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RCORP - Rural Center of Excellence on SUD Prevention

Resources for an Evolving Crisis: Preventing Overdose from Combined Substances

Between May 2020 and April 2021, more than 100,000 people died from an overdose in the U.S., according to provisional data.1 The over 30% rise in overdose deaths in 2020 has been linked to synthetic opioids, stimulants, and the use of substances in combination (polysubstance use).2 In 2016, 80% of overdose deaths related to synthetics like fentanyl involved combination with other opioids, stimulants, benzodiazepines, alcohol, antidepressants, or other substances.3 Naloxone, which reverses the effects of opioid overdose, may be less effective in overdoses involving additional substances.4

In the video:

Tim Wiegand, M.D., associate professor of emergency medicine, University of Rochester Medical Center

Gloria Baciewicz, M.D., medical director of Strong Recovery, University of Rochester Medical Center, co-principal investigator, UR Medicine Recovery Center of Excellence

Patrick Seche, senior director of addiction services, Strong Recovery, University of Rochester Medical Center

Kelly Quinn, Recovery coach and health project counselor, Strong Recovery, University of Rochester Medical Center

In the U.S. in 2020, the number of people who died from a drug overdose spiked by 30 percent. Between May 2020 and April 2021 100,000 died from an overdose.  The rise is attributed to synthetic opioids, stimulants, and use of multiple substances
in combination and is known as the fourth wave. What started in 1999 largely with prescription opioids continued in 2010 with heroin use, then by 2016 was driven by lethal synthetic opioids like fentanyl. And by 2020 stimulants like methamphetamine and
cocaine and depressants like benzodiazepine were being combined with fentanyl to
cause record numbers of overdose deaths. This polysubstance overdose crisis has also struck Appalachia, where in 2020 more than half the calls to poison
control across 23 rural counties in Kentucky, New York, Ohio and West Virginia
involved more than one substance.


Tim Wiegand, M.D.: The fourth wave of the overdose epidemic, while initially was attributed to stimulants and fentanyl use, it’s pretty much now fentanyl is in almost all the drugs. You have adulterated pills on the street so anyone buying an Oxycodone you know 30 milligram tablet they think they're getting Oxycodone -- really, they're getting a bunch of fentanyl.

Patrick Seche:  We're seeing an increase in counterfeit pills and overdose deaths nearly everywhere, so in urban communities as well as in rural communities including areas in Appalachia in Ohio, Kentucky, West Virginia, the Southern Tier of New York.

 Tim Wiegand, M.D.: Even when heroin was truly heroin there
was some variability in how much was in a bag but people generally had an idea on how it would affect them. Now they get fentanyl, and they may get a lot of fentanyl in the bag or they may get a little fentanyl . . . and it's when you have an opioid as potent as fentanyl -- and sometimes mixed with other things that are going to make it stronger potentiate it -- it is really dangerous and really unpredictable.

Kelly Quinn:  I've experienced two overdoses. Both times I went and . . . I'm gonna buy a
small amount . . . usually I would do let's say five bags of heroin at a time.  Well, this time I'm only gonna do one, because that'll keep me safer.  I'll still get an effect from it but I'm not doing so much so that'll kind of better ensure that I don't overdose. And I couldn't even tell you what force it was that made it so that I could still be here, because I was driving my car I pulled out of Tops on North Clinton and the next thing I know I'm getting yanked out of my car by EMTs up on Main Street.  I have no idea how I got to Main Street.  I don't remember any of it, and I was just stopped in the middle of Main Street . . . like my foot wasn't on the break I wasn't in park.  I didn't hit anything my car just stopped and somebody luckily had Narcan on them, called 9-1-1 so they gave me some Narcan, I wasn't quite responding to the first dose, but them giving me that Narcan kept me alive, we'll say, long enough for EMS to show up and give me more Narcan and then I was brought to the hospital. But, when they did my toxicology it was all fentanyl.

Tim Wiegand, M.D:  We get a lot of unintentional overdoses because people don't know what they're getting. In the last couple of days that I was on consult I had one each day one was a patient that had been in a bar, bought a line of cocaine and woke up in the ED. She was with somebody that had naloxone and fortunately was able to be reversed but had she been in the bathroom without you know someone around it would have been
a fatality.

Kelly Quinn:  I had a therapist tell me one time and I hold this very true and remember it because the way he presented it was very blunt and direct. I was complaining because I had to do a screen in outpatient and I was testing positive for substances that I didn't use
and I, you know, was complaining about this I had a problem  ‘well I didn't do that and that's not fair I didn't use’ (I think it was cocaine)  ‘I didn't use cocaine,’ and he looked at me and said “well, yeah, the quality control on street drugs has really gone down.” he meant it in a sarcastic away but it really kind of illustrated the fact that you can go to the same person and buy your substances and feel like you're safe in that, but there is no guaranteed safety out there and that those threads that we're holding onto to convince ourselves that we're keeping ourselves safe or safer are starting to become thinner and thinner and thinner and in a lot of situations they just break.

Tim Wiegand, M.D:  So the counterfeit pills are dangerous for a number of reasons. People, in probably the most common counterfeit pills I see are alprazolam or Xanax. Alprazolam is a very euphoric benzodiazepine, people really like it, so it's a known commodity. It's not surprising that someone will press a pill to look like Xanax; but they don't contain alprazolam they contain other synthetic benzodiazepines sometimes mixes of designer benzodiazepines that the end user doesn't have an idea of the strength often, the duration of effect. Sometimes there's other things in it. There have been clusters of fatalities with designer benzodiazepines that had fentanyl mixed in it. So, if you have an user that's expecting to use maybe a two-milligram dose of alprazolam, that they know what happens when they take it, and they get a much more potent designer benzodiazepine, may be mixed with some fentanyl or some other drugs, it's a perfect setup for overdose and fatality.

Kelly Quinn: I know that I would seek out prescription medication
off the streets before heroin because I felt like well if it's prescription like chemists put this
together the FDA approved it, whatever, I know what I'm getting then. And now with counterfeit pills that's completely changed the game, and I have seen people buy counterfeit pills that they think may be Vicodin or Xanax and it turns out that it's completely just pressed fentanyl.

Patrick Seche:  There's a stabilization phase in treatment, you know, for a lot of people a lot of times that initial, that initial process is getting some medication, getting stabilized physically, and then they can really focus on some counseling that can help them look at recovery on a more long-term level and figure out what is their pathway to recovery.

Tim Wiegand, M.D:  The withdrawal, the dysphoria, anxiety, panic, all those symptoms, people are often . . . once they're physically dependent, not using necessarily for the euphoria anymore, they're using just to feel normal. They live in a dysphoric state; and if you don't have the dysphoric state taken away, that withdrawal syndrome,
you can't then move to the next step, which is to start recovery; to start learning about
addiction; to get the support system in place to work on things like safe housing the rest of overall health.

Kelly Quinn: MAT [Medication Assisted treatment] is vital for people who really need it, because withdrawal is . . . I would not have been able to do it if I did not have access to MAT
to be able to stabilize myself and get into treatment and hear a message, and actually utilize the time that I was in groups and therapy sessions. I wouldn't be here; it would
not have worked, because my entire mindset and existence and everything would have just been focused on how absolutely miserable I feel. And I think that's something that a lot of
people who have not experienced withdrawal, whether it's opiates, benzodiazepines, alcohol, you can't describe it to somebody who hasn't experienced it.

 Patrick Seche:   You know, in rural communities where everybody knows everybody a lot of times it it's hard to even get people to come to treatment. So looking at that aspect of it is a critical, it's a critical area to take a look at how we can reduce the stigma associated with treatment so that more people will access care.

 Kelly Quinn: We have this this wonderful tool, this medication that can help mitigate those symptoms and allow you to get the help that you need, so we need to do that right away, like when it comes to this window of willingness that people who are seeking recovery have, seconds count.

 Gloria Baciewicz, M.D.: So, one of the things that's going on with the fourth wave of the opioid crisis that providers and pharmacists should know about is that people are more frequently mixing drugs. And they are also using stimulant a lot of stimulant medication such as cocaine and methamphetamine, and in terms of the drugs that they're mixing gabapentin and benzodiazepine type drugs are prominent and can cause a lot of problems. And also, they're mixing drugs that they don't even know about because sometimes they're buying drugs on the street, even pills that look like FDA regulated pills but are not, and these pills are counterfeit and they've had various things added to them, most concerningly fentanyl.

Tim Wiegand, M.D:  When you mix drugs depending on the drugs you can get a lot of
different effects but most often when we see fatal overdoses or you know somebody ends up in the ICU, they're mixing depressants and that includes most commonly an opioid, usually fentanyl. It could be from heroin it could be from a counterfeit pill but in addition to the opioid another depressant may be used like a benzodiazepine or a gabapentin
or alcohol even or all of the above and when you have several depressants combined together you have a greater effect on decreasing breathing, the decreased mental status,
the combinations blunt the ability to recognize that the oxygen saturation is low so people are less likely to be breathing when their oxygen drops or when their carbon dioxide rises.
The opioids, the synthetic opioids in particular, work very quickly and you don't have a lot of time to recognize an overdose, in particular if someone's using intravenously. So, you know, historically, if we had prescription opioids taken, we had little bit of time for someone to recognize somebody's passed out on the couch, their breathing is slowed. Now it's very abrupt; fentanyl overdoses happen really quickly. You have not as much time
to react -- great risk of overdose if using alone.

Tim Wiegand, M.D:  Xylazine has been around for a while but just not in the United States
northeast and now it's showing up in the northeast. Xylazine is a horse anesthetic. It is added to the to the heroin because it kicks it in, it potentiates it.  If a user is using Xylazine,
it makes them more dependent. Now if you're using heroin whether it's fentanyl or truly heroin and you have Xylazine, the withdrawal syndrome is going to be a lot worse, the intoxication will be much more significant, and risk for fatal overdose certainly more significant, but if they stop using they have much more severe withdrawal.


Gloria Baciewicz, M.D.: Gabapentin can be a useful medication for many problems but when it's used together with opioids it confers a higher risk upon the person. So
people need to know about this problem. Actually, gabapentin misuse among the general population is on the rare side, but when you look at the opioid using population, those who misuse opioids or have an actual opioid use disorder, the amount of people who misuse gabapentin is increased. One of the very important things to do after you've talked to the patient and asked them about drug use disorder and also investigated
the results of a urine test or mouth swab, the next most important thing to do is check the
state prescription management program to see if they are getting prescribed any other opioids from other doctors or other benzodiazepine types of drugs. And you can also see gabapentin reported in some of these prescription management
program databases -- not in 100 percent of states but in certain states.  It's been mandated to report gabapentin prescriptions as well because of all the problems with gabapentin so examples of states that have mandated such type of reporting are Ohio, Virginia and West Virginia, and there are several others as well and there's movements in other states to get that legislation on the books.


Patrick Seche:   It's important that we're educating people that are at risk as well as the general public – family members, friends -- to be aware of naloxone, to make sure that there's naloxone distribution programs available in those communities and that we're making it available to any and everyone.

Tim Wiegand, M.D:  It's really dangerous to use alone the overdoses occur rapidly and if you don't have someone there with naloxone if an individual uses too much really high risk for fatality.

Kelly Quinn:  So the first thing is the distribution of Narcan {Naloxone} and making Narcan readily available that's the first step. I think that it's important to note that --
and I said this to a counselor one time, I was very high risk I was still using, she
gave me a Narcan kit and I went ‘this is great but if I'm overdosing I can't Narcan myself,’--
which then kind of leads into the next thing, which I think we're doing but we could do a better job, which is minimizing these feelings of guilt and shame around substance use disorder; because that guilt and shame is what caused me to use in abandoned houses and alleys and alone in my car where if I did overdose there was nobody there to help me.

Tim Wiegand, M.D:  I'm talking with the person who's using drugs I try not to lecture,
you know, treat them in a destigmatized way,and try and make them aware that I'm here to help, you know, whether that's if they're not ready to stop using to use safely, you know, then I teach them about things like needle exchange, use with somebody so you're not using alone, test the drugs if you're able to get fentanyl test strips, so you can understand
that you know what you're using, recognize the combinations that you're using could be
more dangerous potentially.

Kelly Quinn:  Avoiding the fear-based messaging, where I'm not trying to explain what the risks are to scare you this isn't a scared straight tactic that doesn't work.  What I'm trying to do is here's the here's the realistic possible outcomes of what you're doing. What do you want your outcome to look like and how can I help you reach that outcome?

Patrick Seche:   I think the most important things for communities to do of course is working with their health care systems their government officials to push and ensure that treatment is readily available.

 Gloria Baciewicz, M.D.: it's important to try and provide as much treatment as possible and to make all of the opioid use disorder medications available to people and that's that's something that, you know, we can, we can do, if we have community willingness and provider willingness.

March 10, 2022

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Polysubstance use and overdose is a complex challenge involving various factors and combinations. Researchers are calling attention to trends such as these:

  • Benzodiazepines and alcohol, which are respiratory depressants, can increase the risk of overdose death when taken with opioids. In 2017, benzodiazepines factored into 33% of prescription opioid overdose deaths and 17% of synthetic opioid overdose deaths. Alcohol was involved in 15% of opioid overdose deaths.5
  • Gabapentin or gabapentinoids, prescribed for various conditions including seizures and nerve pain, can be dangerous in combination with opioids. Prescriptions have increased, but so has nonmedical use, and people with a history of substance use disorder (SUD) are especially at risk.6 Co-prescription of gabapentin and opioids has been shown to increase the risk of opioid-related death by 49%.7
  • Overdoses related to stimulants like methamphetamine and cocaine and those related to polysubstance use have characterized the latest wave of the crisis. Stimulants and opioids (including fentanyl) are being combined more often,8 and fentanyl is being mixed into other illicit substances.Given the prevalence of adulteration, people may not know a substance they are taking contains it. Fentanyl is often found in heroin and cocaine—a trend that has increased since the COVID-19 pandemic. Such “combinations are especially dangerous” since “even a small quantity [of fentanyl] has a powerful effect on depressing respiration.”10

Attention to polysubstance use is urgently needed as we respond to the evolving overdose crisis. The aim of this resource page is to provide communities—including health and human services providers, individuals with SUD, their families and friends, and local leaders—with convenient, evidence-based tools to use and share in addressing these risks.



Gloria headshot

Gloria Baciewicz, M.D.

Since 1986, Gloria Baciewicz has specialized in the treatment of addiction. Professor of clinical psychiatry at the University of Rochester Medical Center, she serves as an addiction psychiatrist at Strong Recovery. Dr. Baciewicz certified in addiction medicine by the American Board of Preventive Medicine and board certified in psychiatry, with added qualifications in addiction psychiatry. Dr. Baciewicz is a co-principal investigator for the University of Rochester’s Recovery Center of Excellence.


Kelly Quinn

Kelly Quinn, CRPA-F, RCP

Kelly Quinn is the Community Outreach Specialist for Strong Recovery at the University of Rochester. She was promoted from the position of Peer Recovery Specialist where she developed peer led support groups and resurrected projects such as the Patient Advisory Committee which Kelly still remains the staff advisor for. Kelly is the founder and Executive Director of Recover Collaborative 501c3 incorporated in 2020 where she provides educational opportunities for individuals seeking CRPA (Certified Recovery Peer Advocate) certification in addition to professional development for those already certified. Kelly is also works as a consultant and partners with community agencies to assist in the development and success of peer service lines. Kelly is a person in recovery and strives for transparency of her own recovery process stating “Just by living authentically we empower others to do the same."

Picture of Patrick Seche

Patrick Seche, MS, CASAC

Patrick Seche is the Senior Director of Addiction Services and a Senior Associate faculty member in the University of Rochester Medical Center’s Department of Psychiatry, and currently oversees three clinics at Strong Recovery, which is a part of Strong Memorial Hospital. On the steering committee for the University of Rochester’s Recovery Center of Excellence, Patrick focuses on substance use disorder, methadone treatment, and community relations.


Tim Wiegand headshot

Timothy J. Wiegand, M.D., FACMT, FAACT, DFASAM

Tim Wiegand has extensive experience in treatment of opioid use disorder (OUD) with buprenorphine in the office-based setting and in the ED and hospital setting. He has served as course faculty for X-waiver trainings for the American Society of Addiction Medicine (ASAM) and American Academy of Addiction Psychiatry and provided mentorship training through the PCSS and other venues. He has published on the use of buprenorphine for the treatment of OUD as well as for pain. Dr. Wiegand is board certified in addiction medicine and medical toxicology. He serves on the board of directors for ASAM and the American College of Medical Toxicology and is president of the New York Society of Addiction Medicine. He was recently awarded the American College of Medical Toxicology Service to the College award and the ASAM 2022 annual award.



[1] Centers for Disease Control and Prevention (CDC). (2021, November 17). Drug overdose deaths in the U.S. top 100,000 annually [Press release].

[2] U.S. Department of Health and Human Services. About the strategy. Overdose Prevention Strategy. Retrieved November 17, 2021.

[3] Jones, C. M., Einstein, E. B., & Compton, W. M. (2018). Changes in synthetic opioid involvement in drug overdose deaths in the United States, 2010-2016JAMA319(17), 1819-1821.

[4] Compton, W. M., Valentino, R. J., & DuPont, R. L. (2021). Polysubstance use in the U.S. opioid crisisMolecular Psychiatry26(1), 41-50, p. 47.

[5] Tori, M. E., Larochelle, M. R., & Naimi, T. S. (2020). Alcohol or benzodiazepine co-involvement with opioid overdose deaths in the United States, 1999-2017JAMA Network Open3(4), e202361. A review of research relating to rural Appalachia found that overdose deaths frequently involved multiple substances, often combination of prescription opioids and benzodiazepines or antidepressants. Schalkoff, C. A., Lancaster, K. E., Gaynes, B. N., Wang, V., Pence, B. W., Miller, W. C., & Go, V. F. (2020). The opioid and related drug epidemics in rural Appalachia: A systematic review of populations affected, risk factors, and infectious diseasesSubstance Abuse41(1), 35-69.

[6] Tharp, A. M., Hobron, K., & Wright, T. (2019). Gabapentin‐related deaths: Patterns of abuse and postmortem levels. Journal of Forensic Sciences, 64(4), 1105-1111; Smith, R. V., Havens, J. R., & Walsh, S. L. (2016). Gabapentin misuse, abuse and diversion: a systematic review. Addiction, 111(7), 1160-1174.

[7] Gomes, T., Juurlink, D. N., Antoniou, T., Mamdani, M. M., Paterson, J. M., & van den Brink, W. (2017). Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control studyPLoS Medicine14(10), e1002396.

[8] Ciccarone, D. (2021). The rise of illicit fentanyls, stimulants and the fourth wave of the opioid overdose crisis. Current Opinion in Psychiatry, 34(4), 344-350.

[9] CDC. Other drugs. National Center for Injury Prevention and Control. Retrieved January 3, 2022.

[10] Niles, J. K., Gudin, J., Radcliff, J., & Kaufman, H. W. (2021). The opioid epidemic within the COVID-19 pandemic: Drug testing in 2020Population Health Management24(S1), S43–S51, p. S49.

March 2022