J Vet Intern Med 2010;24:166–170

Placebo Effect i n C a n i n e E p i l e p s y T r i a l s
K.R. Muñana, D. Zhang, and E.E. Patterson

Background: The placebo effect is a well-recognized phenomenon in human medicine; in contrast, little information exists
on the effect of placebo administration in veterinary patients.
Hypothesis: Nonpharmacologic therapeutic effects play a role in response rates identified in canine epilepsy trials.
Animals: Thirty-four dogs with epilepsy.
Methods: Meta-analysis of the 3 known prospective, placebo-controlled canine epilepsy trials. The number of seizures per
week was compiled for each dog throughout their participation in the trial. Log-linear models were developed to evaluate
seizure frequency during treatment and placebo relative to baseline.
Results: Twenty-two of 28 (79%) dogs in the study that received placebo demonstrated a decrease in seizure frequency
compared with baseline, and 8 (29%) could be considered responders, with a 50% or greater reduction in seizures. For the 3
trials evaluated, the average reduction in seizures during placebo administration relative to baseline was 26% (P 5 .0018), 29%
(P 5 .17), and 46% (P 5 .01).
Conclusions and Clinical Importance: A positive response to placebo administration, manifesting as a decrease in seizure
frequency, can be observed in epileptic dogs. This is of importance when evaluating open label studies in dogs that aim to assess
efficacy of antiepileptic drugs, as the reported results might be overstated. Findings from this study highlight the need for more
placebo-controlled trials in veterinary medicine.
Key words: Clinical trials; Dog; Epilepsy; Statistical modeling.

T he placebo effect is a well recognized, but poorly un-

derstood phenomenon that involves a nonspecific
psychological or physiological therapeutic effect of a
medical intervention that lacks specific activity for the
condition being treated.1 Early medical practices were
based on the placebo effect, wherein placebos were ad-
ministered with the purpose of producing a desired
therapeutic response. More recently, the use of placebos
has focused primarily on its role as a control in random-
ized-clinical trials that allows for an unbiased estimate of
the treatment effects of the agent being evaluated.
Results from numerous human trials have demon-
strated that placebos can improve subjective and
objective outcomes in patients with a wide range of
clinical conditions. A beneficial effect of placebo admin-
istration has been reported in 60–90% of all human
diseases,2 including musculoskeletal, respiratory, car-
diac, dermatologic, gastrointestinal, and nervous system
disorders. Furthermore, a placebo response rate of ap-
proximately 35% is commonly cited in the medical
literature,3 although higher rates have been reported
and are most frequently seen in diseases with clinical
signs that wax and wane, fluctuate, or spontaneously re-
mit.4 Because of the potential magnitude of this effect,
From the Department of Clinical Sciences, College of Veterinary
Medicine (Muñana) and the Department of Statistics (Zhang),
North Carolina State University, Raleigh, NC and the Department
of Veterinary Clinical Science (Patterson), University of Minnesota,
St Paul, MN. Presented at the 26th Annual Forum of the American
College of Veterinary Medicine, San Antonio, TX, June 2008.
Corresponding author: Karen R. Muñana, Department of Clinical
Sciences, College of Veterinary Medicine, North Carolina State Uni-
versity, 4700 Hillsborough Street, Raleigh, NC 27606; e-mail:
karen_munana@ncsu.edu
Submitted April 17, 2009; Revised July 17, 2009; Accepted
September 16, 2009
Copyright r 2009 by the American College of Veterinary Internal
Medicine
10.1111/j.1939-1676.2009.0407.x
placebo-controlled studies are considered necessary to
gauge the true efficacy of a novel intervention, and are
the basis for drug evaluation and approval in human
medicine.
In contrast, the placebo effect has been largely disre-
garded in veterinary medicine, with only 2 publications
identified that address the issue of a placebo effect in an-
imals.1,5 However, with the recent emphasis placed on
evidence based medicine in veterinary practice, it seems
appropriate to consider the effect of placebos in veteri-
nary patients, particularly the extent to which animals
may demonstrate an improvement in disease manifesta-
tions that could be because of nonspecific effects of a
therapeutic intervention.
The hypothesis tested in this study is that nonpharma-
cologic therapeutic effects play a role in response rates
identified in canine epilepsy trials. The specific aim is to
determine the magnitude of the placebo response in ran-
domized-controlled trials evaluating new treatment
modalities for refractory canine epilepsy.
Materials and Methods
Study Design
Data was compiled from 3 clinical trials evaluating the safety and
efficacy of novel treatments for refractory canine epilepsy in which a
placebo arm was a component of the study protocol. The studies
evaluated were performed by 2 of the authors (K.R.M., E.E.P.), en-
abling easy access to the data necessary to undertake the present
analysis. A database search was performed to identify any addi-
tional placebo-controlled canine epilepsy trials that might be
included in the analysis, but none were found. Inclusion criteria
were similar for all 3 studies and consisted of (1) an onset of seizures
between 1 and 5 years of age; (2) a normal diagnostic evaluation,
including physical examination, neurological examination, CBC,
chemistry profile, urinalysis, and bile acid tolerance test; (3) treat-
ment with either phenobarbital and/or potassium bromide at
established therapeutic serum levels; (4) a seizure frequency of at
least 4 seizures per month or a history of cluster seizures; and (5) a 1
year documented history of seizures. All dogs were classified as
 Placebo Effect in Epilepsy
having generalized seizures based on owners’ descriptions of seizure
episodes. Some of the dogs were also reported to have occasional
partial seizures. No attempt was made to further characterize the
seizure type with video monitoring or electroencephalography. The
therapeutic interventions evaluated included a surgical implant,6 di-
etary modification,a and a novel antiepileptic drug (unpublished
data). All studies were placebo controlled and blinded such that
both the owner and veterinary personnel involved in evaluating the
dog were unaware of the treatment being administered. The novel
interventions were evaluated as add-on therapies, and as such, dogs
were maintained on their previously prescribed conventional anti-
epileptic medication throughout the study. The surgical implant and
drug study were cross over in design, and consisted of an 8-week
baseline period followed by 2 treatment periods of 13–16 weeks in
length, with a 4-week washout period between the 2 treatment pe-
riods. The diet trial was designed as a parallel study, and included a
baseline period of 3–6 months followed by a treatment period of 6
months. In each study, the treatment group received the experimen-
tal therapeutic intervention in addition to conventional antiepileptic
drug treatment, and the control group received a matching placebo
in addition to conventional antiepileptic drug treatment.
Seizure monitoring was based on owner observations. Informa-
tion was recorded on study forms that were adapted from those used
for human seizure monitoring. Owners were instructed to complete
a daily diary noting medication administered, the presence of any
seizure activity, and whether any signs of illness, change in activity
or attitude were noted. Owners were asked to complete an addi-
tional form immediately after any observed seizure that captured
information on specific manifestations of the episode. Based on
these observations, a weekly seizure frequency was compiled
for each dog throughout the study. The average weekly seizure
frequency for each of the study periods (baseline, placebo adminis-
tration, and active treatment) was calculated. As is the convention
for human epilepsy trials, a positive treatment response was defined
as a 50% or greater reduction in seizure frequency compared with
baseline. To assess for any changes in drug levels that might affect
seizure frequency, mean serum antiepileptic drug concentrations
obtained at the end of baseline, placebo administration and active
treatment were calculated and compared for each trial.
Statistical Analysis
Log-linear models were developed for each of the study designs
(cross-over and parallel) to evaluate weekly seizure frequency dur-
ing treatment and placebo relative to baseline. Such models account
for the treatment effect as well as the effect of time.
For a cross-over study, the study period can be divided into 3
periods: period 1 corresponding to the baseline followed by 2 peri-
ods for the treatment and placebo. Denote by Yij the seizure count
for the ith dog at the jth week and let mij 5 E(Yij) be the average
seizure count per week. Because the dogs are randomized to the
treatment and placebo, we then consider the following log-linear
model for mij:
logðmij Þ ¼ b0 þ b1 I ðtreatment at period 2Þ þ b2 I ðtreatment at period 3Þ
þ b3 Iðplacebo at period 2Þ þ b4 Iðplacebo at period 3Þ
ð1Þ
where I( % ) is an indicator function. With this model specification, b0
is the log average seizure count per week at period 1 (assumed to be
independent of treatment sequence because of randomization), (b1
1 b2)/2 can be interpreted as the average treatment effect relative to
baseline and (b3 1 b4)/2 is the average placebo effect relative to
baseline. Then b1 & b3 is the treatment effect relative to placebo at
period 2, b2 & b4 is the treatment effect relative to placebo at period
3, and (b1 & b3 1 b2 & b4)/2 is the average treatment effect relative
to the placebo.
167
For a parallel study, the study period is divided into 2 periods:
period 1 for the baseline and period 2 for the treatment or the pla-
cebo. Using the above notations, we consider the following log-
linear model for mij:
logðmij Þ ¼ b0 þ b1 IðtreatmentÞ þ b2 Iðperiod2Þ; ð2Þ
where b0 has the same interpretation as before, b1 is the effect of the
treatment relative to the placebo, and b2 is the placebo effect plus
the possible time effect of period 2 relative to period 1.
The assumption was made that the variance of Yij has the form of
Poisson variance function with a possible overdispersion. To ac-
count for the correlation in the longitudinal data in each patient, the
inference on effect parameters was carried out by the generalized
estimating equation (GEE) methodology with equal correlation ma-
trix as the working correlation matrix.7 A commercially available
software programb was used to implement the analysis.
Results
Thirty-four dogs were included in this study: 9 dogs as
participants in the study evaluating the surgical implant,
14 as participants in the study evaluating novel drug
therapy, and 11 as participants in the study evaluating
dietary modification. In the latter study, which was de-
signed as a parallel study, 5 of 11 dogs were randomized
to placebo treatment while the remaining 6 dogs were
randomized to the active treatment.
Data on seizure frequency during active treatment and
placebo administration relative to baseline for dogs in
the 3 trials are summarized in Table 1 and Figure 1.
Log-linear analysis of weekly seizure frequency for the
population in dogs in each trial identified a reduction in
seizures during placebo administration of 26–46%. The 2
cross-over studies involving the surgical implant and the
drug trial demonstrated a reduction in seizures during
placebo administration compared with baseline of 26%
(P 5 .0018) and 29% (P 5 .17), respectively. For the di-
etary modification trial, which was designed as a parallel
study, dogs administered placebo had a 46% (P 5 .01)
decrease in seizure frequency from baseline.
There were no significant changes in serum concentra-
tions of either phenobarbital or bromide throughout the
study, although dogs in both the surgical implant trial
and the drug trial demonstrated a trend toward increas-
ing serum bromide levels during placebo administration
relative to baseline that was not associated with a change
in potassium bromide dosage. Similarly, mild increases in
both phenobarbital and bromide levels from baseline
were seen in dogs in the placebo arm of the diet trial
(Table 2).
Discussion
Results from this study suggest that a positive response
to placebo administration can be observed in epileptic
dogs. A decrease in seizure frequency was seen in more
than half of the dogs in the trials during treatment with
placebo when compared with baseline values. Eight of 28
dogs (29%) evaluated in this study could be classified as
responders, based on a 50% or greater reduction in sei-
zure frequency. Futhermore, placebo administration was
168 Muñana, Zhang, and Patterson

Table 1. Seizure frequency relative to baseline during administration of active treatment and placebo for dogs in
epilepsy trials.
Number (%) of Dogs with Number (%) of Dogs Number (%) of Dogs
Decrease in Seizures Classified as Respondersa Seizure-free

Active Placebo Active Placebo Active Placebo

Surgical implant 6/9 (67) 6/9 (67) 3/9 (33) 0/9 (0) 0 (0) 0 (0)
Novel drug 12/14 (86) 11/14 (79) 8/14 (57) 5/14 (36) 4/14 (29) 1/14 (7)
Dietary modification 3/6 (50) 5/5 (100) 1/6 (17) 3/5 (60) 0 (0) 0 (0)
a
Responders: dogs with a ' 50% reduction in seizure frequency.

associated with an estimated reduction in seizure fre-
quency of 26–46% in the population of dogs studied.
This response was identified across the different treat-
ment modalities evaluated in these trials, which included
a surgical implant, a novel antiepileptic drug, and a di-
etary modification, suggesting that this effect is not
specific with respect to treatment type.
The findings from this study are consistent with results
from similar studies evaluating the placebo effect in hu-
man epilepsy. A recent meta-analysis of randomized
trials of antiepileptic drugs in human patients identified
a placebo response rate of 9.3–16.6%,8 while an earlier
study comparing data from trials involving 5 antiepilep-
tic drugs demonstrated placebo response rates of 4–18%,
with an average rate of 10% over all studies.9
An obvious difference between the current study and
those involving human subjects involves the inherent na-
ture of the placebo response. In human studies, placebo
effects are primarily because of expectations of an indi-
vidual as a patient being treated in a double-blind
manner. In veterinary studies, the placebo response can
be because of effects on the animal, but more importantly
may be a result of expectations of the pet owner regard-
ing treatment. It is likely that the expectations of the
owner might play a greater role in a study such as this,
where the owners are responsible for administration of
treatment and outcome measures (ie, seizure frequency)
are derived solely from owner observations.
It is possible that the effect observed in the present
study is because of nonspecific antiepileptic properties of

Fig 1. Box and whisker plots of the weekly seizure frequency during baseline, placebo administration, and active treatment for dogs in the
surgical implant trial (a), novel drug trial (b), and dietary modification trial (c). Central lines of the box represent the median, upper and lower
limits of the box represent the 75th and 25th percentiles, and whiskers represent the 95th and 5th percentiles. Mean values are denoted by &.
 Placebo Effect in Epilepsy
Table 2. Serum antiepileptic drug concentrations during baseline, active treatment, and placebo administration for
dogs in epilepsy trials.
Phenobarbital Serum Concentration (mg/mL)
Baseline Active
Surgical implant 27.45 (2.24) 27.02 (1.96)
Novel drug 27.51 (1.59) 27.21 (1.86)
Dietary modification 28.42 (1.18)) 32.35 (4.07)
Values reported as mean (standard error).
the placebo, but this is considered unlikely. Although a
decrease in seizure frequency was observed during pla-
cebo administration, the change in seizure frequency
relative to baseline did not assume significance in all of
the trials (P 4 .05). Rather, it is more likely that the ob-
served effect is because of what has been termed the
‘‘perceived placebo effect,’’ or a change that is observed
after placebo administration that is not directly caused to
placebo.10 The perceived placebo effect includes any
changes associated with the administration of placebo,
including the effect of time. It is important to note
that the statistical models utilized in this study do not
differentiate the treatment effect from the effect of time,
and consequently the analysis performed provides a mea-
sure of multiple potential factors that can contribute to
treatment response. These factors may include regression
to the mean, investigator bias, client bias, the potential
for a higher level of care during the study, and improved
adherence to treatment with active medication that is
being administered in addition to the placebo during the
study.
Regression to the mean is a statistical term used to de-
scribe the fluctuations of biological variables that occur
over time and take the form of a sine wave around the
mean.11 Epilepsy is a waxing and waning disorder, and
fluctuations in seizure frequency are common over the
course of the disease. Owners are most likely to seek a
change in therapy for their pet when seizures are under
poor control. Over the short term, improvement in the
seizure frequency is probable, regardless of the treatment
administered. However, this improvement is often erro-
neously attributed to a recently instituted change in
therapy, whereas in fact it is because of an effect of time.
The potential for bias by individuals involved in the
study cannot be overlooked. Even in blinded studies, ex-
pectations of a response can influence the subjective
interpretation of study data by the investigator. The po-
tential for participant bias, known as the Hawthorne
effect, is a well-recognized phenomenon in clinical trials.
The act of participating in a trial provides individuals
with a better experience because of the focus of interest
toward them, which is rewarding for its own sake.
Consequently, participants document better results re-
gardless of the change provided or the treatment
experienced. Because canine epilepsy trials rely on owner
observations to quantify seizure frequency, an owner’s
expectations of a trial can influence the study results for
their dog. Indeed, it has been shown that the size of the
placebo effect may be associated with the nature of the
169
Bromide Serum Concentration (mg/dL)
Placebo Baseline Active Placebo
27.56 (2.84) 174.04 (23.70) 176.17 (20.70) 186.96 (20.10)
26.94 (2.04) 158.59 (16.17) 158.39 (19.50) 181.62 (21.64)
32.41 (4.95) 169.86 (9.42) 151.78 (14.01) 185.75 (32.15)
outcome measure, with larger effects observed in trials
reporting subjective outcomes.12
Finally, it is possible that improved adherence to the
established antiepileptic drug regimen during participa-
tion in the trial played a role in the present study findings.
Although prescribed dosages of conventional antiepilep-
tic medications stayed constant throughout the studies, a
slight increase in bromide serum concentrations relative
to baseline was identified during placebo administration
in all of the trials, and a similar trend in phenobarbital
serum levels was observed in the diet trial. The differ-
ences in serum drug concentrations were relatively small
and did not approach statistical significance; nonetheless
this may have contributed to the reduction in seizure fre-
quency identified during placebo administration.
A greater placebo response was identified in the paral-
lel study compared with the cross-over studies. Sixty
percent of dogs in the parallel study were classified as
placebo responders, compared with response rates of 0%
and 36% in the cross-over studies. Similarly, the overall
decrease in seizure frequency during placebo administra-
tion compared with baseline for the population of dogs
was 46 % for the parallel study, compared with values of
26% and 29% for the cross-over studies. Although the
total number of dogs in the trials is too low to draw any
conclusions about these percentages, it seems plausible
that owner bias might assume a greater role in a parallel
study design than in a cross-over design. Owners that
choose to enroll their dogs in trials tend to have a positive
attitude toward the new intervention being evaluated and
its potential to help their animal. This desire to have the
treatment be effective can influence owners’ observations
and data collection for the study. The cross-over study
design, in which each dog receives the therapeutic agent
being tested, might minimize this bias. In contrast, the
parallel study design, in which each participant receives
either the test agent or placebo, has the potential to high-
light this source of bias.
The beneficial effects of placebo administration are
well documented in laboratory animals.1 Animal studies
have served as the basis of investigation into the mecha-
nism of the placebo effect for most of the past century.
However, to the authors’ knowledge there is only one
other report that specifically addresses the placebo effect
in clinical veterinary medicine.5 Jæger and colleagues
performed a controlled parallel study to evaluate gold
bead therapy as a treatment for canine hip dysplasia. The
main outcome parameter in the study was a change in
pain signs as assessed by the owner. Owners were also
170 Muñana, Zhang, and Patterson
asked to document what kind of treatment they believed
had been administered to their dog. Results demon-
strated that when owners believed that their dog was
receiving the active treatment, they reported a signifi-
cantly greater improvement in pain signs compared with
those who believed their dog was receiving placebo
or were uncertain about the treatment administered.
The authors concluded that blinding and randomization
are necessary in veterinary studies, particularly where
the outcome is based on owner’s assessment of clinical
improvement.
The treatment of canine epilepsy is evolving as several
new methods of therapy have recently become available.
Nine new antiepileptic drugs have been approved for use
in humans since 1990, and the pharmacokinetics of many
of these drugs support their use in veterinary patients.
Recently, there have been publications reporting on
gabapentin,13,14 zonisamide,15,16 and levetiracetam17 as
treatment for refractory canine epilepsy. All of these
studies evaluated the test drug in an uncontrolled, open
label manner, with the drug being used in conjunction
with phenobarbital, potassium bromide or both. Re-
sponse rates of 41–80% were reported across these
studies, and in several instances these response rates led
to the conclusion that the drug being evaluated was effi-
cacious for refractory canine epilepsy. However, based
on the results obtained from the present study, it is likely
that these results may be overstated and the true efficacy
of these agents remains to be determined. In 2 of the tri-
als reported on here, namely the surgical implant and the
drug study, comparison of seizure frequency between the
active treatment and baseline demonstrated a 27% and
48% reduction in seizures, both of which would be con-
sidered statistically significant on their own (P 5 .0025
and .017, respectively). However, when the reduction in
seizures observed with the active treatment is compared
with the change in seizure frequency between placebo ad-
ministration and baseline, the response to the active
treatment becomes insignificant.
The main limitation to the present study is the low
number of dogs enrolled in each of the trials evaluated,
such that it is not possible to conclusively state the sig-
nificance of the placebo response observed. The lack of
financial and administrative support that is required for
large-scale trials is perhaps the most consistent factor
that limits the ability to perform controlled clinical trials
in veterinary medicine. Nonetheless, findings from this
study justify the need for placebo-controlled trials to
answer key clinical questions in veterinary practice.
Footnotes
a
Patterson EE, Muñana KR, Kirk CA, et al. Results of a ketogenic
food trial for dogs with idiopathic epilepsy. J Vet Intern Med 2005;
19:421 (abstract)
b
PROC GENMOD, SAS Inc, Cary, NC
Acknowledgments
The authors thank Julie Nettifee-Osborne for her tech-
nical assistance with this study. We also acknowledge the
referring veterinarians and clients whose dogs partici-
pated in the epilepsy trials evaluated.
References
1. McMillan FD. The placebo effect in animals. J Am Vet Med
Assoc 1999;215:992–999.
2. Benson H, Friedman R. Harnessing the power of the placebo
effect and renaming it ‘‘remembered wellness’’. Annu Rev Med
1996;47:193–199.
3. Beecher HK. The powerful placebo. J Am Med Assoc
1955;159:1602–1606.
4. Roberts AH, Kewman DG, Mercier L, Hovell M. The power
of nonspecific effects in healing: Implication for psychosocial and
biological treatments. Clin Psychol Rev 1993;13:375–391.
5. Jæger GT, Larsen S, Moe L. Stratification, blinding and pla-
cebo effect in a randomized, double blind placebo-controlled
clinical trial of gold bead implantation in dogs with hip dysplasia.
Acta Vet Scand 2005;46:57–68.
6. Muñana KR, Vitek SM, Tarver WB, et al. Use of vagal nerve
stimulation as a treatment for refractory epilepsy in dogs. J Am Vet
Med Assoc 2002;221:977–983.
7. Zeger SL, Liang KY. Longitudinal data analysis for discrete
and continuous outcomes. Biometrics 1986;42:121–130.
8. Burneo JG, Montori VM, Faught E. Magnitude of the pla-
cebo effect in randomized trials of antiepileptic agents. Epilepsy
Behav 2002;3:532–534.
9. Cramer JA, Fisher R, Ben-Menachem E, et al. New antiepi-
leptic drugs: Comparison of key clinical trials. Epilepsia
1999;40:590–600.
10. Ernst E. Placebo: New insights into an old enigma. Drug
Discov Today 2007;12:413–418.
11. Morton V, Torgerson DJ. Regression to the mean: Treat-
ment effect without the intervention. J Eval Clin Pract 2005;11:
59–65.
12. Hróbjartsson A, G!tzsche P. Is the placebo powerless? An
analysis of clinical trials comparing placebo with no treatment. N
Engl J Med 2001;344:1594–1602.
13. Platt SR, Adams V, Garosi LS, et al. Treatment with gaba-
pentin of 11 dogs with refractory idiopathic epilepsy. Vet Rec
2006;159:881–884.
14. Govendir M, Perkins M, Malik R. Improving seizure control
in dogs with refractory epilepsy using gabapentin as an adjunctive
agent. Aus Vet J 2005;83:602–608.
15. Dewey CW, Guiliano R, Boothe DM, et al. Zonisamide
therapy for refractory idiopathic epilepsy in dogs. J Am Anim Hosp
Assoc 2004;40:285–291.
16. von Klopmann T, Rambeck B, Tipold A. Prospective study
of zonisamide therapy for refractory idiopathic epilepsy in dogs.
J Sm Anim Pract 2007;48:134–138.
17. Volk HA, Matiasek LA, Luján Feliu-Pascual A, et al. The
efficacy and tolerability of levetiracetam in pharmacoresistant epi-
leptic dogs. Vet J 2008;176:310–319.