Encyclopedia
Valtoco
®
is a new FDA-approved nasal spray version of diazepam indicated for the treatment of acute, intermittent, and stereotypic episodes of frequent seizure activity in epilepsy patients six years of age and older. Although IV and rectal diazepam are already used to treat seizure clusters, Valtoco
®
has less variability in plasma concentration compared to rectal diazepam. Furthermore, the intranasal administration of Valtoco
®
is more convenient and less invasive than rectal or IV diazepam, making it ideal for self-administration outside of a hospital setting. Multiple clinical trials have taken place comparing Valtoco
®
to the oral, rectal, and IV forms of diazepam. Aside from mild nasal irritation and lacrimation, Valtoco
®
was found to have no increased safety risk in comparison to traditional forms of diazepam.
- valtoco
- diazepam
- seizure
- GABA
- bezodiazepine
1. Introduction
A seizure is a sudden and uncontrolled electrical disturbance in the brain that can cause changes in movement, behavior, feelings, and consciousness [1]. Based on the International League Against Epilepsy (ILAE) classification of seizures, which was updated in 2017, seizures can be classified as focal, general, or unknown onset [1]. The difference between these types of seizures is determined by where they originate in the brain. Focal onset seizures can originate in one area, hemisphere, or group of cells in the brain. Focal seizures can be classified as aware or impaired awareness [2]. Focal onset aware seizures occur when a person is awake and aware during the seizure. Focal onset impaired awareness seizures occur when a person is confused or their awareness is impaired. Focal onset seizures can have motor and non-motor symptoms [2]. Motor symptoms can include jerking, limp or weak muscles, and tense or rigid muscles. Non-motor symptoms include changes in sensation, emotion, thought, cognition, gastrointestinal symptoms, or a complete lack of movement. General onset seizures affect both sides of the brain (or groups of cells on both sides of the brain) at the same time [2]. General onset seizures have motor and non-motor symptoms. The motor symptoms are similar to focal onset seizure motor symptoms. The non-motor symptoms include staring spells or brief twitches that may affect only one part of the body (e.g., the eyelid) [2]. Unknown onset seizures occur when the cause of a seizure is not known. Usually, this category can be excluded as information is gathered from the patient or family members to narrow down how and why the seizure occurred. Unknown onset seizures can have tonic-clonic (what is generally recognized as a seizure during which the person loses consciousness or has stiff muscles and jerky movements) or epileptic motor spasms. The non-motor seizures in this category include the absence of behavior or staring [2]. Seizure clusters are seizures that start and stop and occur in groups one after another. A cluster can also be considered as two or three seizures in 24 h with recovery between each seizure.
When a patient experiences two or more seizures that are unprovoked, a diagnosis of epilepsy can be given [3]. The antiepileptic drug prescribed for treatment depends on the classification of the seizure. Carbamazepine or lamotrigine are recommended first-line treatments for focal seizures, while sodium valproate is a recommended first-line treatment for generalized tonic-clonic seizures [4][5][6]. For seizure clusters and status epilepticus, the recommended first-line treatment is a benzodiazepine (BZD), such as diazepam or midazolam [7][8][9][10]. Diazepam and other BZDs are used because they bind to gamma-aminobutyric acid (GABA)-A receptors, which causes increased chloride influx and hyperpolarization of the neuron, resulting in decreased neuron excitability and antiepileptic activity [11][12]. This review discusses the original use of diazepam and the epidemiology, pathophysiology, risk factors, presentation, and treatment of diazepam withdrawal. The present manuscript also describes Valtoco
When a patient experiences two or more seizures that are unprovoked, a diagnosis of epilepsy can be given [3]. The antiepileptic drug prescribed for treatment depends on the classification of the seizure. Carbamazepine or lamotrigine are recommended first-line treatments for focal seizures, while sodium valproate is a recommended first-line treatment for generalized tonic-clonic seizures [4,5,6]. For seizure clusters and status epilepticus, the recommended first-line treatment is a benzodiazepine (BZD), such as diazepam or midazolam [7,8,9,10]. Diazepam and other BZDs are used because they bind to gamma-aminobutyric acid (GABA)-A receptors, which causes increased chloride influx and hyperpolarization of the neuron, resulting in decreased neuron excitability and antiepileptic activity [11,12]. This review discusses the original use of diazepam and the epidemiology, pathophysiology, risk factors, presentation, and treatment of diazepam withdrawal. The present manuscript also describes Valtoco
®
, the nasal spray form of diazepam, and its clinical use for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity, in addition to its mechanism of action, pharmacokinetics, and pharmacodynamics. Lastly, clinical trials of Valtoco
®
will be compared to determine its safety and efficacy.
2. Diazepam Withdrawal
2.1. Epidemiology
Benzodiapeines, such as diazepam, have been approved for the treatment of anxiety, acute alcohol withdrawal, skeletal muscle spasm, and epileptic disorders, such as SE. They are also used for “off-label” treatment of conditions like insomnia [13]. In the past, barbiturates were used to treat these conditions, but benzodiazepines have largely replaced them due to their greater safety, lower abuse potential, and CNS specificity. As more conditions (e.g., Dalmane®
or Halcion® for insomnia) have been approved or accepted clinically for treatment by BZDs, the amount of BZD prescriptions have increased. From 1996 to 2013, the amount of people filling a BZD prescription increased from 8.1 million to 13.5 million, a 67% change [14]. Similarly, the percentage of adults filling a BZD prescription increased from 4.1%, with an annual change of 2.5% from 1996 to 2013 [14]. In addition to increased prescription rates, a 29% increase in emergency department visits due to nonmedical use of BZDs was reported in 2011, representing a 149% increase compared to 2004 [15]. Although specific data for BZD use disorder in the United States is unavailable, the lifetime prevalence of sedative use disorders is estimated to be 1.1% [16]. Benzodiazepines are DEA class IV related to safety, misuse, and abuse potential.
for insomnia) have been approved or accepted clinically for treatment by BZDs, the amount of BZD prescriptions have increased. From 1996 to 2013, the amount of people filling a BZD prescription increased from 8.1 million to 13.5 million, a 67% change [14]. Similarly, the percentage of adults filling a BZD prescription increased from 4.1%, with an annual change of 2.5% from 1996 to 2013 [14]. In addition to increased prescription rates, a 29% increase in emergency department visits due to nonmedical use of BZDs was reported in 2011, representing a 149% increase compared to 2004 [15]. Although specific data for BZD use disorder in the United States is unavailable, the lifetime prevalence of sedative use disorders is estimated to be 1.1% [16]. Benzodiazepines are DEA class IV related to safety, misuse, and abuse potential.2.2. Pathophysiology
While patients taking BZDs do not have to be addicted to experience withdrawal symptoms, withdrawal is common after long-term use. It often takes months to taper off of BZDs. Although the exact mechanism is unknown, BZDs increase dopamine levels in the mesolimbic reward system. The ventral tegmental area (VTA), which is part of the mesolimbic reward system, contains GABA interneurons, dopamine neurons, and glutamate neurons [17]. BZDs bind to a specific pocket of GABA-A receptors located between the alpha and gamma subunits. Within the VTA, GABA interneurons with high numbers of GABA-A receptors that contain the alpha-1 subunit were found in mice [17]. The alpha-1 subunit has specifically been implicated in addictive behavior [18]. Once the BZD has bound to the GABA-A receptor, the release of GABA onto dopamine neurons is decreased. This results in disinhibition, since the inhibitory effect of GABA interneurons to dopamine neurons is decreased, leading to increased dopamine release [17].Prolonged use of BZDs like diazepam result in conformational changes in the GABA-A receptor. Studies involving mice that were administered BZDs showed decreased mRNA levels of GABA-A subunits gamma-2 and alpha-1, while mRNA levels of subunit alpha-5 increased [19][20][21]. Allosteric uncoupling of the GABA-A subunits was also observed in mice that were administered BZDs [21][22][23]. These results suggest a mechanism of tolerance to BZDs, but do not explain the dependence after withdrawal from BZDs, since GABA-A subunit levels return to control levels within 72 h of discontinuation of BZDs in mice [21][24].
Prolonged use of BZDs like diazepam result in conformational changes in the GABA-A receptor. Studies involving mice that were administered BZDs showed decreased mRNA levels of GABA-A subunits gamma-2 and alpha-1, while mRNA levels of subunit alpha-5 increased [19,20,21]. Allosteric uncoupling of the GABA-A subunits was also observed in mice that were administered BZDs [21,22,23]. These results suggest a mechanism of tolerance to BZDs, but do not explain the dependence after withdrawal from BZDs, since GABA-A subunit levels return to control levels within 72 h of discontinuation of BZDs in mice [21,24].Benzodiazepines are also thought to alter synaptic plasticity via alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor migration. BZD administration in mice has shown increased AMPA receptor migration from the interior of dopamine neurons to the surface [17]. When these AMPA receptors migrate to the surface of dopamine neurons in the VTA, they are more likely to be stimulated via glutamate, leading to increased dopamine levels [25]. In studies in which mice were administered BZDs and then observed at the cessation of BZDs, an increase in AMPA receptors at the surface of hippocampal CA1 neurons was noted [26][27][28]. This results in hippocampal hyperexcitability, and suggests that increased AMPA receptors at CA1 neurons may contribute to the anxiety symptoms experienced with BZD withdrawal [21][26], and are a potential mechanism of physical dependence [21][29].
Benzodiazepines are also thought to alter synaptic plasticity via alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor migration. BZD administration in mice has shown increased AMPA receptor migration from the interior of dopamine neurons to the surface [17]. When these AMPA receptors migrate to the surface of dopamine neurons in the VTA, they are more likely to be stimulated via glutamate, leading to increased dopamine levels [25]. In studies in which mice were administered BZDs and then observed at the cessation of BZDs, an increase in AMPA receptors at the surface of hippocampal CA1 neurons was noted [26,27,28]. This results in hippocampal hyperexcitability, and suggests that increased AMPA receptors at CA1 neurons may contribute to the anxiety symptoms experienced with BZD withdrawal [21,26], and are a potential mechanism of physical dependence [21,29].2.3. Risk Factors
Multiple risk factors have been identified in regard to BZD dependence. One study that surveyed 599 BZD users showed that the main risk factors in decreasing order of significance are: being a member of a self-help group for medication dependence, younger age, longer time period of BZD use, higher dose of BZD, the interaction of higher BZD dose with a longer time period of BZD use, lower education level, non-native cultural origin, and outpatient treatment for alcohol and/or drug dependence [30]. Another study that interviewed 401 BZD users showed that patients with insomnia, concurrent antidepressant use, and alcohol dependence were at a higher risk of developing BZD dependence [31].Another study that surveyed 43,093 adults representative of the United States population showed that BZD use disorder displayed psychiatric comorbidity with antisocial personality disorder, bipolar I disorder, panic disorder with agoraphobia, other prescription drug misuse, and other substance use disorders [16]. In two separate studies that followed and surveyed patients at methadone maintenance clinics, BZD misuse was found at significantly high rates [32][33]. Additionally, high rates of BZD misuse were found among injection drug users [34].
Another study that surveyed 43,093 adults representative of the United States population showed that BZD use disorder displayed psychiatric comorbidity with antisocial personality disorder, bipolar I disorder, panic disorder with agoraphobia, other prescription drug misuse, and other substance use disorders [16]. In two separate studies that followed and surveyed patients at methadone maintenance clinics, BZD misuse was found at significantly high rates [32,33]. Additionally, high rates of BZD misuse were found among injection drug users [34]. In an analysis of 48 cases of seizures thought to have been caused by BZD withdrawal, brain damage, alcohol addiction, and electroencephalogram abnormalities were found to be risk factors for BZD withdrawal seizures [35]. In an analysis of 20 reports, including studies and large case series of BZD withdrawal, BZDs with a short half-life, high doses of BZD, a long period of BZD use, and abrupt cessation of BZD use were associated with increased BZD withdrawal severity [36].2.4. Presentation
BZD withdrawal can result in a range of symptomatic patterns. Rebound anxiety with insomnia within 1–4 days of BZD cessation is the most common symptom pattern of withdrawal. In most cases, this lasts for 2–3 days [37][38]. In more severe cases, patients can experience a combination of anxiety, insomnia, panic attacks, irritability, tremors, diaphoresis, difficulty concentrating, nausea, vomiting, weight change, headache, heart palpitations, and muscle aches. These symptoms can last for 2–14 days after BZD cessation [37]. In extreme cases, seizures and psychosis have been observed in patients after BZD cessation [39]. The severity and duration of withdrawal symptoms are related to how long the time period of BZD use was, if the BZD had a short or long half-life, and what tapering schedule was used [40][41]. Although most patients will experience symptoms that last no longer than 1–2 weeks, some may have symptoms for an extended time period [42].
BZD withdrawal can result in a range of symptomatic patterns. Rebound anxiety with insomnia within 1–4 days of BZD cessation is the most common symptom pattern of withdrawal. In most cases, this lasts for 2–3 days [37,38]. In more severe cases, patients can experience a combination of anxiety, insomnia, panic attacks, irritability, tremors, diaphoresis, difficulty concentrating, nausea, vomiting, weight change, headache, heart palpitations, and muscle aches. These symptoms can last for 2–14 days after BZD cessation [37]. In extreme cases, seizures and psychosis have been observed in patients after BZD cessation [39]. The severity and duration of withdrawal symptoms are related to how long the time period of BZD use was, if the BZD had a short or long half-life, and what tapering schedule was used [40,41]. Although most patients will experience symptoms that last no longer than 1–2 weeks, some may have symptoms for an extended time period [42].
3. VALTOCO® (Diazepam Nasal Spray) Drug Info
Valtoco
®
is a form of diazepam that is administered intranasally. According to the FDA, it is approved for “acute, 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 six years of age and older.” Valtoco
®
is given in 5 mg and 10 mg doses. It is administered with a single spray in one nostril and a second dose when required 4 h later. See
.
Table 1.
| Dose Based on Age and Weight | Administration | |||
|---|---|---|---|---|
| 6 to 11 Years of Age (0.3 mg/kg) Weight (kg) |
12 Years of Age and Older (0.2 mg/kg) Weight (kg) |
Dose (mg) | Number of Nasal Spray Devices | Number of Sprays |
| 10 to 18 | 14 to 27 | 5 | One 5 mg device | One spray in one nostril |
| 19 to 37 | 28 to 50 | 10 | One 10 mg device | One spray in one nostril |
| 38 to 55 | 51 to 75 | 15 | Two 7.5 mg devices | One spray in one nostril |
| 56 to 74 | 76 and up | 20 | Two 10 mg devices | One spray in one nostril |
The recommended dose of Valtoco® is 0.2–0.3 mg/kg. The maximum dosage is two sprays for a single episode. It should not be used more than once every five days. It is available in 5 mg, 7.5 mg, and 10 mg strengths. There are risks associated with taking this drug with opioids. Opioids may result in sedation, respiratory depression, coma, and death. According to the FDA: “Observational studies have demonstrated that concomitant use of opioid analgesics and BZDs increases the risk of drug-related mortality compared to use of opioids alone.” Therefore, if Valtoco® is used in adjunctive therapy with other opioids, it should be prescribed at the lowest dose for the shortest time possible, and patients should be monitored [43].
The recommended dose of Valtoco® is 0.2–0.3 mg/kg. The maximum dosage is two sprays for a single episode. It should not be used more than once every five days. It is available in 5 mg, 7.5 mg, and 10 mg strengths. There are risks associated with taking this drug with opioids. Opioids may result in sedation, respiratory depression, coma, and death. According to the FDA: “Observational studies have demonstrated that concomitant use of opioid analgesics and BZDs increases the risk of drug-related mortality compared to use of opioids alone.” Therefore, if Valtoco® is used in adjunctive therapy with other opioids, it should be prescribed at the lowest dose for the shortest time possible, and patients should be monitored [44].
Valtoco
®
may induce CNS depression. This drug must be used cautiously if patients are planning on engaging in activities that require mental alertness. It should also not be taken with alcohol or other CNS depressants due to potential respiratory suppression. Using Valtoco
®
has a risk of suicidal thoughts or behaviors. Studies have shown that using antiepileptic drugs, such as Valtoco
®, has twice the risk of suicidal thinking. These side effects were seen as early as one week into treatment, and can continue throughout the course of medication [43].
, has twice the risk of suicidal thinking. These side effects were seen as early as one week into treatment, and can continue throughout the course of medication [44].
Valtoco® can also increase intraocular pressure in narrow angle glaucoma, and is therefore contraindicated. It can, however, be used in patients with open-angle glaucoma if the condition is controlled. The drug is also contraindicated in patients with known hypersensitivity to diazepam [43].
Valtoco® can also increase intraocular pressure in narrow angle glaucoma, and is therefore contraindicated. It can, however, be used in patients with open-angle glaucoma if the condition is controlled. The drug is also contraindicated in patients with known hypersensitivity to diazepam [44].
Valtoco® cannot be used in neonates because of potentially fatal “gasping syndrome” if the neonate is underweight. Gasping syndrome is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. This is due to Valtoco® being a benzyl alcohol-preserving drug. There is not enough data to confirm or refute the safe use of Valtoco® during pregnancy, but the drug is excreted in breastmilk. Related to these side effects, patients should be carefully monitored when taking Valtoco® [43].
Valtoco® cannot be used in neonates because of potentially fatal “gasping syndrome” if the neonate is underweight. Gasping syndrome is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. This is due to Valtoco® being a benzyl alcohol-preserving drug. There is not enough data to confirm or refute the safe use of Valtoco® during pregnancy, but the drug is excreted in breastmilk. Related to these side effects, patients should be carefully monitored when taking Valtoco® [44].
4. Mechanism of Action
Valtoco
®
binds to BZD receptors located between the alpha and gamma subunits of GABA
A
complexes. The GABA
A
receptor consists of five protein subunits arranged in a ring around a central pore. The five protein subunits include two alpha subunits, two beta subunits, and one gamma subunit. BZDs are allosteric GABA
A
receptor modulators, and therefore do not bind to the active site and are not true agonists. BZDs increase the frequency of the chloride ion channel opening, thereby increasing the inhibitory effect of GABA on neuronal excitability. Upon GABA
A
receptor activation, chloride ions flow into the cell. This causes hyperpolarization of the cell and an overall negative charge. Because they are allosteric activators, they do not directly open the chloride channel. BZD effects are especially pronounced in the limbic system, thalamus, and hypothalamus. BZD receptor agonists work through GABA
A receptors to promote sedation by inhibiting brainstem monoaminergic arousal pathways. This is possible through the facilitation of VLPO inhibitory GABAergic projections to arousal centers, such as the anterior hypothalamus TMN, the posterolateral hypothalamic hypocretin neurons, and the brainstem arousal regions, ultimately causing sedation [44].
receptors to promote sedation by inhibiting brainstem monoaminergic arousal pathways. This is possible through the facilitation of VLPO inhibitory GABAergic projections to arousal centers, such as the anterior hypothalamus TMN, the posterolateral hypothalamic hypocretin neurons, and the brainstem arousal regions, ultimately causing sedation [45].
Studies have compared intranasal diazepam to oral and rectal gel diazepam. Compared to oral diazepam, Valtoco
®
has a slower t
max
(time to reach maximum plasma concentration). Intranasal administration has similar t
max
to the rectal gel. Variability (as defined by the percent coefficient of variation of the geometric mean) in the peak plasma concentration was higher in Valtoco
® than oral diazepam. The diazepam rectal gel showed the greatest variability. No major nasal irritation was documented by subjects that participated in the trials; mild complications included minor epistaxis that resolved within 1 min. The significance of the NCBI’s trial was that “Diazepam nasal spray shows predicable pharmacokinetics and represents a potential novel therapeutic approach to control bouts of increased seizure activity (cluster seizures, acute repetitive seizures).” It was shown to be acceptably safe, with less variability than the rectal diazepam route, and showed no damage to nasal mucosa [45]. The types of epileptic condition had no significant effect on the pharmacokinetics of Valtoco
than oral diazepam. The diazepam rectal gel showed the greatest variability. No major nasal irritation was documented by subjects that participated in the trials; mild complications included minor epistaxis that resolved within 1 min. The significance of the NCBI’s trial was that “Diazepam nasal spray shows predicable pharmacokinetics and represents a potential novel therapeutic approach to control bouts of increased seizure activity (cluster seizures, acute repetitive seizures).” It was shown to be acceptably safe, with less variability than the rectal diazepam route, and showed no damage to nasal mucosa [46]. The types of epileptic condition had no significant effect on the pharmacokinetics of Valtoco
® [46]. Valtoco
[47]. Valtoco
®
is specifically marketed for the treatment of cluster seizures. These types of seizures require more hospital visits, and have a greater negative impact on patient lives. The use of antiepileptics and BZDs as “rescue medications” in acute situations can help avoid status epilepticus and decrease hospital visits due to seizures. In the United States, rescue medications are underused, and therefore incur higher healthcare costs due to repeated emergency room visits. Prior to Valtoco
®
, rectal diazepam gel was the only FDA-approved rescue medication for seizure clusters. The intranasal administration of Valtoco
® is more desirable by patients and has less variability than the rectal gel [8]. Diazepam nasal spray safety was consistent with the profile of diazepam [46].
is more desirable by patients and has less variability than the rectal gel [8]. Diazepam nasal spray safety was consistent with the profile of diazepam [47].
5. Conclusions
Diazepam has been widely used and prescribed since its release in 1963. It has helped treat anxiety, muscle spasms, alcohol withdrawal, and seizures for millions of people around the world. Despite diazepam’s ability to help alleviate patients’ suffering, its addictive properties have led to misuse and potentially severe withdrawal symptoms, like anxiety, insomnia, psychosis, and seizures [13]. Since treating diazepam withdrawal aside from symptom management has proven difficult, physicians have begun to question when it is absolutely necessary to prescribe BZDs like diazepam [47]. This has led to more strict guidelines for when to prescribe diazepam, especially in regard to treating anxiety [48]. Valtoco
Diazepam has been widely used and prescribed since its release in 1963. It has helped treat anxiety, muscle spasms, alcohol withdrawal, and seizures for millions of people around the world. Despite diazepam’s ability to help alleviate patients’ suffering, its addictive properties have led to misuse and potentially severe withdrawal symptoms, like anxiety, insomnia, psychosis, and seizures [13]. Since treating diazepam withdrawal aside from symptom management has proven difficult, physicians have begun to question when it is absolutely necessary to prescribe BZDs like diazepam [43]. This has led to more strict guidelines for when to prescribe diazepam, especially in regard to treating anxiety [50]. Valtoco
®, a new FDA-approved nasal spray version of diazepam, has been indicated for the treatment of acute, intermittent, and stereotypic episodes of frequent seizure activity in epilepsy patients six years of age and older [49]. Although IV and rectal diazepam are already used to treat seizure clusters, Valtoco
, a new FDA-approved nasal spray version of diazepam, has been indicated for the treatment of acute, intermittent, and stereotypic episodes of frequent seizure activity in epilepsy patients six years of age and older [69]. Although IV and rectal diazepam are already used to treat seizure clusters, Valtoco
® has less variability in plasma concentration compared to rectal diazepam [45]. Additionally, the administration of Valtoco
has less variability in plasma concentration compared to rectal diazepam [46]. Additionally, the administration of Valtoco
® intranasally is more convenient and less invasive than rectal or IV diazepam, especially when a patient is actively seizing or not in a hospital setting [46]. Multiple clinical trials have taken place comparing Valtoco
intranasally is more convenient and less invasive than rectal or IV diazepam, especially when a patient is actively seizing or not in a hospital setting [47]. Multiple clinical trials have taken place comparing Valtoco
®
to the oral, rectal, and IV forms of diazepam. Aside from mild nasal irritation and lacrimation, Valtoco
® was found to have no increased safety risk in comparison to traditional forms of diazepam [50]. This new intranasal form of diazepam will help improve the lives of patients suffering with epilepsy.
was found to have no increased safety risk in comparison to traditional forms of diazepam [63]. This new intranasal form of diazepam will help improve the lives of patients suffering with epilepsy.
