Hyponatremia with Antidepressant: A Rare Side Effect from Duloxetine in a Child with Acute Leukemia

Introduction

Serotonin/Norepinephrine reuptake inhibitors (SNRI) have been widely used for the treatment of depression and anxiety and chronic pain in both adults and children.^1–3 Duloxetine is an SNRI with multiple indications, including depression, chronic pain, and generalized anxiety disorder, as well as neuropathic pain and stress urinary incontinence. The most common side effects are weight loss, decreased appetite, xerostomia, and drowsiness noticed in greater than 10% of the patients. ⁴ Abnormalities with taste and smell have also been reported in case reports. ⁵ Similarly, rare side effects such as optic neuritis, acute urinary retention, acute kidney injury, and rapid eye movement sleep behavioral disorder have been reported in the literature.^6–8 Another rare side effect reported in adults is hyponatremia due to syndrome of inappropriate antidiuretic hormone (SIADH) secretion induced by duloxetine.^9,10 However, no such report is found in children.

The combination of chemotherapeutic agents with SNRIs can potentially increase the risk of SIADH in patients. Herein we present the first case of a 10-year-old boy who was receiving induction chemotherapy for acute lymphoblastic leukemia and developed hyponatremia after receiving duloxetine.

Materials and Methods

Patient was identified by medical records and a waiver was obtained.

Results

A 10-year-old young boy presented with fever, epistaxis, and hematemesis. His laboratory evaluation showed leukocytosis with a white cell count of 111,000, hemoglobin of 9.2 g/dL, and platelets of 80,000 per microliter. The bone marrow was performed immediately, which showed 91% premature T cell blasts that were Myeloperoxidase (MPO) negative and immunohistochemical staining confirmed the diagnosis of T cell leukemia. The patient was started on induction chemotherapy as per the Children's Oncology Group acute leukemia protocol (COGAALL0434). The patient received vincristine as part of the induction chemotherapy on days 1, 8, 15, and 22. The patient's electrolytes were monitored for tumor lysis throughout the induction therapy.

The sodium level was noted to be 138 mEq/L at the time of initial admission. The patient's sodium levels were 140, 137, 139, and 137 mEq/L on day 1, 8, 15, and 22, respectively (Fig. 1) before receiving vincristine and 136, 141, 139, and 139 mEq/L one day after receiving vincristine, day 2, 9, 16, and 23 respectively. The patient developed mild low-back and leg pain bilaterally on day 30 of his induction chemotherapy, which did not improve with acetaminophen, and therefore, morphine was added for pain relief. The patient's back and leg pain worsened in the next 48 hours, requiring multiple frequent doses of morphine without any significant relief. The patient was also noted to have anxiety related to his new diagnosis and treatment. He was given lorazepam for anxiety with some relief.

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FIG. 1.

Sodium level during induction and after institution of duloxetine and then returning to normal after duloxetine was stopped.

The supportive care team was consulted for pain management. The patient reported the pain to be burning and shooting down his legs bilaterally. He also described the pain as worse at night. The patient endorsed anxiety again and since the pain was not responsive to morphine and was characteristic of chemotherapy-induced neuropathic pain (CINP), he was prescribed duloxetine at the dose of 30 mg nightly. The patient continued to receive morphine as needed, while waiting to see the effects of duloxetine. The patient received two doses of duloxetine, which improved his pain, and he no longer required any breakthrough dose of morphine. However, subsequently, on day 32 of the induction therapy and after two days of therapy with duloxetine, the patient's sodium level dropped from 135 to 131 mEq/mL; therefore, an evaluation for SIADH was performed.

Urine osmolality was noted to be 554/mg/kgH₂O and urinary sodium was 167 mEq/L, which was consistent with SIADH. The patient was asymptomatic from his hyponatremia at the time of SIADH diagnosis. At this time, the patient was not on any intravenous fluid and was not on any other medication that would cause hyponatremia. The patient was fluid restricted, and duloxetine was stopped at the same time. The patient's urine osmolality improved the following day to 322 mg/kgH₂O from 285 mg/kgH₂O and urine sodium also improved to 56 mEq/mL from 167 mEq/mL. The patient's sodium gradually improved to 133 mEq/mL and then 134 mEq/mL on the following two days. The patient's sodium returned to 141 mEq/mL after one week from stopping the duloxetine. The patient did not require any other further intervention. The patient was started on gabapentin for neuropathic pain, which continued to improve his back and leg pain.

Discussion

This case highlights a potentially important side effect of duloxetine in pediatric cancer patients. There is no pediatric randomized control trial (RCT) highlighting the efficacy of duloxetine for neuropathic pain, but an adult RCT has shown benefit in reducing CINP by 30–50% compared to placebo. ¹¹ The mechanism through which SNRIs such as duloxetine cause SIADH is by increasing antidiuretic hormone (ADH) secretion through stimulation of hypothalamic serotonergic and α₁ serotonergic receptors. ¹² A slight female predominance was suggested by earlier adult case reports, but later data suggest adult males can be affected by SIADH as well. ¹³ Most case reports also suggested the development of hyponatremia occurs two to three days after the drug is started.^10,14,15 Our patient developed hyponatremia after two days of therapy with duloxetine and required termination of this therapy.

Hyponatremia has been defined as a serum sodium level <135 mmol/L and is also the most common electrolyte abnormality encountered, occurring in mostly hospitalized and elderly patients. ¹⁰ Hyponatremia has been noted in patients with hematologic malignancies due to central nervous system (CNS) involvement, concurrent primary or secondary hypercholesterolemia (steroid induced), or interleukin-induced ADH secretion. ¹⁶ SIADH presents as euvolemia and low serum osmolality with high urine sodium and high urine osmolality. SIADH can be caused by certain malignancies such as head and neck cancers, neuroblastoma, and some carcinomas, such as small cell lung carcinoma, by inducing ectopic ADH secretion. Some anticancer medications such as vincristine, cyclophosphamide, and platinum-based drugs have also been associated with this side effect. The risk of SIADH is <1%, but patients who receive cyclophosphamide are more prone as they receive hyperhydration to prevent hemorrhagic cystitis. That risk is less in patients who are receiving <6 g/m² of cyclophosphamide. ¹⁷

A recent study of 84 pediatric acute leukemia patients looked at the incidence of SIADH and found vincristine was the strongest risk factor. Most of these events were noticed to be during the induction phase of chemotherapy. Most of these patients developed SIADH within a week of vincristine administration. ¹⁸ Similar results have been reported previously in several case reports and case series.^19–21 Our patient did not develop SIADH with vincristine and tolerated all four doses of his induction chemotherapy. We concluded that duloxetine was the etiology for his SIADH, to the temporal association, and suspect that is why his sodium returned to normal so quickly after removing it.

There are very little data available on risk factors other than chemotherapeutic agents for SIADH in children with leukemia. A study by Kishimoto et al. on 111 pediatric leukemia and solid tumor patients reported age as a significant risk factor for SIADH. As noted in the report, adolescents were at higher risk of developing SIADH. ²² Another study reported the presence of overt CNS leukemia as a risk factor for hyponatremia in patients with leukemia. ¹⁸ The risk factors are listed in Table 1.

The diagnosis of SIADH requires a combination of clinical and laboratory manifestations, including euvolemia, hyponatremia, elevated urine osmolality, and low serum osmolality. Hyponatremia can be variable and can be labeled as mild-moderate or severe. A sodium level of <130 mmol/L is considered severe hyponatremia and the treatment may include ICU admission for neurological monitoring and carefully controlled correction. The management of SIADH starts with the identification of the etiology. The offending agent, if identified, needs to be stopped immediately and depending upon the severity of hyponatremia, further steps need to be taken. These can include fluid restriction, salt tablets, and/or hypertonic saline.

This case report is unique as SIADH secondary to duloxetine has not been previously described in a child, or pediatric cancer patient. It highlights the importance of proper identification of the offending agent in SIADH, and prompt removal of it to remedy the serum sodium. CINP is a common problem among pediatric oncology patients. Duloxetine is an evidence-based intervention for CINP in adults and has been shown to be safe for use in children for anxiety, depression, and fibromyalgia. In an effort to limit polypharmacy, it is reasonable to prescribe duloxetine for CINP in children who are being considered for pharmacologic therapy for anxiety or depression. However, the risk of SIADH must also be considered when prescribing duloxetine for children recently receiving chemotherapy.