Priapism in sickle cell disease: Beware of neuroleptics
Authors: Raphaëlle Quint, Agnès Lillo‐Le Louet, Jacques Pouchot, Jean‐Benoît Arlet
Journal: American Journal of Hematology (2018)

To the Editor: Priapism, a prolonged and painful erection of the penis, is an acute complication of sickle cell disease (SCD), with a prevalence from 35% to 42% in male patients. The median age of the onset is during puberty. Priapism more frequently affects homozygous SS patients, although patients with SC and S-beta thalassemia may also be affected.1-3 Priapism results from an impairment in the physiological mechanisms regulating penile tumescence and detumescence. In SCD, the mechanism is mainly ischemic (low flow or veno-occlusive); the venous outflow from the corpora cavernosa of the penis is impaired, causing hypoxia and acidosis in penile tissue. A minority of cases involve a non-ischemic (high flow or arterial) mechanism (<5%). Repeated episodes of priapism, in particular prolonged, cause tissue damage and fibrosis of the corpora cavernosa, leading to erectile dysfunction. Twenty-one percent of SCD patients with prior episodes of priapism will present with erectile dysfunction.2 SCD patients are at a high risk of anxiety or depressive symptoms4, 5 and, sometimes, of psychotic manifestations that may require the use of antipsychotic medications, particularly during a vaso-occlusive crisis (VOC). Neuroleptics are an underappreciated cause of priapism. Here, we report the case of a 26-year-old male patient with SCD who presented with severe priapism after the introduction of cyamemazine, leading to a loss of erectile function. This SS SCD patient had been treated with hydroxyurea since 1999. His significant chronic SCD complications included avascular osteonecrosis of the right femoral head, osteoporosis, bilateral proliferative retinopathy, silent cerebral vasculopathy, and secondary hemochromatosis. He experienced approximately five VOCs annually, requiring hospitalization, and seven episodes of acute chest syndrome (ACS) in the past. Cyamemazine (25 mg/day) was introduced in March 2016 after a psychiatric evaluation during hospitalization for VOC due to anxiety and sleep disorders. The psychiatric symptoms improved shortly after the initiation of cyamemazine administration, which was continued when he left the hospital. One and a half months after starting this medication, he reported, at home, his first two episodes of stuttering priapism (2 hours’ duration each). In June 2016, he presented to the emergency department with a new episode of priapism, which started 24 hours before, and bone pain. The patient rapidly received repeated irrigations of the corpora cavernosa, followed by etilefrine and then ephedrine injections, without achieving detumescence. Seven hours after his admission, he received an exchange transfusion for this severe episode of priapism, associated with both ACS and VOC. Finally, 60 hours after the onset of priapism, he underwent a surgical distal shunt, which resulted in detumescence, with an uneventful surgical outcome. The treatment with cyamemazine was discontinued 7 days after the admission; the drug was replaced with hydroxyzine and, later, with sertraline for his anxio-depressive disorder. Unfortunately, after a 20-month follow-up, the patient complained of persistent erectile dysfunction. The absence of an episode of priapism before cyamemazine introduction, its occurrence shortly after the first use, and the severity of priapism, without any effect of the irrigation and red blood cell transfusion, support the cyamemazine causality. Priapism may be an adverse drug reaction, and its occurrence has been described upon the use of psychiatric drugs, mainly neuroleptics. It has been reported to occur upon the use of typical and atypical antipsychotics, but atypical neuroleptics are thought to pose a lesser risk.6-8 Cyamemazine is a typical antipsychotic drug of the phenothiazine class, which also has anxiolytic properties. Priapism is a rare adverse effect referenced in pharmacovigilance documents and on the cyamemazine label. In March 2018, a search in the WHO pharmacovigilance database (Vigilyze) concerning priapism in relation to the phenothiazine class found 22 cases of cyamemazine-induced priapism and 93 supplementary cases linked to other phenothiazine neuroleptics. The cases were mainly from the USA (37/115, including 2 cases with cyamemazine) and France (34/115, including 20 cases with cyamemazine), and in 60% of the cases (69/115), a phenothiazine was the only drug suspected of causing priapism. When the information was available, the median delay between the start of cyamemazine and the onset date of priapism was 19 days [1–190]. No case related to the phenothiazine use in a SCD patient was identified in this database. Neuroleptics induce priapism by blockade of alpha-1 adrenergic receptors; they inhibit the sympathetic system response that normally leads to detumescence and enhances the parasympathetic system-mediated vasodilatation. Andersohn et al., using a disproportionality analysis of a spontaneous adverse event database for priapism attributed to neuroleptics (144 patients), have found a link between the degree of alpha-1 adrenergic receptor antagonism by antipsychotics and the occurrence of priapism.6 There is another way that neuroleptics and SCD can interact to precipitate priapism, which is the occurrence of sleep hypoxemia. Accumulating data suggest a link between sleep-disordered breathing and complications of SCD, with an overlap in pathophysiological pathways and the potentiation of complications between the two conditions.9, 10 Notably, Roizenblatt et al. have found an association between sleep hypoxemia and priapism in SCD.11 Sedation and drowsiness are common side effects of antipsychotic medications, mainly at the beginning of the treatment. Neuroleptics are thought to contribute to obstructive sleep apnea, although the data in support of this hypothesis are inconsistent.12, 13 To our knowledge, this is the first reported case of neuroleptic-induced priapism in SCD. It is important to increase physicians’ and patients’ awareness of drug-induced priapism, especially in SCD patients. We draw two recommendations from this observation. First, when introducing a neuroleptic treatment for male patients with SCD, it may be appropriate to select an atypical neuroleptic with a low alpha-1 adrenergic receptor affinity (olanzapine has the lowest affinity). Neuroleptic prescriptions for SCD patients with prior recurrent priapism should be balanced against the risk of priapism flares. Second, in the case of the occurrence of priapism in an SCD patient treated with a neuroleptic, the drug causality must be evaluated, and if possible, neuroleptics should be stopped. Furthermore, in the case of intermittent priapism, a switch to another drug with a reduced alpha-1 adrenergic receptor affinity can be proposed, although there have been reported cases where priapism resumed even after the switch.14 Nothing to report