Bodyweight gain under pregabalin therapy in epilepsy: Mitigation by counseling patients?

Hoppe, Christian; Rademacher, Michael; Hoffmann, Judith M.; Schmidt, Dieter; Elger, Christian E.

doi:10.1016/j.seizure.2007.10.004

Cited by 24 publications

(19 citation statements)

References 8 publications

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“…Accordingly, its deletion in this cell population leads to neuronal hypoactivity, reduced sympathetic tone to white adipose tissue (WAT) and skeletal muscle, and deficits in glycemic and lipid control. These findings help explain previous reports of metabolic disorders in humans prescribed gabapentinoid drugs that inhibit α2δ-1 function (Gee et al, 1996) to combat neuropathic pain and seizure disorders (DeToledo et al, 1997; Hoppe et al, 2008). Importantly, these results inform a central mechanism controlling glucose and lipid homeostasis.…”

Section: Introductionsupporting

confidence: 84%

“…Additionally, α2δ-1 might act on SF1 neurons to negatively regulate serotonin production in the periphery, ultimately affecting lipid metabolism in WAT. The collective findings inform pathological mechanisms underlying metabolic disturbances in individuals administered the anti-epileptic and anti-nociceptive drugs gabapentin and pregabalin, which bind and inhibit α 2 δ-1 (DeToledo et al, 1997; Hoppe et al, 2008). They are interesting, considering a recent human study showing that an individual with a de novo chromosomal truncation encompassing CACNA2D1 , the gene encoding α 2 δ-1, exhibited metabolic alterations, including hyperinsulism (Vergult et al, 2014).…”

Section: Discussionmentioning

confidence: 82%

“…Notably, these actions of α2δ-1 involve effects on the excitatory drive of SF1 neurons and not its canonical calcium channel function. Furthermore, these data reveal a candidate pathological mechanism leading to alterations in glycemic control in lean individuals and patients treated with gabapentinoid drugs, which inhibit α2δ-1 (DeToledo et al, 1997; Gee et al, 1996; Hoppe et al, 2008). …”

Section: Discussionmentioning

confidence: 92%

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Alpha2delta-1 in SF1 + Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis

et al. 2017

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SUMMARY The central mechanisms controlling glucose and lipid homeostasis are inadequately understood. We show that α2δ-1 is an essential regulator of glucose and lipid balance, acting in steroidogenic factor-1 (SF1) neurons of the ventromedial hypothalamus (VMH). These effects are body weight independent and involve regulation of SF1+ neuronal activity and sympathetic output to metabolic tissues. Accordingly, mice with α2δ-1 deletion in SF1 neurons exhibit glucose intolerance, altered lipolysis, and decreased cholesterol content in adipose tissue despite normal energy balance regulation. Profound reductions in the firing rate of SF1 neurons, decreased sympathetic output, and elevated circulating levels of serotonin are associated with these alterations. Normal calcium currents but reduced excitatory postsynaptic currents in mutant SF1 neurons implicate α2δ-1 in the promotion of excitatory synaptogenesis separate from its canonical role as a calcium channel subunit. Collectively, these findings identify an essential mechanism that regulates VMH neuronal activity and glycemic and lipid control and may be a target for tackling metabolic disease.

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Section: Introductionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 92%

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Alpha2delta-1 in SF1 + Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis

et al. 2017

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“…The mean weight gain at study termination compared with baseline was approximately 5 kg, with 44% of patients gaining ≥7% of their initial weight. In contrast to short-term trials which suggested a relationship between weight gain and pregabalin dose, in long-term studies weight gain did not appear to correlate with absolute dose (mg/day), weight-normalized dose (mg/kg/day), or categorized dosage (more or less than 300 mg/day) (Hoppe et al 2008). In one study, extended patient counseling was not found to be effective in preventing the occurrence of weight gain (Hoppe et al 2008).…”

Section: Safety and Tolerability Profilementioning

confidence: 99%

Pregabalin for the management of partial epilepsy

Ryvlin

Perucca

Rheims

2008

NDT

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Pregabalin is one of the latest antiepileptic drugs introduced for the treatment of partial epilepsy. Its effi cacy and safety as adjunctive therapy in refractory partial epilepsy have been established in four double-blind placebo-controlled trials (n = 1396) and 4 long-term open-label studies (n = 1480). In 3 fi xed-dose trials, the proportion of patients with a Ն50% reduction in seizure frequency across the effective dose-range (150-600 mg/day) ranged between 14% and 51%, with a clear dose-response relationship. Suppression of seizure activity could be demonstrated as early as day 2. The most frequently reported CNS-related adverse events included dizziness, somnolence, ataxia and fatigue, were usually mild or moderate, and tended to be dose related. In long-term studies, weight gain was reported as an adverse event by 24% of patients. When pregabalin dose was individualized to according to response within the 150 to 600 mg/day dose range, tolerability was considerably improved compared with use of a high-dose, fi xed-dose regimen (600 mg/day) without titration. In long-term studies up to 4 years, no evidence of loss effi cacy was identifi ed. During the last year on pregabalin, 3.7% of patients were seizure-free. Pregabalin appears to be a useful addition to the therapeutic armamentariun for the management of refractory partial epilepsy.

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“…In another study evaluating the utility of short counseling program to prevent weight gain, showed the mean bodyweight increase, compared to baseline, of 2.5 kg (SD ±3.7 kg; median: 2.0 kg) and 4.0 kg (SD ±4.1 kg; median: 4.0 kg; N =60) at the 3- and 6-month follow-up, respectively 25. The body mass index increment was 0.9 (SD ±1.3; median: 0.6) and 1.4 (SD ±1.4; median: 1.3) for the 3- and 6-month follow-up, respectively 25…”

Section: Postmarketing Epilepsy Studiesmentioning

confidence: 99%

Pregabalin in the management of partial epilepsy

Arain

2009

NDT

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Pregabalin is a new antiepileptic medication that works by binding to alpha 2 delta subunit of the voltage-dependent calcium channels present in presynaptic neurons. Its pharmacokinetic advantages include rapid and almost complete absorption, lack of protein binding, linear kinetics, absence of enzyme induction, and absence of interactions with other drugs. Pregabalin was found effective as adjunctive therapy for refractory partial-onset seizures, with up to 51% responder at a dose of 600 mg/day. The lowest effective dose was 150 mg/day. Pregabalin is also approved for treatment of painful diabetic polyneuropathy, postherpetic neuralgia and pain with fibromyalgia. Studies also suggest a beneficial effect on sleep and generalized anxiety disorders. Its main adverse effects in randomized adjunctive trials in adults have been mild to moderate. Most common side effects were dizziness, ataxia, somnolence and diplopia. Weight gain was not prominent in pivotal pregabalin trials, but was more problematic in long-term postmarketing analyses in epilepsy patients. Pregabalin, with its potent antiseizure effect, favorable pharmacokinetic profile, and effectiveness in common co-morbidities is an important addition to the treatment of epilepsy.

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Bodyweight gain under pregabalin therapy in epilepsy: Mitigation by counseling patients?

Abstract: Pregabalin treatment is associated with a high risk for bodyweight gain which in part depends on total anticonvulsant drug load. This side effect cannot be prevented by extended patient counseling within a standard clinical setting.

Cited by 24 publications

References 8 publications

Alpha2delta-1 in SF1 + Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis

Alpha2delta-1 in SF1 + Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis

Pregabalin for the management of partial epilepsy

Pregabalin in the management of partial epilepsy

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