Disappointing results of increasing benzodiazepine dose after the development of anticonvulsant tolerance.

Haigh, J. R. M.; Gent, J P; Garratt, Jeni C.; Pullar, T; Feely, M.

doi:10.1136/jnnp.51.7.1008-a

Cited by 7 publications

(1 citation statement)

References 6 publications

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“…After this period of prolonged treatment, DZP not only had lost its anticonvulsant effect but also increased the frequency of spontaneous recurrent seizures, indicating that repeated administration of DZP had moved the BZD‐receptor spectrum toward the inverse agonist end (69). Similar disappointing results of increasing BZD dose after the development of anticonvulsant tolerance were reported by Haigh et al (70). To our knowledge, it has not been studied whether such qualitative changes in drug activity in response to prolonged treatment also occur with other AEDs.…”

Section: Experimental Evidence For Tolerance To Antiepileptic Drugssupporting

confidence: 85%

Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs

Löscher

Schmidt²

2006

Epilepsia

213

141

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Summary: Development of tolerance (i.e., the reduction in response to a drug after repeated administration) is an adaptive response of the body to prolonged exposure to the drug, and tolerance to antiepileptic drugs (AEDs) is no exception. Tolerance develops to some drug effects much more rapidly than to others. The extent of tolerance depends on the drug and individual (genetic?) factors. Tolerance may lead to attenuation of side effects but also to loss of efficacy of AEDs and is reversible after discontinuation of drug treatment. Different experimental approaches are used to study tolerance in laboratory animals. Development of tolerance depends on the experimental model, drug, drug dosage, and duration of treatment, so that a battery of experimental protocols is needed to evaluate fully whether tolerance to effect occurs. Two major types of tolerance are known. Pharmacokinetic (metabolic) tolerance, due to induction of AED-metabolizing enzymes has been shown for most firstgeneration AEDs, and is easy to overcome by increasing dosage. Pharmacodynamic (functional) tolerance is due to "adaptation" of AED targets (e.g., by loss of receptor sensitivity) and has been shown experimentally for all AEDs that lose activity during prolonged treatment. Functional tolerance may lead to complete loss of AED activity and cross-tolerance to other AEDs. Convincing experimental evidence indicates that almost all first-, second-, and third-generation AEDs lose their antiepileptic activity during prolonged treatment, although to a different extent. Because of diverse confounding factors, detecting tolerance in patients with epilepsy is more difficult but can be done with careful assessment of decline during long-term individual patient response. After excluding confounding factors, tolerance to antiepileptic effect for most modern and old AEDs can be shown in small subgroups of responders by assessing individual or group response. Development of tolerance to the antiepileptic activity of an AED may be an important reason for failure of drug treatment. Knowledge of tolerance to AED effects as a mechanism of drug resistance in previous responders is important for patients, physicians, and scientists.

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Section: Experimental Evidence For Tolerance To Antiepileptic Drugssupporting

confidence: 85%

Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs

Löscher

Schmidt²

2006

Epilepsia

213

141

View full text Add to dashboard Cite

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Tolerance to the anticonvulsant effect of benzodiazepines

Haigh

Feely

1988

Trends in Pharmacological Sciences

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Cost-effectiveness analysis of antiepileptic drugs in the treatment of Lennox–Gastaut syndrome

Clements

Skornicki

O’Sullivan

2013

Epilepsy & Behavior

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An economic model evaluated the costs and outcomes of adjunctive clobazam therapy for Lennox-Gastaut syndrome (LGS) compared with adjunctive lamotrigine, rufinamide, and topiramate. Clinical data were used to estimate baseline frequency and the percentage of drop-seizure reductions over 3 months (all comparators) and 2 years (rufinamide). Claims data from a large US health care plan were employed to estimate costs. After 3 months, 21.5% of those receiving clobazam were drop-seizure-free. Over a 3-month horizon, clobazam was more effective and less expensive than comparators, with the assumption that >0.77% of drop seizures required medical care. Below this threshold, topiramate was less costly than clobazam. With the base-case assumption that 2.3% of drop seizures were medically attended, costs for patients receiving clobazam totaled $30,147 versus $34,223-$35,378 for comparators. Clobazam was more efficacious and less costly than rufinamide over a 2-year horizon. The percentage of medically attended drop seizures was a driver of results. Clobazam treatment may be cost-saving.

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Disappointing results of increasing benzodiazepine dose after the development of anticonvulsant tolerance.

Cited by 7 publications

References 6 publications

Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs

Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs

Tolerance to the anticonvulsant effect of benzodiazepines

Cost-effectiveness analysis of antiepileptic drugs in the treatment of Lennox–Gastaut syndrome

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