Combination Therapy with Pregabalin and Morphine Relieves Dinutuximab-Induced Pain in a 3-Year-Old Girl: A Case Report

Abstract

Introduction:

Opioids are commonly initiated prior to dinutuximab (DIN)—an anti-disialoganglioside 2 antibody used in the treatment of neuroblastoma—and continued for approximately 2 hours after administration to manage DIN-associated pain. However, pain control remains insufficient with standard opioid treatment.

Methods:

We treated a 3-year-old girl with high-risk neuroblastoma who received DIN after tandem transplantation. During the first treatment cycle, despite scheduled morphine therapy, she developed abdominal pain rated as 5 on the Faces Pain Scale (FPS; range 0–5, where 0 indicates no pain and 5 indicates the worst pain), indicating the need for higher doses, prolonged infusion, and additional bolus analgesia. The dosing period and DIN dosage in the second cycle were similar to those in the first cycle. To improve pain control during the second cycle, pregabalin was initiated at a dose of approximately 1 mg/kg/day 3 days prior to DIN administration.

Results:

This approach significantly reduced abdominal pain, with the maximum FPS score decreasing to 2.

Conclusion:

This case highlights that adding pregabalin to standard opioid therapy can contribute to improved management of DIN-induced pain.

Keywords

dinutuximab pregabalin pain control pediatric neuroblastoma neuropathic pain

Introduction

Dinutuximab (DIN) is a monoclonal antibody used for the management of neuroblastoma after high-dose chemotherapy. DIN targets disialoganglioside 2 (GD2), a glycolipid abundantly expressed on human neuroblastoma cells, and exerts antitumor effects via antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.^1–2 According to standard recommendations, DIN is administered via intravenous infusion once daily over 10–20 hours. Each cycle lasts 28 days, with DIN administered for 4 consecutive days and withheld for the remaining 24 days. A total of six cycles is completed.

Pain occurs in 33%–88% of pediatric patients receiving DIN injections.³ DIN-induced pain is believed to be related to its binding to GD2 expressed on peripheral nerve fibers, leading to pain pathway activation.³ For this reason, the package insert recommends initiating opioid analgesics prior to DIN administration and continuing until 2 hours after infusion is complete. In our institution, the standard pain management protocol for DIN administration, based on a domestic Japanese phase IIb trial,⁴ includes continuous intravenous morphine infusion at 20 µg/kg/h initiated prior to DIN administration and continued for approximately 2 hours after completion. A bolus dose equivalent to 1 hours of infusion is administered at initiation and upon pain onset. In addition, intravenous acetaminophen (10 mg/kg per dose) is administered regularly during DIN therapy (Table 1).

Table 1.

The Standard Pain Management Protocol for DIN Administration

Analgesics	Dosage	Administration timing
Continuous morphine infusion	20 µg/kg/h	From before DIN administration to approximately 2 hours after completion
Morphine bolus administration	A dose equivalent to 1 hours of infusion	Initiation of continuous morphine administration and upon pain onset
Acetaminophen	10 mg/kg per dose	Four times daily during DIN therapy

Meanwhile, DIN-beta is an anti-GD2 antibody approved in Europe and manufactured using hamster cells, whereas DIN is approved in Japan and produced using mouse cells. Although these are distinct agents, both are associated with neuropathic pain during administration.³ The protocol for DIN beta-induced pain includes combinations of gabapentin, nonopioid analgesics, and opioids.³ Pregabalin, an α2δ subunit ligand of voltage-dependent calcium channels similar to gabapentin, is also approved for neuropathic pain and may help reduce pain with lower opioid doses during the perioperative period.⁵ However, there are currently no reports on the use of pregabalin for DIN-induced pain.

Here, we report a case in which pregabalin was introduced during the second DIN treatment cycle for a patient who experienced severe abdominal pain during the first DIN cycle. In this case, the addition of pregabalin resulted in effective pain control.

Case Description

A 3-year-old girl presented with high-risk neuroblastoma with several bone metastatic lesions. After tandem high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation, residual tumors in the left adrenal gland and left retroperitoneal lymph nodes were surgically resected. This resulted in complete remission. Radiotherapy was administered postoperatively, and anti-GD2 antibody therapy with DIN was initiated.

During the first cycle, abdominal pain developed approximately 2 hours after the initiation of DIN administration on day 1 despite the use of the standard pain management protocol. Pain persisted despite a bolus injection of morphine, and the continuous infusion rate was increased to 30 µg/kg/h. On day 2, the patient developed hypotension (systolic blood pressure, 70 mmHg). As both DIN and morphine were considered possible contributing factors, the morphine infusion rate was reduced to 20 µg/kg/h and maintained thereafter. On days 3 and 4, abdominal pain persisted after the completion of DIN administration; thus, the duration of morphine infusion was extended by 2 hours.

Pain management during the first cycle consisted of continuous morphine infusion, regular intravenous acetaminophen, and additional bolus doses of morphine as needed. Nonopioid analgesics, including flurbiprofen and acetaminophen, were also administered on demand. During this cycle, five morphine boluses, three doses of flurbiprofen, and three additional doses of acetaminophen were required (Fig. 1, Table 2).

FIG. 1.

Analgesic usage during the dinutuximab (DIN) administration period. DIN was administered once daily over 11–13 hours. Continuous morphine infusion was started 0–1 hours before daily DIN administration and continued for 2–4 hours after completion. The squares indicate continuous administration of morphine or DIN, while the arrows represent a single administration. The white squares and thin arrows illustrate the standard protocol, while the gray squares and thick arrows indicate additional pain management measures. Dosage per administration: morphine (bolus; 1-hours amount of continuous infusion), acetaminophen (10 mg/kg per dose), flurbiprofen (1 mg/kg per dose), and DIN (17.5 mg/m² per day). Pregabalin was administered at a dose of 12.5 mg once daily starting on day 3 before DIN administration during cycle two.

Table 2.

Progression of Pain, Fever, Frequency of Bowel Movements, and Usage of Symptomatic Treatments in a Pediatric Patient Treated with DIN

	First cycle				Second cycle
	Day 1	Day 2	Day 3	Day 4	Day 1	Day 2	Day 3	Day 4
Maximum FPS score	5	4	2	2	0	0	2	0
Number of bolus doses of morphine	2	0	0	3	0	0	0	0
Frequency of acetaminophen dosing	0	1	1	1	0	0	0	0
Frequency of flurbiprofen dosing	2	1	0	0	0	0	0	0
Maximum body temperature (degrees)	38.7	40.8	41.1	40.2	39.8	40.1	40.1	39.2
Presence (+) or absence (−) of antibiotic administration	+	+	+	+	+	+	+	+
Frequency of bowel movements	0	0	4	5	0	2	6	4

Day 1 was defined as the start of DIN administration. The number of bolus doses of morphine did not include the regular doses at the time of treatment initiation. The number of times analgesics is used only indicates the as-needed use and does not include regular doses.

FPS, Faces Pain Scale.

With assistance from her mother and the assigned nurse, the patient was able to rate her pain level using the 6-point Faces Pain Scale (FPS) (0–5). On day 1, the maximum FPS score was 5, with pain appearing 3 hours after DIN initiation. On day 2 the maximum FPS score was 4, which decreased to 2 on days 3 and 4 (Fig. 2, Table 2). On day 1, the patient was found crouching due to abdominal pain and her scheduled playtime with her caregiver was canceled. On day 2, she cried even before receiving DIN. By nighttime she was lethargic and spent most of the time sleeping. She remained in a bad mood due to abdominal pain.

FIG. 2.

Changes in FPS scores during the DIN administration period. The open circles (○) and closed triangles (▲) indicate Faces Pain Scale (FPS) scores during the first and second cycles, respectively. FPS scores range from 0 to 5.

On day 1 during the first cycle, she developed fever, and antibiotics were initiated due to the risk of infection. Diarrhea occurred on day 3. Diarrhea is reported as a side effect of DIN in 13% of cases,⁶ but may also be an adverse reaction to antibiotics. Notably, abdominal pain appeared immediately after initiating DIN administration, prior to diarrhea. The pain persisted during DIN administration, suggesting that abdominal pain was caused by DIN, not by diarrhea. Given the occurrence of severe pain during the first DIN cycle, pregabalin was added during the second cycle. As the optimal pediatric dosage of pregabalin has not been established in Japan, the dosage was determined based on doses used overseas.⁷ Although pregabalin has been recommended for pediatric neuropathic pain, specific dosing guidance is limited, and available references primarily describe dosing for epilepsy. Therefore, treatment was initiated at the minimum dose, in consideration of safety considerations. The dose is 2–14 mg/kg/day, divided into two doses. The minimum dosage of a pregabalin tablet is 25 mg. As the patient weighed 11 kg, a dose of approximately 2 mg/kg/day, divided into two doses (12.5 mg per dose), was selected, corresponding to half of a 25-mg tablet. However, pregabalin was bitter and difficult for the patient to take. As it also caused mild drowsiness, treatment started with a single dose of 12.5 mg once daily after dinner. As the patient did not exhibit kidney impairment, no dose adjustment due to renal function was required. In line with previous reports for gabapentin,³ pregabalin administration was started 3 days prior to DIN administration to ensure efficacy onset. Pregabalin was administered until the end of DIN dosing for the second cycle. Abdominal pain did not occur on days 1 and 2. On day 3, before DIN administration, the patient rated her pain with an FPS score of 2. However, pain was relieved by a warm compress and remained at a score of 0 thereafter (Fig. 2). Thus, with the exception of pregabalin, only the standard protocol was used in the second cycle. Although the patient’s body weight was similar across the two cycles, the total morphine doses were 16.3 mg in the first cycle and 13.2 mg in the second cycle. As in the first cycle, the patient developed a fever on day 1 and antibiotics were initiated. On day 3, the patient experienced 6 bowel movements and developed diarrhea (Table 2).

Clinical palliative care program

In the present case, the pediatric palliative care team (PPCT) intervened to address the patient’s pain. The PPCT at Kyoto University Hospital consists of six physicians (three pediatricians, two palliative care doctors, and a psychiatrist), one board-certified pharmacist in palliative pharmacy, two oncology-certified nurse specialists, and one child health–certified nurse specialist. The PPCT intervenes only upon request from the primary medical team caring for pediatric inpatients. The PPCT functions as a consulting service for patients and offers recommendations that are at the discretion of the primary physician to put into action. The PPCT operates during weekday business hours, conducts rounds and meetings, and follows each patient until the care team determines that no further interventions are required. Typically, one to two pediatric patients receive PPCT care each day. On active days, the team visits the patients in person or monitors their condition through medical records. As the patient experienced severe pain during the first cycle, the PPCT recommended prophylactic pregabalin administration in the second cycle and monitored its effects and adverse events.

Discussion

DIN-induced pain typically presents as allodynia involving various body regions, particularly the abdomen, extremities, back, and chest.⁸ Although the mechanism underlying anti-GD2 immunotherapy-related pain is not completely understood, various factors have been implicated. As GD2 is expressed on peripheral nerve fibers, pain may be caused by direct activation of these fibers.⁸ A previous study proposed that complement activation plays an important role in anti-GD2-associated pain.⁹ Activation of N-methyl-D-aspartate receptors has also been implicated in the development of this pain.¹⁰ A Japanese phase IIb trial used continuous lidocaine infusion combined with intermittent morphine administration for patients with DIN-induced pain who cannot tolerate morphine because of adverse effects such as itching or a crawling sensation of insects.⁴ As the patient tolerated continuous morphine infusion without significant adverse effects in the present case, lidocaine was not selected. Other studies have reported the use of ketamine, an N-methyl-D-aspartate receptor antagonist, as an adjuvant to opioid analgesia.^8,11 Gabapentin reverses allodynia induced by anti-GD2 ganglioside administration.¹² Ketamine is only available as an injectable drug in Japan, and it is challenging to safely use lidocaine and ketamine in general wards. In Japan, gabapentin is only approved as an anticonvulsant and for restless legs syndrome. In this case, pregabalin was selected as an adjuvant analgesic because gabapentin use is restricted in Japan, it shares a similar mechanism of action as gabapentin, and it is approved for the treatment of neuropathic pain. In addition, pregabalin can be administered orally without requiring intensive monitoring, making it a practical option in the general ward setting. In selected cases, combined pregabalin and morphine therapy may represent a safer, more practical approach for managing DIN-induced pain than other adjuvant analgesics, particularly in settings where gabapentin use is limited.

DIN administration is associated with several adverse effects, including hypersensitivity reactions, capillary leak syndrome, hypotension, and diarrhea, in addition to pain.⁶ For hypersensitivity reactions, capillary leak syndrome, and hypotension, the package insert recommends reducing the infusion rate or temporarily interrupting DIN administration. Diarrhea is generally managed via supportive care, including antidiarrheal agents. Despite a similar DIN dosage and duration across the two cycles in this case, the first cycle required morphine dose escalation, bolus administration, and intermittent use of other analgesics due to pain. DIN or DIN beta-induced pain is generally limited to the time of drug administration.⁸ However, in accordance with the protocol for DIN beta-induced pain, additional morphine can be administered as needed after intravenous morphine weaning.³ As our patient experienced pain after DIN administration, the continuous morphine administration time was extended from 2 to 4 hours after the end of DIN administration on days 3 and 4. For the second cycle, pregabalin was added to the same regimen of morphine and acetaminophen used in the first cycle. No additional pain control was required. In this case, the combination of morphine and pregabalin effectively reduced DIN-induced neuropathic pain.

Despite the use of various pain control strategies in the first cycle, including involvement of the PPCT, changing analgesics, and providing verbal encouragement, significant improvement was not observed. Although pregabalin was introduced as part of various interventions, the 3-year-old patient likely did not understand its intended effect. Thus, a placebo effect, which does occur in adults, is unlikely.^13–14 Accordingly, the observed reduction in pain during the second cycle may be attributed to the pharmacological effects of pregabalin itself.

As the patient’s pain decreased, the total morphine dosage was decreased. Opioids are known to cause adverse events such as hypotension, rash, urticaria, pruritus, nausea, and vomiting.⁸ Hypotension, which occurred in this patient, is a common adverse event during DIN administration and may be exacerbated by opioid use.⁸ Thus, reducing the opioid dosage can inhibit the adverse effects of opioids and enable safer DIN administration. Although the total morphine dose was only reduced slightly between the two cycles, the clinical benefit of pregabalin in this case might not be fully reflected by opioid consumption alone. Notably, the patient’s pain intensity decreased substantially, and no additional rescue analgesics were required during the second cycle. In addition, although mild drowsiness was observed, no serious adverse effects occurred. These findings suggest that pregabalin might have contributed to improved pain control with an acceptable safety profile; however, the balance between its benefits and adverse effects should be carefully considered in each case.

In accordance with guidelines, the pediatric dose of pregabalin is administered twice daily.⁷ However, the A0081107 trial reported that Japanese adults exhibit higher rates of somnolence, lightheadedness, and muscle weakness compared with individuals from other countries.¹⁵ In the present case, the patient complained of drowsiness and the bitter taste of pregabalin and so the dosage was adjusted to once daily. Importantly, the patient’s pain did not worsen during the day. As the initial dose provided a sufficient analgesic effect, dose escalation was not required. The use of a low dosage likely contributed to the absence of adverse effects, with the exception of mild drowsiness.

Pain tends to improve with each DIN cycle due to increased treatment tolerance,⁶ and so opioids can be reduced.⁸ In domestic Japanese phase IIb trials, the reported incidence rates were 43.8% for grade 1 pain, 12.5% for grade 2 pain, and 6.3% for grade 3 pain.⁵ To date, there are no reports of significant improvements in severe pain, defined as an FPS score of 5 (corresponding to grade 3), during the first DIN cycle. Although pain tolerance across treatment cycles can contribute to reduced pain intensity, the present patient experienced a marked reduction in peak pain (FPS 5–2) and no longer required any rescue morphine boluses. These findings suggest that the addition of pregabalin might have contributed to improved pain control beyond cycle-related tolerance.

The patient exhibited signs of distress during the first cycle, such as curling up due to abdominal pain. During the second cycle, she developed fatigue caused by high fever. Nevertheless, she remained able to play with toys. Pain is one of the most distressing symptoms for patients, and a child’s suffering significantly influences the psychological distress experienced by their parents.¹⁶ Thus, effective analgesia can help reduce pain and potentially improve the overall treatment experience for both pediatric patients and their parents.

In conclusion, this case suggests that the addition of pregabalin to opioid therapy can contribute to improved management of DIN-induced pain. As this is a single case study, we hope to collect additional cases to validate the efficacy and safety of pregabalin and establish appropriate dosing.

Authors’ Contributions

M.A.: Conceptualization (lead); writing—original draft (lead); formal analysis (lead); writing—review and editing (equal). Y.S.: Formal analysis (supporting); writing—original draft (supporting); writing—review and editing (equal). K.K.: Writing—review and editing (equal). N.M.: Writing—review and editing (equal). H.K.: Writing—review and editing (equal). T.T.: Writing—review and editing (equal). K.S.: Conceptualization (supporting); writing—original draft (supporting); writing—review and editing (equal).

Ethical Approval and Informed Consent Statements

This case report was prepared with full consideration for the protection of personal information, in accordance with the “Guidelines for the Protection of Patient Privacy in Medical Papers, Including Case Reports and Conference Presentations.” This study was approved by the Kyoto University Graduate School of Medicine and Faculty of Medicine Ethics Committee (R0545-2). The patient’s mother was informed that the clinical data course might be published in a case report, with all measures taken to prevent identification of the individuals; that consent for publication was voluntary; and that refusal would not result in any disadvantage. A written informed consent for the publication of this study was obtained.

Data Availability Statement

The individual-level data reported in this study are not publicly available. Individuals wishing to access the disaggregated data, including the specific data reported in this study, should submit a request to MA (makazawa@kuhp.kyoto-u.ac.jp). Deidentified data (including, as applicable, participant and relevant data dictionaries) will be shared upon approval of analysis proposals, provided that signed data access agreements are in place.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This research did not receive any specific grant from funding agencies, in the public, commercial, or not-for-profit sectors.

Abbreviations Used

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