Doctors in Scotland were amazed when a 66-year-old woman underwent what is normally a very painful operation on her hand for severe arthritis and required little to no pain medication afterward. Similarly, two years ago, she was diagnosed with severe osteoarthritis in her hip with significant joint degeneration, yet she complained of no discomfort before, during, or after her hip replacement surgery.
In fact, the patient told her doctors, there have been times she had burned herself and withdrew her hand from the flame only when she smelled burning flesh. She also scored remarkably low on anxiety and depression tests.
Thinking the woman’s exceptional insensitivity to pain might be rooted in her genes, researchers in the United Kingdom sequenced and analyzed her genome and found a previously unidentified mutation, they reported Wednesday in the British Journal of Anaesthesia. That mutation, in a region they named FAAH-OUT, seems to turn down the activity of a neighboring gene called FAAH, which is known to be involved in pain sensation, mood, and memory.
FAAH is a protein that breaks down anandamide, also known as the “bliss molecule,” which is a neurotransmitter that binds to cannabinoid receptors. These are some of the same receptors that are activated by marijuana. With less FAAH activity, this patient was found to have more circulating levels of anandamide, which may explain her resistance to feeling pain.
While it’s risky to make too much of one patient’s case, the researchers said their discovery could have exciting implications for the treatment of acute and chronic pain. Prior genetic targets for pain treatment have focused on sodium ion channels and the transmission of pain signals from the peripheral nervous system to the brain. The FAAH and FAAH-OUT genes instead alter how pain signals are interpreted by the brain.
While previous studies and trials of experimental drugs directed at FAAH have failed, the researchers said FAAH-OUT may offer a new way to target the endocannabinoid receptor. At a time when about 130 Americans die daily from opioid overdoses, scientists and drug companies are actively pursuing alternative non-opioid medications for acute and chronic pain.
“This discovery opens up numerous possibilities of developing drugs using the endocannabinoid pathway to modify how pain is experienced,” said Dr. Dev Srivastava, one of the investigators and a consultant in anesthesia and pain medicine at Raigmore Hospital in Inverness, Scotland. “This could be developed into a wonder drug to treat surgical patients or those with cancer or chronic pain.”
However, as with the Scottish patient, complete elimination of pain sensation can be problematic. Similar to patients who suffer from painful diabetic neuropathies, the resulting decreased sensation to extremities can sometimes result in repeated injuries that are not noticed by the patient. Dr. James Cox, another author and senior lecturer at the Wolfson Institute for Biomedical Research at University College London, said, “Pain is an essential warning system to protect you from damaging and life-threatening events.”
Another disadvantage to endocannabinoids and their receptor targets is that poor memory and learning may be unwanted byproducts. Researchers said the Scottish woman reported memory lapses, which mirrors what is seen in mice missing the FAAH gene.
The investigators were also quick to caution patients and providers that, while this research demonstrates analgesic effects within the endocannabinoid pathway, this does not mean that recreational cannabis works the same or can be used as a substitute for pain control. The opioid crisis in the United States began with people becoming addicted to legal pain medications and was followed by spikes in use of heroin and illicitly made fentanyl. If endocannabinoid-pathway medications become prevalent, illegal counterparts could similarly become a concern.