In six cohort studies [7, 8, 10,11,12,13] and one qualitative case study [9], opioids used for pain management in children (n = 914) undergoing HSCT included morphine [8,9,10,11,12], fentanyl [10,11,12], and hydromorphone [8, 10, 12], primarily via PCA, for acute pain related to mucositis [8, 10, 12] or graft-versus-host disease [8].

While opioid dosing varied, relatively high doses were necessary for extended periods, particularly in young children. Notable age-related differences were observed in one study reporting PCA initiation around day +3, with average MED (mg/kg/day) as 21 and 16, over durations of 40 and 25 PCA-days, in children younger and older than 6 years, respectively [10]. Another study reported 2–22 days (mean 17.65) of opioid utilization, with MED (mg/kg/day) 0.09–1.88, which was noted to be 3–5.6 times higher than adult doses [9]. Dunbar et al. reported bolus doses of morphine (20 mcg/kg) and hydromorphone (3 mcg/kg), with 8-min lockout intervals, for a PCA duration averaging 19 days [8]. In a study of 230 patients with high-risk neuroblastoma, those treated with carboplatin/etoposide/melphalan (CEM) for autologous stem cell rescue required opioids for a significantly longer duration compared with those treated with busulfan/melphalan (BuMel), especially in the first 30 days after transplant (mean 13.77 versus 9.90 days, p < 0.0001) [13]. Similarly, another study of 578 patients with HSCT with high-risk neuroblastoma found that the duration of opioid use was significantly shorter in the BuMel group (median 9 days) versus the CEM (median 15 days) and tandem groups (median 23.5 days; p < 0.0001) [7]. These two studies highlight that the level of toxicity associated with the conditioning regimen is a key factor that can impact the duration of opioid use post-HSCT.

Opioid tapering practices, PS, and withdrawal symptoms were examined in 45 HSCT recipients, including 12 children aged 7–18 years. Children received significantly higher MED (mean 24.95 mg/kg) than adults during the taper, primarily for mucositis pain, with an average PS of 1–2 on a 0–5 scale, during the first 10 days. Wide variations occurred in tapering, ranging from 67% decreases to 14% increases, with sparse nursing documentation [12]. Opioid-related adverse effects were generally minimal, with no reported cases of respiratory depression, overdose, or opioid misuse [8]. However, withdrawal symptoms were commonly reported during opioid tapering, peaking around taper days 2–6 [12].

One qualitative case study highlighted challenges in managing severe and persistent pain in children undergoing HSCT. Despite representing the foundation of pharmacological pain management, opioids were often insufficient in achieving adequate analgesia, due to the multifactorial nature of pain and the complexities of post-HSCT complications. Multimodal analgesia, combining opioids with adjuvants such as ketamine and clonidine, was utilized. Evidence-based guidelines are necessary to lead to consistent practices [11].

Mucositis, a common adverse effect of chemotherapy and radiation, involves gastrointestinal mucosa ulceration, pain, compromised oral hydration, nutrition, and infection risks [113]. We identified 12 studies (Table 1) focused on opioids for mucositis pain in pediatric oncology [14,15,16,17,18,19,20,21,22,23,24,25]; eight investigated IV (including PCA), subcutaneous, or topical opioids [14,15,16, 18, 20, 21, 23, 25], and four focused on nonopioid agents and used opioids for breakthrough pain [17, 19, 22, 24].

All patients with grade ≥ 3 mucositis required IV opioid therapy for analgesia in a study that investigated the clinical characteristics of children and adolescents post-HSCT [16]. A study of pediatric patients with Ewing sarcoma and esophagitis grade ≥ 2 indicated neutropenia and esophageal radiation therapy as risk factors; effective analgesia was attained with oral hydrocodone, fentanyl patch, and immediate-release morphine, with decreased opioid need within 2–5 days [14].

A prospective evaluation in 16 children and young adults (median age 18 years) with pain from esophagitis/mucositis reported good analgesia with IV/subcutaneous morphine infusions, median dose 0.11 mg/kg/h, over 8 days, but dose-limiting toxicity was noted [25]. Two studies reported PCA delivery for post-HSCT mucositis-related pain [15, 20]. In a prospective randomized study (n = 20), of morphine PCA versus continuous infusion (CI), PCA dosing was bolus 15 mcg/kg every 10 min, with basal infusion added at night equal to the hourly average over the prior 16 h. The CI group started at 15 mcg/kg/h after loading with 45 mcg/kg, with titration by staff as needed. Significant differences were observed in mean cumulative morphine use, as 4.94 and 12.17 mg/kg for PCA and CI, respectively (p < 0.01). There were no significant differences in PS or adverse effects between groups. The PCA group reported less sedation and difficulty concentrating [20].

In a double-blind, crossover study, mucositis-related pain was treated by PCA in ten post-HSCT children; morphine and hydromorphone were alternated between days 1–3 and 4–6, then reverted to the initial opioid on days 7–9. Bolus doses were up-titrated per protocol, by 25–100%, up to four doses per hour. Basal rates increased similarly if the pain persisted. Morphine and hydromorphone groups (defined based on the initial opioid) had similar PS, nausea/vomiting, sedation, and pruritis scores, with no significant differences in efficacy or side effects [15].

Two studies investigated the addition of ketamine to morphine PCA/NCA [18, 23]. Of 33 children aged 0.3–13.6 years (mean 5.1) with mucositis pain treated with morphine PCA boluses, 27 had NCA and 6 had PCA. Due to insufficient analgesia by day 6 (median, day 4), ketamine was added to morphine and infusions lasted 5–32 days (median 16.8). No statistical difference was noted between average morphine use pre- and post-ketamine addition. Ketamine addition led to significant reductions in the proportion of PS ≥ 4, in PCA and NCA groups. Side effects of nausea/vomiting and pruritus were not statistically significant after ketamine addition. There were no reports of significant adverse effects in either group [18].

In a retrospective study of 100 severe mucositis episodes in 82 children (3–14 years), treatment modalities included morphine only PCA or NCA, morphine with ketamine post-PCA initiation, or morphine with ketamine from the outset. Morphine bolus was 20–40 mcg/kg every 5–20 min, with infusion 0–40 mcg/kg/h. Morphine analgesia was insufficient in 26%, more common in older females (median age 12 versus 7 years). Side effects were minimal and similar between groups. Adding ketamine to morphine PCA correlated with reduced morphine use and improved PS in children with escalating morphine requirements [23].

In a retrospective study, 34 children (median age 13.5 years) with severe mucositis received IV tramadol 1 mg/kg every 6 h (maximum 400 mg/day). Unrelieved pain prompted tramadol 2 mg/kg every 6 h. If pain persisted, morphine 0.1 mg/kg IV every 2 h was administered. Patients requiring more than four rescue doses/24 h received morphine PCA in addition to tramadol. Tramadol alone successfully treated 63% of episodes; 28% required IV morphine rescue. Patients needing morphine had higher PS (p < 0.0001), particularly with grades 3–4 mucositis. Side effects were milder in those receiving tramadol alone [24].

Analgesia and absorption characteristics of oral topical morphine were investigated in 12 children (ages 2–17 years) with chemotherapy-induced oral mucositis, receiving an aqueous solution (1 or 2 mg/mL) via atomizing spray, initially 4 mg/kg, adjusted for subsequent patients, administered every 3 h for three doses. Children received acetaminophen and supplemental opioids (morphine PCA or oral morphine/oxycodone) as needed. Six out of seven children experienced reduced PS with topical morphine doses of 0.025–0.4 mg/kg, and three required additional morphine IV or oxycodone. Side effects included a brief burning or itching sensation in the mouth. In the absorption study, five patients received a single dose of 0.05 mg/kg topical morphine, and plasma concentrations remained below the limit of quantification for up to 180 min postadministration [21].

Three prospective RCTs explored non-opioid approaches for oral mucositis prevention or treatment, with opioids reserved for uncontrolled pain. Caphosol, a calcium/phosphate solution resembling saliva, was evaluated in 19 patients with pediatric cancer. Although peak PS were similar between caphosol and placebo groups, patients in the caphosol group experienced pain for a longer duration, required higher morphine peak doses (mean 0.89 mg/kg versus 0.77 mg/kg; p = 0.583), and used morphine for a significantly longer period (15.5 versus 9.1 days; p = 0.035) [22]. Laser photobiomodulation was compared with placebo sham laser in 101 pediatric patients with chemotherapy-related mucositis. While baseline PS were similar, self-reported PS were significantly lower in the laser group and the analgesic consumption was not significantly different [17]. Oral cryotherapy feasibility during chemotherapy was assessed in 53 patients with HSCT. Children with severe mucositis received significantly more opioids than those with lower-grade mucositis in both duration and dose (mean 13 days and 8.8 mg/kg versus 5 days and 1.9 mg/kg; p < 0.001) [19].

The narrative review search identified 14 articles (Table 2) relevant to the role of opioids for NP in pediatric oncology [36, 50,51,52,53,54,55,56,57,58,59,60,61,62]. Mechanisms and etiologies for NP in children with cancer are diverse. A retrospective review (n = 160) reported NP in 16% of children with cancer (excluding leukemia/brain tumor), mean (SD) age 11.8 (4) years, range 5–18 years, most frequently with diagnosis of osteosarcoma (38%). Causes of NP were compression of a nerve/root/spinal cord (35%), limb-sparing (LS) and amputation surgery (28%), and chemotherapy/vincristine (19%). Gabapentin was the first line of treatment for NP (85%); nevertheless, opioid administration became more common with disease progression (p < 0.05), and good or partial responses to treatment were reported in 73% [50].

The use of opioid therapy has been reported for a rare complication of chemotherapy in pediatric oncology patients, which involves a neuropathic type of pain as part of the plantar erythrodysesthesia syndrome (PPES). In a retrospective investigation of 22 patients treated with high-dose methotrexate or cytarabine who experienced PPES, 82% required treatment with opioids for pain, and 23.1% of episodes required admission for parenteral pain management. Although rare in children, PPES symptoms recurred during subsequent courses of chemotherapy in half of the patients, and more than 25% of subsequent chemotherapy courses were complicated by PPES, indicating a high risk of recurrence; older age and genetic variables are suggested associations with PPES within the pediatric population [62].

The literature review identified several NP circumstances: (1) acute NP episodes during immunotherapy with chimeric 14.18 antibodies for high-risk neuroblastoma [51,52,53,54]; (2) chronic NP post-LS and amputation surgeries for bone malignancies [56,57,58,59, 61]; (3) vincristine/chemotherapy-related NP, during treatment for acute lymphoblastic leukemia (ALL) [55, 60]; and (4) NP in the EOL context [