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Three Part Question

In [adults with an acute porphyria presenting to the emergency department with convulsions] are [lorazepam and diazepam safe and effective] at [ terminating the seizures].

Clinical Scenario

A 23 year old female with variegate porphyria presents to the emergency department with generalised seizures. You ask your colleague about the protocol for fitting but she points out that some anticonvulsants may exacerbate porphyric attack.

Search Strategy

Medline 1966- 06/06 via Ovid interface
Embase 1980- 06/06 via Ovid interface
Cinahl 1982- 06/06 Via Ovid interface
The Cochrane Library
Medline:[lorazepam.mp. or exp lorazepam/ or ativan.mp. or exp diazepam/ or diazepam.mp. or valium.mp. or exp benzodiazepines/ or benzodiazepine$ .mp.] AND[exp porphyrias/ or porphyria.mp. or porphyrias.mp. or AIP.mp.] LIMIT human and english
Embase:[exp porphyria/ or porphyria.mp. or porphyrias.mp. or AIP.mp.] AND [lorazepam.mp. or exp lorazepam/ or ativan.mp. or exp diazepam/ or diazepam.mp. or valium.mp. or exp benzodiazepines/ or benzodiazepine$ .mp.] LIMIT humans and english
Cinahl:[exp porphyria/ or porphyria.mp. or porphyrias.mp. or AIP.mp.] AND [lorazepam.mp. or exp lorazepam/ or ativan.mp. or exp diazepam/ or diazepam.mp. or valium.mp. or exp benzodiazepines/ or benzodiazepine$ .mp.] LIMIT humans and English.
Cochrane:porphyria.

Search Outcome

Medline: 20 results 3 relevant
Embase: 99 results, one relevant review with overview of case studies but original articles had already been found in Medline
Cinahl: 1 result 0 relevant
Cochrane: 0 relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Bonkowsky et al 1980 USA	38 year old male with AIP and seizures exacerbated by phenytoin treated with clonazepam for 23 days (initially at a low dose then rising to 20mg/day) and hematin.	Case report (level 3)	Cessasion of seizures	Clonazepam failed to terminate the seizures	Case report
			GOS at 6 months in comparison to worst and best GCS Pre-treatment and post treatment	Using GSC all grades are significantly valid for prediction of outcome p<0.05, especially if the worst pre-treatment score is used p = 0.0001
			Exacerbation of the attack	At doses of 20mg the patients speech and behaviour deteriorated
Larson et al 1978 USA	A 35 year old male with post-traumatic epilepsy and AIP treated with sucessive trials of phenytoin, carbemazepine and clonazepam.	Cohort study (level 3)	GCS as a predictor for mortality at 30 days and 2 years	GCS 15: 30D = 100% p=0.693, 2Y=97% p=1.75; GCS13-14, 30D=94% p=0.664, 2Y=88% p=0.406; GCS 7-12 30D=69% p=0.003, 2Y=65% p=0.230; GCS6-3 30D=20% 2Y=17% p=0.343.	Single patient
			Urinary PBG	No increase in PBG
			Symptoms of acute attack	None occured
			Frequency of seizures	No seizures occured during treatment compared to one every 3 weeks before treatment.
Holroyd S and Seward R 1999 usa	A 65 female with AIP suffering from depression was treated with lorazepam and clonazepam (0.5 mg/d then 1mg/d) on two separate occasions. (She also recieved sertraline, venlafaxine, olanzapine, risperidone, clozapine, buspirone and trazodone).	Case report (level 3)	Symptoms suggestive of an acute attack	No acute attack occured	Case report No urinary PBG or ALA measurements
			Score on Glasgow Outcome Scale at 6 months. Scores 1 and 2 were classed as a good outcome (G) and 3, 4 and 5 as a poor outcome (P)	442 patients, 6 were lost to follow up. GCS 15(205) G177 P28.p<0.001. GCS 12-14 (132) G71 P61 p=0.09. GCS 9-11 (16) G3 P13 p=0.4. GCS 6-8(30)G7 P23 p=0.06. GCS < 6 (53) G4 P49. The p values are for the significance of the adjacent score.

Comment(s)

Drug databases listing safe and unsafe drugs are useful in the management of porphyria.The information they provide is based on published case reports, previously published drug lists, theoretical considerations and clinical experience. Lorazepam has been classified as safe and diazepam as potentially unsafe, caution needed with use, or unclassified by the European Porphyria Initiative (EPI), The Welsh Medicines Information, University of Cape Town Porphyria Service and The Norwegian Porphyria Centre (NAPOS).

Clinical Bottom Line

There is insufficient and conflicting evidence as to the safety of diazepam and more research needs to be undertaken into its use in porphyric patients. It appears Lorazepam is safe to use in acute porphyria and should be used as the first line treatment for seizures.

References

1. Bonkowsky HL, Sinclair PR at al. Seizure management in acute hepatic porphyria: risks of valproate and clonazepam. Neurology 30(6):588-92, 1980 Jun.
2. Larson AW. Wasserstrom WR. Felsher BF et al. Posttraumatic epilepsy and acute intermittent porphyria: effects of phenytoin, carbamazepine, and clonazepam. Neurology 28(8):824-8, 1978 Aug.
3. Holroyd S, and Seward R. Psychotropic drugs in acute intermittent porphyria. Clinical Pharmacology & Therapeutics 66(3):323-5, 1999 Sep.
4. The norweigan porphyria centre. NAPOS. The Drug Database for Acute Porphyria [Online]. 2006 [Accessed 19th July 2006].
5. University of Cape Town Porphyria Service. Drug Safety: Alphabetical Listing [Online]. 2006 [Accessed 19th July 2006].
6. European Porphyria Initative. Drugs and Porphyria [Online]. 2006 [Accessed 19th July 2006].