Haloperidol or amitriptyline for chronic neuropathic pain in adults with sickle cell disease: A systematic review

Chronic pain affects more than half of adults with sickle cell disease (SCD), and a clinically meaningful subgroup—reported in 32% to 70% of cohorts depending on the screening tool—exhibits a neuropathic component that is poorly responsive to opioids and other standard analgesics. The 2020 American Society of Hematology guideline conditionally suggests tricyclic antidepressants (e.g., amitriptyline) for SCD-related chronic pain on the basis of indirect, very-low-certainty evidence extrapolated from fibromyalgia, and is silent on haloperidol despite preclinical and translational evidence implicating Ca²⁺/calmodulin-dependent protein kinase IIα (CaMKIIα) and sigma-1 receptor pathways in SCD pain and in the analgesic activity of butyrophenone and phenothiazine antipsychotics. CaMKIIα activation has been demonstrated in the dorsal root ganglia and in the spinal cord superficial dorsal horn of Berkeley sickle transgenic mice, and CaMKIIα inhibitors (the phenothiazine trifluoperazine and the butyrophenone haloperidol) attenuate evoked and spontaneous pain in preclinical models; trifluoperazine has further shown preliminary analgesic activity in a phase I study in adults with SCD. In this systematic review, we asked whether direct evidence supports the use of haloperidol or amitriptyline for chronic neuropathic pain in adults with SCD. PubMed, CINAHL, and Embase were searched from inception through May 7, 2026, supplemented by reference checking of 26 publications on related topics. No eligible studies were identified for either drug. Adjacent neuropathic-pain evidence supports modest amitriptyline benefit (NNT ∼5; NNH ∼5) and a plausible but unproven CaMKIIα/σ1R-mediated rationale for haloperidol. Adequately powered, phenotypically enriched, safety-monitored SCD-specific RCTs of both agents are an urgent research priority.