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Table 3 Details of number of dogs, 95 % CI affected cases, AED doses and serum levels, treatment period and adverse effects

From: Antiepileptic drugs’ tolerability and safety – a systematic review and meta-analysis of adverse effects in dogs

Studies AED No of dogs treated Prevalence 95 % CI affected cases Doses of AEDs Serum levels of AEDs Treatment period Body system affected and adverse effects Most common adverse effects Adverse effect type
Boothe et al. 2012 PBr 23 78.5 % 61.7 %–95.3 % mean, 30.6; range, 26–35 mg/kg PO BID mean, 1.9 +/− 0.6; range, 0.9–3.3 mg/ml approximately 6 m Neurological (ataxia, hyperactivity, sedation), GI (vomiting, diarrhoea, PP), PU, PD sedation, hyperactivity, ataxia, PD, PU I
Pearce 1990 PBr as an adjunct to PHB 10 40 % 9.6 %–70.4 % PBr: 22 mg/kg PO SID (dose increases occurred)
PHB: median, 3.3; mean, 3.8 mg/kg PO BID (dose was reduced by a mean of 50 % in 7/10 dogs during the PBr treatment)
PBr: mean, 810; range, 500–1625 mg/l
PHB: mean, 29.7; range, 17–45 ug/ml
median, 7; mean, 7.8 m Neurological (ataxia, sedation, hyperactivity), PU, PD ataxia, letargy, PU, PD I
March et al. 2002 PBr 6 20 % −12.0 %−52.0 % 30 mg⁄kg PO BID median, 245; range, 178–269 mg/dL 3.9 m
(adverse effects occurred after this period when dose adjustments occurred (NA))
Neurological (ataxia, paraparesis, hyperactivity) ataxia, paraparesis I
Rossmeisl et al. 2009 PBr as an adjunct to PHB and/or other AEDs 1298 2 % 1.2 %–2.8 % PBr: 44.9+/−1.7 mg/kg PO SID
PHB: 6.3+/−0.4 mg/kg PO SID
PBr: 3.7+/−0.3 mg/ml
PHB: 31.4+/−1.2 μg/dl
NA Neurological (sedation, ataxia, paraparesis, tetraparesis) sedation, ataxia, paraparesis, tetraparesis I
Dayrell-Hart B et al. 1996 PBr 238 10.9 % 6.9 %–14.9 % NA 21 affected dogs had >2.3 mg/ml and 5 affected dogs had <0.5 mg/ml NA Neurological (ataxia, sedation) ataxia, sedation I
Podell and Fenner 1993 PBr as an adjunct to PHB and/or other AEDs 23 78 % 61.1 %–94.9 % PBr: mean, 20.75; range, 13–40 PO BID
PHB: NA
PBr: 161 mg/dl
PHB: 37.8 mcg/ml
mean, 15; range, 4–33 m Neurological (ataxia, sedation), GI (PP), ClinPath (increased serum chloride), PU, PD PU, PD, PP, sedation I
Chang et al. 2006 PBr (monotherapy or as an adjunct to PHB) Monotherapry: 4
Adjunctive Therapy: 10
Monotherapry: 62.5 %
Adjunctive Therapy: 95 %
Monotherapy: 15.0–110.0 %
Adjunctive therapy: 81 %–109 %
NA NA median, 18; range, 3–72 m Neurological (ataxia, hyperactivity), Dermatological (pruritus), GI (PP),
The adjunctive therapy group had also PU, PD and vomiting/diarhoea
Ataxia, hyperactivity, pruritus, PP I
Yohn et al. 1992 PBr as an adjunct to PHB 1 NA NA NA 2.7 mg/ml 1 m Neurological (sedation, ataxia, paraparesis, anisocoria) NA I
Kantowitz et al. 1999 PBr (monotherapy or as an adjunct to PHB) Monotherapry: 15
Adjunctive therapy: 8
NA NA NA Monotherapy: median, 1985; range, 500–3419 mg/dL
Adjunctive therapy: PBr: median, 1399; range, 584–2438 mg/dL. PHB: median, 22.4; range, 10.9–40 μg/ml
Monotherapy: median, 14.5; range, 3–37 m
Adjunctive therapy: PBr: median, 5; range, 3–72 m. PHB: median, 22; range, 3–96 m
Monotherapy: Normal
Adjunctive therapy: Endocrine (decreased total T4, free T4)
NA I
Srivastava et al. 2013 PBr as an adjunct to PHB 6 100 % 100 % PBr: 30 mg/kg PO SID
PHB: Initially 2.5 mg/kg, then 5 mg/kg PO SID.
NA mean, 11.50+/− 1.23; range, 8–15 m (on PHB).
Then, PBr started and 3 m later a reduction of 50 % in the dose of PHB was performed. After 6 m, PHB was completely withdrawn.
Neurological (ataxia), GI (hepatoxicity, anorexia, PP), ClinPath (increased ALT, ALP, AST, bile acids), PU, PD
(polyphagia, PU, PD appeared after 1–1.5 years of PBr therapy)
PU, PD, PP I
Shaw et al. 1996 PBr as an adjunct to PHB 1 NA NA PBr: 20 mg/kg PO SID
PHB: 3.75 mg/kg PO BID
PBr: 1100 mg/l.
PHB: 20.4 μg/ml
Approximately 21 m After PBr initiation: Neurological (sedation, ataxia) NA I
Paull et al. 2003 PBr 5 60 % 17.1 %–102.9 % Initially 100 mg/kg PO BID for 2 days. Then,
30 mg/kg PO SID for 180 days.
range, 88–300 mg/dL (only one dog was >300 mg/dl) 6 m Endocrine (Euthyroid sick syndrome with decreased TT4 and normal TSH)
Placebo group had the same results
NA I
Stabile et al. 2014 PBr as an adjunct to PHB 1 NA NA PBr: Initially, 400 mg/kg divided in six daily doses for four days. Then, 14 mg/kg PO BID
PHB: Initially, 2.7 mg/kg, then 5 mg/kg and finally 6.4 mg/kg PO BID.
PBr: 15.9 mg/ml; PHB: 23.7 μg/ml ≥26 m Neurological (sedation, ataxia, generalised appendicular repetitive myoclonus), ClinPath (pseudohyperchlormia, increased ALP) NA I & II
Gaskill and Kimber 2010 PBr 32 85.9 % 73.8 %–98.0 % NA NA 12 m Neurological (ataxia, sedation, hyperactivity, aggression), GI (PP, anorexia, vomiting, diarrhoea, pancreatitis), Dermatological (skin problems), ClinPath (increased ALP, ALT, amylase, lipase), PU, PD vomiting, sedation, PP, PU, PD I & II
Volk et al. 2008 PBr as an adjunct to PHB (prior to addition of other AEDs) 14 100 % 100 % PBr and PHB: NA but were within normal reference values PBr: 1.7+/−0.4 mg/ml
PHB: 35.5+/−6.3 μg/ml
≥2–6 m Neurological (ataxia, aggression), GI (PP, vomiting, pancreatitis), ClinPath (increased ALT, ALP) PU, PD increased ALT, ALP, ataxia, aggression I & II
Gaskill et al. 2000 PBr as an adjunct to PHB Clinical trial: 6
Case series: 19
Clinical trial: 50 %
Case series: 37 %
Clinical trial: 10.0 %–90.0 %
Case series: 15.3 %–58.7 % (pancreatitis); 47.5 %–89.3 % (increased enzymes only)
Clinical trial: NA
Case series: NA
Clinical trial: NA
Case series: PBr: range, 12.5-37.5 mmol/L; PHB: range, 54–190 imol/L
Clinical trial: approximately 1 year
Case series: NA
GI (pancreatitis, increased amylase and/or lipase activities) pancreatitis, increased amylase and/or lipase activities II
Steinmetz et al. 2012 PBr as an adjunct to PHB 1 NA NA 101.19 mg/kg SID PO (added at the beginning of the 4th year)
PHB: 4.9 mg/kg BID PO
PBr: 45 mmol/l
PHB: 168.52 μmol/l
48 m (adverse effect occurred after the 48 m) Neurological (neuromyopathy with generalised low motor signs) NA II
Mackay and Mitchell 1998 PBr as an adjunct to PHB 1 NA NA PBr: Initially 200 mg/kg PO BID for 3 days, then 30 mg/kg PO SID
PHB: 5 mg/kg PO BID.
PBr: NA.
PHB: 126 umol/L
3 d
(signs started 3 d after the loading dose of PBr was initiated)
ClinPath (artifactual hyperchloraemia and negative anion gap), Neurological (pacing, disorientation), GI (vomiting)
The Neurological and GI signs were attributed to hypercloraemia
NA II
Boynosky and Stokking 2014 PBr as an adjunct to PHB 2 NA NA Initially 40 mg/kg PO SID, then 60 mg/kg PO SID (case 1) or 86 mg/kg PO SID (case 2) Case 1: 2.9 mg/mL; Case 2: initially 0.8, then 3 mg/ml (after 7.5 months of treatment) 12 m
[adverse effects occured 3 (case 1) and 8 (case 2) m after the dose increase]
Dermatological (panicculitis) accompanied by sedation and anorexia NA II
Steiner et al. 2008 PBr (monotherapy or as an adjunct to PHB) Monotherapy: 98
Adjunctive therapy: 121
14 % Monotherapy: 8.2 %–22.4 %
Adjunctive: 5.9 %–17.3 %
NA range, 0.5–4.2 mg/ml (majority of dogs; range, 1–2 mg/ml) NA ClinPath (increased cPLI) NA II
Bizzeti et al. 2006 PBr as an adjunct to PHB 7 43 % 6.1 %–79.4 % NA NA NA Pancreatitis, ClinPath (increased amylase, lipase,cPLI) NA II
  1. Abbreviations: AED(s) anti-epileptic drug(s), BID bis in die (twice daily), Chloraz Chlorazepate, CSF cerebrospinal fluid, CL confidence level, Gaba Gabapentin, IE idiopathic epilepsy, LEV Levetiracetam, m month(s), NA Not Available, PHB phenobarbital, PD polydipsia, PU polyuria, PP polyphagia, PBr potassium bromide, Prim primidone, PO per os, SID semel in die (once daily), TID ter in die (three times daily); TPM Topiramate; w week(s), y year(s)