Raynaud syndrome associated with medication for attention-deficit/hyperactivity disorder: a comprehensive review

Background: Raynaud syndrome (RS) is a peripheral vasculopathy characterised be impaired acral perfusion typically manifesting as skin discolouration with pallor, cyanosis and/or erythema, and increased sensitivity to cold. RS may be primary, or secondary to systemic disease, lifestyle and environmental factors or medication. RS has been reported with medication to treat ADHD, but we found no recent comprehensive overview of the literature. <br/><br/>Methods: we systematically searched PubMed and Embase from inception to 12 June 2024 for articles published in English describing cases of RS in individuals treated with stimulant medication, atomoxetine, guanfacine or clonidine. Identified cases were assessed against the Naranjo Adverse Drug Reaction Scale criteria to determine the probability of a causal relationship with the medication.<br/><br/>Results: the initial search identified 197 articles. Sixty-one cases were identified from 15 case reports, five case series, one retrospective case-control study, and one retrospective cohort study. No randomised, controlled studies were identified. Implicated medications included methylphenidate, (dex)amfetamine and, more rarely, atomoxetine. Most cases were mild and resolved within weeks of discontinuation, dose reduction or switch to an alternative medication. A few cases associated with systemic disease were reported, leading to ulceration, gangrene and the need for amputation or revascularisation in some individuals. Assessment of 28 cases using the Naranjo criteria suggested a "possible" causative role of ADHD medication in 13 cases, a "probable" role in 13 cases and a "definite" role in two cases. <br/><br/>Conclusion: due to the uncontrolled nature of all but one of the available studies, a causal relationship between medication for ADHD and RS could not be determined reliably. However, in view of the possibility of severe sequelae, albeit in rare cases, routine monitoring for signs of RS is recommended in individuals treated with CNS stimulants or atomoxetine, especially when initiating treatment or increasing the dose. Large database studies in which individuals act as their own controls should be conducted to clarify any association between treatment with these medications and RS, controlling for confounding factors. <br/>