Letter to the Editor

Syndrome of severe pain associated with a continuous bumetanide infusion

The current study evaluated the analgesic effects of bumetanide as an adjunctive treatment in managing neuropathic pain following spinal cord injury. The peripheral expression level of Na-K-Cl-cotransporter-1 (NKCC1) and K-Cl-cotransporter-2 (KCC2) genes in polymorphonuclear lymphocytes (PMLs) assessed as a possible biomarker indicating central underlying mechanisms.

This open-label, single-arm, pilot trial of bumetanide (2 mg/day) is an add-on treatment conducted in 14 SCI patients for 19 weeks. The whole duration consisted of three phases: pre-treatment (1 month), titration (3 weeks), and active treatment (4 months). Ultimately, nine patients completed the study. The primary outcome variables were the endpoint pain score measured by the numeric rating scale (NRS), and the short-form McGill Pain Questionnaire. Secondary endpoints included the Short-Form Health Survey that measures the quality of life. Blood samples were collected and used for determining the expression of NKCC1 and KCC2 genes in transcription and translation levels.

Bumetanide treatment significantly reduced average pain intensity according to the NRS and the short form of the McGill Pain Questionnaire scores. The baseline expression of KCC2 protein was low between groups and increased significantly following treatment (P < 0.05). Through the current study, pain improvement accompanied by the more significant mean change from the baseline for the overall quality of life.

These data might be a piece of preliminary evidence for the analgesic effect of bumetanide on neuropathic pain and could support the potential role of the upregulation of KCC2 protein and involvement of GABAergic disinhibition in producing neuropathic pain.

Diuretics are commonly used in the management of hypertension, congestive heart failure, liver disease, renal disease, and edema. The five classes of diuretics are carbonic anhydrase inhibitors, loop, osmotic, thiazides, and aldosterone receptor antagonists. Although this class of medications are beneficial in treating multiple disease states, they are not without risks. Many of the adverse and side effects associated with diuretics include changes in fluid status and electrolyte concentrations that directly act on the kidneys. However, other significant toxicities can occur. This chapter encompasses publications related to adverse events, side effects and toxicity to diuretics published from January 2019 to December 2019.

In physiological conditions, adult neurons have low intracellular Cl⁻ [(Cl⁻)_I] levels underlying the γ-aminobutyric acid (GABA)ergic inhibitory drive. In contrast, neurons have high (Cl⁻)_I levels and excitatory GABA actions in a wide range of pathological conditions including spinal cord lesions, chronic pain, brain trauma, cerebrovascular infarcts, autism, Rett and Down syndrome, various types of epilepsies, and other genetic or environmental insults. The diuretic highly specific NKCC1 chloride importer antagonist bumetanide (PubChem CID: 2461) efficiently restores low (Cl⁻)_I levels and attenuates many disorders in experimental conditions and in some clinical trials. Here, I review the mechanisms of action, therapeutic effects, promises, and pitfalls of bumetanide.

Bumetanide can induce generalized musculoskeletal pain when administered as a continuous infusion, an effect that may be underrecognized. The purpose of this case series is to educate health care providers about the incidence and presentation of pain associated with bumetanide infusions, adding to the existing literature describing this adverse event.

Of 40 critically ill patients, 15 (38%) had increased pain scores after initiation of a continuous infusion of bumetanide, with symptoms commonly occurring 12 to 24 hours after initiation of the infusion. Reported descriptions of the pain included generalized aching, soreness, burning, allodynia, headaches, and exacerbation of underlying pain in localized areas. Increases in patient-reported pain correlated directly with initiation of the continuous infusion of bumetanide.

Four of the 15 bumetanide-associated pain events (27%) were recognized as such by the health care team.

Bumetanide was promptly discontinued in the 4 identified cases. The 11 patients (73%) whose pain was not recognized as related to bumetanide remained on a continuous infusion of bumetanide and received pain medications including opioids. Infusions were stopped when patients transitioned to dialysis (n = 8 [53%]), began receiving comfort care (n = 5 [33%]), or completed diuresis therapy (n = 2 [13%]).

For all patients, pain symptoms resolved within 24 to 48 hours after discontinuation of bumetanide infusion with no significant electrolyte abnormalities.

Bumetanide-induced pain is more common than previously described. Early recognition of this adverse event can prevent patient discomfort and escalation of treatment.