Transient improvement after brief antiepileptic drug withdrawal in the epilepsy monitoring unit—possible relationship to AED tolerance

Azar, Nabil J.; Lagrange, Andre H.; Wang, Lily; Song, Yanna; Abou‐Khalil, Bassel

doi:10.1111/j.1528-1167.2009.02494.x

Cited by 9 publications

(15 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this therapeutic perspective, Azar et al [55] observed in a series of 43 patients with epilepsy that brief anticonvulsant withdrawal resulted in highly significant seizure interval prolongation once the drugs were restarted. This interval prolongation tended to be greater (25.7 days without a seizure) in those with a prior history of antiepileptic drug (AED) tolerance than in those without a tolerance history (14.0 days) [55].…”

Section: Preclinical Tolerance Studies: Implications For Clinical Tolmentioning

confidence: 85%

Tolerance to the Prophylactic Effects of Carbamazepine and Related Mood Stabilizers in the Treatment of Bipolar Disorders

Post

Weiss

2010

CNS Neuroscience & Therapeutics

View full text Add to dashboard Cite

Tolerance development after successful long-term treatment of bipolar disorder is under recognized, as are ways to prevent or show its occurrence or reverse it once it has occurred. We review the clinical literature which suggests that tolerance can develop to most treatment approaches in bipolar illness and present an animal model of tolerance development to anticonvulsant effects of carbamazepine or lamotrigine on amgydala-kindled seizures. In this model tolerance does not have a pharmacokinetic basis, but is contingent upon the drug being present in the brain at the time of amygdala stimulation. The occurrence of seizures in the absence of drug is sufficient to reverse tolerance and re-establish anticonvulsant efficacy. Based on the model, we hypothesize that some episode-induced compensatory adaptive changes in gene expression fail to occur in tolerant subjects and that episodes off medication re-induce these changes and renew drug effectiveness. Approaches that slow or reverse tolerance development in the animal model are reviewed so that they can be tested for their applicability in the clinic. Criteria for assessing tolerance development are offered in the hope that this will facilitate a more systemic literature about its prevalence, prevention, and reversal. Careful longitudinal monitoring of episode occurrence is essential to understanding tolerance development in the affective disorder and its treatment.

show abstract

Section: Preclinical Tolerance Studies: Implications For Clinical Tolmentioning

confidence: 85%

Tolerance to the Prophylactic Effects of Carbamazepine and Related Mood Stabilizers in the Treatment of Bipolar Disorders

Post

Weiss

2010

CNS Neuroscience & Therapeutics

View full text Add to dashboard Cite

show abstract

“…For example, a comparison of real-world use of clobazam and clonazepam in patients with epilepsy in the United Kingdom showed that median clonazepam dosages increased by 25% and 50% for adults and children, respectively, while median clobazam dosages did not change from baseline to the last follow-up (adults, 5.2–5.5 years; children, 5.5–6.3 years). 26 It is also important to note that clobazam is structurally different from classic benzodiazepines: the 2 nitrogen components at the core of all benzodiazepines have a 1,5 configuration in clobazam compared to a 1,4 configuration in the classic benzodiazepines (e.g., diazepam, lorazepam, and clonazepam). Clobazam and its active N -desmethyl metabolite also appear to display significantly greater binding affinity to the α2 vs α1 subunit of the GABA-A receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, although loss of efficacy over time (i.e., tolerance) is most commonly associated with benzodiazepine treatment, it also has been noted clinically with other structurally and mechanistically diverse AEDs. 4,5 Unfortunately, no predictive factors that might lead to eventual pharmacologic tolerance were identified. Future investigations directed toward more detailed individual patient analysis, likely at the genomic level, are certainly warranted.…”

Section: Discussionmentioning

confidence: 99%

“…Tolerance to antiepileptic effects has been suggested for a variety of AEDs, 4,5 most commonly benzodiazepines, 6,7 with variable and unpredictable timing that limits their clinical use. 2,7 One putative mechanism of benzodiazepine tolerance is downregulation of γ-aminobutyric acid (GABA) receptors following prolonged exposure; however, tolerance has been observed in the absence of receptor changes, and evidence has been mixed.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Deconstructing tolerance with clobazam

et al. 2016

View full text Add to dashboard Cite

Objective:To evaluate potential development of tolerance to adjunctive clobazam in patients with Lennox-Gastaut syndrome.Methods:Eligible patients enrolled in open-label extension study OV-1004, which continued until clobazam was commercially available in the United States or for a maximum of 2 years outside the United States. Enrolled patients started at 0.5 mg·kg−1·d−1 clobazam, not to exceed 40 mg/d. After 48 hours, dosages could be adjusted up to 2.0 mg·kg−1·d−1 (maximum 80 mg/d) on the basis of efficacy and tolerability. Post hoc analyses evaluated mean dosages and drop-seizure rates for the first 2 years of the open-label extension based on responder categories and baseline seizure quartiles in OV-1012. Individual patient listings were reviewed for dosage increases ≥40% and increasing seizure rates.Results:Data from 200 patients were included. For patients free of drop seizures, there was no notable change in dosage over 24 months. For responder groups still exhibiting drop seizures, dosages were increased. Weekly drop-seizure rates for 100% and ≥75% responders demonstrated a consistent response over time. Few patients had a dosage increase ≥40% associated with an increase in seizure rates.Conclusions:Two-year findings suggest that the majority of patients do not develop tolerance to the antiseizure actions of clobazam. Observed dosage increases may reflect best efforts to achieve seizure freedom. It is possible that the clinical development of tolerance to clobazam has been overstated.ClinicalTrials.gov identifier:NCT00518713 and NCT01160770.Classification of evidence:This study provides Class III evidence that the majority of patients do not develop tolerance to clobazam over 2 years of treatment.

show abstract

“…Although cross tolerance can occur with drugs that share mechanisms of action, we did not identify any information to suggest that tolerance to 1 category of medication predicts tolerance to unrelated medications. A period of abstinence from opioids or benzodiazepines results in a return of drug response when those medications are re‐introduced 59,60 . This suggests that drug holidays or drug rotation to medications working through non‐opioid mechanisms may be beneficial in patients who become tolerant to migraine medications that work opioid mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Tolerance to the Beneficial Effects of Prophylactic Migraine Drugs: A Systematic Review of Causes and Mechanisms

Rizzoli¹,

Loder²

2011

Headache: The Journal of Head and Face Pain

View full text Add to dashboard Cite

Loss of benefit of a previously effective treatment regimen, also known as tolerance, can be an important barrier to the successful preventive treatment of migraine. We undertook a systematic review of the literature to identify the prevalence and possible mechanisms of drug tolerance in migraine prophylaxis. Results demonstrate that the frequency of tolerance to prophylactic migraine treatment is unknown, but available data support an estimate that it occurs in 1-8% of patients receiving prophylaxis. Four broad types of tolerance were identified that are likely to be relevant to migraine prophylaxis. These are pharmacokinetic, pharmacodynamic, behavioral, and cross tolerance. The mechanisms that underlie these types of tolerance determine whether their effects can be overcome or minimized. For example, certain forms of tolerance may be affected by manipulation of environmental cues associated with drug administration, by the order in which drugs are used, and by the concomitant use of other medications. Many medications used for migraine prophylaxis exert their effects through the endogenous opioid system. The implications of this finding are explored, particularly the parallels between medication overuse headache and tolerance to migraine prophylaxis. Given the many ways in which tolerance to migraine medications may develop, in some ways it is not surprising that migraine-preventive drugs stop working; it is more surprising that in many cases they do not.

show abstract

Transient improvement after brief antiepileptic drug withdrawal in the epilepsy monitoring unit—possible relationship to AED tolerance

Cited by 9 publications

References 31 publications

Tolerance to the Prophylactic Effects of Carbamazepine and Related Mood Stabilizers in the Treatment of Bipolar Disorders

Tolerance to the Prophylactic Effects of Carbamazepine and Related Mood Stabilizers in the Treatment of Bipolar Disorders

Deconstructing tolerance with clobazam

Tolerance to the Beneficial Effects of Prophylactic Migraine Drugs: A Systematic Review of Causes and Mechanisms

Contact Info

Product

Resources

About