Finlepsin
Use during pregnancy and breastfeeding
For women of reproductive age, Finlepsin® is prescribed, if possible, as monotherapy, in the minimum effective dose, because
the incidence of congenital anomalies in newborns from mothers taking combined antiepileptic treatment is higher than with monotherapy. When pregnancy occurs, it is necessary to compare the expected benefits of therapy and possible complications, especially in the first trimester of pregnancy. It is known that children of mothers with epilepsy are predisposed to disorders of intrauterine development, including malformations. Finlepsin® may increase the risk of these disorders. There are isolated reports of cases of congenital diseases and malformations, including spina bifida. Antiepileptic drugs increase folic acid deficiency, which is often observed during pregnancy, which may increase the incidence of birth defects in children, so folic acid supplementation is recommended before and during pregnancy.
In order to prevent hemorrhagic complications in newborns, it is recommended that women in the last weeks of pregnancy, as well as newborns, be prescribed vitamin K.
Carbamazepine passes into breast milk, so the benefits and possible undesirable effects of breastfeeding should be weighed against ongoing therapy. If breastfeeding is continued while taking Finlepsin, the child should be monitored due to the possibility of adverse reactions (for example, severe drowsiness, allergic skin reactions).
Use for liver dysfunction
The drug should be used with caution in cases of liver dysfunction.
Use for renal impairment
The drug should be used with caution in cases of impaired renal function.
Use in children
Can be used in children according to indications.
special instructions
Monotherapy for epilepsy begins with a low initial dose, gradually increasing it until the desired therapeutic effect is achieved.
When selecting the optimal dose, it is advisable to determine the concentration of carbamazepine in the blood plasma, especially during combination therapy. In some cases, the optimal dose may deviate significantly from the recommended initial maintenance dose, for example, due to induction of microsomal liver enzymes or due to interactions during combination therapy.
In some cases, treatment with antiepileptic drugs was accompanied by the occurrence of suicide attempts/suicidal intentions. This was also confirmed in a meta-analysis of randomized clinical trials using antiepileptic drugs. Since the mechanism of suicide attempts when using antiepileptic drugs is not known, their occurrence cannot be excluded during treatment with Finlepsin®. Patients and staff should be warned to monitor for suicidal thoughts/behavior and to seek immediate medical attention if symptoms occur.
Finlepsin® should not be combined with sedative-hypnotics. If necessary, it can be combined with other substances used to treat alcohol withdrawal. During treatment, it is necessary to regularly monitor the content of carbamazepine in the blood plasma. Due to the development of side effects from the central nervous system and the autonomic nervous system, patients are closely monitored in a hospital setting.
When transferring a patient to carbamazepine, the dose of the previously prescribed antiepileptic drug should be gradually reduced until it is completely discontinued. Sudden cessation of carbamazepine may trigger epileptic seizures. If it is necessary to abruptly interrupt treatment, the patient should be transferred to another antiepileptic drug under the cover of the drug indicated in such cases (for example, diazepam administered intravenously or rectally, or phenytoin administered intravenously).
Several cases of vomiting, diarrhea and/or decreased nutrition, convulsions and/or respiratory depression have been described in newborns whose mothers took carbamazepine concomitantly with other anticonvulsants (these reactions may represent neonatal withdrawal syndrome).
Before prescribing carbamazepine and during treatment, liver function testing is necessary, especially in patients with a history of liver disease, as well as in elderly patients. If existing liver dysfunction worsens or active liver disease develops, the drug should be discontinued immediately.
Before starting treatment, it is necessary to conduct a study of the blood picture (including counting platelets, reticulocytes), iron level in the blood serum, general urine analysis, urea level in the blood, electroencephalogram, determination of the concentration of electrolytes in the blood serum (and periodically during treatment, because hyponatremia may develop). Subsequently, these indicators should be monitored weekly during the first month of treatment and then monthly.
In most cases, a transient or persistent decrease in the number of platelets and/or leukocytes is not a precursor to the onset of aplastic anemia or agranulocytosis. However, before starting treatment, and periodically during treatment, clinical blood tests should be performed, including platelet counts and possibly reticulocyte counts, and serum iron levels should be determined. Non-progressive asymptomatic leukopenia does not require discontinuation, but treatment should be discontinued if hypersensitivity reactions or symptoms appear that suggest the development of Stevens-Johnson syndrome or Lyell's syndrome. Mild skin reactions (isolated macular or maculopapular exanthema) usually disappear within a few days or weeks, even with continued treatment or after reducing the dose of the drug (the patient should be under close medical supervision at this time).
The possibility of activation of latent psychoses should be taken into account, and in elderly patients, the possibility of developing disorientation or psychomotor agitation.
Male fertility and/or spermatogenesis disorders are possible, but the relationship between these disorders and carbamazepine has not yet been established.
Intermenstrual bleeding may occur with simultaneous use of oral contraceptives. Carbamazepine may adversely affect the reliability of oral contraceptives, so women of reproductive age should use alternative methods of birth control during treatment. Carbamazepine should only be used under medical supervision.
Patients should be informed of early signs of toxicity, as well as skin and liver symptoms. The patient is informed of the need to immediately consult a doctor in case of adverse reactions such as fever, sore throat, rash, ulceration of the oral mucosa, causeless bruising, hemorrhages in the form of petechiae or purpura.
Before starting treatment, it is recommended to conduct an ophthalmological examination, including slit lamp examination of the fundus and measurement of intraocular pressure. If the drug is prescribed to patients with increased intraocular pressure, constant monitoring of this indicator is required.
Patients with severe cardiovascular diseases, liver and kidney damage, as well as elderly people are prescribed lower doses of the drug.
Although the relationship between the dose of carbamazepine, its concentration and clinical efficacy or tolerability is very small, regular determination of carbamazepine levels may be useful in the following situations: with a sharp increase in the frequency of attacks; to check whether the patient is taking the drug properly; during pregnancy; when treating children or adolescents; if there is a suspicion of impaired absorption of the drug; if toxic reactions are suspected if the patient is taking several medications.
During treatment with Finlepsin, it is recommended to refrain from drinking alcohol.
Impact on the ability to drive vehicles and operate machinery
During the treatment period, it is necessary to refrain from engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.
Finlepsin retard, 50 pcs., 200 mg, extended-release tablets
When assessing the frequency of occurrence of various adverse reactions, the following gradations were used: very often - 10% or more, often - 1-10%, sometimes - 0.1-1%, rarely - 0.01-0.1%, very rarely - less 0.01%.
The development of adverse reactions from the central nervous system may be a consequence of a relative overdose of the drug or significant fluctuations in the concentration of carbamazepine in the blood plasma.
From the side of the central nervous system: often - dizziness, ataxia, drowsiness, general weakness, headache, accommodation paresis; sometimes - abnormal involuntary movements (for example, tremor, “fluttering” tremor - asterixis, dystonia, tics); nystagmus; rarely - hallucinations (visual or auditory), depression, loss of appetite, anxiety, aggressive behavior, psychomotor agitation, disorientation, activation of psychosis, orofacial dyskinesia, oculomotor disorders, speech disorders (for example, dysarthria or slurred speech), choreoathetoid disorders, peripheral neuritis, paresthesia, muscle weakness and symptoms of paresis. The role of the drug in the development of neuroleptic malignant syndrome, especially in combination with antipsychotics, remains unclear.
Allergic reactions: often - urticaria; sometimes - erythroderma, multiorgan delayed-type hypersensitivity reactions with fever, skin rashes, vasculitis (including erythema nodosum as a manifestation of cutaneous vasculitis), lymphadenopathy, signs resembling lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and altered liver function tests (these manifestations occur in various combinations). Other organs may also be involved (eg, lung, kidney, pancreas, myocardium, colon), aseptic meningitis with myoclonus and peripheral eosinophilia, anaphylactoid reaction, angioedema, hypersensitivity pneumonitis, or eosinophilic pneumonia. If the above allergic reactions occur, the use of the drug should be discontinued, rare - lupus-like syndrome, skin itching, erythema multiforme exudative (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), photosensitivity.
From the hematopoietic organs: often - leukopenia, thrombocytopenia, eosinophilia; rarely - leukocytosis, lymphadenopathy, folic acid deficiency, agranulocytosis, aplastic anemia, true erythrocyte aplasia, metal regional anemia, acute intermittent porphyria, reticulocytosis, hemolytic anemia, splenomegaly.
From the digestive system: often - nausea, vomiting, dry mouth, increased activity of gamma-glutamyl transferase (due to the induction of this enzyme in the liver), which usually has no clinical significance, increased activity of alkaline phosphatase; sometimes - increased activity of liver transaminases, diarrhea or constipation, abdominal pain; rarely - glossitis, gingivitis, stomatitis, pancreatitis, cholestatic, parenchymal (hepatocellular) type hepatitis, jaundice, granulomatous hepatitis, liver failure.
From the cardiovascular system: rarely - intracardiac conduction disorders; decrease or increase in blood pressure, bradycardia, arrhythmias, atrioventricular block with fainting, collapse, worsening or development of chronic heart failure, exacerbation of coronary heart disease (including the appearance or increased frequency of angina attacks), thrombophlebitis, thromboembolic syndrome.
From the endocrine system and metabolism: often - edema, fluid retention, weight gain, hyponatremia (decrease in plasma osmolarity due to an effect similar to the action of antidiuretic hormone, which in rare cases leads to dilution hyponatremia, accompanied by lethargy, vomiting, headache, disorientation and neurological disorders); rarely - increased concentration of prolactin (may be accompanied by galactorrhea and gynecomastia); a decrease in the concentration of L-thyroxine and an increase in the concentration of thyroid-stimulating hormone (usually not accompanied by clinical manifestations); disorders of calcium-phosphorus metabolism in bone tissue (decrease in the concentration of Ca2+ and 25-OH-cholecalciferol in the blood plasma): osteomalacia, hypercholesterolemia (including high-density lipoprotein cholesterol), hypertriglyceridemia and enlarged lymph nodes, hirsutism.
From the genitourinary system: rarely - interstitial nephritis, renal failure, impaired renal function (for example, albuminuria, hematuria, oliguria, increased urea/azotemia), frequent urination, urinary retention, decreased potency.
From the musculoskeletal system: rarely - arthralgia, myalgia or convulsions.
From the senses: rarely - taste disturbances, increased intraocular pressure; clouding of the lens, conjunctivitis; hearing impairment, incl. tinnitus, hyperacusis, hypoacusia, changes in the perception of pitch.
Other: skin pigmentation disorders, purpura, acne, sweating, alopecia.
Anticonvulsants, or anticonvulsants, according to one definition, are a group of drugs with different chemical structures that have the ability to prevent or weaken seizures. Anticonvulsants include a number of substances with hypnotic and sedative effects (for example, bromides, chloral hydrate, phenobarbital), as well as substances that have a selective anticonvulsant effect [3]. The first description of the use of potassium bromide as an anticonvulsant dates back to 1857, and synthetic selective antiepileptic therapy dates back to 1912, when the antiepileptic properties of phenobarbital were discovered when the drug was prescribed as a hypnotic. The next important stage in the development of the pharmacology of anticonvulsants was the discovery of phenytoin, which was synthesized in 1908, and studied and described as an antiepileptic drug that does not have a hypnotic effect in 1938 by Merritt and Putnam. Subsequent attempts to find a less toxic drug for the relief of seizure syndromes led to the discovery of ethosuximide in 1958. In the 1960s, carbamazepine, valproic acid and benzodiazepines were introduced into the treatment of epilepsy. A new era in the development of antiepileptic drugs (AEDs) began in 1975, when a program was created in the United States to study the latest anticonvulsant molecules. Since 1990, 16 new AEDs have been registered in Europe and the USA, making up the modern generation of anticonvulsants, such as: tiagabine, vigabatrin, gabapentin, topiramate, oxcarbazepine, felbamate, zonisamide, levetiracetam, pregabalin, lacosamide, rufinamide, etc. Several more new ones molecules are under development [11].
Over the years since the appearance of the first anticonvulsants, an extensive evidence base and experience in the use of these drugs in the treatment of various forms of epilepsy have emerged, while at the same time a number of points of application of these drugs in the treatment of other diseases have emerged. The literature contains results of studies of the effectiveness of AEDs in the following diseases and syndromes: neuropathic pain and fibromyalgia, migraine, anxiety and bipolar disorders, schizophrenia, essential tremor [21].
Prerequisites for the use of anticonvulsants for neuropathic pain
Neuropathic pain, according to the current definition, is a pain syndrome caused by damage to the somatosensory nervous system due to a variety of reasons [33]. The pathophysiological basis for the occurrence of neuropathic pain syndrome is disturbances in the mechanisms of generation and conduction of nociceptive signals in nerve fibers, as well as in the processes of controlling the excitability of nociceptive neurons in the structures of the brain and spinal cord. Due to nerve damage, the number of sodium and calcium channels on the nerve fiber membrane increases, and zones for generating ectopic impulses appear. Increased impulses from the periphery also disorganize the work of central structures, so-called “central sensitization” occurs [1, 2].
A number of pathophysiological mechanisms characteristic of neuropathic pain have analogues in epilepsy. For example, similarities have been identified between the phenomenon of “inflating” that occurs in the dorsal horns of the spinal cord during neuropathic pain, central sensitization and the phenomenon of “kindling” or the formation of “generators of pathological excitation” in hippocampal neurons during epilepsy. Both phenomena, along with other mechanisms, are thought to result from activation of NMDA receptors. It is not surprising that anticonvulsants show their effectiveness both in terms of reducing the number of epileptic attacks and in terms of suppressing the intensity of pain [13, 17, 37].
Mechanisms of action of anticonvulsants in pain syndromes
The mechanisms of action of anticonvulsants for neuropathic pain are different. The anti-pain effect of drugs such as carbamazepine, phenytoin, oxcarbazepine, lamotrigine, valproate, topiramate is usually explained by a decrease in high-frequency repetitive impulses of neurons by blocking voltage-gated sodium and calcium channels in peripheral nerves. A number of drugs (eg, phenobarbital, tiagabine, topiramate, vigabatrin, and valproate) enhance the neural transmission of pain-inhibiting impulses or directly block the neural transmission of excitatory impulses. Pregabalin and gabapentin have a fundamentally different mechanism of action associated with the effect on the alpha-2-delta subunit of voltage-gated calcium channels and the suppression of central sensitization processes in the dorsal horn of the spinal cord and in the brain. Summarized data on the mechanisms of action of anticonvulsants are presented in Table. 1
.
In addition to those listed in table. 1
The proposed mechanisms of action of anticonvulsants are also considered their possible indirect effects on various neurotransmitter systems and influence on intracellular processes. Today, the question is being discussed whether the mechanism for realizing the therapeutic effect of the same anticonvulsant in different conditions: epilepsy, pain syndromes, anxiety, etc. is the same through similar mechanisms or whether these mechanisms differ [21].
The first publication on the use of anticonvulsants for the treatment of neuropathic pain appeared in 1942, when M. Bergouignan showed the effectiveness of phenytoin in the treatment of neuropathic pain in trigeminal neuralgia [8]. 20 years later, from the beginning of the 1960s, carbamazepine was successfully introduced into the practice of treating the same trigeminal neuralgia, which became one of the first drugs officially registered for the treatment of this condition [9]. The beginning of the 90s of the last century was characterized by a kind of boom in the study of antidepressants, which led to the emergence of new effective and safer drugs. A large number of results from evidence-based randomized controlled trials have been published, allowing for further meta-analysis of the data obtained. The summarized results of systematic reviews and meta-analysis are presented in table. 2
[17].
Noteworthy is the large number of studies on the effectiveness of the newest generation of anticonvulsants - pregabalin and gabapentin.
Based on the meta-analysis and systematic reviews, such authoritative international organizations as the European Federation of Neurological Societies, the Group for the Study of Neuropathic Pain at the International Association for the Study of Pain, etc., published recommendations for the treatment of neuropathic pain and identified several areas (lines) of treatment for this condition. Most documents highlight first-line drugs, i.e. those drugs with which treatment should be started, and if ineffective or intolerable, replaced with another drug of the same line, as well as second- and third-line drugs, and some recommendations even suggest selecting fourth-line drugs. The authors of the recommendations agree on one thing: today, among anticonvulsants, only pregabalin and gabapentin are first-line drugs in the treatment of neuropathic pain. Evidence of the effectiveness of carbamazepine is available only for trigeminal neuralgia [32] (Table 3)
.
It is important to emphasize that the approach to the treatment of neuropathic pain under consideration is based on evidence obtained in studies that took into account not only the experience of each specialist, but also relevant global data [32]. The same positions are reflected in the recommendations of a group of Russian experts [4].
A huge number of anticonvulsants are registered in Russia today - more than 200 trade names of different release forms as of 03/01/13. Most of these drugs are indicated for the treatment of various forms of epilepsy as monotherapy or in combination with other drugs. Neuropathic pain is included in the indications for use only in a very limited number of drugs in this group. These include phenytoin, which is registered for the treatment of trigeminal neuralgia, and carbamazepine, indicated for the treatment of trigeminal neuralgia, glossopharyngeal neuralgia and painful diabetic polyneuropathy. Pregabalin (Lyrica) and its predecessor gabapentin are the only drugs registered for the treatment of all types of neuropathic pain in adults[]. Let's look at each of these drugs in more detail.
Phenytoin
(diphenin) is one of the very first AEDs. In addition to anticonvulsant and analgesic, it has membrane-stabilizing, antiarrhythmic and hypotensive effects. Its bioavailability is low and amounts to 20-50%. It is metabolized in the liver and is an inducer of the CYP3A4 and CYP3A5 isoenzymes. As an analgesic, the drug is indicated for the treatment of trigeminal neuralgia only, for which it is prescribed 100-300 mg 1-3 times a day. The most common side effects are ataxia, nystagmus, dizziness, tremor, muscle weakness, nausea, vomiting, toxic hepatitis and others. Very rarely, the development of Stevens-Johnson syndrome and acute epidermal necrolysis is possible. The drug should be prescribed with caution in patients with alcoholism, diabetes mellitus, chronic heart and liver failure. In addition, the drug is characterized by a high risk of developing adverse events due to drug interactions [1].
Carbamazepine
(tegretol, finlepsin, actinerval, zeptol, etc.) belongs to the first generation AEDs and is close in chemical structure to tricyclic antidepressants. Carbamazepine has a wide range of indications, including, among other diseases, conditions accompanied by neuropathic pain: trigeminal neuralgia, glossopharyngeal neuralgia and painful diabetic polyneuropathy. Most well-designed studies have been conducted in patients with trigeminal neuralgia and facial pain, where the drug has proven to be effective. Data on its effectiveness for other types of neuropathic pain are limited (small number of trials conducted and patients enrolled). In this regard, in a number of recommendations for the treatment of neuropathic pain, carbamazepine is recommended as a first-line drug only for trigeminal neuralgia [17]. Carbamazepine is usually taken with or without food, with a small amount of liquid. In adults, treatment is recommended to begin with a dose of 100-200 mg 1 or 2 times a day, gradually increasing it by no more than 200 mg per day until pain is relieved (on average 800-1200 mg per day), and then reducing it to minimum effective dose. In some cases, a dose of 1600 mg per day may be required, which requires careful titration and patient monitoring. Carbamazepine is contraindicated in atrioventricular block, hematopoietic disorders, acute intermittent porphyria, including a history of porphyria, as well as simultaneously with monoamine oxidase inhibitors.
A number of serious side effects have been reported with the use of carbamazepine, such as Stevens-Johnson syndrome (544 cases were registered in the world in 1999), acute epidermal necrolysis, agranulocytosis, aplastic anemia, hepatitis, impaired renal function, and endocrine disorders. The most common side effects (10% or more) of carbamazepine include: dizziness, ataxia, drowsiness, urticaria, multiorgan hypersensitivity reactions, vasculitis, leukopenia, nausea, vomiting, edema, weight gain. The risk of developing these phenomena is increased when taking into account adverse drug interactions. Carbamazepine should be prescribed with caution in elderly patients [5, 6].
Therefore, carbamazepine should only be used under regular medical supervision. Before starting treatment, it is recommended to do a urine test and a complete biochemical blood test, including urea levels. These indicators should be monitored first weekly and then monthly. During treatment, it is also necessary to regularly monitor liver function, blood condition, including the concentration of electrolytes in the serum [14].
Oxcarbazepine
(trileptal) is structurally similar to carbamazepine. It is believed that the effectiveness of these drugs in epilepsy is quite comparable, but oxcarbazepine is better tolerated. For example, not a single case of Stevens-Johnson syndrome has been reported with the use of the drug. Several clinical studies have been conducted for oxcarbazepine in trigeminal neuralgia with positive results. The recommended dosage regimen is 900-1800 mg per day. A number of recommendations for the treatment of neuropathic pain indicate oxcarbazepine as a first-line drug for trigeminal neuralgia. Oxcarbazepine is not registered for this indication in Russia [17].
Gabapentin
in a number of international recommendations it is recognized as a first-line drug for the treatment of neuropathic pain [32]. In addition to the original drug Neurontin, a number of generics have been registered in Russia: Gapentek, Tebantin, Gabagamma, Convalis, etc. Nine large randomized placebo-controlled studies have shown the effectiveness of gabapentin in postherpetic neuralgia and diabetic polyneuropathy. One placebo-controlled study each was conducted for phantom pain, Guillain-Barré syndrome, neuropathic pain of various etiologies, neuropathic pain caused by cancer, and spinal cord injury. According to the results of clinical studies, the drug showed its superiority over placebo in relieving pain and was well tolerated by patients [26].
The mechanism of action of gabapentin is based on the ability to bind to the accessory subunit alpha-2-delta of voltage-gated Ca2+ channels, which is located on the extracellular side of the channel. Strong binding at this site reduces the influx of calcium into nerve endings, resulting in inhibition of the release of a number of neurotransmitters, including glutamate and substance P.
In the absence of neurotransmitters in the synaptic cleft, the propagation of the impulse to the next neuron is blocked [13, 23].
Gabapentin can be taken with or without food. There is no need to measure serum concentrations to optimize treatment. The drug should be titrated starting at 300 mg per day and then increasing the dose by 300 mg per day to a target daily dose of 1800-3600 mg (the titration period to the maximum dose usually takes 12 days). The time between subsequent doses of the drug should not exceed 8 hours. Elderly patients may require dose adjustment, as their renal function is often impaired. The most common side effects include dizziness, drowsiness and ataxia. To avoid falls, physicians need to warn patients, especially older adults, about the possibility of these side effects. Other common side effects are nystagmus, and less commonly observed are diarrhea, headache, nausea, peripheral edema and asthenia.
Pregabalin
(lyrica) is currently positioned in all international and Russian recommendations for the treatment of neuropathic pain and painful diabetic polyneuropathy as a first-line drug of therapy [4, 32]. Pregabalin, like gabapentin, belongs to a class of drugs that have a high affinity for alpha-2-delta protein in the central nervous system. Pregabalin is a derivative of GABA and is essentially its analogue. Studies with the drug have demonstrated a decrease in the release of a number of neurotransmitters (including glutamate, norepinephrine and substance P) in hyperexcited neurons. It is thought to be caused by modulation of the function of the alpha-2-delta subunit of voltage-gated calcium channels. Pregabalin, by reducing the release of neurotransmitters, thus slows down the transmission of a nerve impulse to the next neuron, which ultimately leads to a reduction in pain. It is important to note that pregabalin has an effect only under conditions of neuronal hyperexcitation under pathological conditions; its modulating effect leads to the transition of neurons to a normal state [13, 18, 23].
Although there are similarities between pregabalin and gabapentin, the pharmacokinetic profile of pregabalin has some differences compared to that of gabapentin. Unlike gabapentin, pregabalin has linear pharmacokinetics, which ensures predictable changes in plasma concentrations of the drug as the dose is increased or decreased. Pregabalin is absorbed faster into the blood and has a higher bioavailability (90%) compared to gabapentin (33-66%). As a result, the drug is effective in smaller doses, and the likelihood of side effects is much less. A meta-analysis of randomized clinical trials of both drugs showed that the effectiveness of pregabalin is similar to that of gabapentin in reducing pain intensity, but at significantly lower dosages. It has been demonstrated that the maximum dose of gabapentin (3600 mg) is equal in effectiveness to the average therapeutic dose of pregabalin - 450 mg (for pregabalin the maximum dose is 600 mg) [36]. In addition, pregabalin is characterized by a shorter time to reach maximum concentration with a long period of absorption. This circumstance allows the use of the drug twice a day, in contrast to gabapentin, which must be taken 3 times a day. The time to reach a stable concentration of pregabalin is shorter, therefore a shorter titration period is required, and therapeutic concentrations and, accordingly, clinical effect are achieved faster [1].
In clinical studies, pregabalin has shown high efficacy against neuropathic pain. In total, more than 10,000 patients were treated there. Major studies of the effectiveness of pregabalin have been conducted in postherpetic neuralgia and painful diabetic neuropathy, as these diseases have been accepted by the US Food and Drug Administration (FDA) as standard models of neuropathic pain. All studies, 4 in postherpetic neuralgia, 5 in diabetic neuropathy and 1 in these conditions, were randomized, double-blind, placebo-controlled, lasting up to 13 weeks. Pregabalin dosage was flexible or fixed, ranging from 75 to 600 mg per day. In all studies without exception, at all doses, pregabalin showed higher efficacy compared to placebo, significantly, up to 60% or more; it not only reduced the intensity of pain, but also normalized sleep and increased the quality of life of patients. According to the results of a meta-analysis conducted somewhat later, the effect of the drug was noted already by the end of the 2nd or the beginning of the 3rd day of therapy, continuing until the end of the study, and the number of responders with a 50% or more reduction in pain intensity was about 65%. Some of the studies described above were continued in the open phase; the average duration of pregabalin use was 15 months, and the maximum was 3.5 years. These data allow us to speak of pregabalin as an effective and safe agent for long-term treatment of neuropathic pain [22, 25, 28, 29].
The literature reflects extensive experience with post-marketing use of pregabalin. Thus, in Germany, a study was conducted in the treatment of 10,300 patients with such forms of pathology as diabetic polyneuropathy, back pain with a neuropathic component, postherpetic and trigeminal neuralgia, alcoholic polyneuropathy, various other polyneuropathies and neuropathic pain due to a tumor. A significant decrease in pain intensity was noted already in the 1st week of therapy. By the 6th week of treatment with pregabalin, pain intensity decreased by an average of 62%, while patients' sleep and mood improved [24].
There is experience in using the drug in patients with severe pain that is not relieved by other means. In one open-label study [24], in patients with pain refractory to gabapentin, tricyclic antidepressants, or other medications, pregabalin significantly reduced visual analog scale pain intensity and anxiety and sleep disturbances [25].
The drug was also tested for central neuropathic pain in patients with spinal cord injury in a 12-week randomized, placebo-controlled trial. During pregabalin therapy, the intensity of pain in this group of patients decreased starting from the 1st week of therapy, and the effect persisted until the end of the treatment course. In parallel with pain relief, the use of the drug caused a lasting improvement in sleep. In another study, pregabalin was more effective than placebo in patients with central post-stroke pain [30, 34].
As already indicated, pregabalin is well tolerated. The most common side effects are dizziness and drowsiness. As data from clinical studies show, dizziness and drowsiness while taking pregabalin are transient, occurring after 1-2 days of administration and stopping at 2-4 weeks of therapy [25]. Other side effects include: ataxia, dysarthria, impaired attention, euphoria, irritability, diplopia, dry mouth, fatigue, edema, transient weight gain. Pregabalin is not metabolized in the liver and does not bind to plasma proteins, so the risk of interaction with other drugs is minimal.
The range of daily therapeutic doses of pregabalin is 300-600 mg, divided into 2 doses. The drug can be taken regardless of meals. In Russia, the drug is sold in capsules of 25, 75, 150 and 300 mg. When treating neuropathic pain, the recommended starting dose is 150 mg per day. Depending on the effect and tolerability, the dose can be increased to 300 mg per day after 3-7 days. If necessary, you can increase the dose to the maximum (600 mg per day) after another 7 days. In patients with impaired renal function, treatment is recommended to be initiated and carried out in lower doses. According to the experience gained in clinical studies, in case of discontinuation of the drug, it is recommended to reduce the dose gradually over a week.
Other anticonvulsants for the treatment of neuropathic pain
. Lamotrigine (Lamictal, Convulsan, Lamolep, Lamictor) is a second-generation anticonvulsant and is registered for the treatment of epilepsy and bipolar disorders. For neuropathic pain, the drug's effectiveness has been shown in painful diabetic neuropathy, spinal injury, trigeminal neuralgia, and central post-stroke pain, but some other studies have reported conflicting results. Topiramate (Topamax, Topiromax, Maxitopyr, etc.) has shown effectiveness in reducing pain in diabetic neuropathy and spinal injury; in other studies, the effect was insufficient. Lacosamide (Vimpat), which instilled certain hopes for effectiveness at the stage of clinical trials, did not live up to expectations regarding the treatment of pain syndromes. One should also take into account the absence of neuropathic pain in the official list of indications for all three drugs [18, 20, 38, 39].
Use of anticonvulsants for migraine, anxiety disorders and fibromyalgia
The use of anticonvulsants for migraine is considered only as part of the preventive treatment of attacks. According to the recommendations of the American Academy of Neurology, in order to begin preventive therapy, such attacks must be at least 2 per month, or the attacks must be severe, refractory to treatment and leading to maladjustment of the patient [31]. Among the possible mechanisms of the preventive action of anticonvulsants, their effect on the GABA-glutamate system or on intracellular mediators (ATP, c-AMP, protein kinase C, etc.) through their effect on calcium or sodium channels of the synapse is considered. In the USA, topiramate and valproate are registered by the FDA for the prevention of migraine, but in Russia these indications do not appear [31, 37].
The hypothetical possibility of the use of most anticonvulsants for anxiety disorders is associated with an effect on GABA transmission. The most proven agents for anxiety are tiagabine, gabapentin and pregabalin, with the latter officially registered in both the US and Russia for the treatment of generalized anxiety disorder. The mechanism of the anxiolytic action of pregabalin is associated with presynaptic inhibition of the release of excitatory neurotransmitters, and the results of more than 7 randomized placebo-controlled studies have been published as evidence of its effectiveness [35].
One of the diseases that can also be treated to a certain extent with anticonvulsants is fibromyalgia, or as it is also called, individual hypersensitivity to pain syndrome, a disease that is most difficult to treat. Of the currently known anticonvulsants, only pregabalin has proven effective in its treatment, studied in both short, 8-week and long-term studies lasting more than a year. The presence of sufficient evidence allowed the European League Against Rheumatism to recommend the inclusion of this drug in the complex treatment of fibromyalgia. The mechanism of action of pregabalin in fibromyalgia is associated with its effect on the processes of central sensitization [12, 19].
Thus, the use of anticonvulsants today is possible not only for epilepsy, but also for many other diseases and syndromes. Among these forms of clinical pathology, neuropathic pain stands out, for which anticonvulsants have been especially well studied. First-line drugs for such pain are pregabalin and gabapentin; for trigeminal neuralgia - carbamazepine. Topiramate and valproate are registered in the United States for the prevention of migraine attacks, and pregabalin is increasingly used for the treatment of generalized anxiety disorder. Pregabalin, in addition, is the first and only anticonvulsant in the United States and Russia to date registered for the treatment of such a difficult-to-treat condition as fibromyalgia. Research conducted around the world in recent years on the latest anticonvulsants allows us to hope for further expansion of the scope of use of these drugs for a wide variety of pain syndromes.
[]Instructions for the medical use of the drug https://grls.rosminzdrav.ru/ Instructions for the medical use of the drug Vimpat. Approved 11/16/09; instructions for medical use of the drug Depakine Chrono. Approved 03/29/12; instructions for medical use of the drug difenin. Approved 06/09/09; instructions for medical use of the drug Lamictal. Approved 08/28/12; instructions for medical use of the drug Lyrica. Approved 09.29.11; instructions for medical use of the drug Neurontin. Approved 10/06/08; instructions for medical use of the drug Tegretol. Approved 08/04/12; instructions for medical use of the drug Topamax. Approved 08/13/12; instructions for medical use of the drug Trileptal. Approved 06/18/09.
