Case report A yr old
A 66-yr-old Caucasian female presented to Raigmore Hospital in Inverness, Scotland for orthopaedic surgery, specifically a trapeziectomy with ligament reconstruction and tendon interposition and extensor pollicis longus realignment after a diagnosis of bilateral pantrapezial osteoarthritis. There was significant deformity and deterioration in the use of the right thumb, which was reported as painless before operation. The pre-assessment note classed her as ASA physical status 1, but highlighted that she had a history of vomiting after intake of morphine.
The patient had been diagnosed with YM 022 of the hip, which she reported as painless, which was not consistent with the severe degree of joint degeneration. At 65 yr of age, she had undergone a hip replacement and was administered only paracetamol 2 g orally on Postoperative days 1 and 2, reporting that she was encouraged to take the paracetamol, but that she did not ask for any analgesics. She was also administered a single dose of morphine sulphate 10 mg orally on the first postoperative evening that caused severe nausea and vomiting for 2 days. After operation, her pain intensity scores were 0/10 throughout except for one score of 1/10 on the first postoperative evening. Her past surgical history was notable for multiple varicose vein and dental procedures for which she has never required analgesia. She also reported a long history of painless injuries (e.g. suturing of a laceration and left wrist fracture) for which she did not use analgesics. She reported numerous burns and cuts without pain (Supplementary Fig. S1), often smelling her burning flesh before noticing any injury, and that these wounds healed quickly with little or no residual scar. She reported eating Scotch bonnet chilli peppers without any discomfort, but a short-lasting ‘pleasant glow’ in her mouth. She described sweating normally in warm conditions.
The patient lives with her husband, and has a daughter and a son from her previous marriage. Her family history is unremarkable for neuropathy or painful conditions. Her mother and daughter appear to perceive pain normally. Her father (now deceased) had little requirement for pain killers. Her son also reports of having some degree of pain insensitivity, but not to the same extent as her. She does not take any medication at present, and is fit and active with no medical conditions apart from arthritis (Supplementary Fig. S2). She is talkative and happy with an optimistic outlook. On the Generalized Anxiety Disorder-7 anxiety questionnaire taken at age 70, she scored 0/21, classified as mild (the lowest category). Likewise, on the Patient Health Questionnaire-9 for depression, she scored 0/29, classified as mild. She reported long-standing memory lapses (e.g. frequently forgetting words mid-sentence and placement of keys). She also reported never panicking, not even in dangerous or fearful situations, such as in a recent road traffic accident.
After the painless trapeziectomy surgery and a history of ‘painless operations’, she was referred to and further investigated by pain genetics teams from University College London and the University of Oxford at age 67 yr. Ethical approval was granted from both institutions, and written consent taken from the patient, her two children, and mother. On clinical examination, she had multiple scars around the arms and on the back of her hands. Quantitative sensory testing (Supplementary Fig. S3) demonstrated hyposensitivity to noxious heat both in the hands and feet (see Supplementary data for further clinical details).
Discussion The endocannabinoid system is an important physiological system that performs a wide array of homeostatic functions and is important for pain perception. FAAH is a critical enzyme for the breakdown of a range of bioactive lipids (including the endocannabinoid AEA and related FAAs and N-acyl-taurines) with diverse physiological roles. Mouse modelling of FAAH loss of function mutations and pharmacological inhibition studies have shown a range of phenotypes, including hypoalgesia, accelerated skin wound healing, enhanced fear-extinction memory, reduced anxiety, and short-term memory deficits.6, 13, 18, 19, 20, 21 Furthermore, human hypomorphic FAAH SNPs are associated with a reduced need for postoperative analgesia, increased postoperative nausea and vomiting induced by opioids, and decreased anxiety-linked behaviours.10, 13, 16, 22, 23, 24