Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity

Br J Anaesth. 2019 Aug;123(2):e249-e253. doi: 10.1016/j.bja.2019.02.019. Epub 2019 Mar 28.


The study of rare families with inherited pain insensitivity can identify new human-validated analgesic drug targets. Here, a 66-yr-old female presented with nil requirement for postoperative analgesia after a normally painful orthopaedic hand surgery (trapeziectomy). Further investigations revealed a lifelong history of painless injuries, such as frequent cuts and burns, which were observed to heal quickly. We report the causative mutations for this new pain insensitivity disorder: the co-inheritance of (i) a microdeletion in dorsal root ganglia and brain-expressed pseudogene, FAAH-OUT, which we cloned from the fatty-acid amide hydrolase (FAAH) chromosomal region; and (ii) a common functional single-nucleotide polymorphism in FAAH conferring reduced expression and activity. Circulating concentrations of anandamide and related fatty-acid amides (palmitoylethanolamide and oleoylethanolamine) that are all normally degraded by FAAH were significantly elevated in peripheral blood compared with normal control carriers of the hypomorphic single-nucleotide polymorphism. The genetic findings and elevated circulating fatty-acid amides are consistent with a phenotype resulting from enhanced endocannabinoid signalling and a loss of function of FAAH. Our results highlight previously unknown complexity at the FAAH genomic locus involving the expression of FAAH-OUT, a novel pseudogene and long non-coding RNA. These data suggest new routes to develop FAAH-based analgesia by targeting of FAAH-OUT, which could significantly improve the treatment of postoperative pain and potentially chronic pain and anxiety disorders.

Keywords: anandamide; anxiolytic; endocannabinoids; pain insensitivity; postoperative analgesia.

Publication types

  • Case Reports

MeSH terms

  • Aged
  • Amidohydrolases / blood
  • Amidohydrolases / genetics*
  • Arachidonic Acids / blood*
  • Endocannabinoids / blood*
  • Female
  • Humans
  • Pain Insensitivity, Congenital / blood*
  • Pain Insensitivity, Congenital / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Polyunsaturated Alkamides / blood*
  • Pseudogenes / genetics*


  • Arachidonic Acids
  • Endocannabinoids
  • Polyunsaturated Alkamides
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • anandamide