Pain genetics: sodium channelopathies and opioid pharmacogenetics

One gene, SCN9A (Nav1.7), spans the pain spectrum: loss of function abolishes pain, while gain of function causes erythermalgia, paroxysmal extreme pain disorder or small fiber neuropathy; CYP2D6 genotype changes codeine and tramadol safety.

1. Loss of Nav1.7 abolishes pain. Homozygous nonsense SCN9A mutations in consanguineous families cause congenital inability to experience pain in otherwise healthy people, inherited as an autosomal recessive trait mapped to chromosome 2q24.3 in three families from northern Pakistan ¹.
2. Nav1.7 loss also removes smell. Nav1.7 is required for olfactory synaptic signaling, so people with loss-of-function mutations are anosmic as well as unable to feel pain ².
3. Erythermalgia is a gain-of-function disorder. Primary erythermalgia, autosomal dominant intermittent burning pain with redness and heat of the extremities, results from SCN9A missense mutations ³.
4. PEPD is a different gain of function. Paroxysmal extreme pain disorder, formerly familial rectal pain, causes rectal, ocular or submandibular pain with flushing; its mutations impair fast inactivation and respond to carbamazepine, unlike erythermalgia mutations ⁴.
5. Nav1.7 variants explain some idiopathic small fiber neuropathy. In biopsy-confirmed idiopathic disease, 8 of 28 patients (28.6%) carried gain-of-function SCN9A mutations making DRG neurons hyperexcitable; such channels may cause small axons to degenerate ⁵.
6. CYP2D6 governs codeine and tramadol. CPIC advises avoiding codeine and tramadol in ultrarapid metabolizers because of toxicity, and in poor metabolizers because analgesia is diminished; intermediate metabolizers use label dosing ⁶.

Congenital insensitivity to pain with anhidrosis is caused by TRKA (NGF receptor) mutations and adds anhidrosis, fevers and intellectual disability; normal sweating and cognition point instead to Nav1.7 loss ⁷¹.

• Erythermalgia mutations shift Nav1.7 activation to more negative voltages; PEPD mutations cause persistent current ⁴.
• Carbamazepine selectively blocked PEPD-associated persistent current but not the erythermalgia activation shift ⁴.
• Mutant Nav1.7 channels in Cox's families produced currents no greater than background ¹.
• In ultrarapid metabolizers, codeine forms excess morphine and can be toxic even at low doses ⁶.
• CPIC suggests a non-tramadol opioid if codeine must be avoided, and vice versa ⁶.
• CYP2D6 also contributes to hydrocodone, oxycodone and methadone metabolism, but genotype data for these are limited or weak ⁶.
• CIPA is autosomal recessive and includes self-mutilating behavior ⁷.
• Faber's idiopathic cases required normal strength, reflexes, vibration and conduction studies, reduced fiber density and abnormal quantitative sensory testing ⁵.

• Calling erythermalgia and PEPD the same channel defect ⁴.
• Switching an ultrarapid metabolizer from codeine to tramadol ⁶.
• Diagnosing CIPA in a patient who sweats normally ⁷.
• Ordering OPRM1 or COMT genotypes to guide opioid choice; CPIC finds the data too limited for clinical use ⁶.