Trileptal dosage for bipolar

‹ Where are Piglet and I going? Up I forgot what candles are lit on New Year's Eve... ›

Antiepileptic drugs outside of epilepsy (use of anticonvulsants in the treatment of pain syndromes)

Anticonvulsants, or anticonvulsants, according to one of the definitions - a group of drugs of different chemical structure that have the ability to prevent or relieve convulsions. 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, discovered when prescribing the drug as a hypnotic. The next important step 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 agent without a hypnotic effect in 1938 by Merrit and Putnam. Further attempts to find a less toxic drug for the relief of convulsive syndromes led to the discovery of ethosuximide in 1958 g. In the 1960s, carbamazepine, valproic acid, and benzodiazepines entered the practice of treating epilepsy. A new era in the development of antiepileptic drugs (AEDs) begins in 1975, when a program was established in the United States to study the latest anticonvulsant molecules. Since 1990, 16 new AEDs have been registered in Europe and the United States, constituting the current generation of anticonvulsants, such as: tiagabine, vigabatrin, gabapentin, topiramate, oxcarbazepine, felbamate, zonisamide, levetiracetam, pregabalin, lacosamide, rufinamide, and others. molecules are under development [11]. nine0045

In the years since the introduction of the first anticonvulsants, an extensive evidence base and experience in the use of these drugs in the treatment of various forms of epilepsy has emerged, while at the same time a number of points of application for these drugs in the treatment of other diseases have emerged. The literature contains the results of a study of the effectiveness of AEDs in the following diseases and syndromes: neuropathic pain and fibromyalgia, migraine, anxiety and bipolar disorders, schizophrenia, essential tremor [21]. nine0045

Prerequisites for the use of anticonvulsants in 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 a nociceptive signal in nerve fibers, as well as 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 of generation of ectopic impulses appear. The increased impulsation from the periphery also disorganizes the work of the central structures, resulting in the so-called “central sensitization” [1, 2]. nine0045

A number of pathophysiological mechanisms characteristic of neuropathic pain have analogues in epilepsy. For example, similarities have been found between the phenomenon of “winding up” that occurs in the posterior horns of the spinal cord in neuropathic pain, central sensitization, and the phenomenon of “kindling” or the formation of “pathological excitation generators” in hippocampal neurons in epilepsy. It is believed that both phenomena, along with other mechanisms, arise due to the activation of NMDA receptors. Not surprisingly, anticonvulsants show their effectiveness both in terms of reducing the number of epileptic seizures and in terms of suppressing the intensity of the pain syndrome [13, 17, 37]. nine0045

Mechanisms of action of anticonvulsants in pain syndromes

The mechanisms of action of anticonvulsants in 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 neuron firing by blocking voltage-dependent sodium and calcium channels in peripheral nerves. A number of drugs (eg, phenobarbital, tiagabine, topiramate, vigabatrin, and valproate) increase nerve transmission of pain-suppressing impulses or directly block nerve 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 tab. 1.

In addition to those listed in Table. 1 proposed mechanisms of action of anticonvulsants, their possible indirect effects on various neurotransmitter systems and effects on intracellular processes are also considered. Today, the question is being discussed whether the mechanism of realization of the therapeutic effect of the same anticonvulsant in different conditions: epilepsy, pain syndromes, anxiety, etc. is the same through similar mechanisms or these mechanisms differ [21]. nine0045

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, since the early 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 1990s 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 evidence-based randomized controlled trials have been published, allowing further meta-analysis of the data obtained. Summarized results of systematic reviews and meta-analyses are presented in tab. 2 [17]. Attention is drawn to a large number of studies on the effectiveness of the latest 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 of the International Association for the Study of Pain, etc., published recommendations for the treatment of neuropathic pain and identified several directions (lines) of therapy for this condition . In most documents, first-line drugs are distinguished, i.e. those drugs with which to start treatment, and if ineffective or intolerable, change to another drug of the same line, as well as second and third line drugs, and some recommendations even suggest the allocation of fourth-line drugs. The authors of the recommendations agree on one thing: to date, among anticonvulsants, only pregabalin and gabapentin are first-line drugs in the treatment of neuropathic pain. Evidence for the effectiveness of carbamazepine is only available for trigeminal neuralgia [32] (Table 3) .

It is important to emphasize that the considered approach to the treatment of neuropathic pain is based on evidence obtained in studies that took into account not only the experience of each specialist, but also summarized the relevant world data [32]. The same positions are reflected in the recommendations of a group of Russian experts [4].

In Russia today a huge number of anticonvulsants are registered - more than 200 trade names of various forms of release 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 among 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 ^[1] . Let's consider each of these drugs in more detail.

Phenytoin (Difenin) is one of the very first AEDs. In addition to anticonvulsant and analgesic, it has a membrane-stabilizing, antiarrhythmic and hypotensive effect. Its bioavailability is low and is 20-50%. It is metabolized in the liver and is an inducer of the isoenzymes CYP3A4, CYP3A5. As an anesthetic, the drug is indicated for the treatment of only trigeminal neuralgia, in which it is prescribed 100-300 mg 1-3 times a day. Of the side effects, ataxia, nystagmus, dizziness, tremor, muscle weakness, nausea, vomiting, toxic hepatitis and others are most characteristic. Very rarely, the development of Stevens-Johnson syndrome and acute epidermal necrolysis is possible. The drug should be prescribed with caution in patients with algoholism, diabetes mellitus, chronic heart and liver failure. In addition, the drug is characterized by a high risk of adverse events due to drug interactions [1]. nine0045

Carbamazepine (tegretol, finlepsin, actinerval, zeptol, etc.) belongs to the first generation of AEDs and is similar in chemical structure to tricyclic antidepressants. Carbamazepine has a wide range of indications, including conditions accompanied by neuropathic pain, trigeminal neuralgia, glossopharyngeal neuralgia, and painful diabetic polyneuropathy, among other diseases. Most well-designed studies have been conducted in patients with trigeminal neuralgia and facial pain, where the drug has proven effective. Data on its effectiveness in other types of neuropathic pain are limited (few trials conducted and patients included). 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 start 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 relief (on average, 800-1200 mg per day), and then reduce it to minimum effective dose. In some cases, a dose of 1600 mg per day may be required, which requires careful titration and monitoring of the patient. Carbamazepine is contraindicated in atrioventricular blockade, hematopoietic disorders, acute intermittent porphyria, including history, as well as simultaneously with monoamine oxidase inhibitors. nine0045

When using carbamazepine, a number of serious side effects have been registered, such as Stevens-Johnson syndrome (544 cases were registered in the world in 1999), acute epidermal necrolysis, agranulocytosis, aplastic anemia, hepatitis, impaired renal function, endocrine disorders. The most common side effects (10% or more) of carbamazepine include: dizziness, ataxia, drowsiness, urticaria, multi-organ hypersensitivity reactions, vasculitis, leukopenia, nausea, vomiting, edema, weight gain. The risk of developing these phenomena is increased when taking into account adverse drug interactions. With caution, carbamazepine should be prescribed in elderly patients [5, 6]. nine0045

Therefore, carbamazepine should only be used under regular medical supervision. Before starting treatment, it is recommended to do a urinalysis, a detailed biochemical blood test, including the level of urea. These indicators should be monitored first weekly and then monthly. During treatment, it is also necessary to regularly monitor liver function, blood status, 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, when using the drug, not a single case of Stevens-Johnson syndrome has been registered. Several clinical studies have been conducted with oxcarbazepine in trigeminal neuralgia with positive results. Recommended dosing regimen 900-1800 mg per day. A number of recommendations for the treatment of neuropathic pain indicate that oxcarbazepine is the first-line drug for trigeminal neuralgia. Oxcarbazepine is not registered in Russia for this indication [17].

Gabapentin is recognized in a number of international recommendations 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. In 9 large randomized placebo-controlled trials, the effectiveness of gabapentin in postherpetic neuralgia and diabetic polyneuropathy was shown. One placebo-controlled study 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 trials, the drug showed its superiority over placebo in pain relief and its good tolerability by patients [26]. nine0045

The mechanism of action of gabapentin is based on the ability to bind to the additional subunit of the alpha-2-delta voltage-dependent Ca2 ⁺ channels, which is located on the extracellular side of the channel. Strong binding at this site reduces calcium influx to nerve endings, leading to inhibition of the release of a number of neurotransmitters, including glutamate and substance P.

In the absence of neurotransmitters in the synaptic cleft, the impulse propagation to the next neuron is blocked [13, 23]. nine0045

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 successive doses of the drug should not exceed 8 hours. Elderly patients may require dose adjustment, as they often have impaired renal function. The most common side effects include dizziness, drowsiness and ataxia. To avoid falls, the doctor needs to warn patients, especially the elderly, about the possibility of these side effects. Other characteristic side effects are nystagmus, diarrhea, headache, nausea, peripheral edema and asthenia are less common. nine0045

Pregabalin (lyric) is currently positioned in all international and Russian guidelines for the treatment of neuropathic pain and painful diabetic polyneuropathy as a first-line drug [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. In studies on the background of taking the drug, a decrease in the release of a number of neurotransmitters (including glutamate, norepinephrine and substance P) in hyperexcited neurons was demonstrated. This is believed 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 results in a reduction in pain. It is important to note that pregabalin has an effect only under conditions of hyperexcitation of neurons in pathological conditions; its modulating action leads to the transition of neurons to the normal state [13, 18, 23]. nine0045

Despite the similarities between pregabalin and gabapentin, the pharmacokinetic profile of pregabalin has some differences compared to the profile of gabapentin. Unlike gabapentin, pregabalin has a linear pharmacokinetics, which ensures the predictability of changes in plasma concentrations of the drug with increasing or decreasing doses. Pregabalin is rapidly absorbed 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 conducted 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 as effective as 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 a two-time dose of the drug, in contrast to gabapentin, which is required to 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 the therapeutic concentration and, accordingly, the clinical effect are reached faster [1]. nine0045

Pregabalin has been shown to be highly effective in neuropathic pain in clinical trials. In total, more than 10,000 patients were treated in them. The main studies on the effectiveness of pregabalin have been conducted in postherpetic neuralgia and painful diabetic neuropathy, since 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, up to 13 weeks in duration. The dosage of pregabalin was flexible or fixed at 75 to 600 mg per day. In all studies without exception, at all doses, pregabalin showed a significantly higher efficacy compared to placebo, up to 60% or more; it not only reduced the intensity of pain, but also normalized sleep and improved the quality of life of patients. According to the results of a somewhat later meta-analysis, the effect of the drug was observed 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 duration was 3.5 years. These data allow us to speak about pregabalin as an effective and safe agent for long-term treatment of neuropathic pain [22, 25, 28, 29].

There is extensive post-marketing experience with pregabalin in the literature. Thus, in Germany, it was studied 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. Significant reduction in pain intensity was noted as early as the 1st week of therapy. By the 6th week of treatment with pregabalin, pain intensity decreased by an average of 62%, while patients improved their sleep and mood [24]. nine0045

There is experience with the use of the drug in patients with severe, not relieved by other means, pain. In one open-label study [24], in patients with pain refractory to gabapentin, tricyclic antidepressants, or other drugs, pregabalin significantly reduced visual analog scale pain and anxiety and sleep disturbances [25].

The drug was also studied in central neuropathic pain in patients with spinal cord injury in a 12-week randomized placebo-controlled trial. Against the background of pregabalin therapy, pain intensity in this group of patients decreased starting from the 1st week of therapy, and the effect persisted until the end of the course of treatment. In parallel with anesthesia, the use of the drug caused a persistent improvement in sleep. In another study, pregabalin was more effective than placebo in patients with central post-stroke pain [30, 34]. nine0045

As already mentioned, pregabalin is well tolerated. The most common side effects are dizziness and drowsiness. According to data from clinical studies, dizziness and drowsiness while taking pregabalin are transient in nature, 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. nine0045

The range of daily therapeutic doses of pregabalin is 300-600 mg divided into 2 doses. The drug can be taken regardless of food intake. In Russia, the drug is sold in capsules of 25, 75, 150 and 300 mg. In the treatment of 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 a maximum (600 mg per day) after another 7 days. In patients with impaired renal function, treatment is recommended to be started and carried out at 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. nine0045

Other anticonvulsants for the treatment of neuropathic pain . Lamotrigine (lamiktal, convulsan, lamolep, lamictor) is a second-generation anticonvulsant and is registered for the treatment of epilepsy and bipolar disorder. In neuropathic pain, the effectiveness of the drug has been shown in the painful form of diabetic neuropathy, spinal injury, trigeminal neuralgia, central post-stroke pain, however, in some other studies, conflicting results have been obtained. Topiramate (Topamax, Topiromax, Maxitopyr, etc.) has been shown to be effective in reducing pain in diabetic neuropathy and spinal injury, but in other studies the effect was insufficient. Lacosamide (Vimpat), which at the stage of clinical trials instilled certain hopes for effectiveness, did not live up to expectations in relation to the treatment of pain syndromes. The absence of neuropathic pain in the official list of indications for all three drugs should also be taken into account [18, 20, 38, 39].

Anticonvulsant use for migraine, anxiety disorders and fibromyalgia

The use of anticonvulsants for migraine is only considered in the context of prophylactic treatment of attacks. According to the recommendations of the American Academy of Neurology, in order to start preventive therapy, there should be at least 2 such attacks per month, or the attacks should be severe, refractory to treatment and leading to maladjustment of the patient [31]. Among the possible mechanisms of the preventive action of anticonvulsants, their influence on the GABA-glutamate system or on intracellular mediators (ATP, c-AMP, protein kinase C, etc.) by affecting the calcium or sodium channels of the synapse is considered. In the United States, topiramate and valproate are registered by the FDA for the prevention of migraine, but in Russia these indications do not appear [31, 37]. nine0045

The hypothetical possibility of using most anticonvulsants in anxiety disorders is associated with an effect on GABA transmission. The most proven anti-anxiety effects 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 more than 7 randomized placebo-controlled trials have been published as evidence of its effectiveness [35]. nine0045

One disease that is also to some extent treatable with anticonvulsants is fibromyalgia, or as it is also called, the syndrome of individual hypersensitivity to pain, a disease that is most difficult to treat. Of the currently known anticonvulsants in his treatment, only pregabalin has proven its effectiveness, studied both in short, 8-week studies and in 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 therapy of fibromyalgia. The mechanism of action of pregabalin in fibromyalgia is associated with the 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, in which anticonvulsants are especially well studied. The first-line drugs for such pain are pregabalin and gabapentin; with trigeminal neuralgia - carbamazepine. Topiramate and valproate are registered in the United States for the prevention of migraine attacks, and pregabalin is increasingly being used to treat generalized anxiety disorder. Pregabalin is also the first and only anticonvulsant in the United States and Russia to date registered for the treatment of such a difficult condition as fibromyalgia. Conducted in recent years in the world of research on the latest anticonvulsants allow us to hope for further expansion of the scope of these drugs in a variety of pain syndromes.

• 
  Who inspire you and why
• 
  The nun study positive psychology
• 
  My father has no interest in me
• 
  Anxiety and pressure in the head
• 
  Death of a pet children
• 
  Why relationships change
• 
  How to know my personality type
• 
  Types of sleep cycles
• 
  My husband drinks every day
• 
  Why do people feel empty
• 
  Atypical antipsychotic examples