Abstract: Disclosed herein are methods for determining whether a subject possesses altered pain sensitivity an altered risk of developing acute or chronic pain, or diagnosing a tetrahydrobiopterin (BH4)-related disorder or a propensity thereto. These methods are based on the discovery of GCH1 and KCNS1 allelic variants that are associated with altered pain sensitivity and altered risk of developing acute or chronic pain, and the discovery that a GCH1 “pain protective haplotype” is associated with decreased upregulation of BH4 synthesis in treated leukocytes.