The Journal of Pain, Vol 19, No 4 (April), 2018: pp 382-394

Available online at www.jpain.org and www.sciencedirect.com

Self-Guided Online Cognitive Behavioral Strategies for

Chemotherapy-Induced Peripheral Neuropathy:
A Multicenter, Pilot, Randomized, Wait-List
Controlled Trial

Robert Knoerl,* Ellen M. L. Smith,† Debra L. Barton,† David A. Williams,‡

Janean E. Holden,† John C. Krauss,§ and Beth LaVasseur¶
*Phyllis F. Cantor Center for Research in Nursing and Patient Care Services, Dana-Farber Cancer Institute, Boston,
Massachusetts.
†
School of Nursing, University of Michigan, Ann Arbor, Michigan.
‡
School of Medicine, University of Michigan, Ann Arbor, Michigan.
§
Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
¶
St. Joseph Mercy Hospital, Ann Arbor, Michigan.

Abstract: The purpose of this pilot, parallel, randomized controlled trial was to examine the effi-
cacy of a self-guided online cognitive and behaviorally-based pain management intervention (Proactive
Self-Management Program for Effects of Cancer Treatment [PROSPECT]) to reduce “worst” pain for
individuals with chronic painful chemotherapy-induced peripheral neuropathy (CIPN). Secondary out-
comes included “average” pain, nonpainful CIPN symptom severity, impression of change, and pain
interference. Sixty patients with chronic painful CIPN were recruited from 5 outpatient academic and
community cancer centers. Patients were randomized in a 1:1 ratio to receive either 8 weeks of PROS-
PECT or usual care. A 7-day electronic “worst” pain intensity diary and standardized measures of pain
interference, nonpainful CIPN symptom severity, impression of change, and “average” pain were ad-
ministered pre/post intervention. Postintervention mean scores were evaluated between groups using
analysis of covariance adjusting for baseline. Individuals who received the PROSPECT intervention
(n = 19) had significantly greater improvements in “worst pain” compared with individuals receiving
usual care (n = 19; P = .046, d = .58). There were no significant differences in mean scores between
groups for the secondary outcomes (n = 42). A larger, adequately powered study testing the PROS-
PECT intervention is needed to determine if improvements in pain may be sustained, evaluate the
effect of the intervention on the secondary outcomes, and identify mediators of pain intensity-
related improvement.
Perspective: This study explores the efficacy of an 8-week online cognitive behavioral pain man-
agement intervention for chronic painful CIPN. Intervention use resulted in greater improvements

Received August 8, 2017; Revised September 7, 2017; Accepted Novem-
ber 27, 2017.
This work was supported by the University of Michigan School of Nursing
New Investigator Award and Rackham Graduate Student Research Grant.
The funding source had no role in study design, data collection/
analysis, or manuscript preparation.
Creation of the Proactive Self-Management Program for Effects of Cancer
Treatment Web site was supported by the Damon Runyon Cancer Re-
search Foundation (CI-53-10) to Norah Lynn Henry, MD, PhD. Proactive
Self-Management Program for Effects of Cancer Treatment was adapted
from the Web site, Fibroguide.com, which was developed with support
from Grant numbers R01-AR050044 (National Institute of Arthritis and
Musculoskeletal and Skin Diseases/National Institutes of Health), and DAMD
17-00-2-0018 (Department of Defense).
Dr. Williams has served as a consultant to Community Health Focus, Inc,
served as a grant reviewer for Pfizer independent grants for Learning
and Change, and is currently the President of the American Pain Society.
The other authors have no conflicts of interest to declare.
Address reprint requests to Robert Knoerl, Phyllis F. Cantor Center for
Research in Nursing and Patient Care Services, Dana-Farber
Cancer Institute, 450 Brookline Avenue, Boston, MA 02215. E-mail:
Robert_knoerl@DFCI.Harvard.edu
1526-5900/$36.00
© 2017 by the American Pain Society
https://doi.org/10.1016/j.jpain.2017.11.009

382
Knoerl et al
in “worst” pain than usual care alone. The findings provide preliminary support for the efficacy of a
nonpharmacological intervention for chronic painful CIPN.
© 2017 by the American Pain Society
Key words: Chronic pain, chemotherapy-induced peripheral neuropathy, cognitive-behavioral therapy,
peripheral nervous system disease/chemically induced.
C
hemotherapy-induced peripheral neuropathy (CIPN)
is a common side effect of cancer treatment that
can occur in up to 68% of individuals receiving neu-
rotoxic chemotherapy (eg, platinums, bortezomib, and
taxanes).6,31,51 The symptoms of CIPN include numbness,
tingling, and pain in the hands and/or feet (symptoms
generally present in a symmetrical, stocking-glove
distribution).53 In up to 40% of patients,31,62 CIPN may
become chronically painful and persist for months to years
after the completion of chemotherapy.18,39,56 Patients with
painful CIPN often report decreases in quality of life and
physical function and may be required to stop poten-
tially life-saving neurotoxic chemotherapy regimens.42,57
Despite the known negative effects that painful CIPN
has on physical function and quality of life, there are few
effective treatments for painful CIPN. Duloxetine 60 mg/d
is currently the only medication recommended for the
treatment of painful CIPN.24,54 Because of their efficacy
in other neuropathic pain populations, antidepressants
and anticonvulsants are often used to treat painful CIPN.24
However, adherence to these types of medications is poor
because of side effects or lack of efficacy.20 Use of an ef-
fective, nonpharmacologic intervention for painful CIPN
may decrease the need for drug therapy—potentially re-
ducing the overall side effect burden for cancer survivors
and/or create a synergistic pain-reducing effect by the
use of multiple modalities. Thus, multimodal manage-
ment approaches that incorporate nonpharmacologic
approaches for painful CIPN warrant further study.
One nonpharmacologic treatment used commonly for
the treatment of chronic pain (eg, back/neck, musculo-
skeletal, and fibromyalgia) is therapist-administered
cognitive-behavioral pain management.7,40,46,61,64 This in-
tervention is designed to help patients self-manage pain
and co-occurring symptoms such as anxiety, depression,
and insomnia through cognitive and behavioral strate-
gies such as relaxation, sleep hygiene, activity pacing, and
cognitive restructuring.17,32 Cognitive-behavioral pain man-
agement may reduce pain intensity by inducing structural
changes in the prefrontal cortex (eg, increased gray matter
volume).27,50 This may provide individuals with increased
executive control function and subsequently, a greater
ability to reappraise and gain a greater sense of control
over their pain. Structural changes in the prefrontal cortex
then may lead to the release of neurotransmitters (eg,
norepinephrine and serotonin) that influence descend-
ing pain inhibition mechanisms.27,50 Barriers related to the
delivery of therapist-administered cognitive behavioral
pain management in practice include: 1) lack of access
to a reputable therapist, 2) cost associated with treat-
ment, 3) negative stigma associated with psychological
therapies, and 4) transportation to the clinic.17,34 One way
to overcome these barriers is to offer this treatment in
a self-guided online format. A self-guided cognitive-
The Journal of Pain 383
behavioral pain management intervention provides
patients with access to symptom management strate-
gies that they can practice at their own pace without the
need to travel to meet with a therapist. There is strong
evidence supporting the efficacy of self-guided cognitive-
behavioral pain management for chronic pain.9,34,38,65
However, little is known about the efficacy of self-
guided cognitive-behavioral pain management for chronic
painful CIPN.
Purpose
The purpose of this randomized, wait-list control pilot
study was to test the efficacy of a self-guided cognitive-
behavioral pain management intervention called Proactive
Self-Management Program for Effects of Cancer Treat-
ment (PROSPECT) to reduce worst pain intensity for
individuals with chronic painful CIPN compared with in-
dividuals receiving treatment as usual (ClinicalTrials.gov
Identifier: NCT02760654). Secondarily, we explored the
efficacy of the PROSPECT intervention to improve CIPN
symptom severity (eg, nonpainful numbness and tin-
gling), pain interference, average pain severity, and
patients’ perceived global impression of change. Last, we
explored participant acceptability of and satisfaction with
PROSPECT.
Methods
Design, Setting, and Sample
The study aims were examined via a parallel, 1:1 ran-
domized controlled trial design. Sixty patients were
recruited from 5 outpatient community and/or aca-
demic oncology clinics in Southeast Michigan. Patients
were eligible if they: 1) were older than 25 years of age,
2) self-reported ≥4 of 10 worst CIPN pain that persisted
3 months or longer after the cessation of neurotoxic che-
motherapy, 3) had at least National Cancer Institute
Common Terminology Criteria for Adverse Events grade
1 sensory CIPN,44 4) had a stable analgesic medication
regimen (≤10% change in dosage in the 2 weeks before
study enrollment), and 5) were able to access/use a com-
puter. Participants were excluded if they had: 1) a
prognosis of <3 months, 2) peripheral neuropathy from
other causes, 3) planned to receive neurotoxic chemo-
therapy while enrolled in the study, or 4) participated in
cognitive-behavioral pain management in the past. This
study was approved by the institutional review board as-
sociated with each study site and written informed
consent was obtained from all enrolled participants.
Treatment Groups
Participants were randomly assigned following simple
randomization procedures to either 8 weeks of PROS-
384 The Journal of Pain
PECT or treatment as usual (control) in a 1:1 ratio using
a computer-generated random numbers table. Random-
ization was stratified according to recruitment site to
balance out center effects. The principal investigator gen-
erated the random allocation sequence, enrolled the
patients, and assigned participants to a study group. The
computer-generated random numbers table was stored
on a spreadsheet. The principal investigator did not view
the spreadsheet until informed consent was obtained and
all baseline assessments were completed by the partici-
pant. After informed consent and completion of all
baseline assessments, participants were informed of their
study group assignment. After the administration of the
baseline assessments by the principal investigator, trained
study staff administered all data collection procedures
at the subsequent time points. Health care providers were
not informed of their patients’ study group assignment.
PROSPECT
The password-protected PROSPECT Web site con-
tained cognitive-behavioral pain management strategies
and information designed to help individuals manage pain
and co-occurring symptoms after cancer treatment (eg,
anxiety, depression, sleep, fatigue, and impaired
cognition).16,43,58,60 Content (10 modules; Table 1) is pre-
sented using written as well as video formats and patients
can download worksheets further describing the strat-
egies. At baseline, participants were trained on how to
navigate the PROSPECT Web site and were encouraged
to complete the “Steps for Me” link, which recom-
mends modules on the basis of the patient’s responses
to questions about symptom severity and symptom man-
agement practices. Participants were instructed to use the
modules as much as they desired and did not receive any
additional encouragement from the study staff after ob-
taining access to the PROSPECT Web site.
Wait-List Control
Participants in both groups continued to receive their
usual care from their primary provider (eg, routine on-
Self-Guided Cognitive Behavioral Strategies for Neuropathy
cology follow-up appointments and subspecialty
appointments). Participants randomized to the control
group received access to the PROSPECT Web site after
the completion of all required surveys.
Measures
An 11-point numeric rating scale (NRS) of pain inten-
sity was used to measure worst and average CIPN pain
severity (0, no pain; 10 pain as bad as you can imagine).8,12
The 11-point worst CIPN pain NRS was administered within
a 7-day pain diary pre/post intervention, whereas the
average CIPN pain NRS was administered via a single item
asking about average CIPN pain severity over the past 7
days (worst pain was assessed in similar fashion at week
4). Participants were coached to only report pain result-
ing from CIPN (eg, painful numbness, tingling, burning
in hands/feet), not pain from other sites or causes. The
11-point NRS is recommended by the Initiative on
Methods, Measurement, and Pain Assessment in Clini-
cal Trials (IMMPACT)12 and several trials have supported
its reliability and validity.26,28,36 On the basis of evidence
suggesting that worst pain intensity is more highly cor-
related with average functional interference (r = .65) than
average (r = .60) or current (r = .53) pain intensity,21,52 worst
pain intensity was selected as the primary outcome.
Several other comorbid symptoms were assessed as rec-
ommended by IMMPACT to increase our ability to
compare the results of this study with other trials testing
interventions for chronic pain. The Patient-Reported Out-
comes Measurement Information System (PROMIS) Pain
Interference 4a (4 items; 1, not at all; 5 very much; trans-
formed total score 41.6–75.6) subscale measures the effect
of pain on the social, cognitive, and physical aspects of
one’s life over the past week.1 There is strong evidence
supporting the reliability and validity of the PROMIS pain
interference item bank.1 In addition, to measure impres-
sion of change after completion of the trial, we used the
Patient Global Impression of Change (PGIC). The PGIC is
a self-report item designed to assess patients’ overall im-
pression of improvement over the course of a clinical

Table 1. Summary of PROSPECT Modules

MODULE CONTENT
About Late Effects Education about common cancer treatment-related side effects (ie, pain, fatigue, problems with memory,
emotional distress, sleep problems)
Talk to Your Team Strategies to promote communication between the patient and their provider regarding cancer
treatment-related symptoms
Get Your Body Moving Benefits of physical activity during cancer treatment and provides strategies to start and maintain regular
physical activity
Get a Better Night’s Sleep Sleep hygiene strategies to help individuals fall and stay asleep at night
Slow Your Body Down Step-by-step instructions for various relaxation techniques (ie, deep breathing, guided imagery,
progressive muscle relaxation)
Improve Your Thinking Strategies to combat memory and thinking problems
Set Some Goals Strategies to set realistic goals and carry out planned goals
Don’t Over Do It Activity pacing strategies
Time for You Strategies to overcome barriers and challenges related to taking time out of the day to participate in
enjoyable activities to renew the mind and body
About Peripheral Neuropathy Information about the symptoms of peripheral neuropathy, strategies to treat the symptoms of
neuropathy, and safety precautions to take because of the symptoms of neuropathy

This table describes the content of the 10 modules embedded within the PROSPECT Web site.
Knoerl et al
63
trial. The 7-point scale ranges from “very much worse”
to “very much improved.”63
The European Organization of Research and Treat-
ment of Cancer Quality of Life Questionnaire-
Chemotherapy-Induced Peripheral Neuropathy Scale (QLQ-
CIPN20) measures patient’s symptoms and functional
limitations related to CIPN in sensory, motor, and auto-
nomic function domains (20 items; 1, not at all; 4, very
much).48 The responses from each respective scale are then
transformed and scored from 0 to 100, with higher scores
representing worsening symptoms.48 The internal con-
sistency reliability α coefficient has been reported as .88,
.88, and .78 for the sensory, motor, and autonomic
subscales, respectively.35 Further evidence shows that the
sensory and motor subscales are moderately-highly re-
sponsive to change (Cohen d = .82 and .48, respectively).35
Last, recent evidence supports the electronic adminis-
tration of the QLQ-CIPN20 on the basis of high intraclass
correlations (>.70) with paper/pencil administration.33
Last, we adapted questions from the Acceptability
E-Scale to assess participant acceptability of and satis-
faction with the PROSPECT Web site.3,59 The questionnaire
contains 7 items that are scored on a 1 to 5 scale, with
higher scores representing greater acceptability and sat-
isfaction. Survey questions ask participants how much they
enjoyed using PROSPECT and how helpful the modules
were in improving their symptoms.
Participants completed a demographic survey (ie, sex,
age, race, ethnicity, employment status, marital status,
education, and previous computer use) before the comple-
tion of the baseline assessments. Study staff abstracted
participant cancer diagnosis (ie, disease and stage) and
treatment (eg, chemotherapy type), medication dosage,
and comorbid condition-related information from the pa-
tients’ electronic medical records.
Study Procedures
Baseline
After informed consent (eg, participants were in-
formed of the nature of the PROSPECT and control
groups), participants completed the baseline assess-
ments (11-point worst and average CIPN pain NRS, PROMIS
Pain Interference 4a, QLQ-CIPN20, demographic charac-
teristics) via computer tablet. Participants were then
notified of their study group assignment and e-mailed
the 7-day worst pain diary. After completing the pain
diary, the participants were e-mailed the PROSPECT Web
site link and password, or instructions about the control
group. Also at baseline, study staff abstracted cancer
diagnosis/treatment and medication dosage-related in-
formation from the patients’ electronic medical records.
Week 4 and 8 Time Points
Survey links to the same battery of assessments ad-
ministered at baseline were e-mailed to participants 4 and
8 weeks after randomization. At these same time points,
participants were contacted by telephone as a reminder
to complete the electronic surveys and to answer struc-
The Journal of Pain 385
tured interview questions about changes in medication
dosage/frequency. Unique to the week 8 time point, par-
ticipants in both groups completed the PGIC and
individuals in the intervention group completed the
Adapted Acceptability E-Scale and were contacted via tele-
phone to discuss the most positive and negative aspects
of PROSPECT. Participants were also e-mailed a survey each
week inquiring about the number of minutes spent using
PROSPECT or other symptom management resources. At
the end of the study, control group participants were
e-mailed the link to the PROSPECT Web site.
Statistical Analyses
All data were analyzed using R version 3.4.0.49 Descrip-
tive statistics of the centrality and dispersion of all survey
data and demographic data were calculated. All analy-
ses were calculated on the basis of the total number of
individuals who completed the baseline and week 8
outcome measures. A power analysis was not con-
ducted because of the pilot nature of this work (eg,
determine an effect size to conduct larger studies testing
this intervention) and because there were no previous
studies testing the PROSPECT intervention in individu-
als with painful CIPN on which to base an effect size
estimate.
Primary Outcome
We averaged patient’s responses from the 7-day worst
CIPN pain diary for the baseline and week 8 time points.
Participants must have completed 5 of the 7 daily worst
pain ratings at the baseline and week 8 time points to
be included in the analysis.22 Week 8 mean scores in worst
CIPN pain intensity (0–10 NRS diary) were compared
between groups using analysis of covariance adjusting
for baseline scores. The robustness of our findings was
examined via a post hoc intent-to-treat analysis. Mul-
tiple imputation (50 imputations; 50 iterations) (MICE R
Package)4 was used to handle missing data. The same re-
gression analysis was then repeated using the pooled data
from the multiply imputed data sets.
Secondary Outcomes
Week 8 mean scores in CIPN symptom severity (QLQ-
CIPN20 sensory and motor subscales), average pain
(average CIPN pain NRS), and pain interference (PROMIS
Pain Interference 4a) were compared between groups
using analysis of covariance adjusting for baseline. Fisher
exact test was used to analyze proportional differences
between those who experienced “improvement” (PGIC
score ≥5) and “no improvement” (PGIC score ≤4) in the
2 study arms.
Acceptability and Satisfaction
Descriptive statistics for the items of the Adapted Ac-
ceptability E-Scale were calculated. We also summarized
responses from the semistructured telephone inter-
views to determine the most positive and negative aspects
of PROSPECT and the biggest barriers to accessing and
using the PROSPECT strategies.
386 The Journal of Pain
Results
Patients
Participant recruitment occurred from May 1, 2016 to
October 4, 2016. A review of the study sites’ electronic
medical records revealed 393 potentially eligible partici-
pants (Fig 1). After telephone screening procedures, 311
patients were deemed ineligible on the basis of inclusion/
exclusion criteria. Of these 311 excluded participants, 18
experienced CIPN-related numbness, tingling, and pain,
but rated their worst pain severity as <4 of 10. Also, 22
participants were eligible, but either declined to partici-
pate or were not available to meet in person to provide
informed consent. Sixty participants were randomized to
the PROSPECT intervention (n = 30) or wait-list control
(n = 30) groups. Patient follow-up occurred from May 23,
2016 to December 19, 2016. After randomization, 13 par-
ticipants terminated the study early because of personal
reasons (eg, lack of time) or were lost to follow-up. Par-
ticipants who terminated the study early did not complete
any outcome measurements beyond the baseline time
point. The attrition rate for the study was 22%. Overall,
23 and 24 participants were eligible for analysis in the
PROSPECT and control arms, respectively. There were no
Figure 1. Consolidated Standards of Reporting Trials flow diagram. This shows the flow of participants through the duration of
the study.
Self-Guided Cognitive Behavioral Strategies for Neuropathy
adverse events due to study participation reported by
participants.
Patient characteristics are described in Table 2. Indi-
viduals in the PROSPECT group had higher levels of fatigue
and sleep-related impairment compared with individu-
als in the control group; otherwise, there were no
differences. When comparing protocol completers versus
noncompleters, noncompleters had a greater percent-
age of individuals with stage IV cancer (46%) than
completers (19%), but baseline pain and co-occurring
symptom severity did not differ.
Primary Outcome
Individuals with chronic painful CIPN who received the
8-week PROSPECT intervention had a mean change score
of −.94 (SD = 1.36, range = −3.29 to 1.29, 95% confi-
dence interval [CI] = −1.6 to −.28), whereas individuals in
the wait-list control group had a mean change score of
0 in worst pain intensity (SD = 1.31, range = −3.43 to 2.86,
95% CI = −.63 to .63; Table 3). The difference in worst CIPN
pain intensity improvements between groups was sig-
nificant (B = −.91, P = .046, 95% CI = −1.79 to −.02, d = .58,
n = 38). Three participants receiving PROSPECT and 1
Knoerl et al The Journal of Pain 387

Demographic, Cancer Treatment, and

Table 2. participant receiving treatment as usual experienced a
Medication Use Characteristics of the clinically significant (>30%) reduction in worst CIPN pain
Recruited Sample intensity immediately post-treatment (n = 38; Fig 2).19
Results of the post hoc intent-to-treat analysis (n = 60)
PROSPECT CONTROL
CHARACTERISTIC (N = 30)* (N = 30)* indicated that the difference in worst pain intensity im-
Sex provement between groups was not statistically significant
Female 23 (76.7) 22 (73.3) (B = −.64; P = .09; 95% CI = −1.38 to .10; d = .42).
Male 7 (23.3) 8 (26.7)
Mean age (SD) 58.93 (9.33) 63.37 (8.36)
Race
African American 2 (6.7) 1 (3.3)
White 27 (90) 28 (93.3)
Secondary Outcomes
Unknown 1 (3.3) 1 (3.3) There were no significant differences in mean change
Ethnicity
Hispanic 0 1 (3.3) scores for average pain (P = .18, d = .42), pain interfer-
Non-Hispanic
Unknown
25 (83.3)
5 (16.7)
22 (73.4)
7 (23.3)
ence (P = .98, d = .01), or nonpainful CIPN sensory (P = .41,
Education (n = 59) d = .23) or motor symptoms (P = .95, d = .02; n = 42;
High school or less 4 (13.3) 6 (20.7)
Some college 13 (43.3) 12 (41.4)
Table 3). Trends in average pain and pain interference
College graduate 8 (26.7) 6 (20.7) across time indicated that PROSPECT provided no clear
Postgraduate degree 5 (16.7) 5 (17.2)
Employment status
benefit over usual care. However, trends in nonpainful
Employed 13 (43.3) 7 (23.3) CIPN symptoms suggested that individuals receiving PROS-
Out of work 3 (10) 2 (6.7)
Homemaker 0 1 (3.3) PECT were experiencing considerable improvements as
Retired 9 (30) 17 (56.7) the study progressed. There was also a greater number
Unable to work 5 (16.7) 3 (10)
Marital status of individuals in the PROSPECT group reporting im-
Single 2 (6.7) 2 (6.7) proved impression of change after the completion of the
Married 18 (60) 24 (80)
Separated 1 (3.3) 1 (3.3) trial, but the difference between groups was not sig-
Divorced 7 (23.3) 2 (6.7) nificant (P = .21, d = .48, n = 41; Table 3).
Widowed 2 (6.7) 1 (3.3)
Amount of computer use
Once a month 1 (3.3) 6 (20)
Approximately once a week 1 (3.3) 1 (3.3)
More than once a week 28 (93.3) 23 (76.7) Acceptability and Satisfaction
Cancer stage Overall, acceptability and satisfaction with the study
Early I/II 13 (43.3) 9 (30)
III 10 (33.3) 11 (36.7) and PROSPECT Web site was moderate to high, with mean
Metastatic 6 (20) 9 (30)
Unknown 1 (3.3) 1 (3.3)
Adapted Acceptability E-Scale item scores ranging from
Cancer Type 3.26 to 4.58 of 5 (n = 19; Table 4). Participants reported
Breast 13 (43.3) 10 (33.3)
Gastrointestinal 13 (43.3) 13 (43.3)
that ease of use, the ability to print off work sheets on
Genitourinary 0 1 (3.3) the basis of the strategies they learned, and having access
Lung 1 (3.3) 3 (10)
Multiple 1 (3.3) 2 (6.7)
to many relevant pain symptom management strategies
Lymphoma 2 (6.7) 1 (3.3) were all positive aspects of the PROSPECT intervention.
Chemotherapy Type
Platinums 13 (43.3) 13 (43.3) Conversely, participants thought that there was not enough
Taxanes 12 (41.4) 8 (26.7) information and/or strategies to help manage the symp-
Bortezomib 1 (3.3) 0
Vinca alkaloids 1 (3.3) 2 (6.7) toms of nonpainful neuropathy (eg, numbness and
Multiple 3 (10) 7 (23.3) tingling). Participants also cited lack of time and diffi-
Pain-related symptoms (mean, SD)
Anxiety 54.79 (9.42) 51.58 (7.83) culty changing symptom management practices as barriers
Depression 52.92 (7.98) 49.51 (7.17) to implementing the strategies they learned. Last, par-
Fatigue 59.18 (8.26) 52.73 (8.25)
Sleep-related impairment 58.65 (6.67) 55.07 (6.09) ticipants thought that PROSPECT would have been more
Comorbid conditions
None 12 (40) 7 (23.3)
beneficial if it contained additional cognitive strategies
Chronic lung disease 1 (3.3) 1 (3.3) related to pain management (ie, cognitive restructur-
Coronary artery disease 0 2 (6.7)
Diabetes 0 3 (10)
ing), features to interact with medical professionals to
Gastrointestinal disease 0 2 (6.7) review strategies and symptoms, or was provided in the
Chronic kidney injury 1 (3.3) 0
Obesity 1 (3.3) 2 (6.7)
beginning stages of cancer treatment as they were be-
Hypertension 12 (40) 14 (46.7) ginning to experience painful CIPN symptoms.
Anxiety 3 (10) 4 (13.3)
Depression 5 (16.7) 4 (13.3)
Other 11 (36.7) 15 (50)
Baseline medications
Neuropathic pain medications† 9 (30) 6 (20)
PROSPECT Usage
Other analgesics‡ 6 (20) 8 (26.7) In terms of intervention use, the mean number of
Neuropathic pain medications as well as other analgesics 9 (30) 8 (26.7)
Antianxiety 8 (26.7) 8 (26.7) minutes individuals in the intervention group spent using
Sleep medications 3 (10) 2 (6.7) PROSPECT and other symptom management resources (eg,
Antidepressants§ 4 (13.3) 5 (16.7)
Fatigue medications 0 0 physical therapy, meditation, pool therapy, massage) was
highest at the beginning of the study and declined as
This table describes the demographic characteristics of the recruited sample at baseline. the study progressed. The average amount of time par-
*Data are n (%) unless otherwise specified.
†On the basis of the clinical practice guideline for painful CIPN treatment recommendations,23 ticipants in the control group spent using symptom
neuropathic pain medications included: duloxetine, gabapentin, pregabalin, and
antidepressants. management strategies (eg, ice therapy, massage, stretch-
‡Other analgesics included: oxycodone, morphine, ibuprofen, and acetaminophen. ing, yoga, distraction, exercise) varied across the 8-week
§Three participants (2 in control, 1 in PROSPECT) were receiving nortriptyline, a medication
that has shown efficacy to treat pain in other neuropathic pain patient populations. study period (Table 5). In terms of medication changes,
388 The Journal of Pain Self-Guided Cognitive Behavioral Strategies for Neuropathy

Table 3. Mean Scores for Primary and Secondary Outcomes

INTERVENTION, CONTROL,
OUTCOMES* MEAN (SD) MEAN (SD) CONTRAST BETWEEN GROUPS†
Worst pain (n = 38)
Baseline 5.04 (1.24) 4.78 (1.78) B = −.91, P = .046, 95% CI = −1.79 to .02, d = .58
Week 4 (n = 39) 5.42 (2.32) 5.60 (2.5)
Week 8 4.10 (1.81) 4.78 (1.93)
Average pain (n = 42)
Baseline 4.37 (1.89) 3.91 (2.52) B = −.83, P = .18, 95% CI = −2.05 to .40, d = .42
Week 4 (n = 39) 4.37 (2.11) 5.25 (2.36)
Week 8 4.58 (1.87) 5.35 (1.99)
Pain interference (n = 42)
Baseline 57.81 (8.16) 57.33 (7.07) B = .05, P = .98, 95% CI = −4.36 to 4.46, d = .01
Week 4 (n = 39) 57.47 (8.49) 55.54 (5.90)
Week 8 56.72 (7.96) 56.43 (7.74)
CIPN sensory (n = 42)
Baseline 49.34 (16.68) 45.99 (20.1) B = −3.61, P = .41, 95% CI = −12.43 to 5.21, d = .23
Week 4 (n = 39) 44.80 (23.10) 41.67 (18.70)
Week 8 40.41 (18.66) 41.95 (17.37)
CIPN motor (n = 42)
Baseline 34.21 (17.04) 25.83 (18.41) B = −.23, P = .95, 95% CI = −8.27 to 7.80, d = .02
Week 4 (n = 39) 30.23 (23.59) 23.24 (13.57)
Week 8 26.91 (17.71) 22.75 (13.3)
Impression of change (n = 41)
8 Weeks (improved) 9/19 (47.3%) 6/22 (27.3%) OR = 2.35, P = .21, 95% CI = .55 to 10.84, d = .48
8 Weeks (no change or worse) 10/19 (52.7%) 16/22 (72.7%)

This table describes changes in primary and secondary outcome improvement over time between treatment groups.
*Week 4 data are documented to provide information related to time to response.
†Difference in week 8 mean scores adjusted for baseline scores. Impression of change scores were only compared at the week 8 time point.

there were more individuals in the PROSPECT group that
increased neuropathic pain medication frequency/dose
and pain medication frequency/dose not indicated as a
first-line treatment for painful CIPN and/or neuropathic
pain (“other analgesics”),11,24 but otherwise, there were
no considerable differences in the number of partici-
pants changing medication frequency/dose between
groups (Fig 3). To further explore how changes in pain
medication frequency/dose may have affected worst CIPN
pain intensity improvement in individuals receiving PROS-
PECT (within primary aim protocol completers; n = 38),
we compared week 8 worst pain intensity mean scores
(adjusting for baseline) between groups in 2 ways: 1) re-
moving individuals in the PROSPECT arm who increased
their use of first-line neuropathic pain medications, and
2) removing individuals in the PROSPECT arm who

Figure 2. Percent decrease in worst pain intensity because of use of PROSPECT or treatment as usual (n = 38). This figure shows
the percentage of participants reporting various reductions in worst pain intensity after completion of the study.
Knoerl et al The Journal of Pain 389

Table 4. Adapted Acceptability E-Scale Scores (n = 19)

ACCEPTABILITY AND SATISFACTION; ADAPTED ACCEPTABILITY E-SCALE MEAN SD RANGE
1. How easy was it to access the Web site on your computer? 4.58 .84 2 to 5
2. How understandable was the content presented within the Web site? 4.58 .69 3 to 5
3. How much did you enjoy using the Web site? 3.26 1.05 1 to 5
4. How helpful was it to read and participate in the Web site activities to help manage your symptoms 3.36 .96 1 to 5
related to CIPN (pain, physical functioning, anxiety, sleep disturbance, etc)?
5. Was the amount of time it took to complete the activities presented within the Web site acceptable? 4 1.11 1 to 5
6. Was the amount of time it took to complete the study questionnaires at the baseline, 4-week, and 4.42 1.02 1 to 5
8-week time points acceptable?
7. Overall, how would you rate your satisfaction with the Web site? 3.95 .71 3 to 5

This table describes the descriptive statistics (mean, SD, range) of the Adapted Acceptability E-Scale Items at Week 8.

Table 5. PROSPECT or Other Symptom Management Resource Use According to Week

SYMPTOM MANAGEMENT USE SYMPTOM MANAGEMENT USE
WEEK PROSPECT USE* (INTERVENTION)*,† (CONTROL)*,†
1 25.4 (0–90) (n = 14) 67.3 (0–390) (n = 15) 15.1 (0–120) (n = 10)
2 12.1 (0–60) (n = 12) 63.8 (0–300) (n = 12) 2.5 (0–15) (n = 6)
3 10 (0–20) (n = 6) 60 (0–210) (n = 6) 25 (0–160) (n = 8)
4 17.1 (0–60) (n = 14) 19.2 (0–140) (n = 12) 27.9 (0–360) (n = 19)
5 5.5 (0–30) (n = 10) 23 (0–180) (n = 10) 9.2 (0–60) (n = 10)
6 16.4 (0–72) (n = 13) 49 (0–420) (n = 13) 2.7 (0–25) (n = 15)
7 7.5 (0–35) (n = 13) 26.7 (0–120) (n = 13) 8.1 (0–45) (n = 12)
8 8.6 (0–30) (n = 18) 6.7 (0–60) (n = 17) 32.1 (0–495) (n = 21)

This table describes the mean number of minutes individuals in the intervention or control arm spent using PROSPECT and/or other symptom management re-
sources over time.
*Mean number of minutes (range).
†Symptom management use in the PROSPECT group refers to pain management strategies (eg, physical therapy, meditation, pool therapy, massage) used by par-
ticipants in addition to the strategies embedded within the PROSPECT Web site, whereas symptom management use in the control group refers to strategies used
by participants to manage pain during the study (eg, ice therapy, massage, stretching, yoga, distraction, exercise). Type of symptom management strategies used
by participants in each treatment group varied according to individual.

Figure 3. PROSPECT versus control medication changes during study (n = 45). This figure shows the number of instances that in-
dividuals (protocol completers) increased and/or decreased pain, anxiety, or sleep medication dosages. On the basis of the clinical
practice guideline for CIPN treatment recommendations,23 neuropathic pain medications included: duloxetine, gabapentin, pregabalin,
and antidepressants. Other analgesics included: oxycodone, morphine, ibuprofen, and acetaminophen.
390 The Journal of Pain
increased their use of “other analgesics.” Results from
these analyses indicated that the effect of PROSPECT on
worst pain intensity was still statistically significant when
removing individuals from the PROSPECT arm who in-
creased their use of neuropathic pain medications
(B = −1.07, 95% CI = −1.97 to −.15, P = .02; n = 36) and
when removing individuals from the PROSPECT group
who increased their use of “other analgesics” (B = −1.10,
95% CI = −2.10 to −.10, P = .03; n = 33).
Discussion
This 8-week, randomized controlled pilot trial showed
that a self-guided online cognitive behavioral pain man-
agement program—PROSPECT—significantly improved
worst pain intensity in individuals with chronic painful
CIPN. Further, there were no significant differences in
mean change scores between groups for the secondary
outcomes of pain interference, nonpainful CIPN symp-
toms, average pain, or global impression of change.
Individuals with chronic painful CIPN interacting with
the 8-week PROSPECT intervention reported a mean de-
crease in worst pain intensity of .94. The mean decrease
in pain intensity found in this study is comparable with
the effect of duloxetine, the only pharmacological agent
currently recommended for the treatment of chronic
painful CIPN.24 The authors of a randomized, crossover,
placebo-controlled study reported that use of duloxetine
60 mg/d resulted in a mean decrease of 1.06 in average
pain intensity in individuals with chronic painful CIPN
(P = .003, d = .513).54 On the contrary, PROSPECT had no
effect on the secondary outcome of average pain inten-
sity. The comparison between average pain mean change
scores between studies is challenging because the authors
of the duloxetine trial assessed average pain over the past
24 hours, not 7 days.52,54 Nevertheless, the reported effect
sizes and mean decreases for the 2 studies’ primary out-
comes were similar for PROSPECT and duloxetine.
Although our findings supported the efficacy of PROS-
PECT in improving worst CIPN pain intensity compared
with individuals receiving treatment as usual, results from
post hoc sensitivity analyses suggest that these findings
should be interpreted with caution. Few participants ex-
perienced a clinically significant reduction in worst CIPN
pain intensity after PROSPECT usage. Clinically signifi-
cant improvements in pain intensity represent a 30%
reduction in pain.19 The overall worst CIPN pain inten-
sity mean change score for individuals receiving PROSPECT
was −.94 and only 3 individuals reported a clinically sig-
nificant reduction in pain. Further, results from a post hoc
intent-to-treat analysis with the full sample (N = 60) re-
vealed that the effect of PROSPECT on worst pain intensity
was not statistically significant (P = .09). Finally, because
of the dearth of high-quality trials testing interven-
tions for the treatment of painful CIPN, it is possible that
changes in neuropathic pain medications and “other an-
algesics” may produce an analgesic effect in individuals
with chronic painful CIPN. 23 Thus, changes in the
frequency/dosage of neuropathic pain medications or
“other analgesics” may partially explain the efficacy of
PROSPECT on worst pain intensity. However, the results
Self-Guided Cognitive Behavioral Strategies for Neuropathy
from sensitivity analyses revealed that the effect of PROS-
PECT on worst CIPN pain intensity remained statistically
significant after removing individuals in the PROSPECT
arm who increased their use of neuropathic pain medi-
cations and “other analgesics,” respectively.
There have been no published studies reporting the
effects of cognitive-behavioral pain management for
nonpainful CIPN symptoms. Although nonpainful CIPN
symptoms such as numbness and tingling are a result of
peripheral nervous system damage (eg, dorsal root ganglia
of primary sensory neurons),5,47 nonpainful CIPN symp-
toms are still associated with changes in the central
nervous system. For example, the authors of a recent study
showed that increased CIPN symptoms 1 month after neu-
rotoxic chemotherapy are associated with changes in
perfusion in brain areas associated with nociceptive pro-
cessing (eg, anterior cingulate cortex and frontal gyrus).45
Thus, interventions that target centrally-mediated mecha-
nisms such as cognitive behavioral pain management, may
also be efficacious for the treatment of nonpainful CIPN
symptoms.27,50 The results of this current study support
this conclusion because individuals receiving PROSPECT
had greater improvements in nonpainful CIPN symp-
toms over the 8-week trial period than individuals
receiving usual care, but, the difference was not signifi-
cant. Further research is needed to determine if
interventions targeting centrally-mediated mechanisms
(eg, cognitive-behavioral pain management) can also in-
fluence nonpainful CIPN symptoms.
There were also no significant differences in pain in-
terference between groups. Although physical function
and 7-day recall of worst pain intensity are moderately-
strongly correlated (r = .65),52 self-guided cognitive-
behavioral pain management interventions are most
effective when targeting a specific primary outcome.34
Therefore, perhaps if the PROSPECT intervention was tai-
lored to include more physical activity training and
educational resources, it would have had a greater effect
on pain interference.
On the basis of trends in PROSPECT usage and worst
pain intensity improvement, the results suggest that par-
ticipants interacted with the Web site frequently at first
to learn and practice the strategies, but then could in-
corporate the strategies into their day-to-day activities
to improve pain intensity independent of logging in to
PROSPECT. However, little is known about the optimal
dose of PROSPECT because we did not actively monitor
patient’s usage (eg, electronic tracking or use of strate-
gies in day-to-day activities) and the response rate to the
self-report measures was low. Significant predictors of self-
management intervention usage include health care
professional guidance/support, ample amount of time to
use the intervention, and high satisfaction with inter-
vention content.2 PROSPECT usage may be bolstered in
future studies if: 1) participants have an opportunity to
interact with a health care professional (eg, weekly video
or telephone call with nurses)25,29 to discuss pain-related
symptoms and strategy use, 2) participants have more time
to interact with the strategies of PROSPECT (eg, longer
duration, scheduled time to interact with modules), and
3) additional interactive features within PROSPECT are
Knoerl et al
designed (eg, achievement badges, message boards/
support groups, visually appealing).2,37 Improving self-
guided cognitive-behavioral pain management
intervention usage in future research is critical to estab-
lish an optimal dose that can be prescribed in the clinical
setting and to compare results across trials.
One common limitation of recent placebo-controlled
randomized controlled trials testing interventions for in-
dividuals with chronic pain is high placebo response.13-15,30
Although this study did not contain a placebo control,
psychoeducational interventions are prone to nonspe-
cific effects (eg, study staff-participant interaction,
participant motivation for participation, lack of blind-
ing, credibility of treatment) that may have accounted
for the efficacy of the intervention.10 We attempted to
improve the assay sensitivity of the trial, or the ability
to distinguish an effective treatment from an ineffec-
tive treatment14 by implementing strategies such as: 1)
baseline participant worst CIPN pain intensity of 4 of 10
or greater, participant pain duration of at least 3 months
since completion of chemotherapy, 3) flexible interven-
tion dosing, 4) standardized data collection procedures
for both groups, and 5) <3 treatment arms.14,15 The ef-
ficacy of these strategies in improving the assay sensitivity
of this trial may be evidenced by the lack of control group
improvement in worst pain intensity from the baseline
to week 8 time point. However, an alternate explana-
tion for this finding is that control group participants were
not blinded to the intervention they were receiving (eg,
were informed that the alternative group received PROS-
PECT) and thus, knew they were not receiving the
intervention (nonspecific effect). Additional strategies we
could have implemented to minimize or control for non-
specific effects include using a structurally equivalent
control group and administering manipulation checks to
determine if participants were using the treatment as
intended.10 Nevertheless, future studies should con-
tinue to implement strategies to improve assay sensitivity
to facilitate the identification of effective treatments for
individuals with chronic pain.
There are several limitations to this study. First, the
dropout rate was approximately 22%. This dropout rate
is consistent with other self-guided cognitive behav-
ioral pain management intervention studies38 and the
demographic characteristics of the completers and
noncompleters were similar between groups. However,
because of the high number of individuals with stage IV
cancers dropping out of the study, further research is
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