Gabapentinoid-induced peripheral edema and acute heart failure: A translational study combining pharmacovigilance data and in vitro animal experiments

Largeau, Bérenger; Bordy, Romain; Pasqualin, Côme; Bredeloux, Pierre; Cracowski, Jean‐Luc; Lengelle, Céline; Gras‐Champel, Valérie; Auffret, Marine; Maupoil, Véronique; Jonville‐Béra, Annie‐Pierre

doi:10.1016/j.biopha.2022.112807

Cited by 9 publications

(15 citation statements)

References 39 publications

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“…32 These findings prompt attention to this potential risk with gabapentin, which may be explained by the negative dromotropic effect of gabapentinoids mediated by cardiac Ca v 1.2 blockade. 8 Similarly, there was no significant association between pregabalin or gabapentin and gingival hyperplasia in VigiBase.…”

Section: Discussionmentioning

confidence: 92%

“…8 These cardiovascular ADRs are also reported with gabapentinoids. 8 Interestingly, quite specific off-target ADRs of CCBs such as parkinsonism and gynecomastia are also reported with gabapentinoids. 8 The α2-δ2 subunit is highly expressed in the central nervous system, especially in the cerebellum.…”

Section: Introductionmentioning

confidence: 86%

“…8 Interestingly, quite specific off-target ADRs of CCBs such as parkinsonism and gynecomastia are also reported with gabapentinoids. 8 The α2-δ2 subunit is highly expressed in the central nervous system, especially in the cerebellum. Gabapentinoid binding to this subunit is thought to cause ataxia, a particularly prevalent ADR of these drugs.…”

Section: Introductionmentioning

confidence: 99%

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Drug clustering to anticipate new aspects of drug safety profile: Application to gabapentinoids and other voltage‐gated calcium channel ligand drugs

Viguier,

Agier,

Jonville‐Béra

et al. 2023

Brit J Clinical Pharma

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AIMGabapentin and pregabalin bind to α2‐δ subunit of voltage‐gated calcium channels (Cav). Other drugs targeting Cav include cardiovascular calcium channel blockers (CCBs) and anticonvulsants (levetiracetam, ethosuximide, zonisamide). In addition to pharmacodynamics, the safety profile of gabapentinoids seems to overlap with the one of cardiovascular CCBs (edema) and Cav‐blocking anticonvulsants (suicide, ataxia). The objective of this study was to cluster the safety profile of different Cav‐ligand drugs by focusing on whether gabapentinoids present a distinct adverse drug reactions (ADR) signature from cardiovascular CCBs and anticonvulsants.METHODSWe extracted all ADRs with at least one significant disproportionate reporting (ROR) related to gabapentinoids, CCBs or anticonvulsants in Vigibase. After principal component analysis preprocessing, a hierarchical ascendent classification was performed to cluster gabapentinoids and other Cav‐ligand drugs that share a similar ADR signature. Robustness of the results was performed through four sensitivity analyses, varying on the dataset or the clustering method.RESULTSA total of 16 drugs and 65 ADRs were included. Gabapentinoids were in the cluster #1 including 8 other drugs (isradipine, nicardipine, lacidipine, lercanidipine, ethosuximide, levetiracetam, zonisamide and nimodipine). Cluster #2 contained two drugs (diltiazem, verapamil), and cluster #3 contained four drugs (amlodipine, felodipine, nifedipine and nitrendipine). The clustering results were consistent in all sensitivity analyses.CONCLUSIONThe safety profile of gabapentinoids overlaps with the one of some dihydropyridine CCBs and Cav‐blocking anticonvulsants. These results could be used to anticipate some unidentified ADRs of gabapentinoids from information accumulated with older drugs and sharing a common molecular target and ADR signature.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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Drug clustering to anticipate new aspects of drug safety profile: Application to gabapentinoids and other voltage‐gated calcium channel ligand drugs

Viguier,

Agier,

Jonville‐Béra

et al. 2023

Brit J Clinical Pharma

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“…One possible explanation for findings is that gabapentin and pregabalin can alter arterial myogenic tone and cause fluid retention [4]. Fluid retention causes either an increase in cardiac output or an increase in blood pressure [42].…”

Section: Discussionmentioning

confidence: 99%

“…Both gabapentin and pregabalin can cause fluid retention by altering arterial myogenic tone [4]. Although fluid retention is not a recognized risk factor for cardiovascular disease, every medical condition that causes fluid retention-heart failure, nephrotic syndrome, cirrhosis, hypothyroidism, obstructive sleep apnea and Cushing's syndrome-is associated with an increased risk of myocardial infarcts, strokes, and venous thromboembolic disease [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular risk of gabapentin and pregabalin in patients with diabetic neuropathy

Pan

Davis

Kaebler

et al. 2022

Cardiovasc Diabetol

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Background Gabapentin and pregabalin are commonly prescribed medications to treat pain in patients with diabetic neuropathy. Gabapentin and pregabalin can cause fluid retention, which is hypothesized to be associated with cardiovascular diseases. However, whether long-term use of gabapentin and pregabalin is associated with adverse cardiovascular diseases remains unknown. This study aims to examine the association between gabapentin use, pregabalin use and several adverse cardiovascular events. Methods This retrospective cohort study used propensity score matching within patient electronic health records (EHRs) from a multicenter database with 106 million patients from 69 health care organizations in the US. The study population comprised 210,064 patients who had a diagnosis of diabetic neuropathy and were prescribed diabetic neuropathy medications in their EHRs. The exposure cohort comprised patients who were prescribed gabapentin or pregabalin to treat diabetic neuropathy. The comparison cohort comprised patients who were not prescribed either gabapentin or pregabalin but were prescribed other drugs to treat diabetic neuropathy. The outcomes of interest were myocardial infarcts, strokes, heart failure, peripheral vascular disease, and venous thromboembolic events. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for 3-month and 5-year risk for adverse cardiovascular events between the propensity score-matched cohorts. Results Both gabapentin and pregabalin were associated with increased risk of 5-year adverse cardiovascular events compared with the comparison group. In patients prescribed gabapentin, the highest risk was observed for deep venous thrombosis (HR: 1.58, 95% CI 1.37–1.82), followed by pulmonary embolism (HR: 1.5, 95% CI 1.27–1.76), peripheral vascular disease (HR: 1.37, 95% CI 1.27–1.47), stroke (HR: 1.31, 95% CI 1.2–1.43), myocardial infarction (HR: 1.25, 95% CI 1.14–1.38) and heart failure (HR: 1.14, 95% CI 1.07–1.21). In patients prescribed pregabalin, the highest risk was observed for deep venous thrombosis (HR: 1.57, 95% CI 1.31–1.88), followed by peripheral vascular disease (HR: 1.35, 95% CI 1.22–1.49), myocardial infarction (HR: 1.29, 95% CI 1.13–1.47), pulmonary embolism (HR: 1.28, 95% CI 1.04–1.59), stroke (HR: 1.26, 95% CI 1.12–1.42), and heart failure (HR: 1.2, 95% CI 1.11–1.3). There were significant associations between short-term (3 month) gabapentin use and heart failure, myocardial infarction, peripheral vascular disease, deep venous thrombosis, and pulmonary embolism. Short-term (3 month) pregabalin use was associated with deep venous thrombosis, peripheral vascular disease. Conclusion In patients with diabetic neuropathy who were prescribed gabapentin and pregabalin, there is an increased risk for heart failure, myocardial infarction, peripheral vascular disease, stroke, deep venous thrombosis, and pulmonary embolism with long-term use. Our findings suggest that increased risk for adverse cardiovascular events, along with other side effects, the efficacy of pain control and the degree of tolerance of the patient, should be considered when prescribing gabapentin and pregabalin long-term in patients with diabetic neuropathy.

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Edema related to treatment with psychotropic drugs

Engel,

Haack,

Zolk

et al. 2024

J Neural Transm

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Edema as an adverse drug reaction is a commonly underestimated yet potentially debilitating condition. This study analyzes the incidence of severe psychotropic drug-induced edema (e.g., edema affecting the face, legs, or multiple body parts and lasting for more than 1 week, or in any case necessitating subsequent diuretic use) among psychiatric inpatients. The cases under examination are derived from an observational pharmacovigilance program conducted in German-speaking countries (“Arzneimittelsicherheit in der Psychiatrie”, AMSP) from 1993 to 2016. Among the 462,661 inpatients monitored, severe edema was reported in 231 cases, resulting in an incidence of 0.05%. Edema occurred more frequently in women (80% of all cases) and older patients (mean age 51.8 years). Pregabalin had the highest incidence of severe edema, affecting 1.46‰ of patients treated with pregabalin, followed by mirtazapine (0.8‰). The majority of edema cases showed a positive response to appropriate countermeasures, such as dose reduction and drug discontinuation, and resolved by the end of the observation period. While most instances of drug-induced edema are reversible, they can have a significant impact on patient well-being and potentially result in decreased treatment adherence. It is, therefore, crucial to remain vigilant regarding risk-increasing circumstances during treatment with psychotropic drugs.

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Gabapentinoid-induced peripheral edema and acute heart failure: A translational study combining pharmacovigilance data and in vitro animal experiments

Cited by 9 publications

References 39 publications

Drug clustering to anticipate new aspects of drug safety profile: Application to gabapentinoids and other voltage‐gated calcium channel ligand drugs

Drug clustering to anticipate new aspects of drug safety profile: Application to gabapentinoids and other voltage‐gated calcium channel ligand drugs

Cardiovascular risk of gabapentin and pregabalin in patients with diabetic neuropathy

Edema related to treatment with psychotropic drugs

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