Pain 99 (2002) 91–99

www.elsevier.com/locate/pain

Blinding effectiveness and association of pretreatment expectations with

pain improvement in a double-blind randomized controlled trial
Judith A. Turner a,b,*, Mark P. Jensen b, Catherine A. Warms b, Diana D. Cardenas b
a
Department of Psychiatry and Behavioral Sciences, Box 356560, University of Washington School of Medicine, Seattle, WA 98195-6560, USA
b
Department of Rehabilitation Medicine, Box 356490, University of Washington School of Medicine, Seattle, WA 98195-6490, USA
Received 11 December 2001; accepted 27 February 2002

Abstract
Patient, provider, and clinical investigator expectations concerning treatments are believed to play important roles in patient response. This
study examined the association of patient and research nurse/physician pretreatment expectations of pain relief with actual pain relief, the
accuracy of patient and research nurse guesses about patient medication assignment, and changes in research nurse and patient pain relief
expectations over the course of a randomized double-blind trial of amitriptyline versus an active placebo for patients with chronic pain and
spinal cord injuries (SCI). Patient expectations of pain relief with amitriptyline were associated significantly with actual pain decrease for
patients in the amitriptyline, but not placebo, condition. Research nurse/physician expectations did not predict patient pain relief. Both
patients and the research nurse were able to guess patient medication assignment at a rate significantly greater than chance. The research
nurse’s, but not the patients’, expectations of pain relief with amitriptyline decreased significantly over the course of the study. These findings
have implications for future randomized controlled trials. Fully double-blind conditions are very difficult to achieve, and it is informative to
assess patient and research clinician expectations and guesses regarding medication assignment. q 2002 International Association for the
Study of Pain. Published by Elsevier Science B.V. All rights reserved.
Keywords: Expectations; Blinding; Randomized controlled trial; Nonspecific effects; Pain

1. Introduction Surprisingly, however, little research has prospectively

The role of nonspecific treatment effects (those attributa-
ble to factors other than specific active components of the
treatment; also referred to as placebo effects) in the
outcomes of patients receiving interventions for pain has
been the subject of much interest and controversy. Patient
and health care provider expectations concerning treatments
are believed to be particularly important (Turner et al.,
1994; Turner, 2001). Studies conducted more than two
decades ago found that patients’ expectations concerning
the effects of a medication were significantly associated
with their responses to that medication (Luparello et al.,
1970; Macdonald et al., 1980). More recently, clients’ posi-
tive expectancies of treatment have been shown to be asso-
ciated with improvement in psychotherapy studies (Safren
et al., 1997). Provider expectations related to study medica-
tions have also been found to be associated with patients’
responses to treatment (Shapiro et al., 1954; Gracely et al.,
1985).
* Corresponding author. Tel.: 11-206-543-3997; fax: 11-206-685-1139.
E-mail address: jturner@u.washington.edu (J.A. Turner).
examined whether patient and clinician expectations of
degree of pain relief with the study treatment predict actual
pain relief. One of the few such studies found that physician,
but not patient, expectations of amount of pain amelioration
immediately following a pain-relieving procedure were
associated significantly with patients’ actual pain relief
(Galer et al., 1997). A recent study of patients with low
back pain randomly assigned to receive acupuncture or
massage therapy found that patients with higher pretreat-
ment expectations for the treatment they received were
more likely to have improved function after treatment
(Kalauokalani et al., 2001). Further examination of the asso-
ciations of patient and provider pretreatment expectations of
pain relief with patient outcomes in different patient popu-
lations and with different treatments is needed to increase
scientific understanding of the role of such expectations in
pain treatment response. It is also important to study expec-
tations of other study personnel, such as research nurses,
who have contact with patients in clinical trials. Concern
has been expressed that research nurses in such trials might
influence patients’ responses by behaviors reflecting expec-
tations based on their experience of other patients’ reactions

0304-3959/02/$20.00 q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.
PII: S 0304-395 9(02)00060-X
92 J.A. Turner et al. / Pain 99 (2002) 91–99
(McQuay et al., 1995). To our awareness, however, no
studies have reported whether research nurse expectations
change significantly over the course of a study.
Patient and provider guesses concerning patient treatment
assignment may also potentially influence the results of
double-blind randomized clinical trials. Such studies have
long been thought to be the only method of establishing the
effect of a treatment above and beyond natural history and
nonspecific or placebo effects, with the double-blind
designed to prevent clinical investigator and patient knowl-
edge of treatment condition from biasing the results.
However, even in randomized double-blind controlled
trials, it is possible that the efficacy of the active treatment,
the lack of efficacy of the placebo, the lack of side effects of
the placebo, or the side effects of the active treatment may
‘unblind’ the patient and/or the investigators. Indeed, multi-
ple studies have documented that patients (Marini et al.,
1976; Brownell and Stunkard, 1982; Byington et al.,
1985; Hughes and Krahn, 1985; Rabkin et al., 1986;
Moscucci et al., 1987; Margraf et al., 1991), study clinicians
(Brownell and Stunkard, 1982; Byington et al., 1985;
Rabkin et al., 1986; Margraf et al., 1991), and study evalua-
tors (White et al., 1992; Carroll et al., 1994) can correctly
guess patients’ treatments at high rates, even under double-
blind conditions.
The present study was conducted to examine the role of
patient and research nurse/physician expectations regarding
pain relief in patient treatment response, as well as the
accuracy of and reasons for patient and research nurse
guesses as to patient treatment assignment, in a randomized,
double-blind trial. The study was part of an investigation of
the pain-relieving effects of amitriptyline versus an active
placebo (benztropine mesylate) among individuals with
spinal cord injury (SCI) and chronic pain. The efficacy of
amitriptyline in this study was reported in a separate paper
(Cardenas et al., 2002). The objectives of the present study
were to examine: (1) the association of patient and research
nurse/physician pretreatment expectations of pain relief
with actual pain relief, (2) the accuracy of and reasons for
patient and research nurse end-of-study guesses about
patients’ actual treatments, and (3) the change in research
nurse and patient expectations about pain relief over the
course of the study.
2. Methods
2.1. Study participants
A complete description of the 84 study participants and
the study procedures was provided by Cardenas et al.
(2002). The study inclusion criteria were SCI more than 6
months ago, pain for at least 3 months, and average pain
rating in the last month of at least 3 on a scale of 0 to 10. The
exclusion criteria were as follows: less than 18 or more than
65 years of age, cardiovascular disease, seizure disorder,
abnormalities in a screening electrocardiogram (ECG),
hyperthyroidism, glaucoma, unwilling to use a contracep-
tive during the drug trial (if female with childbearing poten-
tial), pregnant, currently on any type of antidepressant
medication, current consumption of more than two alcoholic
drinks per day, and current major depressive episode.
The mean age of the sample was 41.43 years (SD 10.02,
range 21–64) and 80% were male. Median duration of SCI
was 13.4 years (range 8.5 months to 42.9 years). Thirty
percent were college graduates. There were no significant
differences between the amitriptyline and placebo groups in
age, gender, education, neurological level of injury, etiology
of injury, duration of SCI, ethnic group, marital status, or
employment status.
2.2. Study design and procedures
This was a double-blind randomized placebo-controlled
trial to evaluate the efficacy of amitriptyline in relieving
chronic pain associated with spinal cord injury. Benztropine
mesylate was chosen as an active placebo based on its abil-
ity to produce dry mouth, a common side effect of amitripty-
line. Study participants were solicited through mailing lists,
notices placed in clinics serving patients with SCI, and arti-
cles in newsletters. Potential participants were screened in a
telephone interview conducted by the research nurse to
determine if they met the inclusion/exclusion criteria. The
University of Washington Human Subjects Review
Committee and the Institutional Review Board of Good
Samaritan Hospital, Puyallup, WA, USA, approved the
study, and each participant gave written informed consent.
The consent form included information concerning random
assignment to amitriptyline or benztropine mesylate, and
the possible side effects associated with these medications
(dry mouth, constipation, sedation, lightheadedness, blurred
vision, palpitations, changes in heart rate).
Forty-four patients were assigned randomly to amitripty-
line and 40 to placebo. Although individuals who met
psychiatric diagnostic criteria for a current major depressive
episode were excluded from the study, we expected that
some subjects would have some depressive symptoms.
Because it was possible that subjects with some depressive
symptoms might respond differently to amitriptyline, we
stratified randomization by low versus high level of depres-
sive symptom severity based on the Center for Epidemiolo-
gical Studies-Depression Scale scores (Radloff, 1977). The
cutoff ð,16 versus $16Þ recommended for depression case
identification was used (Radloff, 1977).
Random assignment to medication group and provision of
medication was performed by the University of Washington
Medical Center Pharmacy Investigational Drug Services. A
7-day supply of medication was provided to each patient
each of the 6 study weeks in identical gelatin capsules so
that study personnel and patients were blind to medication
assignment. All patients, regardless of medication assign-
ment, were instructed to take a single capsule 1–2 h before
 J.A. Turner et al. / Pain 99 (2002) 91–99
bedtime each evening. This single capsule contained the
fixed dose of benztropine mesylate (held constant at 0.5
mg/day throughout the study) or the appropriate dose of
amitriptyline (from 10 to 125 mg/day). The amitriptyline
dose schedule protocol was as follows: week 1, 10 mg/
day; week 2, 25 mg/day; then increasing each week there-
after by 25 mg/day to a possible maximum dose of 125 mg/
day. Amitriptyline dosage was titrated to the level of
complete pain relief or maximal dose (up to 125 mg/day)
tolerated over the 6-week trial.
All patients were telephoned by the research nurse on day
4 or 5 of each week to assess pain and medication side
effects. The nurse then communicated with the pharmacy
as if each patient was on amitriptyline. If the patient
reported bothersome side effects, the nurse asked the phar-
macy to hold the medication dosage at the current week’s
level. If reported side effects were intolerable, the nurse
asked the pharmacy to decrease the dosage to the previous
week’s level. If side effects were minimal or tolerable, the
pharmacy was instructed to increase the dosage per the
study protocol. If the medication was benztropine mesylate,
the pharmacy made no change in dose over the trial. The
pharmacy did not inform the research nurse of the patient’s
medication or changes made. Two patients experienced
symptoms of sufficient severity to warrant both medication
discontinuation and unblinding prior to the end of the study;
patient- and research nurse-completed posttreatment
measures (described below) were not completed for these
individuals. Nine (11%) patients discontinued medication
(eight due to symptoms and one due to inability to adhere
to the study protocol) prior to the end of the 6-week trial, but
neither the research nurse nor the patients were unblinded
and both the nurse and the patients completed the posttreat-
ment measures.
All patient-rated measures were completed in telephone
interviews conducted by research assistants blind to patient
medication group assignment. Patients completed measures
prior to randomization and again at the end of the trial,
before unblinding. Each study participant was paid
US$100 for completing the study.
2.3. Measures
2.3.1. Patient-completed measures
2.3.1.1. Treatment expectations and history of amitriptyline
use. Before starting medication, all patients guessed what
their pain relief at the end of the trial would be if they
received amitriptyline and if they received placebo, on
scales from 0 ¼ 0% to 10 ¼ 100% pain relief. In addition,
patients were asked whether they had ever taken amitripty-
line (both generic and brand names were mentioned in the
question) before, and if so, the reasons for taking it and
whether they had a pain problem at the time. Patients who
said they had a pain problem at the time they were on
amitriptyline were asked to rate how helpful it was in reliev-
93
ing their pain on a scale from 0 ¼ not at all to 10 ¼
complete pain relief.
2.3.1.2. Posttreatment guess. At the end of the medication
trial, before unblinding, patients were asked to guess what
drug they were on, amitriptyline or placebo, and to rate their
certainty of this guess on a scale from 0 ¼ not at all to 10 ¼
extremely certain. They were then asked whether this guess
was based on pain relief (this could include no pain relief as
well as some degree of pain relief) and whether the guess
was based on side effects (this could include no or minimal
side effects as well as greater side effects). Patients who
indicated that they guessed based on pain relief were
asked to rate how much pain relief they received on a
scale from 0 ¼ no relief to 100 ¼ complete relief. Patients
who indicated that they made their guess based on side
effects were asked whether this was based on severity or
type of side effect, or both.
2.3.1.3. Outcome measure. Patients were telephoned by a
research assistant three times in the week prior to beginning
medication and in the last week on medication, and asked to
rate their average pain in the past 24 h on a scale from 0 ¼
no pain to 10 ¼ pain as bad as could be. The three ratings
each week were averaged to obtain single scores for
pretreatment and posttreatment average pain intensity. The
outcome measure was pretreatment to posttreatment change
in average pain intensity.
2.3.2. Investigator-completed measures
2.3.2.1. Treatment expectations. At the beginning of the
medication trial, the research nurse (or, in the case of six
subjects recruited from Good Samaritan Hospital in
Puyallup, Washington, the patient’s physician) guessed
how much pain relief the patient would obtain if he/she
received amitriptyline and if he/she received placebo, on a
scale from 0 ¼ 0% to 10 ¼ 100% pain relief. This measure
was added to the study protocol after the study began; thus,
it was available only for the last 59 (70%) study patients.
2.3.2.2. Posttreatment guess. At the end of the medication
trial, before unblinding, the research nurse completed a form
on which she indicated what drug she thought the patient
had received and her certainty about this guess (on a scale
from 0 ¼ not at all certain to 10 ¼ extremely certain). The
nurse also indicated whether the guess was based on the
amount of pain relief (this could include no pain relief as
well as pain relief), the side effects (this could include no or
minimal side effects as well as greater side effects), and/or
other reasons. If the guess was based on the amount of pain
relief, the nurse rated the amount of pain relief from 0 to
100%. If the guess was based on side effects, the nurse
indicated whether this was based on side effect severity,
type, or both.
2.4. Data analysis. The distributions of all measures were
94 J.A. Turner et al. / Pain 99 (2002) 91–99
inspected to ensure they met the assumptions of the
statistical tests performed. Patient expectations of
posttreatment pain relief with placebo were highly
skewed; therefore, log transformed scores of this rating
were used for all parametric analyses that involved this
variable and the Wilcoxon matched-pairs signed-ranks test
was used to compare patient expectations of pain relief with
amitriptyline versus placebo. Patient and research nurse
ratings of amount of patient pain relief with placebo were
also significantly skewed, and square-root transformations
of these variables were used in analyses. Regression
analyses were performed to examine whether patient
expectations, research nurse/physician expectations, and
the interaction of expectations with assigned medication
predicted posttreatment pain intensity, after adjusting for
pretreatment pain intensity and assigned medication
(forced entry). Chi-square tests were used for comparisons
of categorical variables, and t-tests were used for
comparisons involving patient and investigator ratings. To
examine whether patient and research nurse expectations
changed over the course of the study, we used t-tests to
compare the first versus the last 15 ratings made by the
research nurse, and the ratings made by those first 15
versus last 15 patients.
3. Results
Results of comparisons of the two study medications in
terms of efficacy for pain relief were reported separately
(Cardenas et al., 2002). We summarize the results briefly
here, to serve as context for the findings relevant to expecta-
tions and medication guesses. At baseline, there were no
significant differences between the active placebo and
amitriptyline groups on the measures of depressive symptom
severity and average pain intensity. The sample showed
significantly decreased average pain intensity over the 6-
week trial (pretreatment mean ðSDÞ ¼ 5:27 (1.79), posttreat-
ment mean ðSDÞ ¼ 4:25 (1.98); t ¼ 6:98, P , 0:001), with
no significant difference between the amitriptyline and active
placebo groups. Over the course of the study, one or more
side effects, or increased severity of an existing symptom,
were reported by 43 of the 44 (97.7%) patients on amitripty-
line and 36 of the 40 (90.0%) patients on the placebo, a
Table 1
Patient and research nurse/physician pretreatment expectations of pain
relief with amitriptyline and placebo
If amitriptyline If placebo
Rater Mean (SD) Median Mean (SD) Median
Patient 4.61 (2.67) a 5a 1.45 (2.42) b 0b
Nurse/physician 5.76 (1.64) c 6c 2.61 (1.67) c 2c
a Expectation of pain relief
n ¼ 75, excluding nine subjects who gave ‘don’t know’ responses.
b with amitriptyline
n ¼ 82, excluding two subjects who gave ‘don’t know’ responses.
c Drug group £ Expectation
n ¼ 59.
nonsignificant difference (x2 ¼ 2:23, P ¼ 0:14). The most
common side effects or symptoms were identical in the two
groups (from most to least common: dry mouth; drowsiness,
tiredness, or fatigue; constipation; increased spasticity; urin-
ary retention; and sweating). Among patients who remained
on medication through the end of the trial, there were no
statistically significant differences between those on amitrip-
tyline and those on placebo in frequency or severity of any
side effect except for higher severity of increased spasticity in
the amitriptyline group (t ¼ 3:33, P ¼ 0:005).
3.1. Treatment expectations
Patient and research nurse/physician expectation ratings
are shown in Table 1. Not surprisingly, both patients and
investigators had significantly (P , 0:001) higher expecta-
tions of pain relief with amitriptyline than with placebo. The
investigators had higher expectations of both amitriptyline
and placebo than did the patients, with these differences
reaching statistical significance (P , 0:05) for expectations
concerning pain relief with placebo.
3.2. Do patient pretreatment expectations predict pain
relief?
The placebo and amitriptyline groups did not differ
significantly in their pretreatment expectations of pain relief
if assigned to amitriptyline. Table 2 shows the results of the
regression analysis predicting posttreatment average pain
intensity from pretreatment average pain intensity, medica-
tion group, expectations of pain relief with amitriptyline,
and the interaction between medication group and expecta-
tions. Pretreatment average pain intensity explained a large
proportion of the variance in posttreatment average pain
intensity, and neither medication group nor expectations
of pain relief with amitriptyline made a significant addi-
tional contribution. However, there was a significant inter-
action between medication group and expectations. In the
group of patients who actually received amitriptyline, their
expectations of pain relief with amitriptyline were asso-
ciated significantly and moderately with pre- to posttreat-
ment change in pain intensity (r ¼ 0:37, P ¼ 0:02).
Expectations of greater pain relief predicted greater
improvement. In the group of patients who actually received
Table 2
Prediction of posttreatment pain intensity from pretreatment pain intensity,
drug group, expectation of pain relief with amitriptyline, and interaction of
expectation and medication group
Predictor R2 R 2 change F change P
Posttreatment pain intensity
Pretreatment pain intensity 0.55 0.55 87.55 0.000
Drug group 0.55 0.00 0.18 0.67
0.56 0.01 1.23 0.27
0.60 0.04 5.95 0.02
 J.A. Turner et al. / Pain 99 (2002) 91–99
placebo, their expectations of pain relief with amitriptyline
were not significantly associated with change in pain inten-
sity (r ¼ 20:16).
The regression analysis was repeated for patient expecta-
tions of pain relief with placebo. These expectations were
not significantly associated with posttreatment pain inten-
sity after adjusting for pretreatment pain intensity, and the
interaction between expectations and drug group was not
significant. However, it should be noted that most patients
had very low expectations of pain relief with placebo and
thus there was little variance in this measure.
3.3. Do research nurse/physician pretreatment expectations
predict pain relief?
To examine the extent to which research nurse/physician
expectations were associated with pre- to posttreatment
changes in patient pain intensity, we used a regression
model. The dependent variable was posttreatment average
pain intensity and the independent variables were pretreat-
ment average pain intensity, medication group, research
nurse/physician pretreatment expectations of pain relief,
and the interaction between medication group and expecta-
tions. Pretreatment average pain intensity made a large and
statistically significant contribution to the prediction of
posttreatment average pain. None of the other predictors
was associated with posttreatment pain.
3.4. Patient guesses regarding medication assignment
At the end of the 6-week trial, 62.5% of the 80 patients
who made guesses as to what medication they received were
correct (x2 ¼ 5:12, P ¼ 0:02). (Guesses were not made by
the two people who were unblinded before the end of the
trial, one person who could not be contacted before unblind-
ing, and one person who guessed ‘don’t know’). The accu-
racy rate was higher in the amitriptyline (70%) than in the
placebo group (55%). The certainty of guess, regardless of
whether it was correct, was moderately high on average in
Table 3
Patient and research nurse guesses of treatment assignment, certainty of guess, and reasons for guess
Actual treatment Guess n Certainty of guess
Patient guesses
Amitriptyline Amitriptyline 28
Placebo 12
Placebo Amitriptyline 18
Placebo 22
Research nurse guesses
Amitriptyline Amitriptyline 30
Placebo 11
Placebo Amitriptyline 10
Placebo 30
a
Percentage values. Patients and the research nurse were allowed to base their guesses on more than one factor.
95
both groups, and not significantly different between the two
groups (placebo mean 7.58, SD 2.52, median 8, range 0–10;
amitriptyline mean 6.43, SD 3.03, median 7.50, range 0–
10).
Patients’ guesses, guess certainty, and reasons for guesses
are summarized in Table 3. Fewer patients in the amitripty-
line (68%) than in the placebo (85%) group said their guess
was based on the amount of pain relief, and more patients in
the amitriptyline (68%) than in the placebo (53%) group
said their guess was based on side effects. However, neither
difference was statistically significant. Among the patients
who said their guess was based on pain relief, average
reported pain relief was moderate (mean 41.08, SD 35.67,
median 35, range 0–100% pain relief) in the amitriptyline
group and significantly lower (mean 22.61, SD 32.53,
median 5, range 0–100%) in the placebo group (t ¼ 2:11,
P ¼ 0:04). Among patients who reported that their guess
was based on side effects, a higher proportion of the amitrip-
tyline (60%) than the placebo (45%) group indicated that
their guess was based on side effect severity. A somewhat
higher proportion of amitriptyline (92%) than placebo
(85%) group patients indicated that they guessed based on
side effect type. Neither difference was statistically signifi-
cant.
3.5. Research nurse guesses regarding patient medication
assignment
Table 3 summarizes the research nurse’s guesses of
patient treatment assignment, guess certainty, and reasons
for the guess. There was a significant association between
the research nurse’s guess and the actual study medication
(x2 ¼ 18:80, P ¼ 0:000). She correctly guessed 73% of
medication assignments in the amitriptyline group and
75% in the placebo group. The nurse’s certainty of her
guess was somewhat higher for subjects in the placebo
than in the amitriptyline group (placebo mean 5.38, SD
2.65, median 5.50, range 0–9; amitriptyline mean 4.49,
Guess based on a (%)
Mean (SD) Pain relief Side effects
6.75 (2.73) 61 75
5.67 (3.65) 83 50
7.28 (3.01) 83 61
7.82 (2.08) 86 46
4.37 (2.41) 43 77
4.82 (1.89) 55 73
3.50 (2.42) 70 70
6.00 (2.45) 73 77
96 J.A. Turner et al. / Pain 99 (2002) 91–99
SD 2.27, median 5, range 0–9), but this difference was not
statistically significant.
The nurse indicated that her guess was based on the
amount of pain relief for a higher proportion of patients in
the placebo (73%) than in the amitriptyline (46%) group.
For guesses based on pain relief, the nurse ratings of amount
of pain relief were significantly higher in the amitriptyline
than in the placebo group (amitriptyline mean 45.88, SD
34.83, median 50, range 0–90; placebo mean 16.30, median
0, SD 24.20, range 0–80; t ¼ 3:06, P ¼ 0:004).
The nurse indicated that her guess was based on side
effects in comparable and high proportions of patients on
amitriptyline (76%) and placebo (75%). Guesses based on
side effects were said to reflect side effect severity (which
could be either low or high) in more placebo (69%) than
amitriptyline (52%) group patients and side effect type in
more amitriptyline (83%) than placebo (52%) group patients.
Patient and nurse guesses were significantly associated
with one another (x2 ¼ 9:37, P ¼ 0:002) in the whole
sample. Further analysis revealed that patient and nurse
guesses were associated significantly only for the patients
assigned to placebo (x2 ¼ 6:60, P ¼ 0:01), not for the
amitriptyline group.
3.6. Changes in expectations over the course of the study
Patient and research nurse ratings of expectations of pain
relief with amitriptyline and with placebo for the first and
last 15 patients are summarized in Table 4. Patient expecta-
tions concerning amitriptyline and research nurse expecta-
tions regarding the placebo did not change significantly over
time. However, there were significant decreases over the
course of the study in patient expectations concerning the
amount of pain relief with placebo (t ¼ 2:52, P , 0:05) and
the research nurse’s expectations concerning the efficacy of
amitriptyline (t ¼ 2:90, P , 0:01).
3.7. Association of prior amitriptyline use with patient
expectations and guesses
At baseline, 22 (26.2%) of the 84 patients said that they
had been on amitriptyline in the past, 53 (63.1%) said they
had not, and nine (10.7%) were unsure. Among the 22
patients who had taken amitriptyline in the past, three
Table 4
Changes over time in patient and research nurse expectations of pain relief with amitriptyline and placebo
Patient expectations of relief
With amitriptyline With placebo a,*
Study period Mean SD Mean
First 15 patients 3.67 2.46 2.29
Last 15 patients 4.15 3.72 0.29
a
Means are shown in table, but log transformed scores were used in analyses. *Difference between first 15 and last 15 patients statistically significant,
t ¼ 2:52, P , 0:05; **Difference between first 15 and last 15 patients statistically significant, t ¼ 2:90, P , 0:01.
(14%) said they took it for depression, 13 (59%) said they
had taken it for pain, five (23%) said they had taken it for
sleep, and three (14%) said they had taken it for miscella-
neous other reasons. These categories were not mutually
exclusive. Nineteen (86%) said they had a pain problem
while on amitriptyline. In this group, the average reported
pain relief from amitriptyline in the past was 2.61 (SD 2.95)
on the 0 (not at all) to 10 (complete relief) scale. Patients
who had taken amitriptyline in the past, as compared with
those who had not, had significantly lower pretreatment
expectations of pain relief with amitriptyline (mean ðSDÞ ¼
3:24 (2.36) versus 5.17 (2.61), t ¼ 22:90, P ¼ 0:005).
Patients who took amitriptyline previously also showed a
stronger association between pretreatment expectations of
pain relief with amitriptyline and pre- to posttreatment
change in pain intensity (r ¼ 0:28, P ¼ 0:11) than did
those who did not or were unsure whether they had taken
it previously (r ¼ 0:05, P ¼ 0:36), but neither correlation
was statistically significant. Patients who had versus had not
taken amitriptyline previously did not differ significantly in
pre- to posttreatment change in pain intensity (t ¼ 21:35,
P ¼ 0:18). Furthermore, patients who had taken amitripty-
line in the past were no more likely than those who had not
or were unsure to correctly guess their medication assign-
ment at the end of the trial (x2 ¼ 0:02, P ¼ 0:90).
4. Discussion
In this double-blind, randomized controlled trial of
amitriptyline versus an active placebo, SCI patient pretreat-
ment expectations of pain relief from amitriptyline were
significantly associated with pre- to posttreatment change
in average pain intensity only for those who actually
received amitriptyline. This association, which was moder-
ate in size, may reflect an influence of expectations on pain
experience during active treatment (i.e. an enhancement of
the pain-relieving effects of amitriptyline by positive expec-
tations), an influence of expectations on responses to the
measures of pain intensity (i.e. a bias towards reporting a
change consistent with that predicted), the ability of patients
to accurately predict their responses to amitriptyline, or
some combination of these factors.
Nurse expectations of relief
With amitriptyline** With placebo
SD Mean SD Mean SD
3.12 6.20 1.74 2.60 1.30
1.07 4.60 1.24 2.60 1.64
 J.A. Turner et al. / Pain 99 (2002) 91–99
Pretreatment expectations of the research nurse (or, in six
cases, the patient’s physician) did not predict patient
response. Accurate prediction of individual patient response
is hampered by the lack of scientific data concerning the
types of pain most responsive to amitriptyline in this popu-
lation and the fact that most patients have more than one
pain problem (e.g. spinal cord injury pain and mechanical
spine pain). Although there is evidence that amitriptyline is
efficacious for postherpetic neuralgia and diabetic neuropa-
thy pain (McQuay et al., 1996), little is known concerning
whether amitriptyline is efficacious for SCI neuropathic
pain or other SCI pain syndromes (Finnerup et al., 2001).
It is of interest that both patients and the research nurse
had higher expectations for amitriptyline’s efficacy than was
warranted by the study findings. At the beginning of the
study, the research nurse and the other study investigators
were optimistic about the efficacy of amitriptyline in reliev-
ing pain, based on findings in past studies. For example, one
meta-analysis (Onghena and Van Houdenhove, 1992)
reported an average effect size of 0.73 for amitriptyline
across placebo-controlled studies of patients with a variety
of pain syndromes. At the time of this study, many health
care providers who treated patients with chronic pain
believed amitriptyline was effective in relieving pain. We
can only speculate about patients’ expectations, but perhaps
they thought that if this was a funded study to evaluate the
efficacy of amitriptyline, then amitriptyline was quite likely
to be efficacious.
Overall, 62.5% of patients in this study (70% of those on
amitriptyline and 55% of those on placebo) correctly
guessed the medication they had received. This rate was
somewhat lower than that reported in many previous
double-blind placebo-controlled studies of different medica-
tions for different disorders (Brownell and Stunkard, 1982;
Byington et al., 1985; Rabkin et al., 1986; Margraf et al.,
1991; Bystritsky and Waikar, 1994). These previous studies
compared the active medication to an inert placebo; the use
of an active placebo in the present study may well have
reduced the accuracy of guesses, particularly those of
patients on placebo.
Because some patients in the present study had taken
amitriptyline in the past, we examined whether prior
amitriptyline use was associated with pretreatment expecta-
tions, pain improvement, and accuracy of guesses concern-
ing medication assignment. The 22 patients who said that
they had taken amitriptyline previously had significantly
lower pretreatment expectations of pain relief with amitrip-
tyline, as compared with patients who had not. However,
these two groups did not differ significantly in pain
improvement during the study. Patients who took amitripty-
line in the past also showed a stronger association between
their pretreatment expectations of pain relief with amitripty-
line and their actual change in pain intensity pre- to post-
treatment than did patients who had not taken amitriptyline
previously. This association was not statistically significant
in either group; however, the correlation in the group who
97
had taken amitriptyline previously would have been statis-
tically significant if the number of patients in the group had
been larger. Patients who had taken amitriptyline in the past
were no more likely than those who had not to correctly
guess their medication assignment at the end of the trial.
These findings point to the importance of assessing subjects’
prior experiences with medications under study in clinical
trials of drugs that subjects may have taken previously, and
of examining associations of this with subject expectations
and outcomes.
The research nurse was more accurate than were the
patients in guessing patient drug assignment. This was due
to the nurse’s better ability to correctly guess that a patient
had been on placebo. The nurse correctly guessed the medi-
cation for 73% of the amitriptyline group and 75% of the
placebo group. Previous RCTs involving different medica-
tions and patient populations have also found high overall
accuracy (69–88%) of treatment guesses made by physi-
cians and other clinical evaluators (Byington et al., 1985;
Margraf et al., 1991; White et al., 1992; Carroll et al., 1994).
That the nurse was able to guess more accurately than were
the patients is not surprising given her more extensive
knowledge about the side effects associated with amitripty-
line and, especially, the active placebo, benztropine mesy-
late. Although some patients may have been familiar with
amitriptyline’s side effects due to prior personal experience
or discussion with others who had been on amitriptyline, it
is unlikely that any study patient had experience with benz-
tropine mesylate.
That placebo group patient and research nurse guesses
were significantly associated with each other is not surpris-
ing given that they had weekly communication. The
research nurse and patients did not discuss their guesses,
but the medication assignment may have become apparent
to both in some cases due to the degree of pain relief and
side effects. After the end of the study, the nurse reported
that when patients had no or little pain relief by the end of
the drug trial (as reported in the weekly telephone calls), she
guessed that they were on placebo unless they had several
side effects or more severe side effects. In that case, she
guessed that they were on amitriptyline. Most patients in
both medication groups (but more in the placebo group)
indicated that their guess was based on the amount of pain
relief. Among those patients whose guess was based on the
amount of pain relief (but not in the whole sample), pain
relief was rated as greater in the amitriptyline than in the
placebo group. Thus, patients may have guessed that they
were on placebo due to minimal or no pain relief.
Although the medication groups did not differ signifi-
cantly in any side effect type or severity as reported to the
research nurse during the trial (except for the single finding
of greater severity of increased spasticity in the amitripty-
line group), more patients in the amitriptyline than in the
placebo group indicated that their posttreatment guess as to
medication assignment was based on side effects. Of those
on amitriptyline, 60% indicated that the guess was based on
98 J.A. Turner et al. / Pain 99 (2002) 91–99
side effect severity and 92% on the type. Of those on
placebo, 45% indicated that the guess was based on side
effect severity (i.e. mild) and 85% on the type. Previous
studies have also found that side effects play an important
role in patient, clinical investigator, and evaluator guesses
as to patient group assignment in double-blind clinical trials
(Brownell and Stunkard, 1982; White et al., 1992;
Bystritsky and Waikar, 1994).
Despite the better-than-chance accuracy of patient and
research nurse guesses as to patient medication assignment
and the positive and moderate association between patient
pretreatment expectations and pain relief in the amitripty-
line group, amitriptyline was not superior to active placebo
in relieving pain in this study. Furthermore, although the
research nurse’s expectations of patient pain relief with
amitriptyline decreased significantly over the course of the
study, patients’ expectations of amitriptyline did not. This
finding, in combination with the finding that nurse expecta-
tions did not predict patient response, suggests that research
nurse expectations did not have a strong influence on patient
outcomes in this trial. We would recommend that future
studies be designed to enable examination not only of
whether study physician or nurse (whoever has contact
with subjects) expectations change over the course of the
study, but also of whether such changes, if found, are asso-
ciated with changes in study results.
This study’s findings related to expectations and guesses
may not generalize to a study of a new treatment, which may
be associated with greater expectations and less knowledge
on the part of study clinician, investigators, and patients.
Furthermore, findings might differ in studies enrolling
only patients with more severe levels of pain intensity.
We enrolled individuals who rated their average pain inten-
sity as 3 or greater on a 0–10 scale and asked them their
expected percent pain relief. An expectation of 50% pain
relief might well have a different meaning for someone with
an average pain intensity level of 3 than it would for some-
one with an average pain intensity level of 8.
Study limitations include the lack of research nurse/
physician expectation ratings for the first 25 study patients.
In addition, because a single research nurse made 93% of
the pretreatment expectations ratings and all of the post-
treatment guesses, we do not know whether other evalua-
tors would make the same ratings and guesses.
Nonetheless, the results concerning patient and research
nurse guesses are generally consistent with those reported
in other studies of different patient populations and study
treatments. Even under double-blind conditions and with
an active placebo, patients and the research nurse were able
to guess at better-than-chance rates the assigned medica-
tion. This study provides further evidence that fully
double-blind conditions in randomized trials are difficult
to achieve, and that either the placebo group and/or the
active medication group may well become unblinded. We
agree with Moscucci and colleagues (Moscucci et al.,
1987) that all reports of blinded trials should include data
on patient and clinician guesses as to patient assigned
condition. The lack of this information in published articles
may be due to concern about the risk of invalidating results
(White et al., 1992). We strongly recommend that results
of a double-blind trial not be dismissed when complete
double-blindness has not been achieved, as this may be
the situation with many, if not most, trials.
Acknowledgements
This research was supported by grant no. 1 P01 HD/
NS33988 from the National Institutes of Health, National
Institute of Child Health and Human Development and
National Institute of Neurological Disorders and Stroke.
The research was conducted through the Clinical Research
Center at the University of Washington, supported by the
National Institutes of Health grant no. M01RR0037. The
authors gratefully acknowledge the contributions by Amy
Hoffman, Catherine McClellan, and Helen Marshall,
University of Washington Department of Rehabilitation
Medicine, in data collection and database management.
The authors would also like to express appreciation to
Marvin M. Brooke, M.D., for assistance in subject recruit-
ment.
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