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If Lyrica were a character in a movie about neurotransmission, would it be the peacemaker between nerve impulses or the strict guardian controlling the chaos?
How would pain perception change if Lyrica could "talk" to nerve endings and convince them to calm down with logical arguments?
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As dementia becomes more prevalent, concerns about the use of gabapentin and Lyrica are growing due to their potential impact on neurocognitive function. Research suggests these medications may contribute to cognitive side effects (Taipale et al., 2018; Oh et al., 2022).
Glutamate and gamma-aminobutyric acid (GABA) are key neurotransmitters in the central nervous system (CNS). Studies indicate that disruptions in glutamatergic pathways and alterations in GABAergic circuits may increase the likelihood of cognitive impairment and Alzheimer’s disease (Li et al., 2016). Medications affecting the CNS, such as benzodiazepines that target GABA receptors, have also been linked to dementia risk (Gray et al., 2016; Gerlach et al., 2022).
Both gabapentin and Lyrica are structural analogs of GABA and cross the blood–brain barrier with ease (Calandre et al., 2016). Research shows that gabapentinoid levels in cerebrospinal fluid after oral intake reach approximately 9%–14% of their plasma concentrations (Bockbrader et al., 2010). While neither gabapentin nor Lyrica binds directly to GABA receptors, they target the alpha-2/delta-1 subunit of voltage-gated calcium channels in neurons, affecting calcium flow, modulating GABA neurotransmission, and reducing glutamate release (Sills, 2006; Eroglu et al., 2009). This mechanism lowers neuronal excitability, hinders brain plasticity, and disrupts new synapse formation (Hendrich et al., 2008; Eroglu et al., 2009). It has been suggested that these changes in neural connectivity may contribute to cognitive side effects, particularly in cases where α2δ proteins are overexpressed in the hippocampus (Calandre et al., 2016), a brain region critical for memory processing (Yonelinas, 2013).
order lyrica onlineInitially, the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved gabapentin and Lyrica for treating neuropathic pain (e.g., diabetic peripheral neuropathy, spinal cord injury, and post-herpetic neuralgia) and as adjunct therapy for epilepsy, particularly for partial seizures. Taiwan has adopted similar usage guidelines. However, there has been a noticeable increase in off-label prescribing for conditions such as chronic pain, alcohol addiction, anxiety, bipolar disorder, and migraines (Goodman and Brett, 2019). Misuse of gabapentinoids, either alone or in combination with other CNS depressants like opioids, raises concerns about respiratory depression, which in severe cases, can be fatal (Smith et al., 2016; Evoy et al., 2021).
Numerous studies and systematic reviews have explored how gabapentinoid drugs impact cognitive function (Zaccara et al., 2011; Shem et al., 2018; Oh et al., 2022; Oh et al., 2023). However, our study was the first large-scale, population-based retrospective cohort study to examine the link between gabapentin or Lyrica use and dementia risk.
Using NHIRD registration, identification, and medical claims data—including inpatient, outpatient, admission, and prescription records—we conducted our analysis. Patients who took gabapentin or Lyrica were placed in the exposure group, while non-users were matched in a 1:5 ratio based on age, sex, and index date. The index date was defined as the first recorded prescription for Lyrica or gabapentin.
We analyzed data from January 1, 2000, to December 31, 2017, with the index period spanning from January 1, 2001, to December 31, 2016. The pre-index period (January 1, 2000–December 31, 2000) was used to identify preexisting conditions and ensure all participants had at least one year of medical history in the database. The post-index period (January 1, 2017–December 31, 2017) ensured at least one year of follow-up for all patients.
buy lyrica 300 mg online next day deliveryIn clinical settings, the length of gabapentin or Lyrica treatment depends on symptom severity and side effects. A review of existing literature did not provide a clear timeline for when these drugs might contribute to cognitive decline or dementia. To address this, we conducted a preliminary analysis examining exposure periods of 30 and 90 days. The validity of pharmacy records in drug exposure assessment has been supported in past research (Lau et al., 1997).
Prescription drug usage was analyzed using three different approaches: a fixed 30-day window, a fixed 90-day window, and the calculated total duration of prescription use. All three methods demonstrated high specificity and strong predictive accuracy. Among them, the 90-day fixed time window approach had the highest sensitivity (ranging from 0.67 to 1.00). Based on this data, we established a 90-day exposure period as our standard.
Although the NHIRD contains limited details on medication usage, the World Health Organization (WHO) recommends the use of defined daily doses (DDDs) for drug statistics. To quantify the consumption of gabapentin and Lyrica, we applied the following formula: (total dosage administered) ÷ (amount of drug per DDD) = total DDDs. Additionally, cumulative defined daily doses (cDDDs) were used to standardize drug exposure and examine the dose-response relationship between medication use and dementia risk. Hazard ratios (HRs) were then calculated based on cDDD quartiles in the subgroup analysis.
buy lyrica online no prescriptionStatistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). Patient demographics and comorbidities were compared between the two groups using a two-sample t-test for continuous variables and Pearson’s chi-square test for categorical variables. The Kaplan-Meier method was used to estimate the cumulative incidence of dementia, with a log-rank test to compare the groups. Cox proportional hazards regression models helped assess the relationship between gabapentin or Lyrica exposure and dementia risk, adjusting for potential confounders and calculating HRs with 95% confidence intervals (CIs). Additional stratification by sex, age, and comorbidities—including diabetes, hypertension, stroke, dyslipidemia, depression, and head injury—was performed. Statistical significance was set at p < 0.05 for all tests, which were two-tailed.
During the follow-up period, 1,596 dementia cases emerged in the exposure group and 5,375 in the non-exposure group, over a total of 162,757.8 and 887,719.9 person-years, respectively. This corresponded to dementia incidence rates of 980.60 and 605.48 per 100,000 person-years. After adjusting for comorbidities, the HR (95% CI) for dementia in those exposed to gabapentin or Lyrica was 1.45 (1.36–1.55) compared to non-exposed individuals.
The cumulative incidence curve showed that those using gabapentin or Lyrica had a significantly higher risk of developing dementia over the follow-up period (Figure 2; log-rank test p < .001). In the exposed group, the mean (±SD) cDDDs per year was 28.12 (±139.54), while the median (Q1-Q3) was 1.95 (0.50–9.66). Further analysis revealed that as cDDDs increased, so did the dementia risk. Compared to those with cDDDs <0.5, the adjusted HRs were 1.24 (95% CI, 1.09–1.41; p = 0.001) for cDDDs between 0.50–1.95, 1.69 (95% CI, 1.50–1.92; p < 0.001) for cDDDs between 1.96–9.66, and 2.44 (95% CI, 2.14–2.78; p < 0.001) for cDDDs >9.66 (Table 2).
A subgroup analysis stratified by sex, age, and comorbidities showed that the dementia risk associated with gabapentin or Lyrica was significant across all groups except those with depression or head injuries. Interestingly, the highest risk was observed in younger individuals. The adjusted HRs were 3.16 (95% CI, 2.23–4.47) for those under 50, 1.58 (95% CI, 1.24–2.00) for ages 50–59, 1.54 (95% CI, 1.37–1.73) for ages 60–69, and 1.30 (95% CI, 1.19–1.42) for those 70 and older.
Our findings indicate a significant association between cumulative exposure to gabapentin and Lyrica and an increased risk of dementia, with younger individuals and those on higher doses being particularly vulnerable. These results align with previous research. Prior studies have suggested a potential link between gabapentin use and cognitive decline, particularly in patients with spinal cord injuries (Shem et al., 2018). However, that study had a small sample size and lacked a control group.
buy pregabalin 300mg onlineA separate cross-sectional study involving 300 patients with Lyrica misuse and 100 controls found significantly greater cognitive impairment in the misuse group (p < .001) (Mohamed & Emam, 2020). However, no direct correlation between Lyrica dosage and cognitive decline was identified in that study. Another retrospective cohort study using the National Alzheimer’s Coordinating Center Uniform Data Set found that older adults (≥65 years) who started gabapentin (480 initiators vs. 4,320 non-users) exhibited significant neurocognitive decline within two years (Oh et al., 2022). However, that study had limitations, including a relatively short observation period and restricted dosing parameters.
A review of post-marketing surveillance for gabapentin and Lyrica indicated that most patients tolerated these medications well during treatment. However, about 4% of users discontinued due to adverse effects. The most commonly reported neuropsychiatric symptoms included dizziness, drowsiness, fatigue, and confusion (Quintero, 2017). Other notable effects such as hallucinations, agitation, and aggressiveness were also observed (Quintero, 2017). Research by Fuzier et al. (2013) found that neuropsychiatric adverse effects occurred in approximately 29.1% of gabapentin users and 35.2% of Lyrica users. These adverse reactions were generally mild to moderate, dose-dependent, and often resolved with dose adjustments (Bockbrader et al., 2010).
Recent studies and meta-analyses have explored the neuropsychiatric side effects associated with these medications (Ho et al., 2006; Hurley et al., 2006; Zaccara et al., 2011; Wiffen et al., 2017; Derry et al., 2019). While gabapentin and Lyrica are FDA-approved for seizures and neuropathic pain, off-label prescriptions for conditions such as anxiety, mood instability, non-neuropathic pain, and alcohol withdrawal have been increasing (Bonnet & Scherbaum, 2017). Prescription rates for gabapentinoids have risen in the U.S. (Johansen, 2018), the U.K. (Montastruc et al., 2018), and Europe (Persheim et al., 2013; Priez-Barallon et al., 2014).
pregabalin for sale next day deliveryGabapentin and Lyrica are structural analogs of GABA but do not bind directly to GABA receptors. Instead, they attach to the alpha-2/delta-1 subunit of voltage-gated calcium channels in neurons, influencing calcium flux, GABAergic transmission, and glutamate release (Sills, 2006; Eroglu et al., 2009). These medications not only reduce hyperalgesia and central sensitization but also suppress excitatory neurotransmitters such as glutamate, norepinephrine, serotonin, and dopamine (Hendrich et al., 2008; Eroglu et al., 2009). Their potential impact on the dopamine reward system may contribute to the risk of misuse and addiction (Althobaiti et al., 2021). The hippocampus, which contains a high density of alpha-2/delta-1 subunits, is crucial for memory processing, and its disruption by these drugs may lead to cognitive side effects (Yonelinas, 2013; Calandre et al., 2016).
Some patients take gabapentinoids as anticonvulsants. These drugs function by decreasing synaptic transmission through the inhibition of presynaptic voltage-gated calcium and sodium channels (Lasoń et al., 2013). Analyses from Finnish and German healthcare registers and insurance databases linked regular use of antiepileptic drugs (AEDs), including gabapentin and Lyrica, to increased cognitive impairment and dementia risk (Taipale et al., 2018). Studies suggest a potential lifelong association between using these drugs for epilepsy management and an elevated risk of dementia (Knight et al., 2021). However, these findings were derived from patient groups with epilepsy or underlying medical conditions. Prior reviews have noted that up to 48% of individuals with epilepsy experience cognitive deficits and memory issues (Guekht et al., 2007). Multiple factors such as seizure type, duration, underlying cause, and severity may contribute to these cognitive challenges, independent of gabapentinoid use (Park & Kwon, 2008; Eddy et al., 2011). Additionally, encephalitis—especially herpes encephalitis—has been linked to cognitive deficits, intractable epilepsy, and disability (Noppeney et al., 2007; Michaeli et al., 2014). To refine our analysis, we excluded patients with prior diagnoses of seizures or encephalitis.
Gabapentin and Lyrica are sometimes prescribed to older adults for managing behavioral and psychological symptoms of dementia (BPSD). A systematic review of 24 studies suggested that gabapentinoids could help alleviate BPSD in Alzheimer’s patients. However, 15 of these studies were case reports or series, while the remaining 9 were review papers, with no randomized clinical trials to support definitive conclusions.
Our study indicated that the risk of developing dementia associated with gabapentin or Lyrica use was more pronounced in younger individuals compared to older adults. [https://medicaldevicesgroup.net]