ANTIEPILEPTIC	DRUGS’	TOLERABILITY	AND	SAFETY	–	A	SYSTEMATIC	
REVIEW	AND	META-ANALYSIS	OF	ADVERSE	EFFECTS	IN	DOGS		

Charalambous	M1,	Shivapour	SK2,	Brodbelt	D3,	Volk	HA3	
	1	University	College	London,	UK,		2	Iowa	State	University,	Ames,	USA	and	3	Royal	Veterinary	College,	London,	UK				

Background 
Various anti-epileptic drugs (AEDs) are used for the management of idiopathic epilepsy (IE) in dogs. Their safety profile is an important consideration for regulatory bodies, owners and 
prescribing clinicians. However, information on their adverse effects still remains limited with most of it derived from non-blinded non-randomized uncontrolled trials and case reports. 

Aim of the study 
This is the first systematic review and meta-analysis in veterinary medicine which evaluates studies that describe the safety profile 
of AEDs used for the management of IE in dogs, based on objective criteria. 
 

 

Material & Methods 
ü Electronic searches of PubMed, Google Scholar and CAB Direct were carried out (03 January 2016) without date or language 
restrictions. Proceedings of ECVN/ACVIM annual congresses were searched. Peer-reviewed full-length studies describing 
objectively the adverse effects of AEDs in dogs with IE were included.  
ü Studies were selected based on specific inclusion criteria and a two-stage screening process. Final studies were evaluated on 
the grounds of their overall quality of evidence (figure1) as well as outcomes measures (table 1).  

		
	
	

   ca 
VBH 

VBL  
 
 
 

Conclusions & Discussion 
 

ü Adverse effects usually appeared mild in all AEDs 
and subsided once doses and/or serum levels were 
monitored or after the AED was withdrawn.  
ü Although phenobarbital might be less safe than 
imepitoin and levetiracetam, there was insufficient 
evidence to classify it as an AED with a high risk of 
major adverse effects. 
ü It is important for clinicians to evaluate both AEDs’  
effectiveness and safety on an individual basis 
b e f o r e t h e s e l e c t i o n o f t h e a p p r o p r i a t e 
monotherapy or adjunctive AED therapy. 

 

 

     
  
   
  

			
 

  

Overall 
number of 
studies 
detected 

Total number of 
studies evaluated 
after the two-stage 
screening process 

Number of 
studies with the 
highest overall 
quality of 
evidence 

 Level of evidence provided for each AED safety profile 

Strong 
 

Weak 
 

368 90 5 
ü  Phenobarbital, 

Imepitoin, Potassium 
bromide, Levetiracetam 

ü  Zonisamide, Gabapentin, 
Pregabalin, Sodium valproate, 
Felbamate, Topiramate, Primidone 

 Results 

Table 2: Level of evidence for AEDs’ safety profile 

 

  

Figure 3: Staircase of AED’s safety profile hierarchy 
Direct comparisons suggested that imepitoin and levetiracetam might have a better safety profile 
than phenobarbital, whilst the latter might have a better safety profile than potassium bromide. 
However, none of these comparisons showed a statistically significant difference. 
Comparisons between other AEDs were not possible due to lack of relative comparison studies. 
Individual AED assessments indicated that levetiracetam might be one of the safest AEDs, 
followed by imepitoin and then phenobarbital and potassium bromide. The safety profile in other 
AEDs was variable. 

Table 1: Criteria for evaluation of AEDs’ safety profile 

Proportion of 
specific adverse 
effects for each 
AED 

Prevalence and 95 
% confidence 
interval of the 
affected 
population in each 
study 

Comparative odds ratio of adverse effects for AEDs Level of evidence provided for 
the safety profile of 
each AED 

Calculated for 
each AED by 
dividing the 
number of studies 
that reported a 
specific adverse 
effect by the total 
number of the 
studies for this 
AED. 

Calculated for each 
study by dividing 
the number of 
subjects that 
developed adverse 
effects during the 
specified study 
period by the total 
size of the study 
population. 

The odds ratio (OR) was estimated in order to 
indicate the increased or decreased odds of observing 
specific adverse effect(s) in total for an AED compared 
to its control group (comparison AED or placebo or 
untreated animals). The OR for dichotomous data was 
calculated using the random-effects model in Review 
Manager 5.3. Associations were considered to be 
statistically significant at P < 0.05.  

‘Strong ’ evidence was 
provided for the safety profile 
when at least one bRCT 
reported or assessed the 
adverse effects of an AED;  
‘Weak ’ evidence was provided 
for the safety profile when 
bRCTs were not available. 

Overall	
quality	of	
evidence	

Treatment		
group	size	

Quality	of	
subject	

enrolment		

Study	
design	

Overall	risk	
of	bias	

Figure 1: Criteria for evaluation of 
the overall quality of evidence for 
each study 
Blinded randomized clinical trials (bRCTs) with 
large group sizes, clear inclusion criteria and 
diagnostic investigations that included clinical 
signs and thorough test results consistent with 
the diagnosis of IE, describing outcomes 
specific for IE and low overall risk of bias were 
considered to provide the highest available 
quality of evidence. 

bRCT(s); blinded randomized clinical trial(s) 

Figure 2: Risk of bias 
Risk of bias assessment presented as percentages across all 
included studies based on Cochrane and Syrcle’s ‘risk of bias’  
assessment tool. Overall high risk of bias in >90% of the studies.