg 3 times a day) for 6 weeks, as well as a course of individual short-term directive cognitive behavioral psychotherapy - 12-15 sessions, with a frequency of 2-3 sessions per week.
The method of psychotherapy used is based on the idea that patients with panic disorder have a specific cognitive style:
they are unable to realistically perceive their sensations and interpret them catastrophically, tend to consider any inexplicable symptom or sensation as a sign of the onset of a life-threatening condition, while they have irrational beliefs that their vital systems - cardiovascular, respiratory, central nervous - will collapse. In connection with this, cognitive restructuring was chosen as the main technique, and interventions were carried out to correct misconceptions and interpretations of bodily sensations. Due to the fact that dyspnea often occurs against the background of stress, which is assessed as threatening health and provokes or intensifies fear caused by external alarming stimuli, the patients were given training in breathing control followed by cognitive reattribution of the meaning of symptoms. Exercises were performed to attract/distract attention.
A number of scales were also used to assess anxiety and panic symptoms: the Hamilton Anxiety Scale (HAM-A); Clinical Global Impression (CGI); Montgomery-Asberg (MADRS), which allows you to assess the presence of concomitant depressive symptoms, the Spielberger-Hanin anxiety scale, which makes it possible to assess the level of situational and personal anxiety. The patients' condition was assessed at the beginning and end of treatment: before the prescription of spitomin (buspirone), and then on the 7th, 14th, 28th and 42nd days of therapy. The clinical and psychological method was represented by participant observation, which was constant during the treatment of patients throughout the observational program.
During the study, patients in the main group were compared with a group of patients with panic disorder who underwent outpatient treatment only using individual cognitive-behavioral psychotherapy - group 2 (30 people). The selection of subjects in both groups was carried out using the continuous sampling method. The majority of those examined from both groups sought help after visiting somatic specialists, assessing their condition as a manifestation of a cardiac, endocrinological or neurological disease, considering the alarming symptoms secondary, associated with concerns about their health and the lack of adequate care and an accurate diagnosis.
Groups 1 and 2 were homogeneous in all indicators, which made it possible to exclude the negative influence of heterogeneity factors on the reliability of the results obtained. Thus, in the 1st group there were 14 (46.7%) men and 16 (53.3%) women, in the 2nd group there were 12 (40%) men and 18 (60%) women. There were no significant differences in this parameter between the study groups. The study included patients from 18 to 58 years old. The average age in group 1 was 34.8±1.4 years, in group 2 - 35.9±1.5 years (Table 1). There were no significant differences in the average age of patients; The most common diagnosis of panic disorder was observed between the ages of 30 and 39 years.
Table 1. Distribution of patients by age
Characteristics of the social status of patients are presented in Table. 2.
Table 2. Characteristics of the social status of patients
From the table 2 also shows that in terms of social indicators, the selected groups of patients with panic disorder did not differ significantly from each other: Pearson’s χ2 test for the distribution of patients by gender was 2 ( p
<0.157), by age - 20 (
p
<0.22), by education - 6 (
p
<0.199), by marital status - 3 (
p
<0.223), by social status - 12 (
p
<0.213).
For mathematical and statistical processing, a research protocol was drawn up, which included passport, social, anamnestic, clinical and experimental psychological indicators. Further analysis of the data included in it was carried out using the statistical software package Statistica 6, SPSS for Windows - version 12.
special instructions
The patient should have a Naltrexone VF prescription card with him for the information of other health care workers in case of emergency care.
If it is necessary to overcome blocking of opioid receptors (anesthesia, analgesia, if necessary), increasing doses of short-acting opioid analgesics should be used to reduce the risk of respiratory and circulatory depression. Competitive blockade of opioid receptors can be overcome by administering a higher dose of narcotic analgesic.
Before use, it is necessary to exclude subclinical liver failure; during treatment, the activity of liver transaminases should be periodically monitored.
Naltrexone VF should be discontinued at least 48 hours before surgery that will require the use of opioid analgesics.
If emergency analgesia is necessary, opiates are prescribed with caution in higher dosages (to overcome antagonism), since respiratory depression will be deeper and longer lasting.
To prevent the development of acute withdrawal syndrome, patients should stop taking opioids and drugs containing them for at least 7–10 days; It is mandatory to determine opioids in urine and conduct a provocative test with naloxone; If these requirements are not met, withdrawal symptoms may appear 5 minutes after administration and continue for 48 hours.
If you experience abdominal pain, dark urine, or yellowing of the sclera, you should stop taking it and consult a doctor. Persistent loss of appetite and progressive weight loss require discontinuation of therapy.
Ineffective in the treatment of cocaine as well as non-opioid drug addiction.
Introduction
Currently, panic disorder is a widespread, chronic disease that manifests itself at a young, socially active age. Its prevalence, according to epidemiological studies [1], is 3-6% in the general population. The relevance of this problem is also determined by the fact that people diagnosed with panic disorder often do not come to the attention of psychiatrists at all and prefer to be treated by doctors of other specialties. In these cases, less than 50% of patients receive treatment, while less than 30% receive adequate therapy, which contributes to the transition of panic disorder into a chronic form.
Currently, more and more researchers [2–5] are inclined to use combination therapy using pharmacotherapy and psychotherapy for the treatment of panic disorder. Psychopharmacotherapy provides relief of attacks and an increase in the interictal period, and cognitive-behavioral psychotherapy leads to a change in patients’ assessment of their condition, helping them master effective methods of overcoming anxiety and its vegetosomatic manifestations and promoting successful social adaptation and improvement of interpersonal functioning [6].
Considering the need to provide psychotherapeutic assistance to an increasing number of patients with panic disorder in modern socio-economic conditions without increasing material costs while maintaining the effectiveness of therapeutic interventions, the need for the use of short-term methods of psychotherapy becomes obvious [7].
The main drugs for the treatment of panic disorder have traditionally been benzodiazepine anxiolytics and antidepressants of the selective serotonin reuptake inhibitor (SSRI) group and clomipramine. Having good anti-panic activity and effectively reducing anxiety levels, they have a number of disadvantages that limit the possibilities of their use. The main disadvantage of antidepressants is their delayed action, which contributes to the consolidation of anticipatory anxiety, a negative effect on sexual function and body weight, and benzodiazepines can also cause addiction to them and the development of dependence. Under these conditions, the appearance in the doctor’s arsenal of the non-benzodiazepine anxiolytic buspirone (spitomin), new to domestic specialists, opens up additional opportunities for the treatment of panic disorder.
Spitomin (buspirone) is an anxiolytic (anti-anxiety) non-benzodiazepine drug that also has an antidepressant effect. This drug came into practice in the 80s of the last century, and to date a sufficient evidence base has been accumulated for its effectiveness in both paroxysmal panic and generalized anxiety [8-10]. The advantages of its use are the speed of onset of effect, the absence of dependence and addiction, the possibility of combined use with other psychotropic drugs, the absence of negative effects on sexual functioning and body weight [11]. The mechanism of action of buspirone is associated with its effect on the serotonergic and dopaminergic systems. Buspirone does not have a negative effect on psychomotor functions, drug dependence or withdrawal symptoms.
Indications for the use of buspirone are generalized anxiety disorder, panic disorder, autonomic dysfunction syndrome, alcohol withdrawal syndrome, auxiliary therapy of depressive disorders.
The purpose of this study is to study the effectiveness of spitomin (buspirone) in the complex treatment of panic disorder.
