Characterization of chronic pain, pain interference, and daily pain experiences in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study

Supplemental Digital Content is Available in the Text.

A substantial proportion of childhood cancer survivors (41%) experience chronic pain and significant associated interference, with several biopsychosocial risk factors associated with each outcome identified.

Abstract

Although survivors of childhood cancer are at an increased risk, little is known about the prevalence of chronic pain, associated interference, and daily pain experiences. Survivors (N = 233; mean age = 40.8 years, range 22-64 years; mean time since diagnosis = 32.7 years) from the Childhood Cancer Survivor Study completed pain and psychosocial measures. Survivors with chronic pain completed 2-week, daily measures assessing pain and psychological symptoms using mHealth-based ecological momentary assessment. Multivariable-modified Poisson and linear regression models estimated prevalence ratio estimates (PR) and mean effects with 95% confidence intervals (CI) for associations of key risk factors with chronic pain and pain interference, respectively. Multilevel mixed models examined outcomes of daily pain and pain interference with prior day symptoms. Ninety-six survivors (41%) reported chronic pain, of whom 23 (24%) had severe interference. Chronic pain was associated with previous intravenous methotrexate treatment (PR = 1.6, 95% CI 1.1-2.3), respiratory (PR = 1.8, 95% CI 1.2-2.5), gastrointestinal (PR = 1.6, 95% CI 11.0-2.3), and neurological (PR = 1.5, 95% CI 1.0-2.1) chronic health conditions, unemployment (PR = 1.4, 95% CI 1.0-1.9) and clinically significant depression and anxiety (PR = 2.9, 95% CI 2.0-4.2), as well as a diagnosis of childhood Ewing sarcoma or osteosarcoma (PR = 1.9, 95% CI 1.0-3.5). Higher pain interference was associated with cardiovascular and neurological conditions, unemployment and clinical levels of depression and/or anxiety, and fear of cancer recurrence. For male, but not female survivors, low sleep quality, elevated anxiety, and elevated depression predicted high pain intensity and interference the next day. A substantial proportion of childhood cancer survivors experience chronic pain and significant associated interference. Chronic pain should be routinely evaluated, and interventions are needed.

1. Introduction

More than 85% of children diagnosed with cancer will become five-year survivors,²¹ leading to a growing survivor population of more than half a million in the United States.⁵⁰ Unfortunately, treatment advances that have improved survival rates are also well-established to place survivors at significant risk for a range of poor physical and mental health outcomes.²³ Morbidities frequently observed following childhood cancer treatment include severe and disabling chronic health conditions,⁵ distress,⁶ and insomnia.¹² Pain and pain-related interference or disability (ie, the extent to which pain hinders functioning in major areas such as activity and work) are also commonly reported by survivors in adulthood.²⁵ However, studies of pain among childhood cancer survivors have previously lacked validated measures of chronic pain and failed to examine daily measures of pain chronicity—which may have underestimated the prevalence and nature of chronic pain.^1,22,36,46 Moreover, most prior studies used retrospective pain assessment, introducing potential recall bias into results. Ecological momentary assessment (EMA) is one method for overcoming such problems with reliability and validity, and involves the collection of individuals' current experiences, behaviors, and mood as they occur in real time.⁵⁴

To our knowledge, past examinations of chronic pain and pain interference among adult survivors of childhood cancer have also failed to consider cognitive–affective factors that, in other cancer populations, have been found to consistently influence the experience of chronic pain and associated pain interference, such as depression, anxiety, and pain catastrophizing (ie, a negative cognitive response to actual or anticipated pain experience).^{4,13,45,48,66} This exclusion limits our understanding of the development and maintenance of chronic pain in adult survivors of childhood cancer, which is integral to the comprehensive assessment of chronic pain, identification of survivors at risk for developing chronic pain, and the development of targeted and effective interventions for chronic pain among survivors. In addition, daily pain experiences, associated symptoms, and pain management strategies have not been examined among survivors.

Therefore, we conducted the Exploring Aspects of Survivors' Experience of Pain (EASE) study to address these gaps by describing the prevalence of chronic pain, the occurrence of pain interference, and the demographic, diagnostic, treatment-related, and psychosocial risk factors for chronic pain in a subset of adult survivors in the Childhood Cancer Survivor Study (CCSS) cohort. Using EMA, we aimed to characterize daily pain experiences in adult survivors of childhood cancer with chronic pain and investigate associations between daily pain and related variables (ie, mood, anxiety, sleep). We hypothesized that (1) demographics (female sex), cancer-related factors (amputation, chronic medical conditions), and psychosocial factors (depression, anxiety, pain catastrophizing) would be associated with the increased risk of chronic pain and pain interference among survivors; (2) decreased sleep quality (from the night before), increased anxiety, and increased depressive symptoms would be associated with increased pain intensity the following day; and (3) higher pain intensity, decreased sleep quality, increased anxiety, and increased depressive symptoms would be associated with increased pain interference the following day.

2. Methods

2.1. Participants

The CCSS is a multi-institutional retrospective cohort consisting of 25,665 five-year survivors of childhood cancer diagnosed before the age of 21 years and between 1970 and 1999 at one of 31 participating centers in the United States and Canada (https://ccss.stjude.org/).⁵⁰ A random sample of survivors enrolled in the CCSS (n = 700) were recruited to the EASE study through mailed letters, emails, and phone calls and invited to download the Eureka Research app, an mHealth app available on iOS and Android platforms, where all EASE study activities were completed. Inclusion criteria were (1) ≥ 18 years of age, (2) able to speak and read English, (3) smartphone ownership, and (4) access to the Internet. After informed consent was obtained, all participants completed baseline measures. Notably, study recruitment did not specifically target individuals with chronic pain, with recruitment materials emphasizing the need for participants with and without chronic pain to participate. Participants who reported baseline chronic pain completed a brief daily survey for 2 weeks as described below. This ancillary study received St. Jude Children's Research Hospital institutional review board approval in March 2018 as an amendment to the CCSS (clinicaltrials.gov: NCT01120353, registered May 2010).

2.2. Ecological momentary assessment sampling approach

Participants who reported chronic pain at baseline responded to 8 items once daily for 14 days (ie, daily diary) and to 4 items once per week (end of weeks 1 and 2). An event-based prompting strategy with a fixed schedule was employed, and all diary entries were completed using an escalating messaging strategy in the Eureka Research Platform. If participants had not already completed the diary after 24 hours of their previous diary, then one daily push notification was sent through the Eureka app. If a diary was not completed after 3 consecutive days, a text message was automatically sent to the participant. A reminder email at the beginning of both weeks was also automatically sent to a subset of participants regarding completion of the diary.

2.3. Baseline measures: primary pain outcomes

2.3.1. Chronicity

Chronic pain was assessed using 2 items: (1) Do you have any persistent or recurrent pain, more than aches and pains that are fleeting and minor? and (2) How long have you been experiencing this pain? These items are derived from the definition of chronic pain developed by the International Association for the Study of Pain⁶⁵ and recommended for use in epidemiological studies of chronic pain.⁵⁷ Chronic pain was defined as recurrent or persistent pain lasting at least 3 months.⁶⁵

2.3.2. Severity and interference

Among survivors with chronic pain, pain severity and pain interference were assessed using the Brief Pain Inventory (BPI).¹⁰ Two BPI pain severity¹⁰ scale items were used in this study. These asked individuals to rate the intensity of their average pain and their worst pain within the past week using an 11-point Likert scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). Pain interference was assessed using 7 items, which ascertain how much pain has interfered with daily activities. Items are rated on a scale ranging from 0 (does not interfere) to 10 (completely interferes). A total pain interference score was calculated using a mean of the 7 items. The BPI has valid psychometric properties.¹⁰ Pain interference was retained as a continuous variable for analyses given the nature of this construct and the fact that there are no established cutoff scores for pain interference, including when measured by the BPI pain interference subscale.

2.3.3. Location and cause

Participants were asked to indicate the location of their pain using the following response options: (1) arm(s), (2) leg(s), (3) stomach, (4) chest, (5) lower back, (6) neck, (7) head, (8) pelvis (9) feet, (10) hands, and (11) other. Participants could select multiple locations. Perceived cause of pain was assessed by the following item: “What do you think this pain was due to?” Response options included the following: (1) your childhood cancer treatments; (2) medical procedures and tests you had during your childhood cancer; (3) your cancer as a child; (4) medical condition(s) other than your cancer (eg, arthritis); (5) past injury (eg, back injury, muscle strain) (6) not sure; and (7) other.

2.4. Baseline measures: risk factors

Demographic predictors included a priori were sex, race/ethnicity, and age at the time of study. Descriptive sociodemographic variables included marital status, personal annual income, employment status, and educational attainment. Cancer-related predictors included primary cancer diagnosis, age at diagnosis, chemotherapy, cranial radiation therapy exposure, and amputation surgery (yes/no). Cranial radiation therapy exposure was determined based on radiotherapy record abstraction. Chronic medical conditions were categorized and graded based on the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4.03).⁴¹ Conditions graded as 2 to 4 were included in the current analyses.

Anxiety was assessed using the Generalized Anxiety Disorder 7-item Scale (GAD-7).⁵⁶ Items are rated on a 4-point Likert scale ranging from 0 (not at all) to 3 (nearly every day). Higher scores indicate greater severity of anxiety symptoms, and the total score range is 0 to 21. The GAD-7 has excellent psychometric properties.⁵⁶ A total score of ≥10 represents the cut point for moderate or clinically significant anxiety as well as for further clinical evaluation.⁵⁶

Depressive symptoms were assessed using the Patient Health Questionnaire 8-item (PHQ-8).³⁰ Each item is rated on a 4-point Likert scale ranging from 0 (not at all) to 3 (nearly every day) with total scores ranging from 0 to 24.³⁰ Higher scores indicate greater symptom severity. The PHQ-8 has strong psychometric properties.^29–31,39 A total score of ≥10 represents the cut point for moderate or clinically significant depression as well as for further evaluation.³⁰

Fear of cancer recurrence was assessed through the 9-item Fear of Cancer Recurrence Inventory—Short Form (FCRI-SF), which has been well validated among adult cancer survivors.⁵⁵ Items are rated on a 5-point Likert scale. A summed score is created ranging from 0 to 36, with higher scores indicating greater fear of cancer recurrence. A total score of ≥22 has been identified as indicating clinically significant levels of fear of cancer recurrence.¹⁶

Pain catastrophizing was assessed through the Pain Catastrophizing scale (PCS),⁶¹ a 13-item scale with total scores ranging from 0 (no catastrophizing) to 52 (severe catastrophizing). Psychometric properties of the PCS have been studied extensively and are reliable and valid.^42,61 Only survivors with chronic pain completed the PCS.

Sleep quality was assessed with the National Institutes of Health Patient Reported Outcomes Measurement Information Systems—Sleep Disturbance (PROMIS-SD)—Short Form 8a,^9,75 an 8-item measure of perceived sleep difficulties and satisfaction over the past week. Participants rate items on a 5-point Likert scale from 5 (very poor) to 1 (very good). Items are summed and converted to a T score. The PROMIS-SD has demonstrated excellent psychometrics.^9,75

2.5. Ecological momentary assessment daily diary measures

In addition to baseline, pain and pain interference were assessed daily by 3 items adapted from the BPI¹⁰ and that used a 0 to 10 numerical rating scale (NRS). Participants reported their worst and average pain intensity, as well as their interference of pain with general activities, in the past 24 hours on an 11-point Likert scale NRS, with greater scores indicating greater pain or interference. Pain free days were defined as the participant endorsing 0 on the 0 to 10 NRS, and elevated pain or interference was defined as the participant endorsing ≥5 on the 0 to 10 NRS. Research has provided support for the reliability and validity of the NRS in assessing daily pain and pain interference in chronic pain^51,52 and cancer populations.^3,58

Mood and anxiety were assessed by an adapted, ultra-brief 4-item PHQ,³⁵ where participants responded on a 4-point Likert scale, with greater scores indicating greater anxiety or depression over the past 24 hours. Depression was assessed by 2 items (PHQ-2), and anxiety was assessed by 2 items (GAD-2).⁴⁴ Elevated anxiety was defined with a cutoff of ≥3 on the summarized score for the 2 anxiety items and similarly for elevated depression. The PHQ-2 and GAD-2 are both reliable and valid measures,^32–34 including when used to assess mood and anxiety daily.²⁴ Previous research has also provided support for the reliability and validity of daily reports to assess mood and anxiety.^71,72

Sleep quality was assessed by the single item adapted from the Pittsburgh Sleep Quality Index⁸: “For last night, how would you rate your sleep quality overall?” Response options ranged from 0 to 3, with a higher score indicating lower sleep quality and a score of ≥3 indicating poor sleep. Research has provided support for this adapted item in assessing sleep quality,¹⁵ and previous research has provided strong support for the reliability and validity of daily reports to assess sleep.^15,19,68,69

2.6. Ecological momentary assessment weekly diary measures

Pain management was assessed weekly using items adapted from previous EMA and pain research in oncology populations.⁶⁰ Participants were asked to report strategies to reduce pain during the past week and could select as many of the 17 options, which included none, prescription, and nonprescription medication, healthcare provider consultation, alcohol, meditation, and a write-in option. Participants then reported how helpful each strategy was, using 5 response options with higher scores indicating more effectiveness, as well as a “don't know” option. Participants were also asked about when they feel pain, whether they worry their pain in the past week was caused by their cancer coming back or by a new type of cancer, responding on a 0 (don't agree at all) to 5 (agree very much) Likert scale.

2.7. Statistical analyses

We calculated the prevalence of chronic pain and its corresponding 95% confidence interval (CI). As we expected the prevalence of chronic pain to be ≥10%, we directly modelled and reported prevalence ratio (PR) estimates and corresponding 95% CIs using a modified Poisson regression models with robust errors rather than logistic regression models.⁷⁶ Univariate models assessed the relationship between chronic pain and potential risk factors, initially examining associations of chronic pain with a priori selected demographic variables (sex, age at diagnosis, age at baseline survey, race/ethnicity) to form a base model. We subsequently added groups of additional variables to that model, leading to separate multivariable regression analyses examining associations between chronic pain and (1) treatment exposures; (2) chronic health conditions; and (3) psychosocial factors, all adjusted for the base model factors. Aside from the a priori included variables, factors included in final models were selected using a stepwise process, using the Akaike information criterion (AIC) as an aid in determining the candidate model, which best fit the data. Among survivors with chronic pain, separate linear regression analyses were used to examine associations between continuously measured pain interference and (1) treatment exposures; (2) chronic health conditions; and (3) psychosocial factors, using the same approach to determine the most suitable model, reporting model coefficients (B) and associated CIs. Level of significance was set at P < 0.05 with no adjustment for multiple comparisons.

For the EMA daily diary, we calculated rates of completion, as a ratio of observed completed diaries to the “expected” number if all diaries had been completed as scheduled, by key demographic and psychosocial variables. Descriptive statistics were used to calculate mean average pain, worst pain, pain interference, and sleep quality scores across the 2-week study period. In a subanalysis among diaries completed after the first day, we used multilevel mixed models (MLMs) to examine outcomes of daily pain with prior (most recent within 1-3 days) daily scores for sleep, anxiety, and depression and outcomes of pain interference with prior sleep, pain, anxiety, and depression, with one model per outcome/predictor combination. Models accounted for multiple diaries per survivor with a random effect for participant and within-person autoregressive error structure. Each model was adjusted for sex and tested for interactions of sex with the prior daily score variable for that model. Due to small numbers, we treated outcomes as continuous based on their Likert score but tested predictors as both linear and as dichotomized versions based on standard cutoffs. A large number of models indicated significant interactions with sex at P < 0.10. As such, results are presented by sex. No adjustment was made for multiple comparisons. Analyses were conducted using SAS statistical software, version 9.4 (SAS Institute, Cary, NC).

3. Results

3.1. Participant demographics and clinical characteristics

A total of 266 survivors (38%) downloaded the app and 245 (35%) provided informed consent. The final study included 233 survivors (33%) (Supplemental Figure 1, http://links.lww.com/PAIN/C65). We compared demographic and other descriptive data for the EASE participants with the eligible, nonparticipating members of the CCSS cohort, finding only that participants were more likely to be White non-Hispanic (88% vs 79%, P = 0.002, see Supplemental Table 1, http://links.lww.com/PAIN/C65). Participants' mean ages at cancer diagnosis and baseline assessment were 8.3 years (SD = 5.8; median = 8; range = 0-20) and 40.8 years (SD = 9.0; median = 40; range = 22-64), respectively. Common cancer diagnoses included leukemia (33.9%), noncentral nervous system solid tumors (22.7%), lymphomas (20.6%), bone cancer (12.4%), and central nervous system tumors (10.3%). Most survivors identified as White (88.8%). Sample demographics and clinical characteristics for the study population are shown in Table 1.

Table 1.

Demographic and clinical characteristics of the study population.

	Overall (N = 233)		Chronic pain (N = 96)		No chronic pain (N = 137)
	Mean	SD	Mean	SD	Mean	SD
Age at study	40.8	9.0	43.1	8.8	39.3	8.8
Age at diagnosis	8.3	5.8	9.5	5.9	7.5	5.6
Time since diagnosis	32.5	7.9	33.6	7.3	31.7	8.2
	N	%	n	%	n	%
Sex
Male	115	49.4	43	44.8	72	52.6
Female	118	50.6	53	55.2	65	47.4
Race/ethnicity
White/non-Hispanic	207	88.8	83	86.5	124	90.5
Other	26	11.2	13	13.5	13	9.5
Education
Completed high school	30	12.9	16	16.7	14	10.2
Post high school training	150	64.4	63	65.6	87	63.5
≥ College graduate	53	22.7	17	17.7	36	26.3
Employment
Full time	141	66.2	46	54.1	95	74.2
Part time	32	15.0	18	21.2	14	10.9
Not employed	40	18.8	21	24.7	19	14.8
Diagnosis
Leukemia	79	33.9	33	34.4	46	33.6
CNS tumor	24	10.3	10	10.4	14	10.2
Lymphomas (HL, NHL)	48	20.6	22	22.9	26	19.0
Wilms, neuroblastoma, soft tissue sarcoma	53	22.7	14	14.6	39	28.5
Ewing sarcoma or osteosarcoma	29	12.4	17	17.7	12	8.8
Marital status
Married, living as married	132	63.5	53	64.6	79	62.7
Single, widowed, divorced, separated	76	36.5	29	35.4	47	37.3
Location
Metropolitan (RUCA 1-3)	179	79.6	71	77.2	108	81.2
Nonmetropolitan (RUCA 4-10)	46	20.4	21	22.8	25	18.8
Assistance with routine needs
Yes	12	5.3	8	8.8	4	3.0
No	214	94.7	83	91.2	131	97.0
Endocrine condition (grade 2-4)
Yes	81	34.8	40	41.7	41	29.9
No	152	65.2	56	58.3	96	70.1
Respiratory condition (grade 2-4)
Yes	22	9.4	17	17.7	5	3.6
No	211	90.6	79	82.3	132	96.4
Cardiovascular condition (grade 2-4)
Yes	78	33.5	42	43.8	36	26.3
No	155	66.5	54	56.3	101	73.7
Gastrointestinal condition (grade 2-4)
Yes	27	11.6	19	19.8	8	5.8
No	206	88.4	77	80.2	129	94.2
Musculoskeletal condition (grade 2-4)
Yes	21	9.0	14	14.6	7	5.1
No	212	91.0	82	85.4	130	94.9
Neurological condition (grade 2-4)
Yes	34	14.6	21	21.9	13	9.5
No	199	85.4	75	78.1	124	90.5
Physical health status
Poor, fair	35	15.3	23	24.7	12	8.8
Good, very good, excellent	194	84.7	70	75.3	124	91.2
Chemotherapy
Yes	186	84.2	85	93.4	101	77.7
No	35	15.8	6	6.6	29	22.3
Vinca alkaloids
Yes	155	71.4	68	76.4	87	68.0
No	62	28.6	21	23.6	41	32.0
Platinum
Yes	28	12.6	14	15.4	14	10.7
No	194	87.4	77	84.6	117	89.3
IV methotrexate ≥ 10,000 mg/m2
Yes	25	11.5	15	17.0	10	7.7
No	193	88.5	73	83.0	120	92.3
IT methotrexate
Yes	89	40.3	39	43.3	50	38.2
No	132	59.7	51	56.7	81	61.8
Radiation
Yes	99	44.4	44	47.8	55	42.0
No	124	55.6	48	52.2	76	58.0
Radiation to site
None	124	55.6	48	52.2	76	58.0
Other head	10	4.5	3	3.3	7	5.4
Neck	33	14.9	15	16.3	18	13.8
Chest	35	15.8	17	18.5	18	13.8
Abdomen	35	15.8	18	19.6	17	13.1
Pelvis	25	11.3	14	15.2	11	8.5
Limb	8	3.6	6	6.5	2	1.5
Cranial radiation
Yes	46	20.7	20	21.7	26	20.0
No	176	79.3	72	78.3	104	80.0
Radiation to other regions
Yes	64	28.8	29	31.5	35	26.9
No	158	71.2	63	68.5	95	73.1
Surgery
Yes	166	75.1	71	78.9	95	72.5
No	55	24.9	19	21.1	36	27.5
Amputation
Yes	12	5.2	8	8.3	4	2.9
No	221	94.8	88	91.7	133	97.1
Limb sparing
Yes	12	5.2	8	8.3	4	2.9
No	221	94.8	88	91.7	133	97.1

CNS, central nervous system; HL, Hodgkin lymphoma; IT, intrathecal; IV, intravenous; NHL, Non-Hodgkin lymphoma.

3.2. Prevalence and pain characteristics of participants with chronic pain

Ninety-six participants (41.2%, 95% CI 36.5%-49.8%) reported current chronic pain. Table 2 summarizes the pain characteristics of survivors with chronic pain. With respect to duration, 31 (32.3%) reported experiencing chronic pain for >10 years, 18 (18.8%) for >5 to 10 years, 25 (26%) for >2 to 5 years, 11 (11.5%) for >1 to 2 years, and 11 (11.5%) for 3 months-to 1 year. Slightly more than half of survivors with chronic pain (55%) reported their average pain intensity in the past week as mild (ie, score = 1-4), whereas 25% and 17.7% reported moderate (score = 5-6) and severe (score = 7-10) pain intensity, respectively. Common locations of pain included lower back (56.3%), leg(s) (34.5%), neck (33.3%), and feet (29.2%). Among those with chronic pain, difficulty performing daily activities due to pain was common with 24% reporting severe pain interference (ie, score>5), and 47.9% reporting moderate pain interference (score = 2-5). Moreover, 21.9% endorsed severe pain interference with work, 21.9% with walking, 19.8% with mood, and 14.6% with relations with other people. Survivors most frequently perceived their pain as due to their childhood cancer treatments (19.8%), a medical condition(s) other than their childhood cancer (19.8%), and due to a past injury (13.5%). In addition, 16.7% reported that it was due to “other” causes and 15.6% were not sure.

Table 2.

Pain characteristics of survivors with chronic pain (N = 96).

	N (%)	Mean (SD)	Range
Duration of pain
3 mo-1 y	11 (11.5)	126.2 (132.8)	3-584
>1-2 y	11 (11.5)
>2-5 y	25 (26.0)
>5-10 y	18 (18.8)
>10 y	31 (32.3)
Average pain intensity (past week)
None (0)	2 (2.1)	4.2 (2.1)	0-10
Mild (1-4)	53 (55.2)
Moderate (5-6)	24 (25.0)
Severe (7-10)	17 (17.7)
Worst pain intensity (past week)
None (0)	1 (1.0)	5.5 (2.4)	0-10
Mild (1-4)	34 (35.4)
Moderate (5-6)	26 (27.1)
Severe (7-10)	35 (36.5)
Location
Arm(s)	22 (22.9)
Leg(s)	34 (34.5)
Stomach	9 (9.4)
Chest	9 (9.4)
Lower back	54 (56.3)
Neck	32 (33.3)
Head	23 (24.0)
Pelvis	14 (14.6)
Feet	28 (29.2)
Hands	15 (15.6)
Other	15 (15.6)
Pain interference (mean)
None/mild (<2)	27 (28.1)	3.9 (2.4)	0-10
Moderate (2-5)	46 (47.9)
Severe (>5)	23 (24.0)
Activity-related interference
None/mild (<2)	17 (17.7)	4.1 (2.8)	0-10
Moderate (2-5)	60 (62.5)
Severe (>5)	19 (19.8)
Mood-related interference
None/mild (<2)	17 (17.7)	4.0 (2.7)	0-10
Moderate (2-6)	60 (62.5)
Severe (>6)	19 (19.8)
Walking ability interference
None/mild (<2)	29 (30.2)	3.6 (3.1)	0-10
Moderate (2-6)	46 (47.9)
Severe (>6)	21 (21.9)
Normal work interference
None/mild (<2)	21 (21.9)	4.1 (3.2)	0-10
Moderate (2-6)	54 (56.3)
Severe (>6)	21 (21.9)
Relations with other people interference
None/mild (<2)	42 (43.8)	2.8 (2.8)	0-10
Moderate (2-6)	40 (41.7)
Severe (>6)	14 (14.6)
Perceived cause of pain
Cancer as a child	5 (5.2)
Childhood cancer treatments	19 (19.8)
Medical procedures/tests during cancer treatments	9 (9.4)
Medical condition(s) other than childhood cancer	19 (19.8)
Past injury	13 (13.5)
Not sure	15 (15.6)
Other	16 (16.7)

3.3. Psychosocial characteristics of participants with chronic pain

As shown in Table 3, 33.7% of survivors with chronic pain had clinically significant anxiety (ie, score of ≥10 on the GAD-7) and 44.2% had clinically significant depression (ie, score of ≥10 on the PHQ-8). In addition, 13.8% of survivors with chronic pain had elevated levels of fear of cancer recurrence (ie, score of 16-21 on the FCRI-SF) and 25.5% reported clinically significant fear of cancer recurrence.¹⁶ Survivors with chronic pain endorsed similar levels of sleep disturbances (mean T-score = 52.8 on PROMIS-SD) compared with individuals from the general population. Overall levels of pain catastrophizing were generally comparable with those observed in community samples in the general population⁷⁰ and lower than levels observed in adults with chronic pain conditions.⁷⁰

Table 3.

Psychosocial characteristics of survivors with and without chronic pain.

	With chronic pain (N = 96)			Without chronic pain (N = 137)
	N (%)	Mean (SD)	Range	N (%)	Mean (SD)	Range
Anxiety (GAD-7)		7.9 (6.3)	0-21		4.6 (5.0)	0-21
Minimal; mild	63 (66.3)			112 (82.4)
Moderate	13 (13.7)			17 (12.5)
Severe	19 (20.0)			7 (5.1)
Depression (PHQ-8)		8.8 (6.6)	0-24		4.5 (4.5)	0-20
None; mild	53 (55.8)			119 (86.9)
Moderate	23 (24.2)			11 (8.0)
Moderately severe; severe	19 (20.0)			7 (5.1)
Fear of cancer recurrence (FCRI-SF)		13.9 (8.9)	0-31		11.0 (7.8)	0-36
Minimal	57 (60.6)			98 (72.6)
Elevated	13 (13.8)			23 (17.0)
Clinically significant	24 (25.5)			14 (10.4)
Pain catastrophizing (PCS)
Total score		16.7 (12.2)	0-52		—	—
Clinically significant total score (≥30)	18 (18.9)
Rumination subscale		6.4 (4.6)	0-16		—	—
Clinically significant rumination (≥11)	22 (22.9)
Helplessness subscale		7.1 (5.7)	0-24		—	—
Clinically significant Helplessness (≥13)	16 (16.7)
Magnification subscale		3.4 (3.0)	0-12		—	—
Clinically significant magnification (≥5)	30 (31.6)
Sleep (PROMIS-SD)
Total score		11.2 (1.6)	6-15		10.8 (1.6)	7-16
T-score		52.8 (3.1)	41.1-59.8		52.0 (3.1)	43.8-61.7

—, not available as survivors without chronic pain did not complete the PCS; FCRI-SF, Fear of Cancer Recurrence Inventory—Short Form; GAD-7, Generalized Anxiety Disorder 7-Item Scale; PCS, pain catastrophizing scale; PHQ-8, Patient Health Questionnaire 8-Item; PROMIS-SD, Patient-Reported Outcomes Measurement Information Systems—Sleep Disturbance.

3.4. Risk factors associated with chronic pain

All univariate models for the effect of individual risk factors (ie, diagnosis, treatment variables, chronic conditions, and psychosocial variables) on chronic pain can be found in the supplementary materials (Supplementary Table 2, http://links.lww.com/PAIN/C65). In the multivariable model examining a priori selected patient characteristics, older age at the time of the study was associated with an increased risk of chronic pain (per 10-year increments, PR = 1.3, 95% CI 1.05-1.5, P = 0.015), although no statistically significant association between sex, age at diagnosis, and race/ethnicity with risk of chronic pain was observed (Table 4, Model 0). Survivors with a diagnosis of bone cancer were more likely to experience chronic pain when compared with the referent group of Wilms tumor, neuroblastoma, and soft tissue sarcoma with the lowest risk (Table 4, Model 1). The only significant treatment exposure–related risk factor in multivariable analysis associated with likelihood to experience chronic pain was treatment with intravenous (IV) methotrexate (PR = 1.6, 95% CI 1.1-2.3, P = 0.01) (Table 4, Model 2). Notably, treatment risk factors such as limb radiation and amputation were among the candidate variables included in the model-building process (see Supplemental Table 2, http://links.lww.com/PAIN/C65) but were not statistically significant in combination with other risk factors and were eliminated from the final model. In addition, survivors with respiratory conditions (PR = 1.8, 95% CI 1.2-2.5, P = 0.002), gastrointestinal conditions (PR = 1.6, 95% CI 1.1-2.3, P = 0.01), or neurological conditions (PR = 1.5, 95% CI 1.03-2.1, P = 0.03) were more likely to have chronic pain (Table 4, Model 3). A significant association was not observed between musculoskeletal conditions and chronic pain (PR = 1.4, 95% CI 0.9-2.2, P = 0.09).

Table 4.

Risk factors for chronic pain in adult survivors of childhood cancer.

Risk factor	PR	95% CI	P
Model 0: Survivor characteristics
Age at cancer diagnosis (per 10 y)	1.2	0.9, 1.6	0.21
Age at baseline questionnaire (per 10 y)	1.3	1.05, 1.5	0.015
Sex
Female	1.3	0.9, 1.7	0.14
Male	1.0	1.0
Race
Non-White or Hispanic	1.3	0.9, 2.1	0.19
White non-Hispanic	1.0	1.0
Model 1: Diagnosis
Leukemia	1.4	0.9, 2.4	0.16
CNS	1.5	0.7, 3.1	0.26
Lymphomas (HD, NHL)	1.4	0.8, 2.6	0.25
Ewing sarcoma or osteosarcoma	1.9	1.04, 3.5	0.04
Wilms, neuroblastoma, soft tissue sarcoma	1.0
Model 2: Treatment exposures
IV methotrexate, >10,000 mg/m2
Yes	1.6	1.1, 2.3	0.01
No	1.0
Model 3: Chronic health conditions
Respiratory
Yes	1.8	1.2, 2.5	0.002
No	1.0
Gastrointestinal
Yes	1.6	1.1, 2.3	0.01
No	1.0
Musculoskeletal
Yes	1.4	0.9, 2.2	0.09
No	1.0
Neurological
Yes	1.5	1.03, 2.1	0.03
No	1.0
Model 4: Psychosocial factors
Depressive and anxiety symptoms
Both clinically significant	2.9	2.0, 4.2	<0.0001
Either clinically significant	1.8	1.3, 2.5	0.001
Neither clinically significant	1.0
Full-time employment
No	1.4	1.0, 1.9	0.05
Yes	1.0

Models 1 to 4 also adjusted for variables in model 0: age at cancer diagnosis, age at baseline questionnaire, sex, and race/ethnicity. Chronic conditions = grades 2 to 4.

CI, confidence interval; PR, prevalence ratio.

Psychosocial variables included in the multivariable Model 4 included depression, anxiety, and employment status. Survivors who reported clinically significant levels of depression and anxiety (PR = 2.9, 95% CI 2.0-4.2, P < 0.0001) or either clinically significant levels of depression or anxiety (PR = 1.8, 95% CI 1.3-2.5, P = 0.001) were more likely to experience chronic pain. Moreover, lack of full-time employment was associated with chronic pain (PR = 1.4, 95% CI 1.0-1.9, P = 0.05; Table 4). Although significant in univariate models, fear of cancer recurrence and sleep did not contribute significantly in multivariable modelling. Pain catastrophizing was not included in this model as only those participants who reported having chronic pain completed the PCS.

3.5. Risk factors associated with pain interference

All univariate models calculated to assess the effect of individual risk factors (ie, treatment exposures, chronic conditions, and psychosocial factors) on pain interference can be found in the supplementary materials (Supplementary Table 3, http://links.lww.com/PAIN/C65). In the univariate models, no significant associations emerged between pain interference and treatment exposures, and as a result, no multivariable treatment model was calculated. The patient demographic factors selected a priori were not significant in the chronic conditions or psychosocial factors multivariable modelling (Table 5, Model 0). In adjusted multivariate models, no cancer diagnoses were associated with higher levels of pain interference compared with the referent group of Ewing sarcoma and osteosarcoma, although this may be due to small numbers within each diagnostic group (Table 5, Model 1). In the chronic health conditions multivariable model, higher pain interference was positively associated with cardiovascular (B = 9.7, 95% CI 2.9-16.6, P = 0.005) and neurological (B = 11.1, 95% CI 3.4-18.8, P = 0.005; see Table 5, Model 2) conditions.

Table 5.

Risk factors for pain interference in adult survivors with chronic pain.

Risk factor	B	95% CI	P
Model 0: Survivor characteristics
Age at cancer diagnosis (per 10 y)	−2.1	−9.3, 5.1	0.56
Age at baseline questionnaire (per 10 y)	1.7	−3.2, 6.5	0.50
Sex
Female	3.9	−3.2, 10.9	0.28
Male	0
Race
Non-White or Hispanic	−4.6	−14.6, 5.5	0.38
White non-Hispanic	0
Model 1: Diagnosis
Leukemia	−0.5	−10.8, 9.7	0.92
CNS	−7.1	−21.7, 7.5	0.34
Lymphoma (HD, NHL)	−2.9	−13.7, 8.0	0.60
Wilms, neuroblastoma, soft tissue sarcoma	−1.7	−14.7, 11.3	0.79
Ewing sarcoma or osteosarcoma	0.0
Model 2: Chronic health conditions
Cardiovascular
Yes	9.7	2.9, 16.6	0.005
No	0
Neurological
Yes	11.1	3.4, 18.8	0.005
No	0
Model 3: Psychosocial factors
Depressive and anxiety symptoms
Both clinically significant	19.0	9.5, 28.5	<0.0001
Either clinically significant	7.9	1.0, 14.8	0.024
Neither clinically significant	0
Fear of cancer recurrence
Yes	8.7	1.0, 16.5	0.026
No	0
Full-time or part-time employment
No	10.5	3.6, 17.5	0.003
Yes	0

Models 1 to 3 also adjusted for variables from model 0: age at cancer diagnosis, age at baseline questionnaire, sex, and race/ethnicity.

B, slope; CI, confidence interval.

Depression, anxiety, fear of cancer recurrence, and employment status were included in the psychosocial multivariable model for pain interference. Like chronic pain, survivors who reported clinically significant levels of both depressive and anxiety symptoms (B = 19.0, 95% CI 9.5-28.5, P < 0.0001) or either depressive or anxiety symptoms (B = 7.9, 95% CI 1.0-14.8, P = 0.024) reported higher levels of pain interference compared with those with neither. Survivors with clinical levels of fear of cancer recurrence also reported higher levels of pain interference (B = 8.7, 95% CI 1.0-16.5, P = 0.026). Unemployment (B = 10.5, 95% CI 3.6-17.5, P = 0.003) was also associated with increased levels of pain interference (Table 5, Model 3). Of note, when pain catastrophizing was included in the model, the associations between depressive and anxiety symptoms and pain interference were no longer statistically significant, and associations between unemployment and pain interference were attenuated (Supplementary Table 4, http://links.lww.com/PAIN/C65). The only statistically significant association that emerged in this model was for pain catastrophizing (B = 0.8, 95% CI 0.5-1.1, P < 0.0001).

3.6. Ecological momentary assessment daily diary measures

Participants completed 45.5% (510 of 1120) of the total possible daily diaries expected from 80 survivors who participated in the EMA, with a mean of 6.4 (SD = 3.5) per person during the 14-day EMA study period. Completion rates of daily assessments and mean completed daily assessments completed dropped from week 1 (53.9% completion rate; M = 3.8 completed daily assessments) to week 2 (37.1% completion rate; M = 2.6 completed daily assessments). Diary completion rates by day and the percentage of pain free days and elevated pain days are shown in Supplementary Table 5, http://links.lww.com/PAIN/C65. Participants' completion rate of daily assessments by demographics and clinical characteristics can be found in Supplementary Table 6, http://links.lww.com/PAIN/C65. As shown in Supplementary Table 5, http://links.lww.com/PAIN/C65, the completion rate started high on Day 1 (n = 80; 100%) but quickly dropped below 50% by Day 2 for the remainder of the 14-day period, apart from day 7 (52.5% completion). Results also indicated that few survivors experienced pain-free days with these rates ranging from 2.3% (Day 5) to 35.3% (Day 13). With respect to elevated pain days, these ranged from 15.4% to 37.9% across the 14 days. Overall, elevated levels of average pain (≥5) and pain interference (≥5) were endorsed by participants on 28.2% and 24.6% of completed daily assessments, respectively. Participants reported elevated levels of depression (≥3) on 45.3% of completed daily assessments, and anxiety (≥3) on 47.2% of completed daily assessments. Figure 1A shows the mean average pain, worst pain, and pain interference scores across the two-week study period, whereas Figure 1B shows the mean anxiety, depression, and sleep scores across this study period.

Figure 1.

(A) Mean daily average pain, worst pain, and pain interference scores across 2-week period. (B) Mean daily anxiety, depression, and sleep scores across 2-week period.

3.6.1. Multilevel mixed model predicting daily ecological momentary assessment pain intensity and using sleep quality, anxiety, and depressive symptoms

Initial models testing interactions between each predictor and sex indicated a need to stratify these analyses by sex (many interactions' P < 0.10). Models with significant associations of prior measures with daily measures are shown in Table 6. Low sleep quality the night before predicted high pain intensity the next day for males (B = 0.4, 95% CI 0.1-0.6, P < 0.01) but not for females (B = 0.0, 95% CI −0.3 to 0.2, P = 0.86; Table 6). Similarly, elevated anxiety (B = 0.3, 95% CI 0.1-0.5, P < 0.01) and elevated depressive symptoms (B = 0.3 CI 0.1-0.4, P < 0.01) predicted high pain intensity the next day for males but not for females (B = 0.0 CI −0.2 to 0.2, P = 0.94; B = 0.1 CI −0.1 to 0.2, P = 0.45; Table 6).

Table 6.

Multilevel model predicting daily ecological momentary assessment of pain intensity and pain interference.

	Male			Female
	B	95% CI	P	B	95% CI	P
Pain intensity
Sleep quality	0.4	0.1, 0.6	0.004	−0.0	−0.3, 0.2	0.86
Anxiety	0.3	0.1, 0.5	0.003	−0.0	−0.2, 0.2	0.94
Elevated anxiety (≥3)*	0.8	0.1,1.5	0.03	−0.4	−1.3, 0.4	0.28
Depressive symptoms	0.3	0.1, 0.4	0.009	0.1	−0.1, 0.2	0.45
Pain interference
Elevated pain intensity (≥5)†	2.1	1.4, 2.8	<0.0001	0.6	−0.1, 1.3	0.12
Sleep quality	0.3	0.0, 0.7	0.03	−0.0	−0.4, 0.3	0.77
Anxiety	0.2	0.0, 0.5	0.047	0.1	−0.2, 0.3	0.61
Depressive symptoms	0.4	0.2, 0.6	<0.001	0.2	−0.0, 0.4	0.07
Elevated depressive symptoms (≥3)*	1.3	0.6, 2.1	<0.001	−0.1	−0.9, 0.7	0.85

All outcomes and predictors were measured continuously except where otherwise noted.

^*≥3 score on 0 to 6 scale; anxiety and depressive symptoms in the past 24 hours.

^†≥5 pain intensity on 0 to 10 numerical rating scale; pain intensity = average pain intensity in the past 24 hours.

CI, confidence interval.

3.6.2. Multilevel mixed model predicting daily ecological momentary assessment pain interference using pain intensity, sleep quality, anxiety, and depressive symptoms

Elevated pain intensity (>5) predicted high pain interference the next day for males (B = 2.1 CI 1.4-2.8, P < 0.0001) but not for females (B = 0.6 CI −0.1 to 1.3, P = 0.12). Low sleep quality the night before predicted high pain interference the next day for males (B = 0.3 CI 0.0-0.7, P < 0.05) but not for females (B = −0.0 CI −0.4 to 0.3, P = 0.77. Increasing anxiety (B = 0.2 CI 0.0-0.5, P < 0.05) and increasing depressive symptoms (B = 0.4 CI 0.2-0.6, P < 0.001) predicted high pain interference the next day for males but not for females (B = 0.1 CI −0.2 to 0.3; P = 0.61; B = 0.1 CI −0.1 to 0.2, P = 0.07).

3.7. Ecological momentary assessment weekly diary measures

Of survivors that completed the weekly diary measures (n = 79), 62% during week 1 and 64.5% during week 2 endorsed the use of nonprescription medication to reduce pain. Comparatively, only 21.5% during the first week and 17.7% during the second week reported using prescription medications for pain management. Common pain management strategies included rest/sleep (50.6% week 1 and 43.6% week 2), massage/rubbing (32.9% week 1 and 24.2% week 2), and relaxation exercises (25.3% week 1 and 27.4% week 2). Additional data regarding pain management strategies during the 2-week EMA period can be found in Supplemental Table 7, http://links.lww.com/PAIN/C65. Regarding interpretation of pain as a cancer threat, 24% of survivors with chronic pain endorsed agreeing a little or somewhat that “when I feel pain, I worry that the pain is caused by my cancer coming back,” whereas 5.1% endorsed agreeing a lot or agreeing very much. In relation, 22.8% of survivors with chronic pain endorsed agreeing a little or somewhat that “when I feel pain, I worry that the pain is caused by me having a new type of cancer,” whereas 11.4% endorsed agreeing a lot or agreeing very much.

4. Discussion

This is the first published study to characterize the prevalence and risk factors of chronic pain and pain interference, including comprehensive assessment of cognitive affective risk factors in adult survivors of childhood cancer. Approximately 41% of adult survivors from this representative sample of the CCSS population reported chronic pain. A large proportion of survivors with chronic pain reported moderate to severe pain interference (72%) and pain for >10 years (32%). Survivors with chronic pain reported elevated pain intensity and pain interference in approximately one-quarter of all daily assessments. Substantial psychological burden was also observed, with survivors with chronic pain reporting clinically significant depressive symptoms (44%), anxiety (34%), and fear of cancer recurrence (26%). These results underscore the substantial burden and consequences of chronic pain in long-term survivors of childhood cancer.

The prevalence of chronic pain in adult survivors of childhood cancer may be higher than that in the general population (estimated 20%).⁷⁴ As outlined in our developmental model of pain across the childhood cancer trajectory,¹ there are likely several biopsychosocial pathways through which survivors develop chronic pain and which differ from individuals without a cancer history. For example, in pediatric noncancer chronic pain, poorly treated acute pain strongly predicts chronic pain.^1,7,18,49 As most childhood cancer survivors have undergone multiple painful events (eg, surgeries, port access), they likely have more exposures to poorly treated acute pain, placing them at higher risk for chronic pain than the general population.

Studies by Patton et al. (2021, 2022) among pediatric and young adult survivors of childhood cancer (mean age = 17.3 years; range = 8-25 years; average time off treatment = 9 years) reported that only 20% endorsed living with pain,⁴⁶ but when specifically assessing chronic pain, they found 26.1% endorsed with total duration ranging from 6 months to 11 years.⁴⁵ In the current study, survivors were approximately 32 years from diagnosis and 40 year old on average. This is notable as long-term and older survivors may be at an increased risk for chronic pain due to increased risk of physical health-related morbidities.⁵ Indeed, our results indicated older current age was associated with an increased risk of chronic pain, whereas age at diagnosis was not. Therefore, this study adds to the broader pain and survivorship literature, which has shown mixed findings around age and pain.¹

Notably, the prevalence of chronic pain in this study was higher than pain prevalence estimates in prior studies of adult survivors of childhood cancer.^36,64 Such differences may be due to the current sample being slightly older than in previous studies (eg, 10.3% of survivors between 18 and 29 years vs 68.9% in the CCSS study by Lu et al. [2011]). Consistent with our prior observations of the literature,¹ these differences are more likely driven by the substantial variability in pain measurement across studies. For example, in the study by Lu et al. (2011), 3 pain conditions and current pain attributed to cancer or its treatment were assessed—while chronic pain was not. As such, many survivors with chronic pain may not have been included in these estimates.

IV methotrexate was the only treatment exposure associated with chronic pain. This finding differs from previous research in adult survivors of childhood cancer, which has shown associations between pain and platinum-based chemotherapy²⁵ and no associations with treatment exposures, with the exception of amputation and/or limb-sparing surgery.⁶⁴ IV methotrexate may represent a unique treatment exposure or a unique population that places survivors at an increased risk for chronic pain. However, future research is needed to examine this association. Consistent with our theoretical model,¹ several chronic health conditions were risk factors for chronic pain. Many chronic conditions carry the risk of acute and chronic pain, which could be exacerbated by preexisting chronic pain experienced from previous cancer treatments.¹

Survivors with chronic pain were more likely to experience clinically significant levels of either depressive or anxiety symptoms or both, with a particularly robust relationship between chronic pain and depressive and anxiety symptoms observed relative to other risk factors. Survivors with clinically significant levels of either depressive or anxiety symptoms were at lower risk of chronic pain compared with those with both. These results are consistent with findings from the general population.¹⁴ Due to our cross-sectional study design, the directionality of the association between chronic pain and symptoms of depression and anxiety remains unclear and necessitates future research.

Similarly, chronic health conditions and clinically significant levels of depressive and/or anxiety symptoms emerged as risk factors for elevated pain interference. When including pain catastrophizing, depressive and anxiety symptoms did not remain as statistically significant predictors of pain interference, perhaps due to the strong associations in the general population between pain catastrophizing and anxiety and depression.¹⁷ Among younger survivors of childhood cancer (age range = 8-25 years at study completion), higher pain catastrophizing has also been associated with higher fear of cancer recurrence⁶⁶ and chronic pain.⁴⁵ This robust association between pain catastrophizing and interference is consistent with the broader chronic pain literature.¹⁷ In this study, elevated fear of cancer recurrence was also a risk factor for elevated pain interference, which is a unique experience to survivors.

This study is the first to our knowledge to examine daily experiences of pain, mood, anxiety, and sleep among childhood cancer survivors who have chronic pain, including the unique associations between daily pain and related variables. In about one-quarter of all completed daily assessments survivors reported elevated anxiety, depression, pain severity, and pain interference. Consistent with the results from our multivariate models, many survivors with chronic pain face clinically significant pain daily and associated interference, low mood, and elevated anxiety. In addition, consistent with our hypotheses and prior research,^{2,20,59,62,63,69} low sleep quality, elevated anxiety, and elevated depressive symptoms predicted high pain intensity and pain interference the next day. However, these effects were only present among male, not female, survivors. There is some emerging evidence for sex and gender differences when examining the impact of psychological factors and sleep disruption on pain,²⁶ but these findings are mixed and largely based on experimental and non-EMA studies. Some studies also point to differences in pain management strategies, with women and girls reporting more frequent use of social support, and men and boys reporting more reliance on avoidance and/or distraction.^{26,28,37,53,67} Women are also more likely to use over-the-counter and prescription analgesics and to attend pain clinics.^11,38,47 Differential use of daily pain and coping strategies, with heavier reliance on avoidance by men may be one factor underlying the observed sex differences. Moreover, the potential role of environmental factors and societal gender roles cannot be neglected,^26,27 including factors such as family and childcare responsibilities. Because it is impossible to pinpoint the exact cause of these sex differences, these findings should be interpreted with caution and warrant further investigation. Overall, our weekly diary measures showed that survivors used a variety of strategies to reduce pain. In the general population, psychological interventions, such as cognitive behavioural therapy, are among the most effective in treating chronic pain.¹⁴ However, only around one-quarter of survivors endorsed using psychological strategies to manage pain.

Study limitations should be noted. First, the cross-sectional design of the non-EMA portion of the study precludes any inferences regarding causation and future studies using longitudinal designs to determine directionality would be beneficial. Follow-up studies using more diverse and larger samples of survivors are needed as our sample mostly identified as White and we had a relatively small sample of survivors with chronic pain (n = 96). A larger sample size would also allow for improved testing of potential differences in pain between subgroups. Completion rates for the EMA measures dropped off significantly across the 2-week period and were lower than those in previous EMA studies, with less than half (45%) of daily assessments completed, vs among other cancer and chronic pain populations with average completion rates ranging from 50% to 100%.^40,43 Although reminders were sent, the use of additional strategies for increasing completion may be helpful in future EMA pain studies among survivors. Use of monetary incentives may be especially helpful given higher completion rates in comparison to studies without monetary incentives.⁷³ Finally, it is possible mentioning chronic pain in our recruitment materials may have skewed responses, although survivors without pain were also encouraged to participate.

This study suggests chronic pain and elevated pain interference are common problems in adult survivors of childhood cancer. Therefore, it would be advantageous for clinicians to regularly assess for the presence of chronic pain and associated psychological difficulties among survivors. Survivors with chronic health conditions or significant levels of depressive and anxiety symptoms may be at especially high risk of chronic pain. Given the likely bidirectional nature of these associations, attention should also be paid to screening for depression and anxiety among survivors with chronic pain. Focus should also be placed on the unique and complex challenges survivors may face managing both chronic pain and multiple other chronic health conditions. Effective management of chronic health conditions and/or treatment of depression, anxiety, and fear of cancer recurrence in survivors may help prevent or reduce the burden of already present chronic pain and associated pain interference.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Appendix A. Supplemental digital content

Supplemental digital content associated with this article can be found online at http://links.lww.com/PAIN/C65.