Available online 18 August 2023, 101096

Author links open overlay panel, Abstract

The prevalence of opioid use disorder and overdose continues to harm the U.S. population and is further exacerbated by the use of the synthetic opioid, fentanyl, and its analogs. Gender differences in the effects of fentanyl are not well understood. The present article reviews evidence for gender and sex differences in the physiological and behavioral effects of fentanyl in humans and animals. Biological sex seems to be a foundational driver in addiction vulnerability and affects mechanisms related to opioid use including fentanyl. Fentanyl has distinct pharmacodynamics and enhanced efficacy relative to other opioids that highlights the need to investigate how females may be uniquely altered by its use. Behavioral and physiological responses to fentanyl are found to differ by sex and gender in many cases, including outputs like affective symptoms, analgesia, tolerance, and withdrawal emphasizing the need for further research about the role of biological sex on fentanyl use.

Section snippetsIntroduction to the FEN Epidemic

Opioid use disorder (OUD) and opioid overdose are increasingly prevalent in the U.S. (CDC, 2018). Specifically, the illicit use of fentanyl (FEN), a potent synthetic opioid, has become more widespread in recent years contributing to the dramatic increase in FEN-related overdoses and deaths (CDC, 2022b). Notably, more than 107,000 people died due to drug overdose in the United States in 2021 (NIDA, 2023). At least 67% of those reported deaths were related to synthetic opioids including FEN (CDC,

Physiological Responses

The major physiological effects of FEN are similar to other opioids. These include analgesia and numbness, respiratory depression, cough suppression, sedation and anxiolysis, nausea and vomiting, gastrointestinal symptoms including constipation, pupillary constriction, and decreases in body temperature, blood pressure, and heart rate. Opioids can differ in their efficacies in inducing these physiological effects and whether or not sex or gender affects the efficacies of specific physiological

Behavioral Pharmacology: Drug Discrimination and Schedule-Controlled Responding

In addition to physiological responses, the effects of FEN on behavior provide valuable information on potential sex differences in drug effects. Some standard behavioral pharmacology procedures including schedule-controlled responding and drug discrimination offer the ability to assess dose-response functions. In studies of schedule-controlled responding, animals lever press for a food or liquid reinforcer on a specific schedule of reinforcement. The change in rates of lever pressing (i.e.,

Motor Effects and Behavioral Sensitization

FEN and other opioids cause motor effects. Morphine can have delayed effects and is characterized by its biphasic effects on locomotor activity that are dose-dependent (Babbini and Davis, 1972, Kosten and Bombace, 2000). That is, at moderate to high doses, morphine can initially cause decreases in activity levels but a few hours later, enhanced activity levels may be seen. While most studies that assessed the biphasic effects of morphine employed male rodents, it is seen in females. Patti and

Analgesia

A well-known effect of and use for opioids is to reduce pain (i.e., act as an analgesic). Compared to other opioids, FEN has a significantly higher analgesic potency that makes it a highly effective option for pain medication (Comer & Cahill, 2019). Sensory responses to thermal pain are less effectively decreased by morphine in female Sprague-Dawley rats compared to males (Peckham and Traynor, 2006, Craft, 2008) but no sex differences are seen in a warm-water tail-withdrawal assay with FEN (

Effects of Repeated Administration

Repeated exposure to opioids is well known to induce tolerance, such as a decrease in analgesic efficacy, or sensitization, such as increased locomotor stimulation also known as behavioral sensitization, as discussed above. Repeated use can also affect the rewarding efficacy of the drug as described above after long-access drug self-administration sessions. Another study reports that repeated FEN produces tolerance to its rate-decreasing effects in intracranial self-stimulation after 7 days of

Future directions

More research is needed to determine potential sex and gender differences in the behavioral and physiological effects of FEN. For example, future research to determine if FEN response is impacted by the activational effects of ovarian hormones could incorporate ovariectomy and hormone replacement methods in animal studies. These methods have been used to measure various responses (e.g., withdrawal, tolerance, behavioral outputs) to other opioids including morphine, heroin, and oxycodone (Sharp

Conclusions and comparisons

While FEN and other opioids, like morphine or oxycodone, have some overlapping effects, there are differences in the sex effects that appear to be unique to FEN. For example, the differences between FEN and other opioids have been noted in a clinical study that showed that FEN causes significantly increased body temperature compared to morphine (Kahn et al., 2011). Some comparisons of similarities and differences in responses to FEN versus other opioids, usually morphine or heroin, are

Uncited references

Agnoli et al., 2002, CDC (2022a), , 2022.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was supported by NIH/NIAID, GENFD0001789207, and the Michael C. Gibson Addiction Research Program at the University of Houston. The authors thank Dr. Richard A. Meisch for his invaluable input on the manuscript.

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