The efficacy of carbamazepine combinations in epilepsy

Cereghino, James J.; Brock, Joseph T.; Meter, J. C. Van; Penry, J. Kiffin; Smith, Lawrence D.; White, B. G.

doi:10.1002/cpt1975186733

Cited by 71 publications

(34 citation statements)

References 2 publications

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“…In the first design, patients who did not respond to drug A nor to drug B when given separately were then given the combination of A and B (4, 51,55). The second design involved the addition of an investigational AED to different single conventional AEDs (45,46). Using the concept of drug load, further insight is obtained as to whether the increased effectiveness of a particular combination is due to an improvement in efficacy or to enhanced tolerability.…”

Section: Discussionmentioning

confidence: 99%

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Selection of Antiepileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence Reviewed

et al. 2000

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Summary:Purpose: When monothempy with antiepileptic drugs (AEDs) fails, combination therapy is tried in an attempt to improve effectiveness by improving efficacy, tolerability, or both. We reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which cornbinations are associated with increased effectiveness. Because various designs and methods of analysis were used in these studies, it was also necessary to evaluate the appropriateness of these approaches.Methods: Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers.Results: Thirty-nine papers were identified reporting on twodrug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only end point. Conclusions:There is evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with an NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seeins less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and subsequent evaluation of advantageous combinations in clinical trials. Testing procedures in animals should include the isobologram method, and the concept of drug load should be the basis of studies in patients with epilepsy.

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Section: Discussionmentioning

confidence: 99%

“…Another approach that has merit is the one used by Cereghino et al (45) and Brodie et al (46). Tn these studies the investigational AED was used in several twodrug combinations.…”

Section: Human Datamentioning

confidence: 99%

Selection of Antiepileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence Reviewed

et al. 2000

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“…'8 In conclusion, our data indicate that patients treated with therapeutic doses of carbamazepine and phenytoin in combination show significantly less impairment of water clearance than patients on carbamazepine levels during phenytoin therapy. As phenobarbitone has a similar effect on serum carbamazepine levels9 10 it is likely to influence diuretic response in a similar way. Since the reduction in carbamazepine levels is quite marked, the risk of developing water intoxication is likely to be substantially less in patients on combination therapy than in patients receiving carbamazepine alone and clinical evidence supports this conclusion.2 The risk of water intoxication with carbamazepine as sole drug treatment may be particularly high if adjustments in dosage are made without the assistance of drug levels monitoring.…”

Section: Discussionmentioning

confidence: 99%

Reversal by phenytoin of carbamazepine-induced water intoxication: a pharmacokinetic interaction.

Perucca¹,

Richens²

1980

Journal of Neurology, Neurosurgery & Psychiatry

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SUMMARY The hypothesis that phenytoin may antagonise the antidiuretic effect of carbamazepine has been examined by comparing the free water clearance response to a standard water load in 36 patients stabilised on different drug regimes. The diuretic response to the water load was significantly greater in patients receiving chronic treatment with carbamazepine and phenytoin in combination than in matched control subjects receiving carbamazepine as a single drug. Acute administration of phenytoin (1,100 mg), however, had no significant influence on carbamazepineinduced antidiuresis. Evidence is presented that reversal of the antidiuretic effect of carbamazepine by chronic phenytoin administration is secondary to a marked reduction of the serum carbamazepine concentration during combined therapy. These results suggest that the risk of developing water intoxication is greater in patients receiving carbamazepine alone than in those receiving phenytoin in combination. Since the antidiuretic effect is correlated with the serum carbamazepine concentration rather than with the prescribed daily dose, monitoring the serum level of the drug is likely to provide the best rational approach to the prevention of excessive water retention.Carbamazepine has antidiuretic properties which have been shown to be positively correlated with the concentration of the drug in serum.1 2 Excessive water retention is relatively common at serum concentration values close to the upper limit of the therapeutic range (12 to 42 Amol/l) and may be troublesome in some patients, particularly those receiving the drug for the treatment of epilepsy and trigeminal neuralgia.'-5 Interestingly, water intoxication appears to be more common in patients treated with carbamazepine alone than in those receiving phenytoin in combination2 and reversal of carbamazepineinduced antidiuresis by phenytoin has been recently described in one patient.6 Although in the latter report the mechanism of the interaction was assumed to be pharmacodynamic, that is, related to the inhibitory action of phenytoin on the release of antidiuretic hormone (ADH) from the posterior pituitary,7 8 there are no experimental data to support this hypothesis. We now report the results of a study in which this interaction and the mechanisms involved have

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“…Combining AEDs based on their mechanism of action can also provide a rational approach to the challenge 1, 3. While the potential for enhanced neurotoxicity when combining two sodium channel‐blocking AEDs was observed over 40 years ago, evidence for enhanced efficacy with specific combinations remains inconsistent 4, 5, 6…”

Section: Introductionmentioning

confidence: 99%

Lacosamide and sodium channel-blocking antiepileptic drug cross-titration against levetiracetam background therapy

et al. 2016

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ObjectiveTo assess prospectively the effectiveness of lacosamide (LCM) added to levetiracetam (LEV) after down‐titration of a concomitant sodium channel blocker (SCB) among patients with focal epilepsy not adequately controlled on LEV and SCB.MethodsIn this open‐label trial, LCM was initiated at 100 mg/day and up‐titrated to 200‐600 mg/day over 9 weeks; SCB down‐titration started when LCM dose reached 200 mg/day. Patients remained on stable LCM/LEV doses for 12 weeks’ maintenance (21‐week treatment period). The primary outcome was retention rate on LCM.ResultsDue to recruitment challenges, fewer than the planned 300 patients participated in the trial, resulting in the trial being underpowered. Overall, 120 patients (mean age 39.7 years) started and 93 completed the trial. The most frequently used SCBs were lamotrigine (39.2%), carbamazepine (30.8%) and oxcarbazepine (27.5%). Eighty‐four patients adhered to protocol and discontinued their SCB after cross‐titration, but there was insufficient evidence for 36 patients. Retention rate was 73.3% (88/120) for all patients and 83.3% (70/84) for those with evidence of SCB discontinuation. Seizure freedom for patients completing maintenance was 14.0% (13/93). Discontinuation due to adverse events (6.7%) and lack of efficacy (3.3%) occurred primarily during cross‐titration. Most frequently reported adverse events during treatment were dizziness (23.3%), headache (15.0%) and fatigue (8.3%).ConclusionsIn patients with uncontrolled seizures on LEV/SCB, the LCM/LEV combination appeared to be effective and well tolerated. A cross‐titration schedule—flexible LCM up‐titration, concomitant SCB down‐titration and stable background LEV—could present a feasible and practical approach to initiating LCM while minimizing pharmacodynamic interactions with a SCB.

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The efficacy of carbamazepine combinations in epilepsy

Cited by 71 publications

References 2 publications

Selection of Antiepileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence Reviewed

Selection of Antiepileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence Reviewed

Reversal by phenytoin of carbamazepine-induced water intoxication: a pharmacokinetic interaction.

Lacosamide and sodium channel-blocking antiepileptic drug cross-titration against levetiracetam background therapy

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