Separating side effects could hold key for safer opioids

November 16, 2017, NIH/National Institute on Drug Abuse
Credit: CC0 Public Domain

Opioid pain relievers can be extremely effective in relieving pain, but can carry a high risk of addiction and ultimately overdose when breathing is suppressed and stops. Scientists have discovered a way to separate these two effects—pain relief and breathing—opening a window of opportunity to make effective pain medications without the risk of respiratory failure. The research, published today in Cell, was funded by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health.

Opioid medications suppress by binding to specific receptors (proteins) in the brain; these same receptors also produce respiratory suppression. However, the way these receptors act to regulate pain and breathing may be fundamentally different. Studies using mouse genetic models suggest that avoiding one particular signaling pathway led to more favorable responses to morphine (pain relief without respiration effects). The investigators then explored if they could make drugs that would turn on the pathways associated with and avoid the pathways associated with respiratory suppression.

"We are pleased to have uncovered a potential new mechanism to create safer alternatives to opioid medications, ones that would be far less likely to cause the side effects that lead to overdose deaths associated with the misuse of opioids," said NIDA Director Nora D. Volkow, M.D. "We are excited that basic research on how work in the brain has led to this novel approach, and that we continue to make critical progress in this area."

How the pathways split following receptor activation is referred to as biased signaling. The study showed that as the degree of bias (divergence) increased, so too did the ability of an opioid to reduce pain in mice without affecting breathing. Similarly, compounds that favor the produced more respiratory side effects at lower doses. Ultimately, opioids with a larger divergence (bias factor) had a larger margin of safety, or therapeutic window, opening up an opportunity for medication intervention.

"In this study, we demonstrate that this divergence, which we call biased agonism, is not an 'all or none' phenomenon, but rather exists as a spectrum. As such, if a small degree of divergence between pathways in cell culture produces a minimal benefit in living organisms, there is potential to chemically improve the signaling bias and subsequently improve the therapeutic safety window," said Laura M. Bohn, Ph.D., principal investigator on the study from The Scripps Research Institute.

It is unclear how these divergent pathways affect other side effects of opioids, including addiction. However, this finding could represent a new direction in the pharmaceutical development of safer alternatives to current opioid pain relievers, which is part of the NIH initiative to address the crisis.

Explore further: New painkillers reduce overdose risk

More information: Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics, Cell (2017). ,

Related Stories

New painkillers reduce overdose risk

November 16, 2017
Scientists on the Florida campus of The Scripps Research Institute (TSRI) have developed new opioid pain relievers that reduce pain on par with morphine but do not slow or stop breathing—the cause of opiate overdose.

Long-term opioid use does not increase risk of Alzheimer 's disease

October 24, 2017
Opioid use is not associated with an increased risk of Alzheimer's disease, shows a recent study from the University of Eastern Finland. Researchers did not find any risk neither for long-term use nor for higher cumulative ...

Scientists reveal new insights and possible solutions for opioid epidemics using machine

September 13, 2017
Mount Sinai researchers have identified unique structural, biological and chemical insights in the way different opioid drugs activate the receptors and specific signaling pathways responsible for the drug's beneficial and ...

Gabapentin co-use may increase risk of fatal opioid overdose

October 3, 2017
Co-prescription of the anticonvulsant gabapentin is associated with an increased risk of opioid-related death in people who are prescribed opioid painkillers, according to a new study published in PLOS Medicine.

What you can do to help fight the opioid epidemic

September 13, 2017
(HealthDay)—Proper disposal of prescription painkillers and use of safe alternatives to manage pain could help combat America's opioid abuse epidemic, doctors say.

New type of opioid targets pain areas directly avoiding negative side effects

March 3, 2017
(Medical Xpress)—A team of researchers with the Free University of Berlin and Zuse-Institut Berlin has developed a type of opioid that was shown to target pain in rats without causing negative side effects. In their paper ...

Recommended for you

Medicating for mental health—Intense exercise before taking a daily dose could prevent weight gain, diseases

March 21, 2018
Weight gain and Type 2 diabetes are potential side effects in people taking a common medication to treat mental illness.

Certain teens more likely to get hooked on opioids

March 12, 2018
(HealthDay)—Teenagers with any mental health problem are more prone to painkiller dependence after receiving a prescription opioid, a new study finds.

Prescription opioids fail rigorous new test for chronic pain

March 6, 2018
A yearlong study offers rigorous new evidence against using prescription opioids for chronic pain.

Study suggests failed osteoarthritis drug could help treat opioid addiction

February 27, 2018
A new study from Indiana University suggests that a drug proven safe for use in people may prevent opioid tolerance and physical dependence when used in combination with opioid-based pain medications.

Complex inhalers prevent patients from taking medicine

February 23, 2018
Respiratory disease patients with arthritis could struggle to manage their conditions because their inhalers are too fiddly for them to use, University of Bath research has found.

Opioid abuse leads to heroin use and a hepatitis C epidemic, researcher says

February 22, 2018
Heroin is worse than other drugs because people inject it much sooner, potentially resulting in increased risk of injection-related epidemics such as hepatitis C and HIV, a Keck School of Medicine of USC study shows.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.