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. Author manuscript; available in PMC: 2023 Jun 1.
Published in final edited form as: Pain. 2021 Sep 25;163(6):1070–1077. doi: 10.1097/j.pain.0000000000002485

Neuropathic pain and neurocognitive functioning in children treated for acute lymphoblastic leukemia

Marita Partanen 1, Nicole M Alberts 2, Heather M Conklin 3, Kevin R Krull 3, Ching-Hon Pui 3, Doralina A Anghelescu 3, Lisa M Jacola 3
PMCID: PMC8948096  NIHMSID: NIHMS1739969  PMID: 34813516

Abstract

Children with acute lymphoblastic leukemia (ALL) often experience treatment-related neurocognitive deficits and significant pain. Pain may exacerbate these cognitive impairments. This study examined neuropathic pain and neurocognitive outcomes in survivors of childhood ALL treated with contemporary therapy on a clinical trial (NCT00137111). There were 345 survivors (45% female, M=6.9 years at diagnosis) that completed neurocognitive assessments including measures of sustained attention, learning and memory, and parent ratings of attention during at least one of four time points: on-therapy (Induction and Reinduction), end of therapy, and two years post-therapy. At-risk performance was defined as a score at least 1SD below the age-adjusted mean. Data on neuropathic pain (events, duration, and severity according NCI Common Toxicity Criteria) and pharmacologic pain management (opioids, gabapentin) were ascertained. Results showed that 135 survivors (39%) experienced neuropathic pain during treatment. Compared to those without pain, survivors with pain had greater memory impairments at end of therapy (CVLT-Total, 24% vs. 12%, p=0.046). Within the pain group, survivors who experienced a greater number of pain events (CVLT-Total=−0.88, p=0.023) and those who were treated with opioids (versus gabapentin) had poorer learning and memory performance (CVLT-Total=−0.73, p=0.011; Short Delay=−0.57, p=0.024; Long Delay=−0.62, p=0.012; Learning Slope=−0.45, p=0.042) across time points. These are considered medium-to-large effects (SD=0.45–0.88). Neuropathic pain may be a risk factor for learning problems after therapy completion, and treatment for pain with opioids may also adversely impact neurocognitive performance. Therefore, patients who experience pain may require closer monitoring and additional intervention for neurocognitive impairment.

Introduction

Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood. Survival rates are greater than 90%[45] with current treatment protocols, which include intrathecal chemotherapy for central nervous system (CNS)-directed prophylaxis. These treatments have resulted in relatively spared intellectual functioning when compared to protocols with cranial radiation[3; 23]; however, survivors continue to be at-risk for impairments, such as with attention, executive functioning, and processing efficiency[28; 43]. These deficits can persist into long-term survivorship, which impacts their quality of life[29; 34]. Younger age at diagnosis and greater intensity of treatment are established risk factors for poorer neurocognitive outcomes[7; 18; 20], and some evidence suggests that female sex, lower socioeconomic status, or adverse events such as severe infections may also influence outcomes[7; 9; 18; 21; 30].

Acute and chronic pain are commonly experienced during and after cancer treatment. Pain may be due to the underlying disease, treatment factors, or procedures, and it can lead to the development of secondary conditions such as peripheral neuropathy or chronic post-surgical pain[2]. These conditions, and the pain arising from them, can persist and impact a survivor’s quality of life[27]. Pain can also affect cognitive performance, including ability to concentrate or complete tasks efficiently if pain is not properly managed. In adult cancer groups, elevated pain scores[50] or experiencing pain during testing[47] has been associated with poorer cognitive performance. Also, pain that interfered with daily functioning was related to an increased risk of attention and memory impairments in adult survivors of childhood cancer[49]. Chronic opioid use or higher opioid dosage has been associated with poorer attention, reaction speed, and memory in adults with cancer[36]; however, findings for the impact of opioids on cognitive performance have been mixed[35; 42] and have not been examined within pediatric cancer groups.

Neuropathic pain is one type of pain that commonly occurs during cancer treatment. It is caused by a lesion or disease in the somatosensory system[10] and is associated with chemotherapy agents such as vincristine[4]. It has been estimated that 35–44% of children with ALL experience neuropathic pain during treatment[4; 37], and some children may continue to experience peripheral neuropathy[33] or neuropathic pain into survivorship. In the general population, neuropathic pain has been associated with poorer quality of life[48] and cognitive problems[25], although the evidence has been mixed. It is unknown how neuropathic pain impacts neurocognitive performance during treatment or into survivorship in childhood cancer groups.

In the current study, we examined whether exposure to neuropathic pain during treatment for childhood ALL was associated with neurocognitive performance at time points during treatment, at end of therapy, and two years post-therapy. Previous reports have shown that patients with ALL experience attention problems at end of therapy[11] and two years after therapy[30], as well as an increase in learning problems over time[30]. The current analysis focused on a subset of neurocognitive measures that are most likely affected due to pain (i.e., attention, learning, speed [36; 49]). We hypothesized that patients who experienced neuropathic pain would have poorer cognitive performance than those without neuropathic pain. Within those who experienced pain, we also explored whether pain medications (opioids vs. gabapentin) and pain intensity (number and duration of events) were associated with cognitive performance. Results from this study have potential to elucidate the factors contributing to cognitive impairment in patients treated for childhood ALL; in turn, this can inform monitoring and intervention guidelines for neurocognitive functioning and pain during and after treatment.

Methods

This research was approved by the Institutional Review Board (IRB) at St. Jude Children’s Research Hospital (SJCRH). All participants or their parent/guardian provided written informed consent and children provided their assent according to the rules of the IRB.

Treatment

Participants were diagnosed with ALL and were enrolled on a frontline therapy protocol at SJCRH (St. Jude Total Therapy XV, ClinicalTrials.gov, NCT00137111)[44]. Patients received risk-adapted chemotherapy, of which the outcomes have been described previously[44]. Children were classified as having low-risk or standard/high-risk ALL based on presenting clinical features, blast cell immunophenotype and genotype, and early treatment response. All patients received CNS-directed, triple intrathecal chemotherapy (methotrexate, cytarabine, hydrocortisone) starting in Remission Induction (13–18 treatments for low-risk; 16–25 treatments for standard/high-risk). In the Consolidation phase, patients received intravenous high-dose methotrexate followed by leucovorin rescue every other week for 4 cycles (2.5g/m2 for low-risk; 5.0g/m2 for standard/high-risk). During Continuation, intravenous methotrexate was given weekly (40mg/m2) with daily mercaptopurine for 3 weeks, interrupted on week 4 by pulse therapy consisting of vincristine plus dexamethasone (8mg/m2/day for 5 days for low-risk treatment; 12mg/m2/day for 5 days for standard/high-risk treatment), and two reinduction treatments (between weeks 7 and 9; and weeks 17 and 19). Treatment continued for 120 weeks for girls and 146 weeks for boys. None of the patients received prophylactic cranial radiation.

Participants

A total of 498 patients were enrolled on the clinical trial. Of these, 345 participants completed protocol-directed neurocognitive testing at least once during four time points: Induction, Reinduction I (Continuation Week 7–9), Continuation Week 120 (End of Therapy), and Two Years Post-Therapy. The majority of participants completed two or more assessments (n=268; 77.7%). Across time, participants completed one (n=77; 22.3%), two (n=113; 32.8%), three (n=83; 24.1%), or four (n=72; 20.9%) assessments. Participants were not eligible for neurocognitive assessments if they did not speak English as a primary language (n=16) or had Down syndrome or another pre-existing developmental condition (n=10). Missing data for eligible patients were due to various reasons (refusal to participate, scheduling challenges, patients taken off study).

Demographic and Clinical Information

Demographic, clinical, and treatment information were collected as part of the protocol. This included sex, race, age at diagnosis, and treatment risk arm (low-risk and standard/high-risk). Neuropathic pain events were identified as part of the protocol[4]. Neuropathic pain was diagnosed based on subjective descriptors (generalized pain or pain localized to jaw, back, lower extremities, abdomen) or functional impairment (e.g., refusal to bear weight, walk, eat). Descriptors of the quality (e.g., burning, shooting, tingling) at the time of diagnosis of neuropathic pain were also collected. Pain severity was used in the current analyses, which were defined and graded by research staff using NCI Common Toxicity Criteria V2.0[1]. For example, “moderate” pain was identified if it interfered with function but not activities of daily living (Grade 2) and “severe” pain was identified if it interfered with activities of daily living (Grade 3). Neuropathic pain was managed with gabapentin or opioids by the patient’s primary oncologist. Pain events were recorded according to clinical criteria, such as vincristine administration, as previously described[4]. For the current study, patients were identified as having zero or at least one neuropathic pain event during treatment.

Neurocognitive Measures

Patients ≥6 years old completed measures of sustained attention (Conners’ Continuous Performance Test [CPT][12]) and verbal learning and memory (California Verbal Learning Test [CVLT], Children’s[16] or Adult[15] Version). Primary caregivers of patients 3–17 years old completed a rating scale that measured concerns with attention, learning, or impulsivity-hyperactivity (Conners’ Parent Rating Scale, Revised [CPRS-R][13]). Age standardized norms included Z-scores (M=0, SD=1) where lower scores indicate worse performance, slower reaction time, or more ratings of problems (i.e., scores were converted to be on the same scale to assist with interpretation, where lower scores indicate an impairment). An estimated IQ score was obtained using Bayley-II[5] for patients 1–3 years old and age-appropriate Wechsler scales for patients 3 years and older (i.e., Information, Similarities, and Block Design subtests from WPPSI-III[54], WISC-III[52], and WAIS-III[53]). Scores from the Induction or Reinduction phases were used for this analysis. IQ scores are reported as standard scores (M=100, SD=15; lower scores indicate worse performance).

Analysis

Likelihood ratio tests, Fisher’s exact tests, and independent sample t-tests were used to examine differences in demographic and clinical characteristics between pain vs. no pain groups. In the overall cohort, one sample t-tests were used to compare mean performance on neurocognitive measures to standardized age norms and chi-square tests were used to examine frequency of at-risk performance at each time point (i.e., “at-risk” was defined as ≥1SD outside of the standardized mean, where 16% of patients would be expected to perform in this range). Fisher’s exact tests were used to compare whether the frequency of impairment differed between pain vs. no pain groups.

Linear mixed models with restricted maximum likelihood and autocorrelation structure (order 1, continuous) were used to examine relationships between pain and neurocognitive outcomes over time (using nlme package in R). In these models, outcome variables included performance on neurocognitive tests (i.e., sustained attention, learning/memory, ratings of attention/learning problems) and predictor variables included age at diagnosis (continuous in years), sex (male vs. female), risk group (standard/high vs. low), time (phase, continuous), and neuropathic pain group (pain vs. no pain). Within the pain group, predictor variables also included pharmacological pain treatment (opioids vs. gabapentin), total number of pain events (2+ vs. 1 event), and average duration of pain events (months, continuous). For all models, the pain (or medication) groups were modeled at level 1 and patients were maintained within the pain (or medication) group after their first exposure to pain (e.g., a patient could be in ‘no pain’ group at induction, and then ‘pain’ group for reinduction and subsequent time points).

Primary analyses focused on the overall cohort who completed at least one testing time point (n=345). Secondary analyses included the pain group who were treated with opioids or gabapentin (n=122). There were 13 patients who were excluded from pain treatment analyses, as they were treated with both opioids and gabapentin (n=9) or were treated with gabapentin for other central nervous system reasons (n=4). The same analytic approach was used for the overall cohort and the pain treatment group. All statistical comparisons were two-tailed and were considered significant at p<0.05. Analyses were conducted in R-4.0.0 (R-Core Team, Vienna, Austria).

Results

Participant Characteristics

Demographic and clinical information for the overall cohort and the pain comparison subgroups are shown in Table 1. There were no differences in sex, race, treatment risk arm, age at diagnosis, or IQ between pain and no pain groups (p>0.05).

Table 1.

Demographic and clinical information for overall cohort and neuropathic pain subgroups

Category Variable Overall Cohort (n=345) Neuropathic Pain (n=135) No Neuropathic Pain (n=210)
n % n % n % p †
Sex Female 155 44.9 67 49.6 88 41.9 0.18
Male 190 55.1 68 50.4 122 58.1
Race White 269 78.0 111 82.2 158 75.2 0.26
Black 64 18.6 21 15.6 43 20.5
Mixed Race/Other 12 3.5 3 2.2 9 4.3
Treatment Risk Group Low 172 49.9 65 48.1 107 51.0 0.66
Standard/High 173 50.1 70 51.9 103 49.0
M SD M SD M SD p †
Age at Diagnosis Years 6.9 4.6 7.2 4.6 6.7 4.7 0.36
Baseline IQ Standard Score 97.1 16.5 99.0 15.5 96.0 17.1 0.12
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Abbreviations: n: sample size; %: percent; Standard Score: age standardized norms from Bayley or Wechsler Scales (M=100, SD=15) obtained at Induction or Reinduction phases. Neuropathic pain group defined as those who experienced neuropathic pain at least once during treatment.

Notes

†

Fisher’s exact test, likelihood ratio, or independent samples t-test were used to examine differences between neuropathic pain vs. no neuropathic pain groups (p<0.05).

From the overall cohort, 135 patients (39%) experienced neuropathic pain at least once during treatment. Most patients experienced one pain event (n=113, 84%) and fewer experienced two (n=20, 15%) or three (n=2, 2%) events. Onset of pain occurred at a median of 111 days after diagnosis (M=139.5, SD=165.1, range=0–805), which resolved after a median of 39 days (M=217.7, SD=286.7, range=1–1082). Opioids or gabapentin were provided for pain management. Patients who received opioids were younger than those who received gabapentin (M=6.0 vs. 7.8 years, p=0.034; Supplementary Table S1). There were no other significant differences in demographic or clinical features between the two pain treatment groups.

Neurocognitive Performance in the Overall Cohort

Supplementary Table S2 describes neurocognitive performance for the overall cohort. Group means were in the low average to below average range for sustained attention and in the average range for learning/memory and parent ratings for attention and learning. Comparing the overall group mean to age normative data showed that participants performed below age expectations on measures of sustained attention at all time points (CPT Variability/Detectability, p<0.05). They also had poorer performance on measures of learning/memory at Reinduction (CVLT Learning Slope, p<0.001) and End of Therapy (CVLT Learning Slope, p=0.005). Parents rated greater attention or learning problems at End of Therapy (CPRS-R Attention/Learning, p=0.002) and Two Years Post-Therapy (CPRS-R Attention/Learning, p=0.011). The frequency of at-risk performance was greater than expected ranges (16%) across tests and time points, with the highest frequencies of at-risk scores in sustained attention (CPT, 25–50%, p<0.05), followed by learning/memory (CVLT, 22–43%, p<0.05) and ratings of attention/learning problems (CPRS-R, 22–26%, p<0.05).

Neurocognitive Performance in Pain versus No Pain Groups

Estimated performance for the neuropathic pain subgroups is illustrated in Figure 1 and Supplementary Figures S1 and S2, results from Fisher’s exact tests are shown in Table 2, and results from linear mixed models are shown in Tables 3–5. The frequency of impairment was largely similar across pain subgroups; however, the pain group (vs. no pain group) had greater frequency of at-risk scores for learning/memory at End of Therapy (CVLT Total Recall, 24% vs. 12%, p=0.046). Based on the 1SD definition of at-risk performance, 16% would be expected to have scores in this range. In linear mixed models, younger age at diagnosis, female sex, and standard/high-risk treatment group were significant predictors of poorer performance (p<0.05), depending on the outcome variable (Tables 3–5). Also, older age at diagnosis was associated with worse performance on measures of learning/memory (Table 4). After adjusting for covariates of age, sex, and treatment risk arm, there were no significant differences between pain and no pain groups in mean neurocognitive performance or interactions with time (p>0.05; Tables 3–5).

Figure 1.

Figure 1.

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Learning and memory performance for overall cohort and pain treatment group.

Notes: Tx = Treatment. Estimated performance on the learning/memory task (CVLT Total Recall) is shown for the effect of pain vs. no pain in the overall cohort (panel a) and opioids vs. gabapentin in the pain treatment group (panel b). Lower scores indicate worse performance and grey shaded areas indicate 95% confidence intervals. Linear mixed models included age at diagnosis (years, continuous), sex (male vs. female), risk group (standard/high vs. low), time (phase, continuous), and neuropathic pain group (pain vs. no pain). Within the pain group, predictor variables also included pharmacological pain treatment (opioids vs. gabapentin), total number of pain events (2+ vs. 1 event), and average duration of pain events (months, continuous).

Table 2.

Frequencies of at-risk neurocognitive performance in neuropathic pain subgroups

Test Score Testing Phase
Induction (n=132) Reinduction (n=166) End of Therapy (n=242) Two Years Post-Therapy (n=190)
NP Pain (%) No NP Pain (%) p ‡ NP Pain (%) No NP Pain (%) p ‡ NP Pain (%) No NP Pain (%) p ‡ NP Pain (%) No NP Pain (%) p ‡
Sustained Attention (CPT) Reaction Time 30.0 25.0 0.71 22.2 20.3 0.81 23.2 26.7 0.73 14.9 21.6 0.34
Variability 20.0 30.3 0.72 36.1 43.5 0.53 47.6 47.8 >0.99 41.9 40.5 0.88
Detectability 20.0 23.7 >0.99 36.1 39.1 0.83 48.8 46.7 0.88 54.1 47.4 0.46
Learning/ Memory (CVLT) Total Recall 30.0 22.4 0.69 21.1 25.0 0.81 23.5 11.7 0.046 20.5 22.6 0.86
Short Delay Recall 30.0 20.0 0.44 19.4 23.9 0.81 25.9 14.1 0.057# 23.3 24.3 >0.99
Long Delay Recall 20.0 21.3 >0.99 19.4 26.8 0.48 25.9 21.7 0.59 20.5 24.3 0.60
Learning Slope 20.0 33.3 0.49 44.4 42.3 0.84 23.5 34.1 0.13 30.1 22.6 0.30
Attention/Learning Problems (CPRS-R) Attention/Learning 12.5 12.1 >0.99 28.3 19.5 0.23 29.7 22.7 0.24 26.0 22.9 0.72
Impulsivity/Hyperactivity 0.0 16.4 0.13 20.8 22.1 >0.99 20.8 19.9 0.88 20.5 15.6 0.43
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Abbreviations: % = percent at-risk; SE=standard error; CPT: Conners Continuous Performance Test, CVLT: California Verbal Learning Test, CPRS-R: Conners Parent Rating Scale, Revised; NP=neuropathic

Notes: Lower scores indicate slower reaction time, worse performance, or more ratings of problems (M=0, SD=1)

‡

Fisher’s exact tests were used to examine if proportion of participants scoring in the at-risk range (i.e., 16%) was different between neuropathic pain vs. no neuropathic pain groups; grey highlighted cells are considered significant, p<0.05

#

a hashtag indicates a marginal effect (p<0.10).

Table 3.

Predictors of sustained attention performance in neuropathic pain subgroups

Model Predictor Variable Outcome Variables Across Time
Reaction Time Variability Detectability
Estimate (SE) p † Estimate (SE) p † Estimate (SE) p †
Overall cohort (n=345) Intercept −0.08 (0.22) 0.70 −0.67 (0.22) 0.002 −0.43 (0.18) 0.017
Age at diagnosis 0.01 (0.02) 0.47 0.05 (0.02) 0.007 0.01 (0.01) 0.40
Sex (Female vs. Male) −0.16 (0.15) 0.30 −0.37 (0.13) 0.006 −0.16 (0.12) 0.18
Risk (Standard/High vs. Low) −0.49 (0.17) 0.005 −0.39 (0.15) 0.010 −0.11 (0.13) 0.36
Time 0.10 (0.06) 0.08 −0.08 (0.06) 0.17 −0.15 (0.05) 0.002
Pain Group (Pain vs. No Pain) −0.19 (0.24) 0.43 −0.10 (0.29) 0.71 −0.22 (0.22) 0.31
Time * Pain Group 0.18 (0.10) 0.09 0.06 (0.12) 0.63 0.04 (0.09) 0.69
Pain treatment group (n=122) Intercept 0.14 (0.51) 0.79 −0.62 (0.53) 0.24 −0.17 (0.50) 0.74
Age at diagnosis 0.05 (0.03) 0.14 0.05 (0.04) 0.21 −0.02 (0.03) 0.58
Sex (Female vs. Male) −0.29 (0.27) 0.29 −0.34 (0.30) 0.25 0.01 (0.25) 0.99
Risk (Standard/High vs. Low) −0.71 (0.30) 0.019 −0.28 (0.33) 0.40 0.06 (0.28) 0.82
Time 0.23 (0.12) 0.059 −0.07 (0.11) 0.52 −0.26 (0.12) 0.039
Pain Treatment (Opioids vs. Gabapentin) −0.49 (0.29) 0.09 −0.17 (0.32) 0.59 −0.27 (0.27) 0.32
Number pain events (2+ vs. 1) −0.48 (0.39) 0.22 −0.50 (0.43) 0.25 −0.44 (0.35) 0.22
Average length of pain events −0.01 (0.01) 0.73 0.01 (0.01) 0.53 0.01 (0.01) 0.46
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Abbreviations: SE: standard error

Notes: Lower scores indicate slower reaction time or worse performance on sustained attention task (CPT; M=0, SD=1)

†

Linear mixed models were estimated for the overall cohort (n=345) and pain treatment group (n=122). Predictor variables included age at diagnosis (years, continuous), sex (female vs. male), risk group (standard/high vs. low), time (phase, continuous), and neuropathic pain group (pain vs. no pain). Within the pain group, factors also included pharmacological pain treatment (opioids vs. gabapentin), total number of pain events (2+ vs. 1 event), and average length of pain events (months, continuous). Grey highlighted cells are considered significant, p<0.05.

Table 5.

Predictors of attention/learning problems in neuropathic pain subgroups

Model Predictor Variable Outcome Variable
Attention/Learning Hyperactivity/Impulsivity
Estimate (SE) p † Estimate (SE) p †
Overall cohort (n=345) Intercept 0.18 (0.18) 0.33 −0.16 (0.13) 0.26
Age at diagnosis 0.02 (0.02) 0.32 0.04 (0.01) 0.004
Sex (Female vs. Male) −0.09 (0.13) 0.49 −0.12 (0.11) 0.27
Risk (Standard/High vs. Low) −0.47 (0.14) 0.001 −0.34 (0.12) 0.006
Time −0.12 (0.06) 0.027 0.03 (0.04) 0.38
Pain Group (Pain vs. No Pain) −0.06 (0.23) 0.78 0.09 (0.17) 0.59
Time * Pain Group −0.01 (0.11) 0.89 −0.02 (0.07) 0.79
Pain treatment group (n=122) Intercept 0.28 (0.50) 0.58 0.33 (0.37) 0.37
Age at diagnosis 0.01 (0.04) 0.90 −0.01 (0.03) 0.70
Sex (Female vs. Male) −0.25 (0.28) 0.38 0.12 (0.22) 0.58
Risk (Standard/High vs. Low) −0.43 (0.30) 0.16 −0.34 (0.23) 0.16
Time −0.17 (0.12) 0.15 −0.03 (0.08) 0.72
Pain Treatment (Opioids vs. Gabapentin) −0.19 (0.30) 0.53 −0.19 (0.23) 0.42
Number pain events (2+ vs. 1) 0.44 (0.42) 0.30 0.46 (0.32) 0.16
Average length of pain events 0.01 (0.01) 0.61 0.01 (0.01) 0.46
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Abbreviations: SE: standard error

Notes: Lower scores indicate more ratings of attention/learning problems (CPRS-R; M=0, SD=1)

†

Linear mixed models were estimated for the overall cohort (n=345) and pain treatment group (n=122). Predictor variables included age at diagnosis (years, continuous), sex (female vs. male), risk group (standard/high vs. low), time (phase, continuous), and neuropathic pain group (pain vs. no pain). Within the pain group, factors also included pharmacological pain treatment (opioids vs. gabapentin), total number of pain events (2+ vs. 1 event), and average length of pain events (months, continuous). Grey highlighted cells are considered significant, p<0.05.

Table 4.

Predictors of learning and memory performance in neuropathic pain subgroups

Model Predictor Variable Outcome Variables Across Time
Total Recall Short Delay Recall Long Delay Recall Learning Slope
Estimate (SE) p † Estimate (SE) p † Estimate (SE) p † Estimate (SE) p †
Overall cohort (n=345) Intercept 0.05 (0.20) 0.78 0.54 (0.19) 0.004 0.14 (0.20) 0.50 0.14 (0.18) 0.44
Age at diagnosis −0.02 (0.02) 0.19 −0.06 (0.02) 0.001 −0.03 (0.02) 0.10 −0.04 (0.01) 0.011
Sex (Female vs. Male) 0.24 (0.14) 0.09 0.18 (0.13) 0.16 0.19 (0.14) 0.18 0.09 (0.11) 0.40
Risk (Standard/High vs. Low) −0.09 (0.16) 0.58 −0.04 (0.15) 0.78 −0.02 (0.16) 0.89 −0.07 (0.12) 0.58
Time −0.02 (0.05) 0.81 −0.11 (0.05) 0.018 −0.06 (0.05) 0.21 −0.01 (0.05) 0.82
Pain Group (Pain vs. No Pain) −0.34 (0.22) 0.12 −0.36 (0.21) 0.09 −0.22 (0.22) 0.33 −0.06 (0.24) 0.81
Time * Pain Group 0.11 (0.09) 0.26 0.15 (0.09) 0.09 0.10 (0.10) 0.30 −0.03 (0.10) 0.74
Pain treatment group (n=122) Intercept 0.21 (0.49) 0.67 0.50 (0.43) 0.25 0.57 (0.42) 0.18 0.48 (0.43) 0.27
Age at diagnosis −0.01 (0.03) 0.73 −0.07 (0.03) 0.027 −0.05 (0.03) 0.12 −0.05 (0.03) 0.07
Sex (Female vs. Male) −0.09 (0.26) 0.73 0.18 (0.23) 0.45 0.06 (0.23) 0.78 0.39 (0.20) 0.06
Risk (Standard/High vs. Low) −0.45 (0.29) 0.12 −0.17 (0.25) 0.51 −0.12 (0.25) 0.65 0.05 (0.23) 0.82
Time 0.14 (0.12) 0.22 0.05 (0.10) 0.60 −0.01 (0.10) 0.90 −0.16 (0.12) 0.19
Pain Treatment (Opioids vs. Gabapentin) −0.73 (0.28) 0.011 −0.57 (0.25) 0.024 −0.62 (0.24) 0.012 −0.45 (0.22) 0.042
Number pain events (2+ vs. 1) −0.88 (0.38) 0.023 −0.49 (0.22) 0.15 −0.57 (0.32) 0.09 −0.29 (0.28) 0.30
Average length of pain events 0.01 (0.01) 0.30 0.01 (0.01) 0.38 0.01 (0.01) 0.28 −0.01 (0.01) 0.80
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Abbreviations: SE: standard error

Notes: Lower scores indicate worse performance on learning and memory task (CVLT; M=0, SD=1)

†

Linear mixed models were estimated for the overall cohort (n=345) and pain treatment group (n=122). Predictor variables included age at diagnosis (years, continuous), sex (female vs. male), risk group (standard/high vs. low), time (phase, continuous), and neuropathic pain group (pain vs. no pain). Within the pain group, factors also included pharmacological pain treatment (opioids vs. gabapentin), total number of pain events (2+ vs. 1 event), and average length of pain events (months, continuous). Grey highlighted cells are considered significant, p<0.05.

Neurocognitive Performance in Opioid versus Gabapentin Treatment Groups

Estimated performance for opioid and gabapentin treatment groups are illustrated in Figure 1 and Supplementary Figures S1 and S2, and results from linear mixed models are shown in Tables 3–5. Similarly to the overall cohort, standard/high-risk treatment group and older age at diagnosis for learning/memory performance were significant predictors (p<0.05). Differences between males and females did not reach significance (p>0.05). After adjusting for covariates of age, sex, and treatment risk arm, patients who were treated with opioids (vs. gabapentin) had poorer learning and memory performance (CVLT Total Recall, Estimate=−0.73, p=0.011; Short Delay Recall, Estimate=−0.57, p=0.024; Long Delay Recall, Estimate=−0.62, p=0.012; Learning Slope, Estimate=−0.45, p=0.042; Table 4). This corresponds to a 0.45–0.73 SD difference between opioid and gabapentin groups (or 7–11 standard score points where M=100, SD=15). Furthermore, patients who experienced two or three pain events had lower learning and memory performance compared to those who experienced only one pain event (CVLT Total Recall, Estimate=−0.88, p=0.023). This corresponds to a 0.88 SD difference between pain event groups (or 13 standard score points where M=100, SD=15). The frequency of impairment was similar between pain treatment groups based on chi-square analyses (p>0.05).

Discussion

Children with ALL who are treated with chemotherapy are at risk for neurocognitive impairments during and after treatment, and common adverse events such as pain may be an additional risk factor for impairment. In the current study, a large group of patients with ALL completed neurocognitive testing at protocol-directed time points and exposure to neuropathic pain was identified prospectively as part of a clinical trial. Participants had significant attention and learning impairments across time points and 39% experienced neuropathic pain; these results are consistent with previous reports examining cognitive[11; 28; 30] or neuropathic pain[4; 37] outcomes in ALL. The current study showed that exposure to neuropathic pain and receiving opioids for treatment of pain may place a patient at higher risk for neurocognitive deficits, particularly on measures of learning and memory. Patients who experienced neuropathic pain (vs. no neuropathic pain) had greater frequency of learning impairments immediately after treatment. Furthermore, patients who experienced two or three neuropathic pain events (vs. one event) and those who were treated with opioids (vs. gabapentin) had poorer learning performance across time points. The difference between groups is considered a medium to large effect, such that two or three pain events was associated with 0.88 SD lower memory scores than one pain event and treatment with opioids was associated with 0.45–0.73 SD lower memory scores than gabapentin. In terms of standard scores (where M=100, SD=15), this corresponds to a 7–13 standard score difference between groups and could also reflect a clinically significant finding. Duration of pain events did not appear to have an impact on neurocognitive outcomes. As most patients experienced neuropathic pain at the beginning phases of treatment, these results suggest that elevated pain during treatment may result in other factors that influence subsequent cognitive functioning. This suggests that cognitive difficulties may persist after pharmacologic pain treatment is discontinued, which could impact daily functioning or quality of life for this group of patients.

In adult cancer populations[47; 50] or adult survivors of childhood cancer[49], experiencing pain or receiving opioids for pain management may influence neurocognitive performance, although results for the impact of opioids on cognition have been mixed[35; 36; 42]. In pediatric groups, youth with chronic pain[38; 55] or with sickle cell disease and persistent pain[14] may also experience neuropsychological deficits, particularly in areas of attention, learning, and executive functioning. Furthermore, executive functioning skills may mediate the relationship between pain coping and quality of life in youth with sickle cell disease[39]. However, it remains inconclusive whether using opioids[32] or ketamine[6] for pain treatment impacts neurocognitive performance in children. The current study found that learning and memory was associated with pain or pain treatment, but sustained attention performance and parent ratings of attention/learning problems were not significantly associated. This could be related to power or because the learning task also relies on working memory, which is therefore a more mentally challenging task than the sustained attention task that involves adequate processing efficiency and executive skills. Also, it has been argued that neuroinflammation[19; 40] may explain the pathogenesis and overlap between pain, cognitive impairment, and other symptoms (e.g., depression, fatigue, stress) that are frequently experienced by patients with cancer. For example, chronic pain is associated with depression and sleep disruption, both of which can impact neurocognitive function. Also, chemotherapy may lead to increased inflammation, oxidative stress, and disruption of the blood-brain barrier, which results in poorer neurocognitive performance and affective symptoms[46]. Overall, these findings suggest that neuro-immune interactions may be similarly involved in pain and cancer treatment, which then impacts neurocognitive functioning. However, further longitudinal studies would be needed to examine the biological similarities between pain and neurocognitive impairment in children or adults with cancer. Future research could examine these underlying processes of neuropsychological functioning and associations with pain, and potentially how biological approaches (e.g., MRI, inflammatory markers) could assist in elucidating these relationships.

The current results suggest that it will be important to monitor patients who experience pain to ensure that pain management interventions are implemented in a timely manner. Also, it will be important to emphasize evidence-based non-pharmacologic interventions for pain (e.g., cognitive-behavioral therapy, relaxation, hypnosis[24]) given the potential impact of opioids on neurocognitive performance. For example, patients can complete brief monitoring or screening evaluations (e.g.,[22; 51]) of neurocognitive outcomes and pain scores at systematic time points; if there is concern from the screening evaluation, additional assessment or targeted interventions can be provided. The purpose of this type of monitoring would be to identify deficits at an early phase in any patient with ALL. Future studies would be needed to determine if other pediatric cancer groups who frequently experience pain (e.g., bone tumor) also experience cognitive deficits in relation to pain or its treatment.

This study examined a common pain occurrence (neuropathic pain) during treatment for ALL, which is often related to the administration of vincristine[4]. The occurrence and severity of neuropathic pain was graded prospectively according to NCI Common Toxicity Criteria; however, self-report and parent-report measures of neuropathic pain[41] and pain-related disability were not included in this study. Furthermore, other types of pain (e.g., post-surgical pain, chronic pain, acute pain due to painful procedures) as well as anxiety, depression, or stress in children or parents were not collected in the current study. Previous research has shown that adult survivors of childhood cancer who experience pain with daily interference have poorer neurocognitive outcomes [49] and that both child and parent psychological factors (e.g., child stress, parent pain catastrophizing) may influence a child’s functioning[17]. Future research should use a comprehensive approach to examine additional measures of pain and interacting factors such as child and parent psychological functioning on neurocognitive outcomes. It is suggested that future research explore these relationships with larger samples, preferably in multi-center clinical trials. Finally, patients who were treated with opioids for pain were younger than those who were treated with gabapentin. This difference in age between groups may explain some of the results in the pain treatment group, as young age has been shown as a risk factor for neurocognitive impairments in ALL[7] (although results have been mixed, see [8]). However, age at diagnosis and other covariates were included in statistical modeling to help account for these factors and the finding for opioids (vs. gabapentin) were shown on a measure where older age (not younger age) was a risk factor for poorer performance. Therefore, poorer performance for opioids compared to gabapentin does not appear to be driven by age factors alone. In future research, it will be important to examine the influence of different types of medications (e.g., opioids, gabapentin) for various age groups through randomized control (vs. observational) trials.

Attention and learning problems are common in children who receive treatment for ALL but are variable among those undergoing similar treatment. Experiencing neuropathic pain or receiving opioids for treatment for pain may explain some of this variability in learning problems. These results suggest that patients who experience pain may require closer monitoring and additional intervention for neurocognitive impairment. For example, recent findings describe how monitoring is considered the first step in the intervention process[31] and potential approaches may include compensatory strategies, pharmaceutical medications, cognitive remediation, computerized training, or increasing physical activity[26]. Future longitudinal research should examine relationships between pain and neuropsychological performance in other patient samples and with complementary measures (e.g., child/parent ratings of pain) to examine the generalizability and long-term effects of pain in children with cancer.

Supplementary Material

Supplementary Materials: figures, tables

Footnotes

Conflict of Interest Statement

The authors have no conflicts of interest to disclose.

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Supplementary Materials: figures, tables
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