Self-Guided Online Cognitive Behavioral Strategies for Chemotherapy-Induced Peripheral Neuropathy: A Multicenter, Pilot, Randomized, Wait-List ...
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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- Dr. Williams has served as a consultant to Community Health Focus, Inc,
ber 27, 2017. served as a grant reviewer for Pfizer independent grants for Learning
This work was supported by the University of Michigan School of Nursing and Change, and is currently the President of the American Pain Society.
New Investigator Award and Rackham Graduate Student Research Grant. The other authors have no conflicts of interest to declare.
The funding source had no role in study design, data collection/ Address reprint requests to Robert Knoerl, Phyllis F. Cantor Center for
analysis, or manuscript preparation. Research in Nursing and Patient Care Services, Dana-Farber
Creation of the Proactive Self-Management Program for Effects of Cancer Cancer Institute, 450 Brookline Avenue, Boston, MA 02215. E-mail:
Treatment Web site was supported by the Damon Runyon Cancer Re- Robert_knoerl@DFCI.Harvard.edu
search Foundation (CI-53-10) to Norah Lynn Henry, MD, PhD. Proactive 1526-5900/$36.00
Self-Management Program for Effects of Cancer Treatment was adapted © 2017 by the American Pain Society
from the Web site, Fibroguide.com, which was developed with support https://doi.org/10.1016/j.jpain.2017.11.009
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).
382Knoerl et al The Journal of Pain 383
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) behavioral pain management intervention provides
is a common side effect of cancer treatment that patients with access to symptom management strate-
can occur in up to 68% of individuals receiving neu- gies that they can practice at their own pace without the
rotoxic chemotherapy (eg, platinums, bortezomib, and need to travel to meet with a therapist. There is strong
taxanes).6,31,51 The symptoms of CIPN include numbness, evidence supporting the efficacy of self-guided cognitive-
tingling, and pain in the hands and/or feet (symptoms behavioral pain management for chronic pain.9,34,38,65
generally present in a symmetrical, stocking-glove However, little is known about the efficacy of self-
distribution).53 In up to 40% of patients,31,62 CIPN may guided cognitive-behavioral pain management for chronic
become chronically painful and persist for months to years painful CIPN.
after the completion of chemotherapy.18,39,56 Patients with
painful CIPN often report decreases in quality of life and Purpose
physical function and may be required to stop poten-
The purpose of this randomized, wait-list control pilot
tially life-saving neurotoxic chemotherapy regimens.42,57
study was to test the efficacy of a self-guided cognitive-
Despite the known negative effects that painful CIPN
behavioral pain management intervention called Proactive
has on physical function and quality of life, there are few
Self-Management Program for Effects of Cancer Treat-
effective treatments for painful CIPN. Duloxetine 60 mg/d
ment (PROSPECT) to reduce worst pain intensity for
is currently the only medication recommended for the
individuals with chronic painful CIPN compared with in-
treatment of painful CIPN.24,54 Because of their efficacy
dividuals receiving treatment as usual (ClinicalTrials.gov
in other neuropathic pain populations, antidepressants
Identifier: NCT02760654). Secondarily, we explored the
and anticonvulsants are often used to treat painful CIPN.24
efficacy of the PROSPECT intervention to improve CIPN
However, adherence to these types of medications is poor
symptom severity (eg, nonpainful numbness and tin-
because of side effects or lack of efficacy.20 Use of an ef-
gling), pain interference, average pain severity, and
fective, nonpharmacologic intervention for painful CIPN
patients’ perceived global impression of change. Last, we
may decrease the need for drug therapy—potentially re-
explored participant acceptability of and satisfaction with
ducing the overall side effect burden for cancer survivors
PROSPECT.
and/or create a synergistic pain-reducing effect by the
use of multiple modalities. Thus, multimodal manage-
ment approaches that incorporate nonpharmacologic Methods
approaches for painful CIPN warrant further study.
One nonpharmacologic treatment used commonly for
Design, Setting, and Sample
the treatment of chronic pain (eg, back/neck, musculo- The study aims were examined via a parallel, 1:1 ran-
skeletal, and fibromyalgia) is therapist-administered domized controlled trial design. Sixty patients were
cognitive-behavioral pain management.7,40,46,61,64 This in- recruited from 5 outpatient community and/or aca-
tervention is designed to help patients self-manage pain demic oncology clinics in Southeast Michigan. Patients
and co-occurring symptoms such as anxiety, depression, were eligible if they: 1) were older than 25 years of age,
and insomnia through cognitive and behavioral strate- 2) self-reported ≥4 of 10 worst CIPN pain that persisted
gies such as relaxation, sleep hygiene, activity pacing, and 3 months or longer after the cessation of neurotoxic che-
cognitive restructuring.17,32 Cognitive-behavioral pain man- motherapy, 3) had at least National Cancer Institute
agement may reduce pain intensity by inducing structural Common Terminology Criteria for Adverse Events grade
changes in the prefrontal cortex (eg, increased gray matter 1 sensory CIPN,44 4) had a stable analgesic medication
volume).27,50 This may provide individuals with increased regimen (≤10% change in dosage in the 2 weeks before
executive control function and subsequently, a greater study enrollment), and 5) were able to access/use a com-
ability to reappraise and gain a greater sense of control puter. Participants were excluded if they had: 1) a
over their pain. Structural changes in the prefrontal cortex prognosis of384 The Journal of Pain Self-Guided Cognitive Behavioral Strategies for Neuropathy
PECT or treatment as usual (control) in a 1:1 ratio using cology follow-up appointments and subspecialty
a computer-generated random numbers table. Random- appointments). Participants randomized to the control
ization was stratified according to recruitment site to group received access to the PROSPECT Web site after
balance out center effects. The principal investigator gen- the completion of all required surveys.
erated the random allocation sequence, enrolled the
patients, and assigned participants to a study group. The
Measures
computer-generated random numbers table was stored
An 11-point numeric rating scale (NRS) of pain inten-
on a spreadsheet. The principal investigator did not view
sity was used to measure worst and average CIPN pain
the spreadsheet until informed consent was obtained and
severity (0, no pain; 10 pain as bad as you can imagine).8,12
all baseline assessments were completed by the partici-
The 11-point worst CIPN pain NRS was administered within
pant. After informed consent and completion of all
a 7-day pain diary pre/post intervention, whereas the
baseline assessments, participants were informed of their
average CIPN pain NRS was administered via a single item
study group assignment. After the administration of the
asking about average CIPN pain severity over the past 7
baseline assessments by the principal investigator, trained
days (worst pain was assessed in similar fashion at week
study staff administered all data collection procedures
4). Participants were coached to only report pain result-
at the subsequent time points. Health care providers were
ing from CIPN (eg, painful numbness, tingling, burning
not informed of their patients’ study group assignment.
in hands/feet), not pain from other sites or causes. The
11-point NRS is recommended by the Initiative on
PROSPECT
Methods, Measurement, and Pain Assessment in Clini-
The password-protected PROSPECT Web site con- cal Trials (IMMPACT)12 and several trials have supported
tained cognitive-behavioral pain management strategies its reliability and validity.26,28,36 On the basis of evidence
and information designed to help individuals manage pain suggesting that worst pain intensity is more highly cor-
and co-occurring symptoms after cancer treatment (eg, related with average functional interference (r = .65) than
anxiety, depression, sleep, fatigue, and impaired average (r = .60) or current (r = .53) pain intensity,21,52 worst
cognition).16,43,58,60 Content (10 modules; Table 1) is pre- pain intensity was selected as the primary outcome.
sented using written as well as video formats and patients Several other comorbid symptoms were assessed as rec-
can download worksheets further describing the strat- ommended by IMMPACT to increase our ability to
egies. At baseline, participants were trained on how to compare the results of this study with other trials testing
navigate the PROSPECT Web site and were encouraged interventions for chronic pain. The Patient-Reported Out-
to complete the “Steps for Me” link, which recom- comes Measurement Information System (PROMIS) Pain
mends modules on the basis of the patient’s responses Interference 4a (4 items; 1, not at all; 5 very much; trans-
to questions about symptom severity and symptom man- formed total score 41.6–75.6) subscale measures the effect
agement practices. Participants were instructed to use the of pain on the social, cognitive, and physical aspects of
modules as much as they desired and did not receive any one’s life over the past week.1 There is strong evidence
additional encouragement from the study staff after ob- supporting the reliability and validity of the PROMIS pain
taining access to the PROSPECT Web site. interference item bank.1 In addition, to measure impres-
sion of change after completion of the trial, we used the
Wait-List Control Patient Global Impression of Change (PGIC). The PGIC is
Participants in both groups continued to receive their a self-report item designed to assess patients’ overall im-
usual care from their primary provider (eg, routine on- 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 The Journal of Pain 385
63
trial. The 7-point scale ranges from “very much worse” tured interview questions about changes in medication
to “very much improved.”63 dosage/frequency. Unique to the week 8 time point, par-
The European Organization of Research and Treat- ticipants in both groups completed the PGIC and
ment of Cancer Quality of Life Questionnaire- individuals in the intervention group completed the
Chemotherapy-Induced Peripheral Neuropathy Scale (QLQ- Adapted Acceptability E-Scale and were contacted via tele-
CIPN20) measures patient’s symptoms and functional phone to discuss the most positive and negative aspects
limitations related to CIPN in sensory, motor, and auto- of PROSPECT. Participants were also e-mailed a survey each
nomic function domains (20 items; 1, not at all; 4, very week inquiring about the number of minutes spent using
much).48 The responses from each respective scale are then PROSPECT or other symptom management resources. At
transformed and scored from 0 to 100, with higher scores the end of the study, control group participants were
representing worsening symptoms.48 The internal con- e-mailed the link to the PROSPECT Web site.
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 Statistical Analyses
sensory and motor subscales are moderately-highly re- All data were analyzed using R version 3.4.0.49 Descrip-
sponsive to change (Cohen d = .82 and .48, respectively).35 tive statistics of the centrality and dispersion of all survey
Last, recent evidence supports the electronic adminis- data and demographic data were calculated. All analy-
tration of the QLQ-CIPN20 on the basis of high intraclass ses were calculated on the basis of the total number of
correlations (>.70) with paper/pencil administration.33 individuals who completed the baseline and week 8
Last, we adapted questions from the Acceptability outcome measures. A power analysis was not con-
E-Scale to assess participant acceptability of and satis- ducted because of the pilot nature of this work (eg,
faction with the PROSPECT Web site.3,59 The questionnaire determine an effect size to conduct larger studies testing
contains 7 items that are scored on a 1 to 5 scale, with this intervention) and because there were no previous
higher scores representing greater acceptability and sat- studies testing the PROSPECT intervention in individu-
isfaction. Survey questions ask participants how much they als with painful CIPN on which to base an effect size
enjoyed using PROSPECT and how helpful the modules estimate.
were in improving their symptoms.
Participants completed a demographic survey (ie, sex, Primary Outcome
age, race, ethnicity, employment status, marital status, We averaged patient’s responses from the 7-day worst
education, and previous computer use) before the comple- CIPN pain diary for the baseline and week 8 time points.
tion of the baseline assessments. Study staff abstracted Participants must have completed 5 of the 7 daily worst
participant cancer diagnosis (ie, disease and stage) and pain ratings at the baseline and week 8 time points to
treatment (eg, chemotherapy type), medication dosage, be included in the analysis.22 Week 8 mean scores in worst
and comorbid condition-related information from the pa- CIPN pain intensity (0–10 NRS diary) were compared
tients’ electronic medical records. 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-
Study Procedures tiple imputation (50 imputations; 50 iterations) (MICE R
Package)4 was used to handle missing data. The same re-
Baseline gression analysis was then repeated using the pooled data
After informed consent (eg, participants were in- from the multiply imputed data sets.
formed of the nature of the PROSPECT and control
groups), participants completed the baseline assess- Secondary Outcomes
ments (11-point worst and average CIPN pain NRS, PROMIS
Week 8 mean scores in CIPN symptom severity (QLQ-
Pain Interference 4a, QLQ-CIPN20, demographic charac-
CIPN20 sensory and motor subscales), average pain
teristics) via computer tablet. Participants were then
(average CIPN pain NRS), and pain interference (PROMIS
notified of their study group assignment and e-mailed
Pain Interference 4a) were compared between groups
the 7-day worst pain diary. After completing the pain
using analysis of covariance adjusting for baseline. Fisher
diary, the participants were e-mailed the PROSPECT Web
exact test was used to analyze proportional differences
site link and password, or instructions about the control
between those who experienced “improvement” (PGIC
group. Also at baseline, study staff abstracted cancer
score ≥5) and “no improvement” (PGIC score ≤4) in the
diagnosis/treatment and medication dosage-related in-
2 study arms.
formation from the patients’ electronic medical records.
Acceptability and Satisfaction
Week 4 and 8 Time Points Descriptive statistics for the items of the Adapted Ac-
Survey links to the same battery of assessments ad- ceptability E-Scale were calculated. We also summarized
ministered at baseline were e-mailed to participants 4 and responses from the semistructured telephone inter-
8 weeks after randomization. At these same time points, views to determine the most positive and negative aspects
participants were contacted by telephone as a reminder of PROSPECT and the biggest barriers to accessing and
to complete the electronic surveys and to answer struc- using the PROSPECT strategies.386 The Journal of Pain Self-Guided Cognitive Behavioral Strategies for Neuropathy
Results adverse events due to study participation reported by
participants.
Patients Patient characteristics are described in Table 2. Indi-
Participant recruitment occurred from May 1, 2016 to viduals in the PROSPECT group had higher levels of fatigue
October 4, 2016. A review of the study sites’ electronic and sleep-related impairment compared with individu-
medical records revealed 393 potentially eligible partici- als in the control group; otherwise, there were no
pants (Fig 1). After telephone screening procedures, 311 differences. When comparing protocol completers versus
patients were deemed ineligible on the basis of inclusion/ noncompleters, noncompleters had a greater percent-
exclusion criteria. Of these 311 excluded participants, 18 age of individuals with stage IV cancer (46%) than
experienced CIPN-related numbness, tingling, and pain, completers (19%), but baseline pain and co-occurring
but rated their worst pain severity asKnoerl 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 medication frequency/dose may have affected worst CIPN
increased neuropathic pain medication frequency/dose pain intensity improvement in individuals receiving PROS-
and pain medication frequency/dose not indicated as a PECT (within primary aim protocol completers; n = 38),
first-line treatment for painful CIPN and/or neuropathic we compared week 8 worst pain intensity mean scores
pain (“other analgesics”),11,24 but otherwise, there were (adjusting for baseline) between groups in 2 ways: 1) re-
no considerable differences in the number of partici- moving individuals in the PROSPECT arm who increased
pants changing medication frequency/dose between their use of first-line neuropathic pain medications, and
groups (Fig 3). To further explore how changes in pain 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 Self-Guided Cognitive Behavioral Strategies for Neuropathy
increased their use of “other analgesics.” Results from from sensitivity analyses revealed that the effect of PROS-
these analyses indicated that the effect of PROSPECT on PECT on worst CIPN pain intensity remained statistically
worst pain intensity was still statistically significant when significant after removing individuals in the PROSPECT
removing individuals from the PROSPECT arm who in- arm who increased their use of neuropathic pain medi-
creased their use of neuropathic pain medications cations and “other analgesics,” respectively.
(B = −1.07, 95% CI = −1.97 to −.15, P = .02; n = 36) and There have been no published studies reporting the
when removing individuals from the PROSPECT group effects of cognitive-behavioral pain management for
who increased their use of “other analgesics” (B = −1.10, nonpainful CIPN symptoms. Although nonpainful CIPN
95% CI = −2.10 to −.10, P = .03; n = 33). 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-
Discussion toms are still associated with changes in the central
This 8-week, randomized controlled pilot trial showed nervous system. For example, the authors of a recent study
that a self-guided online cognitive behavioral pain man- showed that increased CIPN symptoms 1 month after neu-
agement program—PROSPECT—significantly improved rotoxic chemotherapy are associated with changes in
worst pain intensity in individuals with chronic painful perfusion in brain areas associated with nociceptive pro-
CIPN. Further, there were no significant differences in cessing (eg, anterior cingulate cortex and frontal gyrus).45
mean change scores between groups for the secondary Thus, interventions that target centrally-mediated mecha-
outcomes of pain interference, nonpainful CIPN symp- nisms such as cognitive behavioral pain management, may
toms, average pain, or global impression of change. also be efficacious for the treatment of nonpainful CIPN
Individuals with chronic painful CIPN interacting with symptoms.27,50 The results of this current study support
the 8-week PROSPECT intervention reported a mean de- this conclusion because individuals receiving PROSPECT
crease in worst pain intensity of .94. The mean decrease had greater improvements in nonpainful CIPN symp-
in pain intensity found in this study is comparable with toms over the 8-week trial period than individuals
the effect of duloxetine, the only pharmacological agent receiving usual care, but, the difference was not signifi-
currently recommended for the treatment of chronic cant. Further research is needed to determine if
painful CIPN.24 The authors of a randomized, crossover, interventions targeting centrally-mediated mechanisms
placebo-controlled study reported that use of duloxetine (eg, cognitive-behavioral pain management) can also in-
60 mg/d resulted in a mean decrease of 1.06 in average fluence nonpainful CIPN symptoms.
pain intensity in individuals with chronic painful CIPN There were also no significant differences in pain in-
(P = .003, d = .513).54 On the contrary, PROSPECT had no terference between groups. Although physical function
effect on the secondary outcome of average pain inten- and 7-day recall of worst pain intensity are moderately-
sity. The comparison between average pain mean change strongly correlated (r = .65),52 self-guided cognitive-
scores between studies is challenging because the authors behavioral pain management interventions are most
of the duloxetine trial assessed average pain over the past effective when targeting a specific primary outcome.34
24 hours, not 7 days.52,54 Nevertheless, the reported effect Therefore, perhaps if the PROSPECT intervention was tai-
sizes and mean decreases for the 2 studies’ primary out- lored to include more physical activity training and
comes were similar for PROSPECT and duloxetine. educational resources, it would have had a greater effect
Although our findings supported the efficacy of PROS- on pain interference.
PECT in improving worst CIPN pain intensity compared On the basis of trends in PROSPECT usage and worst
with individuals receiving treatment as usual, results from pain intensity improvement, the results suggest that par-
post hoc sensitivity analyses suggest that these findings ticipants interacted with the Web site frequently at first
should be interpreted with caution. Few participants ex- to learn and practice the strategies, but then could in-
perienced a clinically significant reduction in worst CIPN corporate the strategies into their day-to-day activities
pain intensity after PROSPECT usage. Clinically signifi- to improve pain intensity independent of logging in to
cant improvements in pain intensity represent a 30% PROSPECT. However, little is known about the optimal
reduction in pain.19 The overall worst CIPN pain inten- dose of PROSPECT because we did not actively monitor
sity mean change score for individuals receiving PROSPECT patient’s usage (eg, electronic tracking or use of strate-
was −.94 and only 3 individuals reported a clinically sig- gies in day-to-day activities) and the response rate to the
nificant reduction in pain. Further, results from a post hoc self-report measures was low. Significant predictors of self-
intent-to-treat analysis with the full sample (N = 60) re- management intervention usage include health care
vealed that the effect of PROSPECT on worst pain intensity professional guidance/support, ample amount of time to
was not statistically significant (P = .09). Finally, because use the intervention, and high satisfaction with inter-
of the dearth of high-quality trials testing interven- vention content.2 PROSPECT usage may be bolstered in
tions for the treatment of painful CIPN, it is possible that future studies if: 1) participants have an opportunity to
changes in neuropathic pain medications and “other an- interact with a health care professional (eg, weekly video
algesics” may produce an analgesic effect in individuals or telephone call with nurses)25,29 to discuss pain-related
with chronic painful CIPN. 23 Thus, changes in the symptoms and strategy use, 2) participants have more time
frequency/dosage of neuropathic pain medications or to interact with the strategies of PROSPECT (eg, longer
“other analgesics” may partially explain the efficacy of duration, scheduled time to interact with modules), and
PROSPECT on worst pain intensity. However, the results 3) additional interactive features within PROSPECT areKnoerl et al The Journal of Pain 391 designed (eg, achievement badges, message boards/ needed to examine the feasibility of administering PROS- support groups, visually appealing).2,37 Improving self- PECT in individuals with advanced cancer. Second, we did guided cognitive-behavioral pain management not conduct a power analysis because of the pilot nature intervention usage in future research is critical to estab- of this study. Nevertheless, it is highly unlikely that this lish an optimal dose that can be prescribed in the clinical study was adequately powered to detect differences setting and to compare results across trials. primary or secondary outcomes between groups because One common limitation of recent placebo-controlled of the small sample size and high dropout rate. Third, randomized controlled trials testing interventions for in- although worst pain intensity improved after PROS- dividuals with chronic pain is high placebo response.13-15,30 PECT use, little is known as to what components led to Although this study did not contain a placebo control, these improvements. The identification of mediators of psychoeducational interventions are prone to nonspe- pain intensity improvement may allow for the develop- cific effects (eg, study staff-participant interaction, ment of self-guided cognitive behavioral pain participant motivation for participation, lack of blind- management interventions containing the strategies hy- ing, credibility of treatment) that may have accounted pothesized to improve the mediators. Fourth, greater use for the efficacy of the intervention.10 We attempted to of other symptom management resources by individu- improve the assay sensitivity of the trial, or the ability als in PROSPECT may have confounded the results of the to distinguish an effective treatment from an ineffec- primary outcome. Fifth, we cannot generalize the results tive treatment14 by implementing strategies such as: 1) of this study to individuals with CIPN resulting from a spe- baseline participant worst CIPN pain intensity of 4 of 10 cific neurotoxic agent because we examined the PROSPECT or greater, participant pain duration of at least 3 months intervention in individuals who received varying types of since completion of chemotherapy, 3) flexible interven- neurotoxic drugs. Sixth, participants were not blinded to tion dosing, 4) standardized data collection procedures what treatment (PROSPECT or wait-list control) they were for both groups, and 5)
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