Table 1.
Details of number of dogs, 95 % CI affected cases, AED doses and serum levels, treatment period and adverse effects
| 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 | PHB | 20 | 78.5 % | 60.5 %–96.5 % | mean, 4.11+/−1.1; range, 3.9–4.9 mg/kg PO BID | mean, 27+/−6; range, 12.4–36 μg/mL | 6 m | Neurological (ataxia, hyperactivity, sedation), GI (vomiting, diarrhea, PP), PU, PD, ClinPath (increased ALP, decreased albumin) | ataxia, sedation, increased serum ALP, decreased albumin | I |
| Heynold et al. 1997 | PHB | 37 | 35 % | 19.6 %–50.4 % | mean, 2.5 mg/kg PO BID | range, 15–40 μg/ml | mean, 50; range, 8–108 m | Neurological (ataxia, sedation, aggression), GI (PP), Dermatological (itching) | sedation | I |
| Löscher et al. 2013 | PHB | 8 | NA | NA | range, 10–40 mg/kg PO SID | 14.7 μg/ml | 2.5 m | Neurological (sedation, ataxia), PU, PD | sedation, ataxia, PU, PD | I |
| Gaskill et al. 2000 | PHB | 22 | 32 % | 12.5 %–51.5 % | At 3 w: mean, 3.6+/−1.3; range, 1.3–6.0 mg/kg At 6 m: mean, 3.7+/−1.4; range, 1.3–8.3 mg/kg At 12 m: mean, 3.7+/−1.6; range, 1.3–8.3 mg/kg PO SID |
At 3 w: mean, 58.6+/−15.0; range, 33–85 mmol/L At 6 m: 62.5+/−25.7; range, 8–120 mmol/L. At 12 m: mean, 62.2+/−23.51; range, 11–116 mmol/L |
12 m | Endocrine (decreased total T4 levels, increased TSH levels, normal TSH stimulation test) | euthyroid sick syndrome | I |
| Steinberg 2004 | PHB (monotherapy prior to the addition of other AEDs) | 14 | 26.6 % | 4.8 %–52.1 % | NA | PHB: mean, 32.1+/−14.4 μg/ml. | median, 17; range, 3.3–58.5 m | GI (chronic hepatotoxicity) | chronic hepatotoxicity | I |
| von Klopmann et al. 2006 | PHB | 34 | 68 % | 52.3 %–83.7 % | NA | NA | NA | Endocrine (decreased total T4 levels, normal TSH levels, normal TSH stimulation test) | euthyroid sick syndrome | I |
| Chang et al. 2006 | PHB | 11 | 92.5 % | 76.9 %–108.1 % | NA | NA | median, 18; range, 3–72 m | Neurological (ataxia, hyperactivity, sedation), GI (vomiting, diarrhea, PP), Dermatological (itching), PU, PD | PD, PU, PP, sedation, hyperactivity | I |
| Tipold et al. 2014 | PHB | 110 | 57.3 % | 48.1 %–66.5 % | range, 2–6 mg/kg PO BID | <45 μg/mL | 5 m | Neurological (sedation), GI (PP, diarrhea), PU, PD, ClinPath (increased ALP, γ-GT, ALT and GLDH) | sedation, PP, PU, PD | I |
| Fredso et al. 2015 | PHB | 6 | 93 % | 70 %–114 % | median, 2.7; mean, 3; range 2.2–3 mg/kg PO BID | median, 77; mean, 77.3; range 55–111 μmol/L | 2–12 m | Neurological (sedation, ataxia, hyperactivity, disobedience), GI (PP), PU, PD | PD, PP | I |
| Schwartz-Porsche et al. 1985 | PHB | 15 | 93 % | 80.1 %–105.9 % | range, 5–17 mg/kg PO SID | range, 19–57 μg/ml | mean, 15; range, 7.3–32 m | Neurological (sedation, ataxia), GI (PP), PD, ClinPath (ALT, ALP, GLDH) | ataxia, sedation, PP, PD | I |
| Gaskill et al. 2005 | PHB | 12 | NA | NA | median, 5; range, 2.1–12.9 mg/kg PO SID | mean, 22.8; range, 9.7–44.2 μg/ml | median, 20.4; range, 4–78 m | ClinPath (increased ALT, ALP) | increased ALT, ALP | I |
| Farnbach et al. 1984 | PHB | 42 | 2.4 % | −2.2 %−7.2 % | range, 0.3–19.9 mg/kg PO SID | mean, 24.3; range, 6.5–81.3 μg/ml | NA | Neurological (hyperactivity) | hyperactivity | I |
| Gaskill and Kimber 2010 | PHB | 30 | 80 % | 65.7 %–94.3 % | NA | NA | 12 m | Neurological (ataxia, sedation, hyperactivity, aggression), GI (PP, anorexia, vomiting, diarrhoea), Dermatological (skin problems), ClinPath (increased ALP, ALT, lipase), PU, PD | PP, PU, PD, vomiting, skin problems, hyperactivity | I |
| Aitken et al. 2003 | PHB | 95 | 40 % | 30.1 %–49.8 % | <2–> 10 mg/kg PO SID | <65–> 120 μmol/l | <3–> 12 m | ClinPath (increased ALT, ALP, γ-GT, GLDH, cholesterol, bile acids) | increased ALP, ALT, GLDH | I |
| Dayrell-Hart et al. 1991 | PHB | 18 | NA | NA | median, 10.4; range, 3.1–27 mg/kg PO SID | mean, 49.7; range, 16–60 μg/ml (12 dogs had >40) | median, 39; range, 5–82 m | GI (hepatotoxicity) (also all dogs were ataxic and sedated) |
NA | I |
| Andrik et al. 2010 | PHB | 30 (15 epileptic and 15 non-epileptic) | NA | NA | Epileptic dogs: 2 mg/kg PO BID (increased if necessary) Non-epileptic dogs: Initially at 2 mg/kg PO SID, then increased at 8 mg/kg PO SID |
NA | Epileptic dogs: range, 12–60 m Non-epileptic dogs: 5 m |
GI (chronic hepatotoxicity), ClinPath (increased ALP, ALT, AST, total bilirubin, decreased albumin and total protein) | increased ALT, ALP | I |
| Litchfield et al. 1972 | PHB | 4 | NA | NA | range, 5–40 mg/kg IV SID | NA | 0.5 m | ClinPath (increased ALP) | NA | I |
| Foster et al. 2000 | PHB | Experimental dogs: 6 Epileptic dogs: 10 |
70 % | Experimental dogs: 0 % Epileptic dogs: 41.6 %–98.4 % |
Experimental dogs: mean, 6 mg/kg; range, 5.9–6.4 mg/kg PO SID Epileptic dogs: range, 3.9–14.4 mg/kg PO SID |
Experimental dogs: mean, 63+/−15, range, <65–194 μmol/L Epileptic dogs: mean, 110; range, 72–171 μmol/L |
Experimental dogs: 3 m Epileptic dogs: range, 14–92 m |
ClinPath (increased ALP, ALT, cholesterol) | increased ALP | I |
| Gaskil et al. 1999 | PHB | 78 | 40 % | 28.8 %–50.6 % | median 4; range, 1–16.4 mg/kg PO SID | median, 17.6; range, 4–70 μg/ml | median, 12.5; range, 0.3–96 | Endocrine (decreased total T4, free T4, increased TSH) Also, ClinPath abnormalities were reported, i.e. increased ALT, ALP, AST, γ-GT, fasting bile acids and cholesterol, but no further details are provided. |
eythyroid sick syndrome | I |
| Muller et al. 2000 | PHB | 12 | 91.6 % | 100 % or 50.5 %–99.5 % | mean, 5; range, 4.8–6.6 mg/kg PO BID | range, 20–40 μg/mL | 7.1 m | Endocrine (decreased total T4, free T4, increased TSH, cholesterol and total T3), Neurological (sedation for the first 3 days) No significant PHB’s effect on either of the adrenal function tests |
euthyroid sick syndrome | I |
| Muller et al. 2000 | PHB | 12 | 87.5 % | 75.9 %–107.3 % | mean, 5; range, 4.8–6.6 mg/kg PO BID | range, 20–40 μg/ml | 7.1 m | ClinPath (increased ALP, ALT, γ-GT, decreased albumin), Neurological (sedation for the first 3 days) | increased ALP, ALT, γ-GT | I |
| Kantrowitz et al. 1999 | PHB | 55 | NA | NA | NA | median, 25.3; range, 8.0–74.3 μg/ml | median, 7 m; range, 1–120 m | Endocrine (decreased T4, increased TSH) | eythyroid sick syndrome | I |
| Chauvet et al. 1995 | PHB | 5 | 100 % | 100 % | NA | range, 20–47 μg/ml | 13 m | Endocrine (increased ACTH, altered ACTH stimulation and dexamethasone supression test), ClinPath (increased ALT, ALP, decreased albumin, cholesterol), PU, PD | increased ACTH, altered ACTH stimulation and dexamethasone supression test, increased ALT, ALP, decreased albumin, cholesterol | I |
| Balazs et al. 1978 | PHB | 4 | 100 % | 100 % | 40 mg/kg PO SID | NA | 1.8 m | ClinPath (increased ALP) | increased ALP | I |
| Conning and Litchfield 1971 | PHB | NA | NA | NA | NA | NA | NA | ClinPath (increased ALP) | increased ALP | I |
| Sturtevant et al. 1977 | PHB | 2 | 100 % | 100 % | 4.4 mg/kg PO TID | NA | 1 m | ClinPath (Increased ALT, ALP) | increased ALT and ALP | I |
| Thrift et al. 2010 | PHB | 1 | NA | NA | 6.4 mg/kg PO BID | NA | 2 m | ClinPath (anemia, increased ALT, ALP, AST) | idiosyncrasic anemia | I & II |
| Kube et al. 2006 | PHB | 1 | NA | NA | Initially 5 mg/kg PO BID for 4 days, then 3 mg/kg PO BID | NA | 2 m | Dyskinesia (twitching episodes) | NA | II |
| Steiner et al. 2008 | PHB | 118 | 14.4 % | 8.1 %–20.7 % | NA | Unclear | NA | ClinPath (Increased cPLI) | NA | II |
| Gaskill et al. 2000 | PHB | 88 | 9 % | 3.0 %–15.0 % | NA | range, 39–130 mol/L | 16 m | GI (pancreatitis, increased amylase and/or lipase activities) | increased amylase and/or lipase activities | II |
| March et al. 2004 | PHB | 11 | NA | NA | mean, 12.4+/−5.7; range, 3.8–19.8 mg/kg PO SID | mean, 43.5+/−15.1; range, 22.8–66 μg/ml | median, 6; range, 20.4–132 m | Dermatological (superficial necrolytic dermatitis) | NA | II |
| Weiss 2005 | PHB | 3 | NA | NA | NA | NA | NA | Blood dyscrasias (bone marrow necrosis-myelofibrosis) | NA | II |
| Jacobs et al. 1998 | PHB | 2 | NA | NA | Case 1: 2.2 mg/kg PO BID; Case 2: 4.4 mg/kg PO BID | NA | Case 1: 5 m; Case 2: 3 m | Blood dyscrasias (neutropenia, thrombocytopenia), ClinPath (increase ALP) | NA | II |
| Weiss et al. 2002 | PHB | 1 | NA | NA | NA | NA | NA | Blood dyscrasias (myelofibrosis) | NA | II |
| Bevier et al. 2010 | PHB | 1 | NA | NA | NA | NA | NA | Dermatological (superficial necrolytic dermatitis) | NA | II |
| Bersan et al. 2014 | PHB | 16 | NA | NA | median, 3; mean, 2.75+/−0.43; range, 1.60–7.25 mg/kg PO BID | median, 19; mean, 22.4+/−5.5; range, 13.2–30.5 μg/ml | median, 69.5; mean, 72.1+/−sd 45.8; range, 14–157 m | Blood dyscrasias (anemia and/or thrombocytopenia and/or neutropenia and/or pancytopenia) | anemia, pancytopenia | II |
| Volk et al. 2008 (case series) | PHB (monotherapy prior to the addition of other AEDs) | 8 | NA | NA | NA but was within normal reference values | NA | Approximately 2–3 m | Blood dyscrasias (bone marrow suppression) | NA | II |
| Habock and Pakozdy 2012 | PHB | 37 | 22 % | 16.8 %–57.2 % | NA | NA | >1 m | Blood dyscrasias (anemia and/or thrombocytopenia and/or neutropenia and/or pancytopenia) | NA | II |
| Von Klopmann et al. 2006 | PHB | 1 | NA | NA | 2 mg/kg PO BID | NA | Blood dyscrasias (pancytopenia) | NA | II | |
| Bizzeti et al. 2006 | PHB | 7 | 14.4 % | −11.6 %−40.2 % | NA | NA | NA | Pancreatitis, ClinPath (Increased amylase, lipase, cPLI) | NA | II |
| Mathis et al. 2014 | PHB | 1 | NA | NA | 2.1 mg/kg PO BID | 27.5 μg/dL | 6 m | Blood dyscrasias (bone marrow supression) | NA | II |
| Daminet et al. 1999 | PHB | 9 | 0 % | 0 % | Initially 1.8–3 for one week, then 2.7–4.5 mg/kg PO BID | range, 65–150 pmol/L | 0.8 m | No adverse effects | NA | NA |
| Dyer et al. 1994 | PHB | 6 | 0 % | 0 % | 5 mg/kg PO BID | range, 18–37 μg/ml | 2 m | No PHB’s effect on endogenous ACTH and ACTH stimulation test | NA | NA |
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)