Pain phenotypes in advanced peripheral arterial disease

/Abstract Lower extremity chronic limb-threatening ischemia (CLTI) is the most advanced form of peripheral arterial disease (PAD) and is a life-limiting condition associated with a 25% risk of mortality and a 20% risk of major limb amputation at one year. CLTI is characterized by a spectrum of findings including non-exertional foot pain (“rest pain”), non-healing wounds, and frank gangrene, and pain is a nearly universal feature. Pain is also an important factor in decision-making around treatment, which may be non-procedural (pain control and wound care), amputation, open surgery (e.g., leg bypass), or endovascular intervention (e.g., angioplasty and stenting). These options necessarily involve substantial tradeoffs among patient goals such as mobility, invasiveness of treatment, likelihood of limb salvage, and post-treatment pain. Despite the centrality of pain in presentation and decision-making, treatment guidelines neglect pain as an outcome and focus on restoration of arterial perfusion to achieve limb salvage. The underlying assumption that treatment of the underlying arterial insufficiency will treat pain is poorly founded. Clinical observation suggests that in many cases pain in CLTI is driven by mechanisms independent of arterial perfusion; however, understanding pain in CLTI has not been a focus of research: there are 0 English-language publications systematically characterizing pain and its features. Furthermore, in a study of PAD patients fewer than half of patients used non-opioid adjuncts (e.g., gabapentin) for pain control, suggesting both a lack of a systematic approach to pain management as well as a lack of understanding of pain mechanisms. Precision treatment of pain and incorporation of pain into prognostication and patient-centered decision-making is impossible without a rigorous real-world characterization of pain in patients with CLTI including its features, such as severity, frequency, and associations with patient and disease-related factors. This knowledge gap directly contributes to deficits in effective decision-making around CLTI treatment and optimal pain management. Therefore, we propose to systematically characterize pain, including identification of clusters of pain features (“pain phenotypes”) in patients living with CLTI and to identify patient and clinical factors associated with these phenotypes. To accomplish this, we will recruit 100 patients living with CLTI facing treatment to 1) characterize pain using validated instruments (e.g., Graded Chronic Pain Scale) and to determine if phenotypes exist and 2) determine the association of phenotypes with patient (e.g., sex) and disease features (e.g., CLTI stage). This work will contribute meaningfully to my development as a leader in patient-centered outcomes and decision-making around CLTI. Most importantly, this proposal lays the groundwork for an R01 focused on 1) understanding the association between pain features and phenotypes and CLTI prognosis, and 2) a granular understanding of pain mechanisms using quantitative sensory testing and other tools with a view towards developing guidelines for precision pain treatment in patients suffering from CLTI. Project Number: 1R03HL183012-01 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Samir Shah | Institution: UNIVERSITY OF FLORIDA, GAINESVILLE, FL | Award Amount: $114,375 | Activity Code: R03 | Study Section: Special Emphasis Panel[ZRG1 RCCS-B (93)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R03HL18301201