Higher Risk for Neurocognitive Deficits in Children With ALL With Neuropathic Pain and Opioid Exposure

Cross-Section of Brain
Researchers assessed the effect of neuropathic pain and opioid exposure in children receiving treatment for acute lymphoblastic leukemia.

Neuropathic pain and opioid exposure may be risk factors for poor neurocognitive functioning in children with acute lymphoblastic leukemia (ALL) receiving treatment, according to results of a study published in Pain.

The objective of the study was to examine neuropathic pain and neurocognitive outcomes in children with ALL receiving treatment in a clinical trial (ClinicalTrials.gov Identifier: NCT00137111).

Patients (N=345) with ALL were enrolled in the study from St Jude Children’s Research Hospital. Stratified by sex, girls received 120 weeks of ALL treatment and boys received 146 weeks of treatment. None of the patients received prophylactic cranial radiation. Neurocognitive testing was performed at induction, reinduction, continuation, and at 2 years after treatment. The patients completed 1 (22.3%), 2 (32.8%), 3 (24.1%), or 4 (20.9%) of the neurocognitive assessments. Risk for poor neurocognitive functioning was evaluated.

Of the total cohort, 55.1% were boys; mean age was 6.9±4.6 years; 78.0% were White; 50.1% received standard or high-risk treatment; and baseline intellectual quotient was 97.1±16.5.

A total of 39% of patients reported neuropathic pain. Among these, 84% had 1 pain event, 15% had 2 events, and 2% had 3 events. Pain onset occurred at a median of 111 days (range, 0-805 days) after diagnosis, resolving at a median of 39 days (range, 1-1082 days). Opioids or gabapentin were prescribed. Opioids were more often prescribed to younger patients (median, 6.0 vs 7.8 years; P =.034).

Compared with age-normative data, the patients performed below age expectations and had poorer learning or memory at reinduction (P <.001) and at the end of therapy (P =.005). Parents rated their children as having attention or learning deficits at the end of therapy (P =.002) and at 2 years (P =.011). High at-risk scores were observed across time points for sustained attention, learning or memory, and ratings of attention or learning deficits (all P <.05).

More children in the pain vs no pain group had at-risk scores for learning or memory at the end of therapy (24% vs 12%; P =.046). Depending on the outcome, risk predictors for poorer performance included younger age at diagnosis, the female sex, and standard or high-risk treatment. For learning and memory, older age at diagnosis was a risk factor.

After adjusting for age, sex, and treatment risk, patients who received opioids compared with those who received gabapentin had poorer total recall (estimate, -0.73; P =.011), short delay recall (estimate, -0.57; P =.024), long delay recall (estimate, -0.62; P =.012), and learning slope (estimate, -0.45; P =.042). Patients who had more pain events had poorer total recall (estimate, -0.88; P =.023).

This study was limited by the focus on neuropathic pain, as graded by the National Cancer Institute Common Toxicity Criteria, and did not include self- or parent-reported pain.

Researchers concluded, “…patients who experience pain may require closer monitoring and additional intervention for neurocognitive impairment.”


Partanen M, Alberts NM, Conklin HM, et al. Neuropathic pain and neurocognitive functioning in children treated for acute lymphoblastic leukemia. Pain. Published online September 25, 2021. doi:10.1097/j.pain.0000000000002485