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Phenytoin for controlling seizures in tricyclic antidepressant overdose

Three Part Question

In [patients with TCA overdose who develop prolonged seizures] does [phenytoin or benzodiazepines] lead to [quicker and more reliable termination of seizures with fewer complications]?

Clinical Scenario

An adult male is brought to the Emergency Department following a significant tricyclic antidepressant overdose. While in the Emergency Department he has several seizures. You wonder whether to load with intravenous phenytoin or simply manage prolonged seizures with benzodiazepines.

Search Strategy

MEDLINE 1966 – 2007 March Week 3 Ovid interface
EMBASE 1980 – 2007 Week 13. Ovid interface.
MEDLINE: (exp Amitriptyline/ OR exp Nortriptyline/ OR exp Dothiepin/ OR exp Desipramine/ OR exp Clomipramine/ OR exp Doxepin/ OR exp Lofepramine/ OR exp Nortriptyline/ OR exp Trimipramine/ OR exp Imipramine/ OR exp Antidepressive Agents, Tricyclic/ OR (tricyclic$ OR TCA OR amitriptyline OR nortriptyline OR imipramine OR dothiepin OR dosulepin OR desipramine OR clomipramine OR doxepin OR lofepramine OR nortriptyline OR trimipramine).mp.) AND (exp Phenytoin OR OR limit to human and English language
EMBASE: (exp Antidepressive Agents, Tricyclic/ OR OR OR exp Amitriptyline/ OR OR exp Desipramine/ OR OR exp Clomipramine/ OR OR exp Doxepin/ OR OR exp Dothiepin/ OR OR exp Imipramine/ OR OR exp Lofepramine/ OR OR exp Nortriptyline/ OR OR exp Trimipramine/) AND (exp Phenytoin OR OR AND (exp Benzodiazepines/ OR exp Diazepam/ OR exp Clonazepam/ OR exp Midazolam/ OR exp Temazepam/ OR exp Nitrazepam/ OR (benzodiazepin$ OR diazepam OR clonazepam OR nitrazepam OR clonazepam OR midazolam OR temazepam).mp.) AND (exp Seizure/ OR (seizur$ OR convuls$ OR fiting OR fit OR fits).mp.) limit to human and English language

Search Outcome

286 papers were identified in MEDLINE and 216 in EMBASE. None directly answered the three-part question. Several papers discussed the use of phenytoin in TCA overdose. These are discussed.

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses


Intravenous phenytoin is licensed for use in status epilepticus. Its use in the context of TCA overdose is controversial. There have been sporadic case reports of the successful use of intravenous phenytoin for the treatment of patients with severe TCA overdose who have developed cardiac conduction abnormalities (Hagerman and Hanashiro 1981; Cantrill 1983). It is proposed that this may result from its class Ia antiarrhythmic action. However, there is evidence of interaction between the two drugs, with TCA's increasing phenytoin levels (Perucca and Richens 1977; Shin et al, 2002). Due to the narrow therapeutic window of phenytoin, this interaction is of concern. Further, in an animal model phenytoin was found to increase the likelihood of ventricular arrhythmias when TCA's were also infused (Callaham et al, 1988). In light of this potential interaction, guidelines from the National Poisons Information Service state that phenytoin should be avoided in patients who have taken a TCA overdose (National Poisons Information Service 2008).

Clinical Bottom Line

Phenytoin has not been compared to benzodiazepines in patients with TCA overdose. Evidence for the benefit of phenytoin in TCA overdose comes only from sporadic case studies. As there are doubts regarding the safety of phenytoin in these patients, it should be avoided.

Level of Evidence

Level 3 - Small numbers of small studies or great heterogeneity or very different population.


  1. Hagerman GA; Hanashiro PK Reversal of tricyclic antidepressant induced cardiac conduction abnormalities by phenytoin Annals of Emergency Medicine 1981; (2): 82-6
  2. Cantrill S Prophylactic phenytoin in tricyclic overdose Journal of Emergency Medicine 1983; 1(2): 169-77
  3. Perucca E; Richens A Interaction between phenytoin and imipramine British Journal of Clinical Pharmacology 1977; 4(4): 485-6
  4. Shin J-G; Park J-Y; Kim M-J; Shon J-H; Yoon Y-R; Cha I-J, et al Inhibitory effects of tricyclic antidepressants (TCAs) on human cytochrome P450 enzymes in vitro: Mechanism of drug interaction between TCAs and phenytoin. Drug Metabolism & Disposition 2002; 30(10): 1102-7
  5. Callaham M; Schumaker H; Pentel P Phenytoin prophylaxis of cardiotoxicity in experimental amitriptyline poisoning Journal of Pharmacology & Experimental Therapeutics 1988; 245(1): 216-220
  6. National Poisons Information Service TOXBASE 2008