title: Characterization of Prostacyclin-associated Leg Pain in Patients with Pulmonary Arterial Hypertension.
abstract: BACKGROUND
  Prostacyclin-associated leg pain is a potentially debilitating adverse effect of prostacyclin therapy for patients with pulmonary arterial hypertension (PAH). However, to our knowledge, this entity has not been systematically studied.
  
  
  OBJECTIVE
  To characterize the clinical features and metabolic risk factors for prostacyclin-associated leg pain.
  
  
  METHODS
  At one academic medical center, we assembled and analyzed a case series of patients with PAH and prostacyclin-associated leg pain.
  
  
  RESULTS
  Over a period of 2 years, we identified 11 patients with PAH and prostacyclin-associated leg pain who agreed to participate in this study. Subjects underwent a standardized clinical evaluation, electrodiagnostic assessment, and serologic screen for metabolic causes of peripheral neuropathy. All 11 patients were female; their mean (SD) age was 50 (±9) years; their median (interquartile range) PAH duration was 56 (20-96) months; and their prostacyclin therapy duration was a median (interquartile range) of 20 (14-36) months. All patients reported leg pain beginning soon after prostacyclin initiation and varying with dose. All described a neuropathic pain in a symmetric, distal, stocking distribution. Neurologic examination revealed a sensory, small-fiber, predominantly peripheral neuropathy in seven (78%) patients. Results of autonomic reflex testing and thermoregulatory sweat testing were abnormal in 82% and 90% of patients, respectively, suggesting small-fiber neuropathy. Serologic evaluation identified a new, previously unrecognized contributor to neuropathy in eight (73%) patients, including vitamin B12deficiency in six (55%), uncompensated hypothyroidism in three (27%), and diabetes mellitus in one (9%).
  
  
  CONCLUSIONS
  Chronic prostacyclin-associated leg pain is associated with a small-fiber neuropathy. Treatable metabolic contributors (vitamin B12deficiency, thyroid dysfunction, or diabetes) appear to be common possible "second hits" that may be underrecognized. We recommend screening for possible metabolic contributors in patients who have otherwise unexplained leg pain in the setting of PAH and current or anticipated prostacyclin therapy.
authors.affiliation: 1 Department of Neurology.
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Pagani-Estévez
authors.affiliation: 2 Center for Palliative and Supportive Care, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama; and.|3 Birmingham VA Medical Center, Birmingham, Alabama.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Swetz
authors.affiliation: 4 Cardiovascular Division, Department of Medicine, and.
authors.forename: Michael D
authors.initials: MD
authors.lastname: McGoon
authors.affiliation: 4 Cardiovascular Division, Department of Medicine, and.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Frantz
authors.affiliation: 4 Cardiovascular Division, Department of Medicine, and.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Tointon
authors.affiliation: 4 Cardiovascular Division, Department of Medicine, and.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Karnyski
authors.affiliation: 3 Birmingham VA Medical Center, Birmingham, Alabama.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Durst
authors.affiliation: 1 Department of Neurology.|5 Pain Division, Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.
authors.forename: James C
authors.identifier: http://orcid.org/0000-0002-1164-8588
authors.initials: JC
authors.lastname: Watson
mesh_terms: D000328:Adult; D011464:Epoprostenol / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D007866:Leg / Q000503:physiopathology*; D008875:Middle Aged; D008910:Minnesota; D010146:Pain / Q000139:chemically induced*; D059408:Pain Management; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D000070857:Walk Test
chemical_list: D011464:Epoprostenol
keywords: metabolic; neuropathy; pain; prostacyclin; pulmonary hypertension