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Characterization of Prostacyclin-Associated Leg Pain in Patients with Pulmonary Arterial Hypertension

James Watson


Michael McGoon


Robert Frantz


S. Tointon

A. Karynski

Louise Durst


Keith Swetz


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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 06.22.2012

Presentation Type: Abstracts

Watson JC, McGoon MD, Frantz RP, Tointon S, Karynski A, Durst L, Swetz KM

Mayo Clinic, Rochester, MN, USA

BACKGROUND: Leg pain is a common debilitating side effect of prostacyclin therapy for pulmonary arterial hypertension (PAH). Despite its frequency and significant impact on quality of life, treatment is often empiric and lacks a robust evidence base. To our knowledge, the nature of the leg pain, its associated neurologic deficits, electrophysiologic peripheral nerve abnormalities, and potential metabolic risk factors have not been systematically studied and elucidated.

METHODS: An IRB-approved, single-center, prospective case series of patients with PAH and prostacyclin-associated leg pain. Patients who agreed to neurologic assessment underwent a standardized evaluation including: neurologic history and examination, electrodiagnostic studies, and serologic screen for treatable and confounding metabolic causes of peripheral neuropathy. Neuropathic pain management was maximized at the end of the evaluation based on the findings.

RESULTS: Eleven patients agreed to participate. All were females (mean age 50 years) on parenteral prostanoids (5 treprostinil, 6 epoprostenol) for a median of 20 months. All patients reported their leg pain began temporally with prostacyclin initiation, and pain intensity waxed and waned with changes in prostacyclin dosing. All reported pain with a symmetric distal stocking distribution and typical neuropathic pain descriptors. Hand involvement was rare (n=1). Four patients had superimposed musculoskeletal pain, while five had symptoms of non-cardiac dysautonomia. One patient reported a family history of neuropathy, while five had known diabetes mellitus or thyroid disease that was felt well-controlled at time of referral.

Neurologic exam revealed a small fiber, sensory-predominant peripheral neuropathy in 89% of patients (n=10). Electromyogram demonstrated a large fiber peripheral neuropathy in two patients (18%). Small nerve fiber testing was abnormal in 91% (abnormal thermoregulatory sweat testing in 10 of 11 patients; abnormal autonomic reflex screening in 10 of 11 patients, but 7 of these has a pattern not fully explained by heart failure.

Serologic evaluation identified a previously unrecognized contributor to neuropathy in 73% of patients (n=8), including 55% (n=6) with new B12 deficiency, 27% (n=3) with uncompensated hypothyroidism, and one with new diabetes mellitus. Two had more than one untreated metabolic contributor. Gabapentin was an effective treatment for prostacyclin-associated pain, but required high dosages in this cohort.

CONCLUSIONS: Prostacyclin-associated leg pain is commonly neuropathic with evidence of a small fiber predominant peripheral neuropathy, clinically and electrophysiologically. Treatable metabolic contributors (B12, thyroid, diabetes) were common possible “second hits” that may be under-recognized, and should be screened for in PAH patients with leg pain on prostacyclin therapy. Treatment with gabapentin is common, but further study may be warranted.