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Application ofTopiramate inRefractory Epilepsy
Bresnahan R etal. reviewed 12 trials of topiramate as an add-on therapy, including
a total of 1650 patients with drug-resistant focal epilepsy. These trials compared the
effects of topiramate with those of a placebo drug for up to 18weeks. The review
revealed that topiramate was almost three times more effective than the placebo for
reducing the number of drug-resistant focal seizures when used with other drugs.
However, adding topiramate to patients’ usual treatment increased adverse effects,
such as ataxia, concentration difculties, dizziness, fatigue, “thinking abnormally,”
paresthesia, and weight loss. Patients taking topiramate were also more than twice
as likely to drop out of treatment as those taking placebo, most likely due to adverse
effects [428].
A meta-analysis systematically evaluated the clinical effects of valproate alone
or in combination with topiramate in the treatment of refractory epilepsy [433]. A
total of 10 studies involving 976 patients with epilepsy were included in the analysis, and the results showed that the overall response rate to valproate combined with
topiramate was greater than that to valproate alone (OR=3.52; 95% CI 1.47–8.47).
The frequencies of absence seizures, atonic seizures, and tonic–clonic seizures in
the combination group were lower than those in the monotherapy group. In addition, there was no clear difference in adverse events between the two groups.
Therefore, valproate combined with topiramate is more effective than valproate
alone in the treatment of epilepsy.
Application ofTopiramate inRefractory Status Epilepticus
To evaluate the efcacy and tolerability of topiramate in patients with refractory
status epilepticus (RSE) and superrefractory status epilepticus (SRSE), Fechner A
etal. [434] studied a total of 106 patients with a mean age of 67.4±18.1years. The
median latency time from the onset of status epilepticus to the initiation of topiramate treatment was 8.5days. The median initial topiramate dose was 100mg/day,
which was followed by escalation to a maintenance dose of 400mg/day. Patients
with SE had previously failed to achieve remission with a median of ve other antiseizure drugs. Topiramate was the last drug used in 42 of 106 patients (39.6%), with
a resultant response attributed to TPM observed in 29 of 106 (27.4%) patients.
Topiramate was associated with a response in 21 of 66 RSE patients (31.8%) and 8
of 40 SRSE patients (20%). Topiramate-related adverse events occurred in two
patients (pancreatitis and perchloric acid poisoning), and hyperammonemia
occurred in 38 patients (35.8%). Based on these results, topiramate could be used to
treat RSE and SRSE.
To provide evidence for the use of topiramate in refractory status epilepticus, a
systematic review of nine studies of topiramate use in refractory status epilepticus
patients using descriptive and qualitative analysis revealed that response rates,
dened as the termination of hospitalization within 72h after topiramate administration, ranged from 27% to 100%. Mortality rates ranged from 5.9% to 68%.
Positive long-term functioning was observed in patients in seven of these studies
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with outcomes including rates of discharge, return to baseline, or recovery between
4% and 55%. Most studies reported no or only mild adverse effects. Thus, topiramate is effective in terminating refractory epilepsy states in patients, has a relatively
low mortality rate and is well tolerated [435].
To develop an intravenous topiramate regimen for the treatment of refractory and
ultrarefractory status epilepticus, two parenteral formulations of TPM have been
developed. One solution is to use sulfobutylether-β-cyclodextrin (SBE-β-CD;
Captisol®) as an excipient. A 1% TPM solution in 10% Captisol® was well tolerated
in safety studies in healthy volunteers and patients with epilepsy or migraine.
Another solution uses the FDA and EMA-approved excipients of the amino sugar
meglumine. Meglumine was more effective than Captisol® in dissolving TPM in
water. A 1% TPM solution was obtained with 0.5–1% meglumine [436].
Moreover, another team analyzed and compared topiramate dissolved in doubledistilled water with or without meglumine for the treatment of SE in rats and found
that the amino sugar meglumine signicantly enhanced the water solubility of
TPM. Comparison with data obtained using sulfobutylether-β-cyclodextrin
(Captisol®) for the dissolution of TPM showed that meglumine solubilized TPM to
a higher extent. The tolerability of the meglumine-based TPM solution and the combination of meglumine-based TPM in normal rats and rat uid percussion injury and
pilocarpine-induced SE models demonstrated the excellent tolerability of the novel
drug solutions. Preclinical studies of antiseizure efcacy in SE models are currently
underway [437].
Application ofTopiramate inSpecial Populations
Marissa Vawter-Lee etal. [438] conducted a multicenter retrospective cohort study
involving 75 neonates and reported that three (4%) developed necrotizing enterocolitis (NEC) after exposure to topiramate. There was no difference in gestational age,
birth weight, etiology of epilepsy, body weight at the initiation of topiramate, or
topiramate dose between groups, with the most common side effect being weight
loss (5%). Sixty-one percent of patients responded to topiramate, and most infants
(72%) continued to take topiramate when they were discharged from the hospital.
Burns etal. [439] evaluated cognitive symptoms in children treated with topiramate, levetiracetam, lamotrigine, oxcarbazepine, or sodium valproate monotherapy
for at least 12months. Children prescribed valproate sodium or topiramate demonstrated weaker working memory and verbal uency than children prescribed other
ASMs. Additionally, parents of children prescribed topiramate reported greater
executive functioning and adaptive skills decits. The pattern of ndings suggested
that children prescribed valproate sodium or topiramate generally demonstrated a
greater risk of cognitive and behavioral impairments than did those prescribed
other ASMs.
This systematic review aimed to delineate the impact of in utero exposure to
these newer ASMs on child neurodevelopment. Most studies have examined LTG
exposure and have reported nonsignicant effects on child neurodevelopment.
Fewer high-quality studies on levetiracetam are available, limiting conclusions
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W. Jing et al.
regarding the ndings to date. Data for topiramate, gabapentin, and oxcarbazepine
are so limited that rm conclusions could not be drawn. However, no studies have
investigated eslicarbazepine, lacosamide, perampanel, or zonisamide. A lack of data
cannot be inferred to represent the safety of newer ASMs, which are yet to be investigated [440].
To determine the transplacental transport of topiramate to colostrum, mature
breast milk, and breastfed infants, Kacirova I’s team examined data from 27 women
treated with topiramate between 2004 and 2020 [441]. The results showed that the
levels of topiramate in maternal serum and umbilical cord serum were 1.0–7.1mg/L
and 0.8–6.2mg/L, respectively, for an average umbilical cord/maternal serum ratio
of 0.93±0.11. The concentrations of topiramate ranged from 1.4 to 8.4mg/L in
maternal serum, from 1.5 to 8.6mg/L in breast milk, and from 0.3 to 4.4mg/L in
infant serum at 3–4days after delivery, with a mean milk/maternal serum ratio of
0.99±0.45 and a mean infant/maternal serum ratio of 0.25±0.15. Maternal serum
levels ranged from 1.9 to 9.7mg/L, breast milk levels ranged from 2.3 to 10.6mg/L,
and infant serum levels ranged from 0.3 to 6.5mg/L at 7–30days after delivery. The
average milk/maternal serum ratio was 1.07±0.31, and the average infant/maternal
serum ratio was 0.51±0.27. The study concluded that the serum concentration of
topiramate was lower in breastfed infants than in the mothers.
To determine the adaptive behavioral outcomes of children exposed to topiramate in utero, Knight etal. studied 34 women with epilepsy, 26 of whom completed
follow-up, and found signicant associations between offspring birth weight, topiramate dose, and VABS-III score in six children exposed to topiramate who were
small for gestational age at birth. The topiramate-exposed children were born small
for gestational age and showed a signicant dose-dependent relationship after correction for parental education level [442].
Topiramate-Related Adverse Reactions
Junyeong Choi’s team observationally analyzed adverse events associated with the
use of topiramate in South Korea from 2010 to 2017 and reported a total of 1300
adverse events, with the proportion of women of childbearing age in the topiramate
group being more than twice that of women in the other antiseizure drug group.
Among the cases of topiramate-induced adverse reactions, the most common events
involved the central and peripheral nervous systems (29.6%), followed by psychiatric disorders (20.4%), such as cognitive impairment, inattention, memory loss, and
sensory loss [443]. Blanka Koristkova did not nd an association between plasma
levels of topiramate and the occurrence of adverse drug reactions to different concentrations of topiramate in the population [444].
In addition, topiramate has been reported to cause ocular side effects, such as
transient myopia or narrowing of the anterior chamber angle [445], bilateral anterior
chamber purulent uveitis with choroidal detachment [446], and bilateral angleclosure glaucoma [447].
To understand urinary metabolic disorders in patients taking topiramate and their
reversibility after drug withdrawal, Pelzman etal. enrolled 93 patients and analyzed
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their urine samples. The results showed that 24-h urine samples from 67 patients
had a mean citrate excretion of 331±322mg/day, a mean pH of 6.6±0.5, and a
mean calcium phosphate supersaturation of 1.9±1.1. According to the subgroup
analysis, urinary citrate excretion increased from 225 to 614mg/day (P<0.01), and
the pH decreased from 6.59±0.54 to 6.33±0.47 (P=0.06) after the discontinuation of topiramate. In addition, 114 stone events occurred in 73 different patients, of
which 50% of the stones were composed of pure or high (≥50%) calcium phosphate. This study suggested that hypouricemia and elevated pH occur more often
with topiramate use compared with the general population, resulting in a greater
rate of calcium phosphate stone formation, and that these metabolic disorders
appear to be reversible following discontinuation [448].
Basic Research onTopiramate
One study evaluated the early effects of topiramate and lacosamide treatment on
oxidative stress and inammatory damage in a pilocarpine-induced model of status
epilepticus. The experiment revealed that both topiramate and lacosamide were successful at reducing the number of seizures after 30 min of administration.
Pilocarpine-induced status epilepticus reduced superoxide dismutase (SOD) activity and glutathione (GSH) levels but increased catalase (CAT) activity and malondialdehyde (MDA) and IL-1β levels compared to those in the control group. Two
antiseizure medications restored CAT activity and MDA levels to normal levels.
The study suggested that the antioxidant effects of topiramate and lacosamide may
contribute to their anticonvulsant effects on pilocarpine-induced status epilepticus
[449]. One study evaluated the anticonvulsant effects of systemic use of low-dose
gamma rays (LDRs) alone or in combination with topiramate for pantoprazole
(PTZ)-induced epilepsy. Male Wistar rats were pretreated with a single dose of lowdose radiation (0.5Gy), topiramate (50 mg/kg, p.o., 7days), or topiramate with
LDR prior to PTZ injection. The results showed that PTZ treatment induced behavioral changes (high Racine score, short latency and long duration), increased malondialdehyde (MDA) and nitric oxide (NO) levels, and decreased glutathione (GSH)
levels. Treatment with topiramate alone or in combination with LDR ameliorated
PTZ-induced toxicity and signicantly ameliorated behavioral changes, and inhibited the m-TOR signaling pathway, oxidative stress, and histological changes in the
hippocampus. LDR may play a role in the treatment of convulsions by modulating
the AkT/m-TOR signaling pathway, reducing oxidative stress, and modulating brain
amino acids and may ameliorate the oxidative stress side effects of topiramate [450].
The use of topiramate during pregnancy is associated with a signicant increase
in the risk of cleft lip and palate (OFC) in newborns. To identify the possible underlying mechanism, Syed K Ra’s team [451] rst tested the effect of topiramate on
human embryonic palatine mesenchymal (HEPM) cells using unbiased antibody
array analysis. Among the known OFC-related genes, only expression of TGFβ1
was signicantly upregulated. Topiramate can increase the expression of TGFβ1
and phosphorylation of its downstream target gene Smad2in primary mouse embryonic palatal mesenchymal cells and increase the expression of SOX9in primary
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W. Jing et al.
MEPM cells. Its overexpression in chondrocytes can cause cleft palate in mice.
These results suggest that topiramate mediates the upregulation of TGFβ-1 signaling by activating palatal GABA receptors. TGFβ1 and SOX9 expression play
important roles in oral and maxillofacial morphogenesis, and their aberrant overexpression provides a possible molecular mechanism for topiramate-related
teratogenesis.
Forced exercise acts as a neuroprotective factor and a cognitive enhancer. To
evaluate the effects of forced exercise on topiramate-induced cognitive impairment,
topiramate antiseizure activity, and the neurodegenerative state after seizures, Zahra
Soleimani Meigoni’s group measured biomarkers of oxidation, inammation, and
apoptosis after 21days of forced exercise in adult male rats divided into groups
subjected to treatment with saline, topiramate (100mg/kg), or topiramate combined
with forced exercise. The results showed that the combination of forced exercise
and topiramate could eliminate the cognitive impairment caused by topiramate and
enhance its antiseizure activity. In addition, topiramate treatment decreased malondialdehyde (MDA), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and
Bax protein levels while increasing superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) activity. The results of the study
propose that forced exercise seems to be useful as an adjunctive therapy to topiramate to manage related cognitive impairment and could also enhance the antiseizure
and neuroprotective effects of topiramate [452].
Topiramate was administered daily at a dose of 41 mg/kg to male rats aged
16–28days. Half of the rats were evaluated at 24h after birth, and the rest were
evaluated in adulthood. There was a reduction in precision (p=0.018), total length
(p=0.035), and interstitial tissue volume (p=0.018) but an increase in interstitial
cell number/testis number (p=0.013) at postnatal day (PND) 120. The results of
this study contribute to the understanding of the effects of topiramate treatment at
the juvenile stage on the reproductive system of adult rats, suggesting that rats are
more sensitive to topiramate exposure during this period than during puberty [453].
Use ofTopiramate inOther Diseases
Koolen-de Vries syndrome (KdVS) is mainly characterized by mild or moderate
intellectual disability, especially affecting language development, accompanied by
other clinical ndings such as seizures, muscle hypotonia, joint hypermobility, or
joint dysplasia. Approximately half of patients with KdVS have seizures with a
broad phenotype throughout their lives, but most affected children have focal to
bilateral tonic–clonic seizures that may not respond to initial medical therapy.
Piccinelli Paolo [454] described a case of a female infant with KdVS and epilepsy.
At the age of 2years and 1month, the patient began to experience epileptic symptoms, which evolved from focal unconsciousness seizures to bilateral tonic–clonic
seizures and were not effectively controlled by oral levetiracetam treatment.
Seizures were completely controlled with the addition of low-dose topiramate. This
case suggests that topiramate may be an antiseizure agent with good efcacy in
treating focal epilepsy in patients with KdVS syndrome. However, it is necessary to
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further extend the follow-up time and perform related studies in children with KdVS
in multiple centers to clarify its role.
Impulsivity is an important feature of many psychiatric disorders and a marker of
poor prognosis. Topiramate is widely used to reduce impulsivity in individuals with
various neuropsychiatric disorders, but no systematic review or meta-analysis has
been conducted to explore whether there is evidence to support its clinical use.
Sophie Athena Chapron etal. [455] analyzed seven studies involving 578 participants that assessed the efcacy of topiramate in adults with high impulsivity based
on psychometric or neuropsychological measures. It was found that topiramate
reduced impulsivity levels in two studies using the Barratt Impulsivity Scale (BIS)
(401 participants) and one study using neuropsychological measures (63 participants). Four other studies found no effect of topiramate on impulsivity.
Following schizophrenia onset and the use of antipsychotic drugs, cardiovascular
disease has a high mortality rate in these patients. Topiramate can be used for weight
loss and to improve the psychopathology of schizophrenia patients. In a randomized, double-blinded controlled trial in Sri Lanka, the effects of 100mg/day topiramate were compared with those of a placebo for weight and mental health
improvement in overweight/obese adults with schizophrenia who had been taking
antipsychotics for at least 1year. Compared with placebo, topiramate addition signicantly reduced body mass index and improved symptoms, as measured by the
Brief Neuropathy Rating Scale (BPRS), but there were more reports of loss of appetite in the topiramate group than in the placebo group [456].
2.1.2.4 Gabapentin
Drug Characteristics
[Chemical name] 11-Aminomethyl-cyclohexaacetic acid
[Chemical structure formula]
[Molecular formula] C9H17NO2
[Molecular weight] 171.24
[Indications] (1) Postherpetic neuralgia: For the treatment of postherpetic neural-
gia in adults. Epilepsy: For the adjuvant treatment of partial seizures in adults and
children over 12years of age with or without secondary generalized tonic–clonic
seizures. It can also be used as an adjunct treatment for partial seizures in children
aged 3–12years.
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W. Jing et al.
[Packing specications] 0.1 g, 0.3 g
[Usage and dosage]
Postherpetic neuralgia: 0.3g once on the rst day; on the second day, 0.6g is taken
in two doses. On the third day, 0.9g is taken in three separate doses. Subsequently,
according to need, the dose can be gradually increased to 1.8g/day, divided into
three times; efcacy is comparable in the range of 1.8–3.6g.
Epilepsy: Patients over 12years old: 0.3g on the rst day; on the second day,
0.3g, twice a day; on the third day, 0.3g, three times a day. The usual dose range is
1.8–2.4g. Pediatric patients 3–12years old: Starting dose 10–15mg/kg/day, three
times a day, reaching effective dose in approximately 3 days. The effective dose of
gabapentin for patients older than 5years is 25–35mg/kg/day, three times a day.
The effective dose for pediatric patients aged 3–4years is 40mg/kg/day, three times
a day. The interval between doses should not exceed 12h. The rst dose in elderly
patients is affected by renal function and requires reference to creatinine clearance.
[Adverse reactions] Vertigo, drowsiness, peripheral edema, fatigue, infection,
headache, abdominal pain, diarrhea, constipation, dry mouth, nausea, vomiting,
atulence, weight gain, hyperglycemia, ataxia, nystagmus, depression, abnormal
thinking, abnormal gait, etc. Aggressive behavior, emotional instability, hyperactivity, and fever have been observed in children under 12 years of old.
Clinical Application andPreclinical Research
The Historical Evolution ofGabapentin
Gabapentin, chemically known as 1-(aminomethyl)-cyclohexane acetic acid, is a synthetic amino acid with a structure similar to 1-aminobutyric acid (GABA). Gabapentin
was rst developed by the American company Warner-Lanbert and was rst marketed
in the UK in 1993 as an antiseizure treatment. In 2002, it was approved by the US
FDA as a rst-line treatment for postherpetic neuralgia. China approved production in
2003. As an analog of the inhibitory neurotransmitter GABA, the original aim of
Gabapentin was to increase the lipophilicity of GABA by adding cyclohexyl to the
structure of GABA, in order to improve its properties across the central nervous system while retaining its pharmacological properties. The bioavailability of gabapentin
is inversely dependent on the dose, and the bioavailability decreases when the dose is
increased. The bioavailability of 300mg oral gabapentin is 60%, and that of 600mg
oral gabapentin is 40%. Gabapentin is mostly unbound to plasma protein in circulation (protein binding rate <3%), the maximum blood concentration is reached by oral
administration for 3h, and the elimination half-life is 5–7 h; patients may require
administration three times a day. Gabapentin is not metabolized in the human body,
but is cleared by the kidney, and the drug is excreted in the urine.
Gabapentin is mainly used to treat focal seizures and chronic neuropathic pain
and postoperative pain; it has a good effect especially for neuropathic pain, diabetic
neuralgia, and postherpetic neuralgia.
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Application ofGabapentin inEpilepsy
Gabapentin is recommended primarily as a monotherapy or additive treatment for
focal seizures and for drug-resistant focal seizures with or without secondary generalized seizures. A review of six studies summarized the evidence from randomized controlled trials of gabapentin as an additional therapy for drug-resistant focal
epilepsy. The results suggested that the overall hazard ratio for 50% or greater
reduction in seizure frequency in the GBP group compared with the placebo group
was 1.89. Dose regression analysis showed that the efcacy of gabapentin as additional therapy for refractory focal epilepsy increased with increasing dose, with
16.0% of patients responding to treatment when the dose was increased to 900mg
and 25.3% of patients responding when the dose was increased to 1800mg. The
adverse reactions with high correlation with GBP use were dizziness, lethargy,
ataxia, fatigue, headache, etc. In conclusion, gabapentin is effective and welltolerated in patients with drug-resistant focal epilepsy, but its efcacy still needs to
be conrmed in future long-term clinical studies [457].
A review analyzed ve randomized controlled trials (3167 participants) comparing gabapentin with other ASMs for the treatment of focal epilepsy. The results
suggested that gabapentin monotherapy may not be as effective in controlling seizures as other ASMs (lamotrigine, CBZ, oxcarbazepine, and topiramate). Compared
with CBZ, gabapentin is better-tolerated [458].
Use ofGabapentin forTreating Neuropathic Pain
In 2002, the US FDA approved gabapentin as a rst-line treatment for postherpetic
neuralgia. Gabapentin and pregabalin are both recommended for the treatment of
neuropathic pain. A meta-analysis [459] included 14 RCTs, with a total of 3545
patients, to evaluate the clinical efcacy of pregabalin and gabapentin in the treatment of postherpes zoster neuralgia. The results showed that pregabalin was superior to gabapentin for reducing pain and improving the overall perception of pain
and sleep changes, but gabapentin had a lower incidence of adverse reactions and
greater safety. Clinicians should consider patient factors comprehensively and prescribe medicine individually.
In a study comparing clinical differences in waist pain, patients were randomized
to receive either pregabalin (300mg/day) or gabapentin (800mg/day) for 6weeks.
The results showed that pregabalin improved pain relief, and gabapentin improved
anxiety, insomnia, and fatigue symptoms [460]. A review summarized the risks and
benets of gabapentin and pregabalin for perioperative pain control. Perioperative
gabapentin reduced opioid requirements and pain scores for various procedures.
The use of such drugs may reduce postoperative nausea, vomiting and itching,
which may be a feature of reduced opioid intake. However, side effects such as dizziness, ataxia and cognitive dysfunction can occur. Gabapentin use also increases
the risk of respiratory depression, especially when combined with opioids.
Therefore, routine use of these drugs for perioperative pain management is not recommended, and individualized, patient- and surgery-centered treatments are
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recommended [461]. In women with severe pain after cesarean section, supplemental gabapentin therapy did not reduce opioid withdrawal time, pain, anxiety, depression, or fatigue time or improve physical function [462].
Pain is the main symptom of diabetic foot patients. Network meta-analysis
revealed that the most favorable treatments for diabetic foot patients with a benet/
risk ratio were gabapentin, venlafaxine, and pregabalin. Gabapentin not only has the
best efcacy but also shows the best balance between efcacy and safety [463]. A
systematic review revealed that 1800–3600mg/day gabapentin provides good analgesic effects in some patients with chronic neuropathic pain (postherpetic neuralgia
and diabetic peripheral neuropathy), with side effects including dizziness (19%),
drowsiness (14%), peripheral edema (7%), and gait disturbance (14%) [464].
Regarding pain caused by cancer, the National Comprehensive Cancer Network
(NCCN) guidelines recommend gabapentin and pregabalin as the most common
pain relief drugs [465].
Neuralgia is one of the main factors that affects the quality of life of patients with
diabetic peripheral neuropathy. In 2012, a consensus on the diagnosis and treatment
of painful peripheral neuropathy formulated by the Neurology Branch of the
Chinese Medical Association recommended gabapentin to alleviate neuralgia in
patients with diabetic peripheral neuropathy.
Application ofGabapentin inSpecial Populations
The pregnancy safety rating of gabapentin is Class C.Gabapentin is actively
transported through the placenta and may accumulate in the fetus but is not
concentrated in breast milk. The plasma concentration of breastfed infants is
12% or less of the mother’s plasma concentration, and no adverse effects have
been observed [466, 467]. One study examined pregnancy outcomes in 223 gabapentin-exposed pregnancies and 223 unexposed pregnancies. The incidence of
major malformations was similar between the two groups. However, the preterm
birth rate and low birth weight in the gabapentin group were greater than those
in the control group, so gabapentin is not recommended for pregnant
women [468].
Adverse Effects ofGabapentin
Common adverse effects of gabapentin are drowsiness, fatigue, double vision, paresthesia, forgetfulness, dizziness, and ataxia. Atopy side effects are rare. Other possible adverse reactions include hyperglycemia and, occasionally, hypoglycemia
[469]. Gabapentin is not metabolized in the liver, so the mechanism of liver injury
is not clear. However, it has been reported that gabapentin may cause liver toxicity,
so it should be considered individually for each patient [470].
Gabapentin and pregabalin are ligands of the α2-δ subunit of voltage-gated calcium channels and have been implicated in the development of peripheral edema
and acute heart failure. Pregabalin is more likely to cause peripheral edema and
acute heart failure than gabapentin. All cases of peripheral edema or heart failure
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involving gabapentin or pregabalin reported to the French Pharmacovigilance
Centre between 1994 and 2020 were included in a description of their onset patterns. A total of 58 reports were included (gabapentin, n=5; pregabalin, n=53).
The male to female ratio was 4:1, and the median age was 77years (32–95years).
The median onset times of noncardiogenic edema and acute heart failure were
23 days and 17 days, respectively. Cardiogenic and noncardiogenic peripheral
edema often occur after the drug dosage is increased, and the disease improved
rapidly after gabapentin was discontinued [471].
Gabapentin does not produce euphoria, and there is no evidence of addiction
when taken [472]. However, in recent years, there has been a gradual increase in
gabapentin abuse. A systematic review of studies in the last 5years conrmed that
gabapentin is being increasingly abused or misused; gabapentin use alone can produce desirable effects but is often used in conjunction with other drugs, and opioid
use is the greatest risk factor for gabapentin abuse. There is increasing evidence that
abuse of gabapentin and pregabalin is associated with patient harm, including
increased rates of hospitalization and increased risk of opioid-related overdose
death [473].
Previous case reports and observational studies have suggested that gabapentin use may be associated with an increased risk of atrial brillation, especially
in patients over 65years of age with comorbidities. New case reports have suggested that gabapentin can also induce new atrial brillation in young people [474].
ASMs such as gabapentin can increase the risk of hypogammaglobulinemia. In
case–control studies, hypogammaglobulinemia was associated with the use of antiseizure drugs, with the exception of topiramate. The use of phenytoin sodium, CBZ,
and lamotrigine was associated with low IgA levels. If a patient receiving gabapentin or other ASM therapy has an abnormal or recurrent infection, the clinician
should check the immunoglobulin levels [475].
In addition, gabapentin is a drug that may induce acute pancreatitis [476]. The
type and severity of eye-related adverse reactions vary among different ASMs.
Adverse reactions related to macula were associated with gabapentin [355].
Preclinical Research
The exact mechanism of action between gabapentin and GABA receptors is not
wellunderstood. Gabapentin is structurally related to the neurotransmitter GABA
but does not interact with GABA receptors; it is neither metabolized as GABA nor
as a GABA agonist nor is it an inhibitor of GABA uptake or degradation. In vitro
studies have shown that the binding sites of gabapentin in the rat brain are distributed in the neocortex and hippocampus, and its high-afnity binding proteins, especially α2δ-1, have been conrmed to be auxiliary subunits of voltage-gated calcium
channels (VGCCs). It appears to inhibit the release of excitatory neurotransmitters
in the presynaptic region involved in the development of epilepsy. VGCCs consist
of multiple subunits: α1, β, γ, and α2δ. The α1 subunit allows calcium to enter, and
extracellular α2δ binds to the γ subunit, where the α2δ-1 subunit is involved in