What is the FDA’s safety announcement regarding Lamictal (lamotrigine). How does lamotrigine use relate to aseptic meningitis. What are the symptoms of aseptic meningitis in Lamictal users. How should healthcare professionals respond to potential cases of lamotrigine-induced meningitis. What actions should patients taking Lamictal take if they experience meningitis symptoms.

The FDA’s Safety Communication on Lamotrigine and Aseptic Meningitis

On August 12, 2010, the U.S. Food and Drug Administration (FDA) issued a crucial safety announcement regarding Lamictal (lamotrigine), a medication widely prescribed for seizures in children aged two and older, as well as for bipolar disorder in adults. The FDA informed the public that Lamictal can cause aseptic meningitis, a serious inflammation of the protective membranes covering the brain and spinal cord.

In response to this finding, the FDA took decisive action by revising the Warnings and Precautions section of the drug label and updating the patient Medication Guide to include information about this risk. This move underscores the importance of vigilance in monitoring the safety of widely used medications, even years after their initial approval.

Understanding Aseptic Meningitis

Aseptic meningitis is a form of meningitis where tests do not detect bacteria in patients exhibiting signs and symptoms of meningeal inflammation. Various factors can cause this condition, including:

• Viruses and other non-bacterial infections
• Toxic agents
• Certain vaccines
• Malignancy
• Specific medications, including Lamictal

The distinction between bacterial and aseptic meningitis is crucial, as it significantly impacts treatment approaches and patient outcomes. Recognizing the potential for Lamictal to induce aseptic meningitis adds an important consideration for healthcare providers in diagnosing and managing this condition in patients using the medication.

Recognizing the Symptoms of Lamotrigine-Induced Aseptic Meningitis

Identifying the symptoms of aseptic meningitis in patients taking Lamictal is critical for early intervention and appropriate management. The FDA’s communication highlights several key symptoms that patients and healthcare providers should be aware of:

• Headache
• Fever
• Stiff neck
• Nausea
• Vomiting
• Rash
• Sensitivity to light (photophobia)
• Drowsiness
• Confusion

These symptoms can develop rapidly and may vary in intensity among patients. It’s important to note that the onset of these symptoms can occur anywhere from 1 to 42 days after starting Lamictal treatment, with an average onset of 16 days.

The Importance of Prompt Diagnosis

When meningitis is suspected in a patient taking Lamictal, rapid diagnosis of the underlying cause is crucial. This allows for timely initiation of appropriate treatment, which can significantly impact patient outcomes. Healthcare providers must consider Lamictal-induced aseptic meningitis as a potential diagnosis while also evaluating for other possible causes of meningitis.

FDA’s Data Analysis: The Scope of Lamotrigine-Associated Aseptic Meningitis

The FDA’s decision to revise the Lamictal label was based on a comprehensive review of adverse event reports submitted to the agency over a significant period. From December 1994, when Lamictal was first approved, through November 2009, the FDA identified 40 cases of aseptic meningitis in patients taking the medication.

This finding is particularly noteworthy when considering the widespread use of Lamictal during this period. It’s estimated that over 46 million prescriptions for Lamictal were dispensed in the same timeframe. While the incidence of aseptic meningitis appears relatively low compared to the number of prescriptions, the severity of the condition warrants serious attention.

Key Findings from the FDA’s Review

1. Out of the 40 identified cases, 35 patients required hospitalization, highlighting the potential severity of the condition.
2. In most cases, symptoms resolved after discontinuation of Lamictal.
3. 15 cases reported a rapid return of symptoms when patients restarted Lamictal, with symptoms recurring within 30 minutes to 24 hours (mean of 5 hours) after re-initiation.
4. In rechallenge cases, symptoms were often more severe upon re-exposure to the medication.
5. One death was reported, although it was not thought to be directly related to aseptic meningitis.

These findings underscore the importance of careful monitoring and prompt action when symptoms of aseptic meningitis occur in patients taking Lamictal.

Guidelines for Healthcare Professionals Managing Patients on Lamotrigine

The FDA’s safety communication provides crucial guidance for healthcare professionals treating patients with Lamictal. These guidelines aim to enhance patient safety and improve outcomes in cases of suspected lamotrigine-induced aseptic meningitis.

Key Recommendations for Healthcare Providers

• Be aware that Lamictal can cause aseptic meningitis.
• Evaluate patients for other potential causes of meningitis if symptoms occur.
• Consider discontinuing Lamictal if no other clear cause of meningitis is identified.
• Advise patients to contact a healthcare professional immediately if they experience signs and symptoms of meningitis while taking Lamictal.
• Report adverse events involving Lamictal to the FDA MedWatch program.

These recommendations emphasize the need for a comprehensive approach to patient care, combining vigilance, thorough evaluation, and prompt action when necessary. By following these guidelines, healthcare professionals can better manage the risk of aseptic meningitis in patients taking Lamictal and ensure timely intervention when needed.

Patient Guidance: Navigating Lamictal Treatment Safely

For patients prescribed Lamictal, understanding the potential risks and knowing how to respond to concerning symptoms is crucial. The FDA’s communication provides clear guidance for patients to ensure their safety while using this medication.

Essential Actions for Patients

1. Contact your healthcare provider immediately if you experience any symptoms of meningitis, including headache, fever, chills, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, drowsiness, or confusion while taking Lamictal.
2. Read the Medication Guide provided with each Lamictal prescription carefully. This guide explains the risks and benefits of the medication.
3. Report any side effects experienced to the FDA MedWatch program.
4. Do not stop taking Lamictal without consulting your healthcare provider, as abrupt discontinuation can lead to other serious health issues.

By staying informed and vigilant, patients can play an active role in managing their health while on Lamictal therapy. Open communication with healthcare providers is key to ensuring safe and effective treatment.

The Broader Implications of the FDA’s Safety Communication

The FDA’s safety announcement regarding Lamictal and aseptic meningitis has broader implications for pharmacovigilance and patient care. This case illustrates the ongoing need for post-market surveillance of medications, even those that have been widely used for many years.

Lessons for Drug Safety Monitoring

• Long-term vigilance is crucial: Adverse effects may become apparent years after a drug’s approval.
• Rare but serious side effects matter: Even with a relatively low incidence, the severity of aseptic meningitis warrants significant attention.
• Prompt communication is key: The FDA’s rapid dissemination of information helps healthcare providers and patients make informed decisions.
• Continuous evaluation of benefit-risk profiles: As new safety data emerges, the balance between a drug’s benefits and risks must be reassessed.

This safety communication serves as a reminder of the dynamic nature of drug safety profiles and the importance of ongoing monitoring and reporting of adverse events. It underscores the collaborative effort required among regulatory bodies, healthcare providers, and patients to ensure medication safety.

Balancing the Benefits and Risks of Lamotrigine Treatment

While the FDA’s safety communication highlights a serious potential side effect of Lamictal, it’s important to consider this risk in the context of the medication’s benefits. Lamotrigine remains an effective treatment for seizures and bipolar disorder for many patients.

Considerations for Continued Use

When weighing the benefits and risks of Lamictal treatment, healthcare providers and patients should consider several factors:

• The patient’s individual medical history and risk factors
• The severity of the condition being treated
• Alternative treatment options available
• The patient’s response to Lamictal therapy
• The potential consequences of discontinuing treatment

For many patients, the benefits of Lamictal in managing their condition may outweigh the risk of aseptic meningitis, especially given its relatively rare occurrence. However, this decision should be made on a case-by-case basis through careful consultation between patients and their healthcare providers.

Enhancing Patient Safety Through Education

Education plays a crucial role in maximizing the benefits of Lamictal while minimizing risks. Patients should be thoroughly informed about:

1. The potential symptoms of aseptic meningitis
2. The importance of prompt reporting of any concerning symptoms
3. The need for regular follow-ups and monitoring
4. The risks associated with abrupt discontinuation of the medication

By empowering patients with knowledge and encouraging open communication, healthcare providers can help ensure the safe and effective use of Lamictal.

Future Directions: Research and Surveillance

The FDA’s safety communication on Lamictal and aseptic meningitis opens up several avenues for future research and ongoing surveillance. Understanding the mechanisms behind this adverse effect and identifying potential risk factors could lead to improved patient care and safety.

Key Areas for Further Investigation

• Identifying genetic or physiological factors that may predispose certain individuals to lamotrigine-induced aseptic meningitis
• Exploring potential interactions between Lamictal and other medications that might increase the risk of aseptic meningitis
• Developing strategies to predict or prevent the occurrence of aseptic meningitis in patients taking Lamictal
• Investigating the long-term outcomes of patients who have experienced lamotrigine-induced aseptic meningitis
• Evaluating the effectiveness of current monitoring practices and exploring potential improvements

Continued research in these areas could lead to more personalized approaches to Lamictal therapy, potentially allowing healthcare providers to identify patients at higher risk of developing aseptic meningitis and tailor treatment plans accordingly.

The Role of Pharmacovigilance

Ongoing pharmacovigilance efforts are crucial in monitoring the safety profile of Lamictal and other medications. This includes:

1. Encouraging healthcare providers and patients to report adverse events to the FDA MedWatch program
2. Conducting regular analyses of adverse event reports to identify emerging safety concerns
3. Collaborating with international regulatory agencies to share data and insights
4. Utilizing advanced data analytics and artificial intelligence to detect patterns in adverse event reports that might not be immediately apparent

These efforts ensure that the medical community remains vigilant and responsive to potential safety issues, ultimately contributing to improved patient care and outcomes.

FDA Drug Safety Communication: Aseptic meningitis associated with use of Lamictal (lamotrigine)

Safety Announcement
Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary

Safety Announcement

[08-12-2010] The U.S. Food and Drug Administration (FDA) is informing the public that Lamictal (lamotrigine)^†, a medication commonly used for seizures in children two years and older, and bipolar disorder in adults, can cause aseptic meningitis. FDA is revising the Warnings and Precautions section of the drug label and the patient Medication Guide to include information about this risk.

Meningitis is an inflammation of the protective membranes (the meninges) that cover the brain and spinal cord. Aseptic meningitis is generally diagnosed when tests of a patient with signs and symptoms of meningitis do not detect bacteria. Causes of aseptic meningitis include viruses and other non-bacterial infections, toxic agents, some vaccines, malignancy, and certain medications, including Lamictal.

Symptoms of meningitis may include headache, fever, stiff neck, nausea, vomiting, rash, and sensitivity to light. In cases of meningitis, it is important to rapidly diagnose the underlying cause so that treatment can be promptly initiated.

Healthcare professionals should be aware that Lamictal can cause aseptic meningitis. If meningitis is suspected, patients should also be evaluated for other causes of meningitis and treated as indicated. Discontinuation of Lamictal should be considered if no other clear cause of meningitis is identified.

Patients who experience headache, fever, chills, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, drowsiness, or confusion while taking Lamictal should contact their healthcare professional right away.

The decision to revise the Lamictal label is based on FDA’s identification of 40 cases of aseptic meningitis in patients taking Lamictal (from December 1994 to November 2009). During this same time period, it is estimated that over 46 million prescriptions for Lamictal were dispensed. In most cases, the patients’ symptoms were reported to have resolved after Lamictal was discontinued. In 15 cases, symptoms returned when patients restarted Lamictal (see Data Summary below).

^†Lamictal is also sold as an orally disintegrating tablet (Lamictal ODT), a chewable, dispersible tablet (Lamictal CD), and as an extended release product (Lamictal XR).

Additional Information for Patients

• Aseptic meningitis is a rare, but serious side effect of Lamictal.
• Contact your healthcare professional right away if you experience headache, fever, chills, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, drowsiness, or confusion while taking Lamictal.
• Read the Medication Guide given to you each time you are dispensed your Lamictal. It will explain the risks and benefits of Lamictal.
• Report any side effects you experience to the FDA MedWatch program, using the information in the “Contact Us” box at the bottom of the page.

Additional Information for Healthcare Professionals

• Aseptic meningitis has been reported in patients taking Lamictal.

• Advise patients to contact a healthcare professional immediately if they experience signs and symptoms of meningitis while taking Lamictal.
• If meningitis is suspected, patients should also be evaluated and treated, as indicated, for other causes of meningitis. Discontinuation of Lamictal should be considered if no other clear cause of meningitis is identified.
• Report adverse events involving Lamictal to the FDA MedWatch program using the information in the “Contact Us” box at the bottom of this page.

Data Summary

The decision to revise the Warnings and Precautions section of the Lamictal label and patient Medication Guide is based on FDA’s review of adverse event reports submitted to the agency from December 1994 (when the drug was approved) through November 2009. A total of 40 cases of aseptic meningitis occurring in pediatric and adult patients taking Lamictal were identified.

In the 40 cases, headache, fever, nausea, vomiting, nuchal rigidity, rash, photophobia and myalgias were noted. Symptoms occurred 1 to 42 days after starting Lamictal (mean of 16 days). There was one reported death, although the death was not thought to be the result of aseptic meningitis. Thirty-five of the 40 patients required hospitalization. In the majority of cases, symptoms resolved after Lamictal was discontinued. Fifteen cases reported a rapid return of symptoms following re-initiation of Lamictal; symptoms recurred within 30 minutes to 24 hours following re-initiation of Lamictal (mean of 5 hours). In these rechallenge cases, symptoms were frequently more severe after re-exposure.

Twenty five reported cases contained data on cerebrospinal fluid (CSF) findings. CSF analysis was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein. In addition, cerebrospinal fluid white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases.

Some of the patients treated with Lamictal who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases. In addition, some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that some of the cases of Lamictal-associated meningitis were part of a hypersensitivity or generalized drug reaction.

Related Information

• Lamotrigine (marketed as Lamictal) Information
• FDA: Aseptic Meningitis Risk with Use of Seizure Drug Lamictal
• FDA Drug Safety Podcast: Aseptic meningitis associated with use of Lamictal

Lamotrigine reduces migraine aura and migraine attacks in patients with migraine with aura

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Short report

Lamotrigine reduces migraine aura and migraine attacks in patients with migraine with aura

Free

1. C Lampl1,
2. Z Katsarava2,
3. H-C Diener2,
4. V Limmroth3

1. ¹Department of Neurology and Psychiatry, Pain and Headache Centre, Linz General Hospital, 4020 Linz, Austria
2. ²Department of Neurology, Essen University Hospital, Essen, Germany

1. Correspondence to:
 Dr C Lampl
 Department of Neurology and Psychiatry, Pain and Headache Centre, Linz General Hospital, 4020 Linz, Austria; christian. lamplakh.linz.at

Abstract

This study examined the efficacy of lamotrigine in the prevention of migraine aura. Fifty nine patients suffering from migraine with aura received lamotrigine in a controlled three year prospective open study. Treatment response was defined as a reduction of aura frequency each month by at least 50%. Primary endpoint was reached by three quarters of the patients. Lamotrigine significantly reduced both frequency of migraine aura (mean, 1.5 (SD, 0.6) each month before v 0.4 (0.7) after treatment; p < 0.001) and aura duration (mean, 27 (SD, 11) minutes before v 8 (14) after treatment; p < 0.001). Furthermore, more than three quarters of those patients with a reduction of aura symptoms experienced a significant reduction of frequency of migraine attacks (mean, 2.1 (SD, 1.0) each month before v 1.2 (1.1) after treatment; p < 0.001). Lamotrigine was highly effective in reducing migraine aura and migraine attacks. The strong correlation between reduction of aura symptoms and migraine attacks stresses the potential role of aura-like events and possibly cortical spreading depression as a trigger for trigeminal vascular activation, and subsequently the development of migraine headaches.

• CSD, cortical spreading depression
• df, degrees of freedom

• anticonvulsant
• aura without migraine
• cortical spreading depression
• lamotrigine
• migraine with aura

http://dx.doi.org/10.1136/jnnp.2005.063750

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• CSD, cortical spreading depression
• df, degrees of freedom

• anticonvulsant
• aura without migraine
• cortical spreading depression
• lamotrigine
• migraine with aura

Ten to fifteen percent of all patients with migraine suffer from migraine with aura. For most of these patients the aura phase encompasses visual or sensory deficits for 30 to 60 minutes, and in a few cases for several hours. Using high field functional magnetic resonance imaging with near continuous recording during visual aura, cortical spreading depression (CSD)-like events in the human occipital cortex could be visualised,¹ confirming the concept of a transient slowly spreading excitation (depolarisation), followed by long lasting depression as the underlying mechanism of migraine aura. Despite the recent development of abortive migraine drugs such as 5-hydroxytryptamine 1B/D agonists, suitable agents for suppressing the frequency and duration of migraine aura have not been identified. Based on concepts of emphasising CSD-like events in migraine pathogenesis, anti-glutamatergic strategies have been suggested as a potential avenue for the treatment of migraine auras.²

Lamotrigine is a potent sodium channel inhibitor with anti-glutamatergic actions. ³ In line with other sodium channel inhibitors, lamotrigine did not prevent migraine attacks.⁴ In two short term pilot studies, however, lamotrigine was shown to decrease aura frequency, duration, and symptoms.^5,6 Data from one of these studies⁵ indicated that the successful treatment of migraine aura may also reduce migraine attack frequency in this subgroup of patients. Therefore, the aim of our study was to confirm the effects of lamotrigine on migraine aura after longterm treatment in a larger study population, and to investigate whether a reduction in migraine aura frequency is followed by a reduction of migraine attacks.

METHODS AND PATIENTS

Our study was designed as a prospective, controlled, open, longterm dose titration study. Enrolment took place between February 1995 and December 2000. Informed consent was given by all patients. The study was approved by the local ethics committee (27/95).

Study design

Inclusion and exclusion criteria

Patients between 19 and 60 years of age were eligible if they had suffered from migraine with aura and migraine aura without headache for at least one year (diagnosis according to IHS criteria). One attack each month was the minimum attack frequency for enrolment, with an intensity described as moderate to severe on a four step scale (none, light, moderate, and severe). Exclusion criteria included patients taking prophylactic headache treatment within the three months before the beginning of the trial; previous lamotrigine treatment of epileptic seizures; cardiac, hepatic, or renal diseases; and pregnancy or the risk of pregnancy.

Treatment and evaluation of drug effects

Aura type, frequency, and duration were determined by headache diaries for at least two months before treatment initiation. All patients had to maintain a headache diary and were obliged to document auras and migraine attacks. Control visits were performed each month with evaluation of the diaries, recording of aura symptoms, frequency and duration, and frequency of migraine attacks.

Dose regimen and titration

Lamotrigine treatment was started with a dose of 25 mg daily during the first month. If no reduction in migraine aura symptoms was seen, the dosage was increased by 25 mg monthly, not exceeding 300 mg/day. If the primary outcome criteria were reached and maintained for at least two months, the lamotrigine dosage was reduced, but not before six months of treatment. When a positive response was maintained for at least two months, lamotrigine was reduced by 25 mg, but not below a basic dose of 50 mg/day. If aura symptoms recurred for two months, dosage was increased by 25 mg monthly again until frequency or duration improved. This dosage was the final maintenance dose for the remainder of the study.

Data analysis

The predetermined primary outcome measure was defined as percentage of patients with a reduction of migraine aura frequency by at least 50%. Secondary outcome measures were the reduction of aura frequency (mean, attacks each month) and the aura duration (mean, minutes) in addition to reduction of frequency of migraine attacks (mean, each month). Non-responders were defined as patients with continuing aura symptoms despite treatment for a minimum of three months on a minimum dosage of 100 mg for at least two months.

Statistics

A paired t test was used to compare mean frequency of migraine aura, mean duration of aura, and mean frequency of migraine attacks. The level of significance was set at 0.5. Pearson’s correlation was used to assess a possible correlation between the reduction in frequency of aura and migraine attacks. All statistics were performed using SPSS10.0.

RESULTS

Patient population

Table 1 provides details of migraine and aura presentation, patient demographics, dosages of lamotrigine, and treatment duration.

Table 1

 Migraine and aura characteristics, patient demographics, dosages of lamotrigine, and treatment duration

Treatment effects

Effects on aura

A positive response to treatment was seen in 44 of the 59 patients (table 2). Lamotrigine significantly reduced the frequency of migraine aura (mean, 1.5 (SD, 0.6) each month before v 0.4 (0.7) after treatment; degrees of freedom (df)  =  58; t  =  10. 5; p < 0.001) and the duration of aura symptoms (mean, 26.9 (SD, 10.8) minutes before v 8.3 (13.6) after treatment; df  =  58; t  =  10.8; p < 0.001). Treatment effects were not different for different types of aura.

Table 2

 Treatment response to lamotrigine

Effects on migraine attacks

The frequency of migraine attacks was significantly reduced also (mean, 2.1 (SD, 1.0) each month before v 1.2 (1.1) after treatment; df  =  55; t  =  7.7; p < 0.001). A significant correlation was found between the reduction in frequency of aura and migraine headache attacks (table 2).

DISCUSSION

Lamotrigine was highly effective in reducing the frequency and intensity of migraine aura. Furthermore, in more than three quarters of those patients who experienced improvement, a significant decrease in migraine frequency was also seen, whereas this effect was not seen among non-responders. These data confirm the results of pilot studies conducted with lamotrigine for the treatment of migraine aura,^5,6 and suggest that the drug may also be useful in the treatment of patients with more severe types of aura (such as familiar hemiplegic migraine). For most patients, dosages in the range of 75 and 150 mg were sufficient to achieve a consistent response over the entire treatment period. Interestingly, once patients reached their “final” daily dosage, the treatment effect was sustained in almost all patients for the rest of the observation period. The fact that it took almost five months to reach the primary endpoint indicates that patients should be treated for at least six months before this treatment can be considered as ineffective. It also suggests that clinical trials for the prevention of migraine should ideally cover a treatment and evaluation phase of at least six months.

Limitations of our study

Our study had some limitations. First, there was no placebo group comparison. However, we considered placebo treatment for six or more months not appropriate and unethical.⁷ Second, we did not measure serum concentrations of lamotrigine. Although in several pain studies, a significant association was found between analgesia and plasma lamotrigine concentrations, the dosage in this titration design was guided by the clinical response (reduction of aura symptoms) only. Therefore, measurements were without additional value for the dose finding procedures.

Lessons for migraine pathophysiology and treatment

Recently, Bolay et al demonstrated elegantly that meningeal afferents can be activated by CSD in animals.⁸ The fact that the patients in our study not only experienced a reduction in migraine aura, but also a significant reduction in migraine frequency, suggests that the inhibition of CSD-like events may subsequently prevent migraine headache in this subgroup of patients. Our results also suggest that aura as a possible clinical entity initiates a complex neuronal pathway, resulting in typical migraine headache. In patients with migraine without aura, however, other (still unknown) mechanisms, such as a temporary impairment of the periaqueductual grey, probably play a crucial role in the activation of the trigeminal vascular system.⁹

Therefore, our study may provide the first clinical evidence consistent with the concept that CSD-like events activate the trigeminal vascular system under specific circumstances in the human cortex. Because there is now compelling evidence that CSD-like events may either be caused by extensive glutamate release or reduced clearance from the synaptic cleft,¹⁰ treatment by downregulating NMDA receptor activity provides an important approach to managing patients with migraine with aura.

REFERENCES

1. ↵

   Hadjikhani N, Sanchez Del Rio M, Wu O, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A 2001;98:4687–92.

2. ↵

   Kaube H, Herzog J, Kaufer T, et al. Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology 2000;55:139–41.

3. ↵

   Wang SJ, Huang CC, Hsu KS, et al. Presynaptic inhibition of excitatory neurotransmission by lamotrigine in the rat amygdalar neurons. Synapse 1996;3:248–55.

4. ↵

   Steiner TJ, Findley LJ, Yuen AW. Lamotrigine versus placebo in the prophylaxis of migraine with and without aura. Cephalalgia1997;17:109–12.

5. ↵

   Lampl C, Buzath A, Klinger D, et al. Lamotrigine in the prophylactic treatment of migraine aura—a pilot study. Cephalalgia 1999;19:58–63.

6. ↵

   D’Andrea G, Granella F, Cadaldini M, et al. Effectiveness of lamotrigine in the prophylaxis of migraine with aura: an open pilot study. Cephalalgia 1999;19:64–6.

7. ↵

   Linde M, May A, Limmroth V, et al. Headache masters programme. Ethical aspects of placebo in migraine research. Cephalalgia 2003;23:491–5.

8. ↵

   Bolay H, Reuter U, Dunn AK, et al. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002;8:136–42.

9. ↵

   Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous migraine attacks. Nat Med 1995;1:658–60.

10. ↵

    Moskowitz MA, Bolay H, Dalkara T. Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes. Ann Neurol2004;55:276–80.

Footnotes

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Lamotrigine

Lamotrigine is an anticonvulsant drug used to treat various forms of epilepsy and mood disorders in bipolar disorder.

Synonyms Russian

Lamictal, lameptil, convulsan, lamitor, lamolep, lamotriks, seizar, triginet.

English synonyms

Lamotrigin, Lamictal.

Test Method

Gas Chromatography-Mass Spectrometry (GC-MS).

Units

μg/mL (micrograms per milliliter).

What biomaterial can be used for research?

Venous blood.

How to properly prepare for an examination?

• Do not eat for 2-3 hours before the examination, you can drink pure non-carbonated water.
• Children under 1 year of age should not eat for 30-40 minutes prior to testing.
• Do not smoke for 30 minutes before the test.

Overview of the study

Lamotrigine is a broad-spectrum antiepileptic drug for various forms of epilepsy that may have beneficial effects on mood in bipolar disorders. The drug is used as mono- or additional therapy for partial and generalized convulsive seizures, seizures with Lennox-Gastaut syndrome, with typical absences, as well as for the prevention of mood disorders (depression, mania, hypomania) in patients with bipolar disorder. In addition, lamotrigine is being considered for migraine, trigeminal neuralgia, and treatment-refractory depression.

Its pharmacological action is associated with the blocking of voltage-gated sodium channels, stabilization of the nerve cell membrane and suppression of the release of glutamic acid.

The bioavailability of lamotrigine is very high at 98%. After oral administration, the drug is quickly and fairly completely absorbed from the gastrointestinal tract, food intake slows down the absorption process, but does not reduce its effectiveness. The maximum concentration in the blood is observed 2.5 hours after ingestion. Binding to blood proteins is not more than 55%. Therapeutic concentration in the blood is 2. 5-15 mcg / ml. Lamotrigine is metabolized in the liver by conjugation with glucuronic acid using the enzyme glucuronyl transferase and without the participation of the cytochrome P450 system. The elimination half-life of lamotrigine is 24-35 hours and depends on the co-administered medicinal products. The drug is excreted from the body mainly by the kidneys in the form of glucuronides or unchanged (10%), and about 2% – through the intestines.

While taking lamotrigine, headache, fatigue, drowsiness or insomnia, nausea, vomiting, a decrease in the number of leukocytes and platelets in the blood, skin rashes and allergic reactions may occur, in rare cases, Stevens-Johnson syndrome, Lyell’s syndrome may develop. In some cases, abrupt discontinuation of the drug can provoke epileptic seizures, so when you cancel lamotrigine, the dose should be reduced gradually.

The concentration of the drug in the blood should be monitored and corrected in case of hepatic and renal insufficiency, while taking with other drugs. It is also important to consider fluctuations in blood levels of lamotrigine during pregnancy and postpartum ( Fetal Category FDA – C). During pregnancy, there is a decrease in the concentration of lamotrigine in the blood due to an increase in body weight and increased excretion under the influence of estrogens. This circumstance can lead to a worsening of the course of the disease. On the other hand, after childbirth, due to the reverse development of the above processes, physiological conditions are created for the appearance of signs of intoxication. Therefore, when planning pregnancy in women taking lamotrigine, it is advisable to determine the level of the drug in the blood and monitor it during pregnancy and after childbirth.

What is research used for?

• Blood drug concentration monitoring;
• drug interaction assessment;
• diagnosis of overdose;
• detection of violations of the drug regimen.

When is the examination scheduled?

• If symptoms persist or worsen while taking lamotrigine;
• while prescribing other anticonvulsants that affect the concentration of lamotrigine in the blood;
• if the patient has impaired liver and kidney function;
• before and during pregnancy and after childbirth;
• for adverse events likely to be related to lamotrigine and suspected drug overdose.

What do the results mean?

Reference values: 4 – 10 µg/ml.

What can influence the result?

• The concentration of lamotrigine in the blood increases:
  • when taking valproic acid;
  • for violations of the liver and kidneys.
• Medicines that can reduce the concentration of lamotrigine in the blood: phenytoin, carbamazepine, phenobarbital, primidone, oral contraceptives, estrogens.

Important Notes

• It is recommended to take blood for research 30-60 minutes before the scheduled intake of the drug.
• Treatment, dose adjustment of this drug and concentration monitoring is carried out strictly under the supervision of a physician. It is unacceptable to independently change the mode of administration and dose of the drug.

Also recommended

[02-014] CBC

[06-003] Alanine aminotransferase (ALT)

[06-010] Aspartate aminotransferase (AST)

[06-036] Bilirubin total

[ 06-021] Serum creatinine

[15-001] Valproic acid

[15-006] Topiramate

Who orders the test?

Psychiatrist, psychotherapist, neurologist, clinical pharmacologist.

Literature

• Adab N. Therapeutic monitoring of antiepileptic drugs during pregnancy and in the postpartum period: is it useful? CNS Drugs. 2006;20(10):791 – 800.
• Cassels C. Lowering of Lamotrigine blood levels linked to increased seizure risk during pregnancy. Medscape. Nov 28, 2007.
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Lamotrigine in the treatment of chronic pain syndromes

Lamotrigine in the treatment of chronic pain syndromes

E. V. Ekusheva, MD, prof., head. Department of Nervous Diseases1-2’3

¹ Academy of Postgraduate Education Federal State Budgetary Institution “Federal Research and Clinical Center for Specialized Types of Medical Care and Medical Technologies” FMBA of Russia, Moscow

² Academician A. Vein 3 Belgorod State National Research University, Belgorod

Lamotrigine in treatment of chronic pain syndromes

E. V. Ekusheva

Academy of Postgraduate Education of the Federal Research and Clinical Center for Specialized Medical Care and Medical Technologies, Clinic for Headache and Autonomic Disorders n. a. Academician A. Wein; Moscow; Belgorod National Research University, Belgorod; Russia

Summary

Chronic pain syndromes represent a significant socio-economic problem for health care and society as a whole due to the insufficient effect of the treatment, a pronounced decrease in the quality of life and a significant degree of maladjustment of this category of patients. Therapy of chronic pain syndromes with first-line drugs from the group of anticonvulsants (gabapentin, pregabalin, carbamazepine, valproic acid and topiramate) does not always have the expected effect, and various side and undesirable effects are often observed. This involves the search for opportunities and prospects for the use of other new generation anticonvulsants, one of which is lamotrigine, as pharmacological tools. The article discusses a wide range of effective and safe use of Lamitor in a variety of diseases accompanied by chronic pain.

Key words: chronic pain, migraine with aura, neuropathic pain, trigeminal neuralgia, lamotrigine, Lamitor.

Summary

Chronic pain syndromes represent a significant socio-economic problem for health care and society as a whole due to the insufficient effect of the treatment, a pronounced decrease in the qualify of life and a significant degree of maladjustment of this category of patients. Treatment of chronic pain syndromes with first-line drugs from the group of anticonvulsants (gabapentin, pregabalin, carbamazepine, valproic acid and topiramate) does not always give the expected effect, and various side and undesirable effects are often observed. This implies the search for opportunities and prospects for the use of other new generation anticonvulsants, one of which is lamotrigine, as a means of pharmacological action. The article discusses a wide range of effective and safe use of Lamitor for various diseases accompanied by chronic pain.

Key words: chronic pain, migraine with aura, neuropathic pain, trigeminal neuralgia, lamotrigine, Lamitor.

Despite the enormous progress and achievements of modern medical science, there are still many neurological diseases in the treatment of which only a temporary effect is achieved, or it is not observed at all. This leads to the search for new technologies and therapeutic strategies to expand the capabilities of clinicians in the management of patients with diseases of the nervous system. Chronic pain syndromes represent a significant socio-economic problem for health care and society as a whole due to the insufficient effect of the treatment, a pronounced decrease in the quality of life and a significant degree of maladjustment of this category of patients. First of all, these are chronic neuropathic pain, various forms of migraine and SUNCT (Short-last ing Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing

The use of drugs from the group of anticonvulsants for the treatment of pain syndromes of various etiologies began in the middle of the 20th century. The analgesic action of various representatives of this group is based on such mechanisms as blockade of voltage-dependent Na+ channels, voltage-dependent Ca ² + channels of the membrane of nociceptive neurons, which limits the conduction of sodium and calcium ions through the channels, potentiation of GABAergic transmission and inhibition of glutamatergic transmission and, thus, a decrease in sensitization and excitability of central and peripheral nociceptors [1].

And in the treatment of chronic pain syndromes of various etiologies, in particular migraine, trigeminal neuralgia and other variants of chronic neuropathic pain, gabapentin, pregabalin, carbamazepine, valproic acid and topiramate are considered as first-line drugs. At the same time, these drugs do not always have the expected effect, various side and undesirable effects are often observed, which suggests the search for opportunities and prospects for the use of other representatives of the new generation of anticonvulsants, one of which is lamotrigine, as tools for the pharmacotherapy of pain syndromes.

Lamotrigine has a proven effect on the leading links in the pathogenesis of chronic pain syndromes, realizing all of the above antinociceptive mechanisms [2, 3, 4], in addition, the effect on a4B2-nicotinic and transmembrane receptors is discussed as the basis of the analgesic effect of lamotrigine [5, 6]. This drug is characterized by a pronounced selectivity of the effect on the functional activity of neurons of the nociceptive and antinociceptive systems, which, along with a wide therapeutic potential, allows reasonable use of lamotrigine in the treatment of chronic pain of various etiologies.

Table 1

Use of lamotrigine in the treatment of chronic pain syndromes

Disease	Daily dose of lamotrigine, mg	Studies
Migraine
Migraine with aura	50-300 mg/day. (mean 100 mg/day)	Pascual J. et al., 2004; Lamp C. et al., 2005; Viana M. et al., 2018; Buch D. et al., 2019
Basilar migraine	100 mg/day	Pascual J. et al., 2004; Lamp C. et al., 2005; Cologno D. et al., 2013; d’Onofrio F. et al., 2007
Hemiplegic migraine	50-300 mg/day (mean 100 mg/day)	Pascual J. et al., 2004; Liguori C. et al., 2013; Pelzer N. et al., 2014; Camia F. et al., 2017
Migraine with typical aura without headache	50-200 mg/day. (average 100 mg/day)	Pascual J. et al., 2004
Vestibular migraine	100 mg/day	Bisdorff A.R. et al., 2004; Zhang L. et al., 2014; Dieterich M. et al., 2016
Complications of migraine
Persistent aura without infarction	50-200 mg/day.	Thissen S. et al., 2014; Viana M. et al., 2018
Visual snow	100-300 mg/day. (average 150-200 mg/day)	Chen W.T. et al., 2001; Pascual J. et al. , 2004; Lamp C. et al., 2005; Thissen S. et al., 2014; Schankin C. J. et al., 2015; Traber G. L. et al., 2019
Chronic neuropathic pain
Trigeminal neuralgia	400 mg/day.	Alves T.C. et al., 2004; Gronseth G., 2008; Al-Quliti K.W., 2015; Bendtsen L., 2019
Painful form of diabetic neuropathy	200-400 mg/day. (average 250 mg/day)	Eisenberg et al., 2001; Singleton et al., 2005; Vinik et al., 2007; Chong et al., 2007
Central pain after stroke	200 mg/day	Finnerup N.B. et al., 2002; Vestergaard K. et al., 2004; Frese A. et al., 2006; Kalita J. et al., 2017
HIV-related neuropathic pain	300 mg/day.	Simpson D.M. et al., 2003
Other diseases
SUNCT	25-600 mg/day. (mean 300 mg)	Lambru G. et al., 2013; Cohen A. et al., 2014

Migraine

Migraine is in second place among the causes of disability and severe maladjustment caused by a neurological disease, and in sixth place among the leading medical causes of a decrease in the quality of life of the population in the world [7]. One variant of this disease is migraine with aura, which often causes problems in therapy, in particular in patients with basilar migraine (1.2.2), hemiplegic migraine (1.2.3), typical aura without headache (1.2.1.2), vestibular migraine (A1.6.6) and migraine complications such as persistent aura without infarction (1.4.2) and visual snow (A1.4.6) [8].

Analysis of all studies of the use of lamotrigine in the treatment of migraine in the PubMed database (more than 100 works) up to February 2019 [9] demonstrated its high effect, good tolerability and safety in the preventive treatment of patients with various types of migraine with aura (Table 1) , including difficult-to-treat and resistant to other means of preventive therapy. A significant decrease in the frequency of seizures by half or more (from 4.2 to 0.7 per month) and the duration of the aura were shown after a 6-month course of therapy with lamotrigine in different types of the disease [9], in particular in patients with basilar migraine [4, 10-13], familial hemiplegic migraine types 1 and 2 [13, 14-16], migraine with prolonged aura and typical aura without headache [12, 17 ]. In some cases, a complete reduction in attacks was observed: in patients with basilar migraine after a 12-month course of lamotrigine, they were not observed over the next 5 years [10], as well as in patients resistant to therapy with other drugs [9, 17]. Thus, the high potential for efficacy and safety, the low profile of possible adverse events, and the low cost of a course of therapy make it possible to consider lamotrigine as the drug of choice in patients with frequent migraine attacks with aura, persistent aura, and severe disadaptation [12, 17].

Vestibular migraine (VM) occurs in approximately 10% of patients with migraine [18] and is characterized by excruciating attacks of headache accompanied by moderate or severe dizziness, vomiting, photo- and phonophobia. Data from randomized controlled trials of CM prophylactic therapy [18-21] have demonstrated the efficacy of lamotrigine along with first-line drugs. In particular, in a retrospective open study [20] of 19 patients with CM, seizures were more than halved in 18 of 19patients, and a quarter of them are absent while taking lamotrigine. There was also a significant decrease in the severity and frequency of dizziness (from 18.1 to 5.4 days per month) [20]. In another study [21], 65 patients with CM taking prophylactic lamotrigine showed significant improvement in 58 (85%) of them in the form of a reduction in the frequency of headache attacks and episodes of dizziness, as well as high adherence to lamotrigine therapy.

The high effect of prophylactic therapy with lamotrigine has been repeatedly shown in patients with visual snow, which in clinical practice is difficult to treat and significantly reduces the quality of life of patients [4, 13, 17, 22-24]. Longitudinal follow-up of patients with visual snow who received lamotrigine as a prophylactic therapy showed a pronounced effect in 75-84% of patients, which persisted for several subsequent years [4, 13, 23].

Chronic neuropathic pain

Chronic neuropathic pain is a complex and sometimes unpredictable task for the doctor, as it is characterized by recurrent course, the occurrence of side or adverse events during first-line therapy, as well as a decrease in their effectiveness during long-term treatment. All this leads to the search for new, more active and safe means for the treatment of pain syndrome of various origins.

In the European and American clinical guidelines for the treatment of trigeminal neuralgia [25, 26], lamotrigine is considered as a second-line drug used in the absence of effect or intolerance to carbamazepine or oxcarbazepine, as well as in complex therapy with first-line drugs in case of their insufficient effect (Table 1). 1). A number of studies have shown the effect of lamotrigine in the treatment of resistant trigeminal neuralgia [27, 28]. Its high efficiency in the treatment of another variant of central post-stroke pain, which is complex from the point of view of analgesic therapy, has been demonstrated [29-32], including in the form of a decrease in the severity of the pain syndrome by half or more, according to the visual analogue scale [32]. Lamotrigine has been shown to be effective in the treatment of pain in diabetic polyneuropathy [33–36], chronic neuropathic pain in multiple sclerosis, postherpetic neuralgia, HIV-associated neuropathy [37] associated with spinal cord injury [38], or other etiologies [2] .

Other headaches

Lamotrigine is considered as the first-line drug and the most effective treatment for painful and intractable SUNCT attacks [39, 40].

It is important to note that slow titration of the drug (addition of 25 mg per day for 1-2 weeks) will minimize adverse events during its use, and the rational use of lamotrigine (adequate daily dose and required duration of therapy) will allow its full therapeutic potential to be realized.

Thus, to date, extensive positive experience has been accumulated with the use of lamotrigine in various types of chronic pain syndromes, which makes it possible to safely and effectively help these patients. One such drug is Lamitor (Torrent Pharmaceuticals), which is therapeutically equivalent to the original drug (Class A – Orange Book, FDA). Lamitor is characterized by good tolerance, without complicating daily functioning, efficiency and breadth of the clinical and pharmacological spectrum, on the one hand, having antidepressant and anti-anxiety effects, and on the other hand, the ability to use it in children from 3 years old, in women during pregnancy, in the elderly people, including those suffering from diabetes (see the instructions for the drug). These properties are of particular clinical value, as they allow Lamitor to be effectively and safely used for the pharmacotherapy of patients with a variety of chronic pain syndromes.

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