Pregabalin (Lyrica) Associated with Increased Suicidal Behavior and Other Hazards: Population-Based Study in Sweden

Objective: To examine associations between gabapentinoids and adverse outcomes related to coordination disturbances (head or body injuries, or both and road traffic incidents or offences), mental health (suicidal behaviour, unintentional overdoses), and criminality.

Design: Population based cohort study.

Setting: High quality prescription, patient, death, and crime registers, Sweden.

Participants: 191,973 people from the Swedish Prescribed Drug Register who collected prescriptions for gabapentinoids (pregabalin or gabapentin) during 2006 to 2013.

Main outcome measures: Primary outcomes were suicidal behaviour, unintentional overdoses, head/body injuries, road traffic incidents and offences, and arrests for violent crime. Stratified Cox proportional hazards regression was conducted comparing treatment periods with non-treatment periods within an individual. Participants served as their own control, thus accounting for time invariant factors (eg, genetic and historical factors), and reducing confounding by indication. Additional adjustments were made by age, sex, comorbidities, substance use, and use of other antiepileptics.

Results: During the study period, 10,026 (5.2%) participants were treated for suicidal behaviour or died from suicide, 17,144 (8.9%) experienced an unintentional overdose, 12,070 (6.3%) had a road traffic incident or offence, 70,522 (36.7%) presented with head/body injuries, and 7,984 (4.1%) were arrested for a violent crime. In within-individual analyses, gabapentinoid treatment was associated with increased hazards of suicidal behavior and deaths from suicide, unintentional overdoses, head/body injuries (, and road traffic incidents and offences. Associations with arrests for violent crime were less clear (1.04, 0.98 to 1.11). When the drugs were examined separately, pregabalin was associated with increased hazards of all outcomes, whereas gabapentin was associated with decreased or no statistically significant hazards. When stratifying on age, increased hazards of all outcomes were associated with participants aged 15 to 24 years.

Conclusions: This study suggests that gabapentinoids are associated with an increased risk of suicidal behavior, unintentional overdoses, head/body injuries, and road traffic incidents and offences. Pregabalin was associated with higher hazards of these outcomes than gabapentin.

Epilepsy Research Findings: June 2019

This month’s round-up of epilepsy news features an announcement about a new antiepileptic rescue medication, NAYZILAM®. This therapy is the first FDA-approved nasal treatment option for people with epilepsy who experience episodes of frequent seizure activity.

We also highlight many research advances, from the discovery of a compound found in fruit and honey which can inhibit seizures to the development of a new drug to treat Dravet syndrome. Research in the cannabidiol (CBD) space has also advanced, with the creation of a synthetic form of CBD which may be easier to purify and does not need to be cultivated from hemp plants.

In more sobering news, reports over the past month show that one-third of epilepsy cases go without appropriate treatment for up to three years following diagnosis. In addition, people with psychogenic nonepileptic seizures (PNES) as well as epileptic seizures may be at a higher risk for sudden unexpected death in epilepsy (SUDEP)during the years immediately following diagnosis with PNES.

Summaries of all highlighted studies follow below. I’ve organized the findings into three categories: Treatment Advances, Research Discoveries, and Also Notable.

Treatment Advances

FDA Approves NAYZILAM® Nasal Spray to Treat Intermittent, Stereotypic Episodes of Frequent Seizure Activity in People Living with Epilepsy in the US
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The FDA has approved a New Drug Application for UCB’s newest antiepileptic drug NAYZILAM® (midazolam) nasal spray. This therapy is a benzodiazepine indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) distinct from a patient’s usual seizure pattern in individuals with epilepsy who are 12 years of age and older.

Study Advances More Effective Laser Ablation and Standard Epilepsy Surgery 
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In the largest study of its kind to date, researchers across 11 centers analyzed data on a relatively new minimally invasive alternative surgery for epilepsy. These researchers discovered changes that could make the procedure more effective in both laser ablation and standard surgery.

Research Discoveries

Brain Network Activity can Improve in Epilepsy Patients after Surgery
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Successful epilepsy surgery can improve brain connectivity similar to patterns seen in people without epilepsy, according to a new study published in the journal Neurosurgery. The study of 15 people with temporal lobe epilepsy is the first to show improvements in brain networks after surgery compared to a group of healthy subjects.

New Drug Could Help Treat Neonatal Seizures
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A new drug that inhibits neonatal seizures in rodent models could open new avenues for epilepsy treatment in human newborns. Researchers have found that gluconate—a small organic compound found in fruit and honey—acts as an anticonvulsant, inhibiting seizures by targeting the activity of channels that control the flow of chloride ions in and out of neonatal neurons.

Research Looks to Halt Stress-Induced Seizures Following Brain Injury
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The likelihood of developing epilepsy increases significantly with a traumatic brain injury. Stress and anxiety increase that likelihood even more dramatically. Researchers have been able to demonstrate that an injured brain responds differently to stress hormones than a healthy brain. The research team showed abnormal electrical activity in the brain tied to these stress-induced seizures and, most importantly, found a way to stop this activity from occurring.

Synthetic Version of Cannabidiol (CBD) Treats Seizures in Rats
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A synthetic, non-intoxicating analogue of CBD was found to be effective for treating seizures in rats. Researchers note the synthetic CBD alternative is easier to purify than a plant extract, eliminates the need to use agricultural land for hemp cultivation, and could avoid legal complications associated with cannabis-related products.

AZD7325 Has Seizure-Protective Effect in Mouse Model of Dravet Syndrome, Study Says
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Treatment with AZD7325, a compound that stimulates an inhibitory receptor in the brain, has a seizure-protective effect in a mouse model of Dravet syndrome. This treatment significantly increased the temperature threshold animals could withstand without experiencing any seizures during a hyperthermia-induced seizure test.

Children’s Brains Reorganize after Epilepsy Surgery to Retain Visual Perception
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Children can keep their full ability to process and understand visual information after brain surgery for severe epilepsy, according to a study funded by the National Eye Institute, part of the National Institutes of Health. This new report from a study of children who underwent epilepsy surgery and suggests that the lasting effects on visual perception can be minimal, even among children who lost tissue in the brain’s visual centers.

One-Third of Epilepsy Cases Go Untreated up to 3 Years After Diagnosis
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A small yet substantial subset of patients with newly diagnosed epilepsy go without appropriate treatment approximately 3 years after diagnosis. This gap in treatment may be increasing the risk for medical events and hospitalization in these patients.

Study Suggests ‘High Risk Period’ for SUDEP for People with Psychogenic Nonepileptic Seizures in Addition to Epileptic Seizures 
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Findings of a recently published study suggest that patients with comorbid epileptic seizures (ES) and Psychogenic Nonepileptic Seizures (PNES) can die from SUDEP and that there may be a high?risk period after the diagnosis of PNES is made. The authors state such patients should be closely monitored and provided with coordinated care of both their epilepsy and psychiatric disorder(s).

Also Notable

Fralin Biomedical Research Institute Neuroscientist Awarded Grant to Study Epilepsy
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Featuring CURE Grantee Dr. Sharon Swanger

Dr. Sharon Swanger of the Fralin Biomedical Research Institute was recently awarded a $1.7 million grant through the National Institute of Neurological Disorders and Stroke to study the role of glutamate receptors in the thalamus – an area of the brain involved in seizure generation. “If we can figure out how each [receptor] subtype functions and modulate select subtypes, then maybe we can target therapies to the circuit where the disease originated while leaving healthy circuits intact,” said Dr. Swanger.

Tool Helps GPs Predict Risk of Seizures in Pregnancy
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Doctors, midwives, and others can use a new risk calculator to identify those pregnant women at high-risk of seizures and to plan early referral for specialist input. The specialist could determine the need for close monitoring in pregnancy, labor, and after birth, and assess antiepileptic drug management, according to new research in PLOS Medicine. The study authors added that the model’s performance is unlikely to vary with the antiepilepsy drug dose management strategy – and that it could save maternal and infant lives.

Development of Epilepsy Prediction Device to Improve Independence for People with Epilepsy
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The University of Sydney’s Faculty of Engineering and Information Technologies is developing a system, NeuroSyd, which aims at real-time monitoring and processing of brain-signals while driving in a group of people living with epilepsy. NeuroSyd will be developed to deliver an early warning of the likelihood of an epileptic seizure.

Pfizer’s Lyrica at Doses 5mg and 10mg Fails Phase 3 Trial in Epilepsy
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Pfizer’s Lyrica has failed to meet its primary endpoint in a phase 3 trial in primary generalized tonic-clonic (PGTC) seizures. The study evaluated two doses of the drug – 5 mg and 10 mg – over a period of 12 weeks. Treatment with the drug did not result in a statistically significant reduction in seizure frequency versus placebo. Another phase 3 trial in May 2018 was successful, showing that a 14 mg dose of Lyrica resulted in a statistically significant reduction in seizure frequency versus placebo.

Zebinix Effective as Adjunctive Therapy in Epilepsy Patients with Psychiatric Comorbidities

Bial and Eisai have announced clinical practice data from the Euro-Esli study demonstrating clinical effectiveness of eslicarbazepine acetate, and that it is generally well tolerated as an adjunctive therapy in focal epilepsy patients with psychiatric comorbidities, including intellectual disability, compared with people with no psychiatric comorbidities.

The data, which add to the body of evidence on eslicarbazepine acetate as adjunctive therapy from Phase III studies, were published in Journal of the Neurological Sciences.

Psychiatric comorbidities, including intellectual disability and depression, are common for adults who have epilepsy. Prevalence of psychiatric comorbidities may be twofold higher in adult patients with epilepsy compared to the general public, and up to a quarter of people diagnosed with epilepsy are estimated to have an intellectual disability. Psychiatric comorbidities can exacerbate the effects and increase the impact of epilepsy. Furthermore, antiepileptic treatments can interfere with treatments for the psychiatric comorbidities, and thus adversely affect these psychiatric conditions. There are many considerations for treating this patient population, thereby complicating treatment choice.

Increased Behavioral Problems in Children of Mothers with Epilepsy Prenatally Exposed to Antiepileptic Drugs, as Reported by Parents

OBJECTIVE: To examine the behavioral functioning of children prenatally exposed to carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or valproate (VPA) monotherapy.

METHODS: In collaboration with the European Registry of Antiepileptic Drugs and Pregnancy (EURAP), the Dutch EURAP & Development study was designed, a prospective observational study. Between January 2015 and March 2018, the Child Behavior Checklist and the Social Emotional Questionnaire were used to examine the nature and severity of behavioral problems. VPA-exposed children were compared to children exposed to CBZ, LTG, or LEV, taking potential confounders into account. A direct comparison was also made between LTG and LEV, as these are first-choice treatments for many women with epilepsy of childbearing potential.

RESULTS: Of the 405 invited, 181 children were included; 26 were exposed to VPA, 37 to CBZ, 88 to LTG, and 30 to LEV. For most children, both parents completed the behavioral questionnaires. Across all four antiepileptic drug (AED) exposure groups, high percentages of children with clinically relevant behavior problems were found, with behavioral problems occurring in 32% of VPA-exposed children, 14% of CBZ, 16% of LTG, and 14% of LEV. After controlling for potential confounders, VPA-exposed children had significantly more social problems than those exposed to lamotrigine, and significantly more attention problems than levetiracetam-exposed children. Lamotrigine-exposed children had significantly more attention deficit, but significantly less anxious behavior when compared to levetiracetam-exposed children.

SIGNIFICANCE: Compared to population norms, a high proportion of children of mothers with epilepsy exposed prenatally to monotherapy with four common antiepileptic drugs had clinical behavioral problems reported by parents. Different patterns were seen, with some but not all subscales raised for all antiepileptic drug exposure groups. It is important that prenatally antiepileptic drug-exposed children are regularly screened for behavioral problems so that appropriate help can be provided.

Pfizer’s Lyrica at Doses 5mg and 10mg Fails Phase 3 Trial in Epilepsy

Pfizer’s Lyrica has failed to meet its primary endpoint in a phase 3 trial in primary generalised tonic-clonic (PGTC) seizures. The study evaluated two doses of the drug – 5 mg and 10 mg – over a period of 12 weeks.

Treatment with the drug did not result in a statistically significant reduction in seizure frequency versus placebo.

The safety profile was similar to that observed in other studies.

The trial was conducted as a post-marketing requirement by the FDA.

Pfizer is investigating the drug as part of its wider Lyrica Pediatric Epilepsy Program, which is composed of six studies in patients with epilepsy evaluating Lyrica as adjunctive therapy, five of which have been completed.

Another phase 3 trial in May 2018 was successful, showing that in paediatric patients with epilepsy a 14 mg dose of Lyrica resulted in a statistically significant reduction in seizure frequency versus placebo – however no statistically significant reduction was observed with a 7 mg dose.

Midazolam Nasal Spray Superior to Placebo in Providing Rapid Seizure Control: Results of Randomized, Placebo-Controlled Trial

OBJECTIVE: To evaluate the safety and efficacy of a novel formulation of midazolam administered as a single-dose nasal spray (MDZ-NS) in the outpatient treatment of patients experiencing seizure clusters (SCs).

METHODS: This was a phase III, randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov NCT01390220) with patients age 12 years or older on a stable regimen of antiepileptic drugs. Following an in-clinic test dose phase (TDP), patients entered an outpatient comparative phase (CP) and were randomized (2:1) to receive double-blind MDZ-NS 5 mg or placebo nasal spray, administered by caregivers when they experienced an SC. The primary efficacy end point was treatment success (seizure termination within 10 minutes and no recurrence 10 minutes to 6 hours after trial drug administration). Secondary efficacy end points were proportion of patients with seizure recurrence 10 minutes to 4 hours, and time-to-next seizure >10 minutes after double-blind drug administration. Safety was monitored throughout.

RESULTS: Of 292 patients administered a test dose, 262 patients were randomized, and 201 received double-blind treatment for an SC (n = 134 MDZ-NS, n = 67 placebo, modified intent-to-treat population). A significantly greater proportion of MDZ-NS- than placebo-treated patients achieved treatment success (53.7% vs 34.4%; P = 0.0109). Significantly, fewer MDZ-NS- than placebo-treated patients experienced seizure recurrence (38.1% vs 59.7%; P = 0.0043). Time-to-next seizure analysis showed early separation (within 30 minutes) between MDZ-NS and placebo that was maintained throughout the 24-hour observation period (21% difference at 24 hours; P = 0.0124). Sixteen patients (5.5%) discontinued because of a treatment-emergent adverse event (TEAE) during the TDP and none during the CP. During the CP, 27.6% and 22.4% of patients in the MDZ-NS and placebo groups, respectively, experienced 1 or greater TEAE.

SIGNIFICANCE: MDZ-NS was superior to placebo in providing rapid, sustained seizure control when administered to patients experiencing a seizure cluster in the outpatient setting and was associated with a favorable safety profile.

What’s the Right Amount of ‘Zapping’ in Epilepsy Laser Surgery?

In the largest study of its kind to date, researchers across 11 centers analyzed data on a relatively new minimally invasive alternative surgery for epilepsy, and discovered changes that could make the procedure more effective in both laser ablation and standard surgery.

“The field hasn’t had a unified approach to laser ablation surgery for epilepsy,” says corresponding author, neurosurgeon Chengyuan Wu, MD, Associate Professor in the Department of Neurological Surgery at Jefferson (Philadelphia University + Thomas Jefferson University) and the Vickie & Jack Farber Institute for Neuroscience – Jefferson Health. “With this study, we were able to answer the question: ‘How much ablation is enough, how much is too much, and exactly where should we be targeting?'”

The researchers, including co-first authors from the University of Miami, Jackson Memorial Hospital and Vanderbilt University analyzed the charts and images of 234 patients who underwent laser ablation therapy for epilepsy in 11 centers across the United States. During the procedure, a small laser catheter is placed under MRI-guidance in the part of the brain felt to be responsible for the patient’s epilepsy. Surgeons then deliver precise pulses of laser ablation to that particular region until the tissue is eliminated, in order to prevent further seizure. “The procedure has effects similar to open-brain surgery, which removes part of the brain,” says Dr. Wu. “But there’s significantly less trauma to the surrounding brain tissue with this approach.”

Review: New Anti-Seizure Medication for Elderly Patients with Epilepsy

Introduction: Epilepsy treatment in older people requires specific consideration owing to more physical co-morbidities, the risk of drug-to-drug interactions through polypharmacy, and differences in pharmacodynamics and pharmacokinetics. There are many ‘newer’ antiepileptic drugs (AEDs) widely used for various seizure types and seizure disorders. However, there is limited specific evidence for the efficacy, safety, and tolerability of these treatments in the elderly population.

Areas covered: This review summarizes the current and most robust evidence available for the use of the newer AEDs belonging to generation two and three in elderly people with epilepsy. The article provides practical evidenced based clinical information to help prescribers choose the most appropriate AED from the drugs discussed.

Expert opinion: Diagnosing new onset epilepsy in the elderly population requires specialist assessment. Treatment plans need to be tailored to accommodate an individual’s co-morbidities, concurrent medications, and general health status. To date, few clinical investigations consider the elderly population specifically despite the increased risk factors. There is a need for large quality trial data to assess the impact of the newest AEDs on seizure control and quality of life in this population with complex needs.

UCB announces NAYZILAM® (midazolam) nasal spray now approved by FDA to treat intermittent, stereotypic episodes of frequent seizure activity in people living with epilepsy

UCB announces NAYZILAM® (midazolam) nasal spray now approved by FDA to treat intermittent, stereotypic episodes of frequent seizure activity in people living with epilepsy in the US.

  • NAYZILAM® (midazolam) nasal spray CIV is a nasally administered benzodiazepine indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 12 years of age and older.
  • NAYZILAM allows for administration by a non-healthcare professional in patients actively seizing when and where a seizure cluster occurs.
  • Approval of NAYZILAM adds to UCB’s already existing anti-epilepsy drug portfolio, reinforcing the company’s position as a global leader in epilepsy.

UCB announced the FDA has approved a New Drug Application for the company’s newest anti-epileptic drug (AED) NAYZILAM® (midazolam) nasal spray CIV, a benzodiazepine indicated for the acute treatment of intermittent, stereotypic episodes of  frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 12 years of age and older. NAYZILAM now provides patients and caregivers with the first and only FDA-approved nasal option for treating seizure clusters.

It is estimated that more than 150,000 people in the US with uncontrolled epilepsy also experience seizure clusters.1 Rescue treatment of seizure clusters is critical because when left untreated, seizure clusters can increase the risk of physical injury, neurological damage, prolonged seizures, and status epilepticus.2 Despite the impact of seizure clusters, many diagnosed patients may go untreated because currently available treatment options are not preferred.3, 4, 5, 6 

NAYZILAM is a short-term treatment for seizure clusters in patients with epilepsy. The nasal spray is designed as a single-use treatment that can be carried with a patient. NAYZILAM allows for administration by a non-healthcare professional in patients actively seizing when and where a seizure cluster occurs. NAYZILAM can provide value to patients who are experiencing these disruptive seizures.

1 Chen B, Choi H, Hirsch L, Katz A, Legge L, Wong R, Jiang A, Kato K, Buchsbaum R, Detyniecki K. Prevalence and risk factors of seizure clusters in adult patients with epilepsy. Epilepsy Research. 2017;133: 98-102.
2 Penovich PE, Buelow J, Steinberg K, Sirven J, Wheless J. Burden of seizure clusters on patients with epilepsy and caregivers: survey of patient, caregiver, and clinician perspectives. Neurologist. 2017;22(6):207-214.
3 Nunley S, Glynn P, Rust S, Vidaurre J, Albert DVF, Patel AD. A hospital-based study on caregiver preferences on acute seizure rescue medications in pediatric patients with epilepsy: intranasal midazolam versus rectal diazepam. Epilepsy Behav. 2019;92:53-56.
4 Holsti M, Dudley N, Schunk J, et al. Intranasal midazolam vs rectal diazepam for the home treatment of acute seizures in pediatric patients with epilepsy. Arch Pediatr Adolesc Med. 2010;164(8):747-753.
5 de Haan GJ, van der Geest P, Doelman G, Bertram E, Edelbroek P. A comparison of midazolam nasal spray and diazepam rectal solution for the residential treatment of seizure exacerbations. Epilepsia. 2010;51(3):478-482
6 Bhattacharyya M, Kalra V, Gulati S. Intranasal midazolam vs rectal diazepam in acute childhood seizures. Pediatr Neurol. 2006;34(5):355-359.

New Drug Could Help Treat Neonatal Seizures

A new drug that inhibits neonatal seizures in rodent models could open up new avenues for the treatment of epilepsy in human newborns. Researchers have identified that gluconate—a small organic compound found in fruit and honey—acts as an anticonvulsant, inhibiting seizures by targeting the activity of channels that control the flow of chloride ions in and out of neonatal neurons. A paper describing the research, from an international team of scientists led by Penn State researchers, appears May 15, 2019 in the journal Molecular Brain.

“Neonates are the most vulnerable population to seizures but there is still no effective medication for the treatment of neonatal epilepsy,” said Gong Chen, professor of biology and the Verne M. Willaman Chair in Life Sciences at Penn State and the leader of the research team. “The incidence of epilepsy is highest in the first year of life, with two to four infant babies suffering from neonatal epilepsy for every 1,000 live births in the United States. Unfortunately, so far there is no effective drug available that is specifically developed for neonatal epilepsy patients.”