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As opioid overdose deaths in the U.S. from 2014 to today, both , and , cemented reputations as hotspots of the crisis.

In Philadelphia, over 1,170 people , the last year for which complete data is available. More than 300 more .

Research indicates that for many people with opioid use disorder, misuse .

As neuroscientists who study the , we are working to better understand why some people are at greater risk for developing opioid dependence and addiction when taking prescribed opioids.

We are also striving to discover better treatments that can reduce drug cravings and prevent relapses in recovering users.

Sex differences and opioid addiction

There is some evidence that biological sex may play a role in both opioid addiction liability and relapse vulnerability.

For example, findings indicate that women are . They also from .

Moreover, some studies have found that when trying to stay clean, women self-report and may experience symptoms. This suggests that women may also be at a greater risk for relapse.

What might underlie these sex differences in opioid misuse and relapse susceptibility? One possible factor is the difference between men and women in the levels of the major sex hormones: testosterone, estrogen and progesterone.

Because estrogen and progesterone levels fluctuate naturally across the menstrual cycle in women – as well as during different stages of life such as pregnancy and menopause – we are examining whether opioid use and cravings vary as levels of these hormones change.

Hormones and drug cravings

To unravel the relationship between hormonal fluctuations and opioid rewards, many researchers have turned to rodent models. Rats in particular serve as an excellent model organism because their reproductive cycle, referred to as the estrous cycle, is brief – lasting four to five days. Also, the pattern of fluctuations in rat estrogen and progesterone levels is .

In , we have found that levels of cocaine cravings . Specifically, cocaine cravings increase around the time of ovulation, after estrogen and progesterone levels have peaked.

In humans, around the time of ovulation, when estrogen levels are elevated.

However, much less is known about whether these hormonal fluctuations similarly affect opioid rewards or cravings.

Hormones and pain relief

To date, most of what we know regarding hormonal influences on opioid drugs in humans comes from studies focused on their pain-relieving effects.

Although there are some conflicting reports, the data seem to suggest that opioid-induced pain relief is greatest in women during the phase of the menstrual cycle . This is when estrogen levels are increasing and progesterone levels are low.

Opioid drugs relieve pain by binding to and activating proteins called opioid receptors at various nodes in the brain and spinal cord. The brain also makes its own natural version of opioids, called endogenous opioids. Research indicates that increasing estrogen levels can increase both and the in various parts of the brain.

These changes could contribute to differences in opioid-induced pain relief across the menstrual cycle.

Hormones and opioid rewards and cravings

We and other researchers are working to determine whether estrogen and progesterone levels also influence the rewarding effects of prescription opioids, or cravings for these drugs.

In one set of studies, scientists trained rats to press a lever in order to receive intravenous infusions of heroin. The researchers found that the rats took less heroin , when levels of estrogen and progesterone were elevated.

later revealed that the rise in estrogen, but not progesterone, .

Newer evidence suggests that this phenomenon may extend to prescription opioids. In the , we have discovered that the rewarding effects of the prescription opioid painkiller oxycodone are similarly reduced during cycle stages surrounding ovulation in which from peak levels.

Meanwhile, unpublished studies from the Loweth Lab found similar reductions in oxycodone craving across the rat estrous cycle. However, another recent study using slightly different methods of the estrous cycle on oxycodone cravings.

Such discrepancies highlight the need for further research to tease apart precisely how and when hormones affect the risk for former users of prescription opioids to experience a relapse.

This information could play an important role in how health care providers prescribe opioid medications – perhaps taking both biological sex and hormonal status into account – in order to minimize the risk of transitioning to prescription opioid misuse.

Ultimately, such efforts could reduce the incidence of opioid addiction and help combat the ongoing opioid crisis.

Jessica Loweth receives funding from the Osteopathic Heritage Foundation for Primary Care Research and has previously received funding from the ³Ô¹ÏÍøÕ¾ Institute on Drug Abuse.

Daniel Manvich receives funding from the Osteopathic Heritage Foundation Endowment for Primary Care Research and has previously received funding from the New Jersey Health Foundation and the ³Ô¹ÏÍøÕ¾ Institute on Drug Abuse.