Breaking the vicious cycle of chronic pain and sleep disorders

Getting a good night’s rest may be an impossible dream for the estimated 1.5 billion people around the world who live with chronic pain. Many people live in a vicious cycle where chronic pain disrupts their ability to sleep and, conversely, sleep disruptions make their pain worse. Until recently, no one understood why.

In a study published in the journal Brain Earlier this year, researchers at Arizona University of Health Sciences discovered a biological mechanism that may be behind the chronic pain-sleep disturbance cycle. The hope is that the discovery will lead to new treatments for sleep deprivation and chronic pain.

“The therapeutic implication is that if you treat sleep, you will also treat pain,” said Frank Porreca, PhDAssociate Department Head and Professor of Pharmacology at UArizona College of Medicine – Tucson and Fellow of the UArizona Health Sciences Comprehensive Pain and Addiction Center.

The purpose of pain

Simply put, pain is the body’s warning system. It can signal the presence of an injury and serve as a warning of potential bodily harm.

“If you think about it from an evolutionary perspective, if an animal is injured and in pain, then there is an increased vulnerability to danger and predators,” Dr Porreca said. “Thus, pain disruption of sleep is likely beneficial in the short term for increasing alertness and alertness to increase chances of survival.”

Chronic pain is not exclusive to humans, as veterinarians treat chronic pain due to osteoarthritis and other conditions in pets.  If pain is present, regardless of species, the neural mechanisms that lead to sleep disruption are the same.Most people are not at risk of being attacked by a lion, but neural mechanisms that are conserved in all species lead to sleep disruption if they experience pain. According to the National Sleep Foundation’s 2015 Sleep in America survey, 1 in 4 people with chronic pain also have a sleep disorder. A review by Finan, Goodin and Smith in The Journal of Pain found that sleep disturbances are present in 67-88% of chronic pain disorders and at least 50% of people with insomnia – the most commonly diagnosed sleep – suffer from chronic disorders. pain.

Alternatively, studies have shown that in people without chronic pain, acute sleep deprivation increases pain reactivity. Either way, it’s clear that the link between pain and sleep is a two-way street.

“The problem is that the more this happens – if the pain is chronic – then you get sleep debt and homeostatic pressure to sleep. And it strengthens and supports the pain,” Dr. Porreca said. “So it’s a vicious circle of anticipation that, over time, becomes maladjusted. And it reinforces and supports chronic pain.

Discover a mechanism to break the cycle

Dr. Porreca and collaborator Edita Navratilova, PhDbelieve that the key to stopping the sleep deprivation-chronic pain cycle lies in the brain circuits that express kappa opioid receptors.

“The therapeutic implication is that if you treat sleep, you will also treat pain.”
Frank Porreca, PhD

Kappa opioid receptors (KORs) have long been studied for their role in drug addiction. Preclinical and clinical studies have suggested that inhibiting KORs can block the negative emotional state associated with depression, anxiety, and drug-seeking behavior.

KORs are part of the body’s endogenous opioid system. They are activated by dynorphin, a neurotransmitter involved in pain, addiction and stress responses. Dynorphin levels can be increased by chronic pain, which activates stress circuits in the brain.

Using this knowledge, Drs. Porreca and Navratilova examined the effects of dynorphin/KOR signaling on sleep. They found that activation of KOR signaling promoted deep wakefulness and arousal in normal animals. Conversely, inhibition of KOR signaling normalized sleep in animal models of chronic pain.

Dr. Porreca's research suggests that dynorphin, a neurotransmitter involved in pain, addiction, and stress responses, is a key factor in how chronic pain induces insomnia.

“That’s pretty cool, because this is a new mechanism that regulates sleep, and it’s never been reported before,” Dr. Porreca said.

Moreover, KOR antagonists, which inhibit KOR signaling, did not produce direct hypnotic effects in painless animals, suggesting that dynorphin is a key factor in how chronic pain induces insomnia.

This marks an important distinction between KOR antagonists and orexin antagonists, a relatively new class of sedative-hypnotic drugs approved by the Food and Drug Administration for sleep onset and sleep maintenance insomnia. Orexin antagonists, marketed under the brand names Quviviq, Dayvigo, and Belsomra, produce sleep in the absence of chronic pain, which may limit their daytime use.

A potential therapeutic target

Due to the extensive research already done on kappa opioid receptors, there are at least two KOR antagonists currently in clinical development for stress-related problems, including generalized anxiety, anhedonia, and depression. If either drug were to gain FDA approval, it would pave the way for additional clinical trials focused on chronic pain and sleep.

Some sleeping pills commonly used to treat sleep disorders can have a sedating effect.  Dr. Porreca's research on kappa opioid receptor antagonists could lead to a non-hypnotic treatment to treat sleep disorders and treat chronic pain.“The translational value comes from the fact that there is a drug in phase 2 clinical trials and another in phase 3 clinical trials that works on this mechanism,” Dr. Porreca said. “These drugs have not yet been approved, but in addition to their evaluation for depression, anxiety and anhedonia, they could be useful for treating both chronic pain and sleep disorders. Most neurological disorders are associated with disturbed sleep and this mechanism may be relevant for conditions other than chronic pain.

While the idea of ​​a new treatment to treat chronic pain and sleep disorders is exciting, Dr. Porreca is also optimistic about what could be a new biological sign to test if painkillers are working.

“What’s really exciting is that any medicine that relieves pain should have positive effects on sleep disturbances. So, in a way, sleep – the improvement of disturbed sleep – in chronic pain becomes a biomarker of the effectiveness of new painkillers,” he said. “That has never been demonstrated before either, and those implications exist now.”

Because pain and sleep have a two-way relationship, the researchers noted that the improvement in sleep observed when KOR signaling was blocked could be due to pain relief or, alternatively, pain improvement could be the result of improved sleep. Their future studies will determine whether improved sleep is a direct effect of reduced KOR signaling or an indirect effect via improved pain.

Either way, they shed light on the kappa opioid receptor as a new way to break the damaging vicious spiral of chronic pain and disrupted sleep.

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