FRCA Notes

Genetics of Pain

Curriculum

"Effect of genetics and cultural differences as well as mental health and adverse childhood experiences on clinical pain perception and management" (Final FRCA)

"Pharmacogenetics: pharmacokinetic variation eg pseudocholinesterase, acetylation, CYP450 variants" (Primary FRCA)

Resources


  • Some individuals are more vulnerable to developing chronic pain than others; this reflects an interaction between inherited genome and environmental, behavioural and social factors
  • Heritability (h2) describes the proportion of variation in a trait (e.g. chronic pain) within a population that is attributable to genetic factors
  • There is significant overlap between the genetics of chronic pain and that of mood, cognition and brain structure
    • 'Negative affect' (a cluster of negative emotions, thoughts and behaviours) is itself a risk factor for chronic pain

Family clustering studies

  • Express risk as a risk ratio (RR): the risk to a relative of developing the condition compared with the general population
    • e.g. sibling RR for fibromyalgia is ~13
  • Suggest a heritability for chronic pain of 6.7–30% depending on the condition studied
  • Limited by the difficulty of separating genetic influence from a shared household environment

Twin studies

  • Compare monozygotic (MZ) twins, who share ~100% of DNA, with dizygotic (DZ) twins, who share ~50%
  • Heritability can be estimated using Falconer's formula:
    • h2 = 2(rMZ − rDZ), where r is the concordance rate
  • Suggest a heritability for chronic pain of 27–59% (from chronic TMJ pain to chronic rheumatological pain)
  • Discordance between MZ twins suggests a condition is not purely monogenic

Adoption studies

  • Compare the prevalence of chronic pain in biological versus adoptive relatives, helping to separate heredity from family environment

  • Rare disorders in which a mutation in a single gene causes either:
    • Inherited painlessness: congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN)
    • Inherited painful conditions: e.g. primary erythromelalgia, paroxysmal extreme pain disorder (PEPD), episodic pain syndromes
  • More than 20 causative genes have been identified
  • Their discovery has improved understanding of nociceptor biology and identified new analgesic drug targets
  • Mutations cause disease through neurodegeneration, developmental defects or altered excitability of peripheral nociceptors

SCN9A and NaV1.7

  • SCN9A encodes the NaV1.7 voltage-gated sodium channel, found in nociceptors and olfactory neurones
  • The same gene can produce opposite phenotypes:
    • Loss-of-function (autosomal recessive): CIP with anosmia, in otherwise healthy individuals
    • Gain-of-function (autosomal dominant): primary erythromelalgia, PEPD and painful small fibre neuropathy

Other examples


Gene (protein) Disorder Key features
SCN10A (NaV1.8) Familial episodic pain syndrome; small fibre neuropathy Paroxysmal pain of the distal lower limbs; burning neuropathic pain
SCN11A (NaV1.9) CIP (HSAN7) or familial episodic pain syndrome Loss of pain with pruritus and GI dysmotility; or episodic limb pain
NTRK1 (TrkA) and NGF HSAN4 and HSAN5 Loss of pain; anhidrosis (with fever episodes); painless fractures; corneal lesions
FAAH-OUT (non-coding RNA) CIP Loss of pain; reduced anxiety; fast wound healing; due to raised endocannabinoid (anandamide) levels
CACNA1A (CaV2.1) Familial hemiplegic migraine Hemiplegic migraine; ataxia; seizures


  • The genome contains many common (present in >1% of people), low-impact SNPs
  • Rather than directly causing chronic pain, these modulate susceptibility to it, often only under certain environmental conditions
  • Genome-wide association studies (GWASs) genotype large numbers of unrelated individuals with a condition against healthy controls to identify associated SNPs
  • Most associated SNPs lie in non-coding DNA, where they are thought to regulate gene expression
  • Results are displayed on a Manhattan plot:
    • x-axis: SNPs ordered by chromosome and position
    • y-axis: −log10(p-value); the higher the dot, the more significant the association

Examples

  • Migraine: 123 risk loci identified, enriched in vascular and CNS tissue, supporting a neurovascular mechanism
    • Included loci for CGRP and the 5-HT1F receptor, both targets of migraine-specific drugs
  • Back pain (UK Biobank): 13 loci significant for chronic back pain but none for acute back pain
    • Heritability was mostly attributed to genes expressed in the brain, suggesting central mechanisms drive the transition to chronicity

Advantages Disadvantages
Hypothesis-free; can identify novel genes and pathways Associated SNPs often have small effect sizes and unclear function
Large sample sizes using biobank data Association does not prove causation; SNPs may simply be linked to the true functional variant
Can highlight existing or new drug targets 'Winner's curse': initial effect sizes tend to be exaggerated, so replication studies are underpowered
Gives insight into differing mechanisms between pain conditions Heterogeneous pain phenotypes; most studies predate the ICD-11 chronic primary/secondary pain classification


  • Likely to be the most immediate clinical application of pain genetics
  • Genetic variation can alter both:
    • Pharmacokinetics: absorption, distribution, metabolic activation/inactivation and elimination
    • Pharmacodynamics: how the target receptor responds to the drug
  • e.g. there is a 10-fold variation in the optimal dose of nortriptyline due to CYP2D6 activity

CYP2D6 and codeine

  • Codeine is a prodrug; it is converted to morphine in the liver by CYP2D6
  • CYP2D6 is highly polymorphic, giving four metaboliser phenotypes:

Phenotype Genotype Effect of codeine
Poor (5–10%) No functional alleles Little morphine formed; inadequate analgesia; avoid codeine
Intermediate (2–11%) One reduced and one non-functional allele Reduced morphine formation; consider an alternative if no response
Extensive (normal) Two functional alleles, or one functional plus one reduced/non-functional Expected morphine formation; standard dosing
Ultrarapid More than two copies of functional alleles (gene duplication) Excess morphine formed; risk of respiratory depression and death; avoid codeine

  • The prevalence of ultrarapid metabolisers varies by ethnicity: ~1–2% in Northern Europeans, but up to ~29% in Ethiopian populations
  • Following deaths in children given codeine after tonsillectomy, the MHRA restricted codeine:
    • Only for acute moderate pain in children >12 years, when not relieved by paracetamol or ibuprofen
    • Contraindicated in under-18s undergoing tonsillectomy or adenoidectomy for obstructive sleep apnoea
    • Contraindicated in known CYP2D6 ultrarapid metabolisers and in breastfeeding mothers

Other analgesics

  • Tramadol: metabolised by CYP2D6 to its active metabolite (O-desmethyltramadol); shows the same poor to ultrarapid spectrum as codeine
  • Oxycodone: metabolised by CYP2D6 to oxymorphone, which has ~60-fold higher affinity for the μ-opioid receptor
  • Fentanyl: dealkylated by CYP3A4/5 to inactive norfentanyl
  • Buprenorphine: metabolised by CYP3A4
  • Tricyclic antidepressants (e.g. nortriptyline, amitriptyline): CYP2D6 activity determines plasma levels, efficacy and side-effects

Testing in practice

  • Pharmacogenetic testing is now offered routinely in the NHS, although on a limited scale
    • e.g. HLA-B*57:01 testing before prescribing abacavir, to identify those at risk of hypersensitivity
  • Direct-to-consumer genotyping is available privately, but results should be interpreted by a doctor or genetic counsellor in the context of the patient's whole care

New analgesic targets

  • NaV1.7 was an obvious target given that loss-of-function causes painlessness in otherwise healthy people
  • Small molecule NaV1.7 inhibitors have been disappointing, with autonomic side-effects a major problem
  • Lacosamide (acts on NaV1.7, 1.3 and 1.8) has shown modest benefit in NaV1.7-related small fibre neuropathy
  • Small molecule FAAH inhibitors have similarly had limited success in human trials

Gene therapy

  • CRISPR interference: a modified Cas9 enzyme is used to silence (rather than cut) a target gene
    • Silencing Scn9a in mice reduced inflammatory and neuropathic pain behaviour
    • Targeting the dorsal root ganglia using viral vectors may avoid autonomic side-effects
    • CRISPR interference at FAAH-OUT suppresses FAAH expression in human cells

Barriers

  • Manufacturing cost
  • Drug delivery to the target tissue
  • Safety concerns

Areas of research

  • Re-mapping genetic vulnerability using the ICD-11 classification of chronic primary and secondary pain
  • GWASs for postoperative pain
  • Epigenetics: control of gene activity without changing the DNA sequence; a likely link between environmental factors and chronic pain