'Treat These Patients With Compassion': Expert Discusses Pharmacists' Role in Counseling Benzodiazepine Use

Brian Anderson, PharmD, RPh, director of technical assistance at EMO Health, sat down for an interview with Pharmacy Times® to discuss benzodiazepines, including the history of the drug class and the current trends surrounding them. Additionally, Anderson provides an in-depth explanation of the substance use disorder epidemic in the United States, and how benzodiazepine misuse and abuse can be a major factor.

Misuse or abuse of benzodiazepines are a major contribution to the national substance use crisis in the United States. | Image Credit: © BillionPhotos.com | stock.adobe.com

Pharmacy Times: Could you start by discussing the history that led to the development of benzodiazepines and the significance of the drugs?

Brian Anderson, PharmD, RPh: This is a topic that I like to cover any time I lecture on a drug, or in this case, a class of drugs. I’m a big believer in starting from the beginning and really giving the full historical context, because I believe that helps give people a sense of how certain chemicals have come to take the place they have in medicine and in culture. So, in the middle of the 20th century, there was what we might call a revolution in the field of psychopharmacology that dramatically changed the way we think about the mind and how we treat patients with mental health diseases. We had drugs like chlorpromazine (Thorazine) and haloperidol (Haldol; Johnson & Johnson) come to the market that allowed for patients with mental health diseases to be treated on an outpatient basis, rather than in a mental institution. We had antidepressants coming along around this time, which really shifted the landscape and the treatment of clinical depression, of course. Psychopharmacology was becoming a very attractive area of research for a lot of pharmaceutical companies. Now, as our understanding of psychopharmacology expanded, there was a subsequent, and I would argue not coincidental, increase in the number of officially recognized psychiatric diseases. Prior to this, most mental health diseases were viewed as defects of character or personality, rather than a diagnosable illness with an underlying path of physiological or chemical mechanism.

The mid-1900s is where we really begin to see a radical shift in this thinking. As far as anxiety itself, we can go all the way back to the 18th century and see patients being diagnosed with conditions like neurasthenia or nervous exhaustion, the treatment for which was usually some type of rest cure or psychoanalysis, when that emerged in the late 19th century with Sigmund Freud. There were some early drugs; chloral hydrate was invented in 1831 that was really the first sedative hypnotic drug, and indeed, the research that went into developing chloral hydrate laid the groundwork for some of the more refined sedative hypnotic drugs that would come much later, like the barbiturates and, of course, the benzodiazepines. So anyway, in 1960 we're in the throes of this rising notion in culture and in medicine that the various ailments of the mind were the result of defects in its underlying chemistry and could therefore be cured or alleviated with a psychoactive drug. That's when we see the first benzodiazepine come to market. The first one was a chemical that was then called meth amino chlordiazepoxide, later shortened a little bit to chlordiazepoxide, better known by its trade name, Librium, a drug that's still used today of course. They tested it on mice and cats and monkeys; animals that were once very aggressive and mean became very nice and docile on the new drugs. Studies in humans supported these results.

And then, of course, 3 years later, Valium, or diazepam, one of the biggest blockbuster drugs of all time, came to market in 1963. These drugs proved to be more effective and safer than their predecessors, drugs like the barbiturates, and they were also backed by a very aggressive marketing campaign, and they became some of the most prescribed drugs in the US. And of course, after the success of Valium and Librium, many other drugs were developed in the following decades by both Roche, the company behind the initial 2 drugs, and their competitors. So, the drugs have become a very effective tool for clinical providers in the treatment of anxiety and some other mental health conditions, but they're also some of the most misunderstood and mis-prescribed drugs that we have out there.

PT: What are the primary uses of the medication, and how are they different from other medications used to treat these conditions?

Anderson: Research has shown that benzodiazepines have a profound enhancement effect on a neurotransmitter called gamma-aminobutyric acid (GABA). Specifically, these drugs, benzodiazepines, act as agonists at the GABA-A receptor. GABA is the most abundant inhibitory neurotransmitter in the central nervous system (CNS), we find GABA receptors on just about every neuron in the CNS. GABA reduces the activity of the nerves in the brain and the spinal cord, resulting in anxiolytic, sedative, hypnotic, anticonvulsant, amnesiac, and skeletal muscle relaxing effects. Benzodiazepines, of course, then could be used to treat many conditions because they have this wide range of pharmacodynamic effects. Primary reasons for use include treating seizures, treating severe anxiety and panic disorder in the short-term, and treating severe insomnia or sleep disturbances in the short-term; severe, usually meaning having a serious impact on a person's day to day life, short-term, generally meaning about 2-to-4 weeks in most cases. Some other indications include nausea and vomiting, especially that which is associated with chemotherapy treatment, muscle spasms, general anesthesia, used for sedation prior to surgery or diagnostic procedures. They can be used in alcohol and drug withdrawal, primarily today, especially in patients who are having acute psychotic episodes.

PT: What are the current trends for benzodiazepines, and what is the current state of the substance use disorder epidemic in the US?

Anderson: Well, I'll start with your second question first, because I think the answer is a little clearer. The current data on substance use disorder in the US is still dire. We've moved from an opioid epidemic to an overdose or a poisoning epidemic. According to the CDC, there was an estimated 107,543 overdose deaths last year, which was a decrease of 3% from the previous year. That was the first annual decrease we saw since 2018. I suppose that's some good news, a sign that maybe we're heading in the right direction, but we'll see what the data shows for 2024 of course. Either way, this is far more preventable death than we should be seeing. As far as the role of benzodiazepines, we must ask ourselves first, why are people misusing these drugs in the first place? According to the National Institute on Drug Abuse, most people said that their most recent misuse of benzodiazepines was to relax or relieve tension or to help them fall asleep, which is not surprising, but it is an important point. Benzodiazepines are Schedule 4 drugs for a reason; they have a lower potential for addiction and misuse than drugs in schedules 1 through 3, obviously. These are not extremely euphoric drugs, like very potent opioids or stimulants, like methamphetamine. Don't get me wrong—they have addictive potential. They release dopamine in the mesolimbic system, just like any other drugs with addictive potential, but not to the same degree as some of these other drugs that are out there, especially today. I would say rarely—I won't say never, I've learned never to say never working in addiction medicine—but very rarely will you find a person say, robbing a convenience store or a liquor store to get a fix of a benzodiazepine. These days, the culprit there is usually fentanyl or methamphetamine in certain parts of the country, more potent drugs, not pharmaceutical products.

So why am I making this point? Because generally, if we see people misusing these drugs—benzodiazepines—they're likely doing it for one of a couple of reasons. Either number 1, as I said, they're trying to relieve the symptoms of anxiety, insomnia or other mental health conditions. They may be under-treated for these conditions, or they may not have access to mental health care. But for whatever reason, they feel like they need these drugs to treat an underlying mental health condition. Or reason number 2, they're using benzodiazepines to complement or to enhance the effects of their primary substance of choice. Maybe they use these drugs to compliment the feelings of relaxation of a fentanyl high, or increase the nod, or enhance the effects of alcohol, or they use them to say, relax after coming off of a stimulant binge. It could be trying to alleviate some of the anxiety that comes with cannabis use. More likely the most dangerous trend we're seeing right now is not misuse of or addiction to prescription benzodiazepines, but rather counterfeit products that are being sold both on the street and on the Internet, usually through social media. Overdoses involving counterfeit tablets, many of which are made to resemble genuine benzodiazepine pharmaceutical products, doubled from 2019 to 2021, which is the most recent data we have from the CDC. And these are cases in which there was evidence of counterfeit pill use. I would argue that these numbers could be even higher. There might be a lot of cases where there may not have been evidence of counterfeit pill use, though they may have been involved. I know that in 2023 the DEA seized more than 80 million fentanyl-laced counterfeit pills. And according to the DEA, 7 out of 10 counterfeit tablets seized contained a potentially lethal dose of fentanyl or fentanyl analogs. Now a lot of people, of course, folks with substance use disorder, opioid use disorder (OUD), they know what they're getting in these counterfeit pills, and they seek them out. There's no question about it. However, there are counterfeit pills that look almost exactly like 2 milligrams Xanax tablet, or a 10-milligram diazepam tablet, and they're being sold on the Internet and through social media. There are a lot of kids out there, or people who are just curious, or, again, looking for a way to sleep or relax or and perhaps are being under-treated for these conditions. People who may be naive to the current climate and purchasing these tablets without knowing the risk that they're taking. Whether these products contain fentanyl or fentanyl analogs or illicit benzodiazepines, which we know very little about, it's obviously a very big risk.

PT: What is the role of the pharmacists in preventing drug overuse, misuse, or substance use disorder for patients?

Anderson: It's a good question. It can be a difficult question to answer, because I think it really depends on your setting and your role. For community pharmacists, for those who are interacting with the public on a day-to-day basis, I would say it simply starts with not stigmatizing or marginalizing these patients because of their disorder. I know that's easier said than done. I'm sure many pharmacists out there reading this have been yelled at by a buprenorphine/naloxone (Suboxone; Indivior) patient who is a couple days early to pick up their script or is having insurance issues or something like that. But we really must, as a profession, treat substance use disorder as the complicated disease state that it is with biological, psychological, and social components. We must treat these patients with respect and human dignity.

Think about it like this: there are a lot of unhealthy choices that patients make that lead to serious health conditions. For example, a person may live a sedentary lifestyle and eat unhealthy foods and end up with diabetes or hypertension or obesity, at which point our role is to help treat the patient. A person may not wear sunscreen, for example, and lay out in the sun every day and end up with melanoma. Again, our role is to help treat that patient. Substance use disorder, like many of these conditions, it starts with a choice, there's no question about it, and that choice, over time, can lead to a disease state, at which point our role as pharmacists is really to help the patient. However, substance use disorder seems to be the only condition where withholding treatment is considered acceptable by some in the medical community, and it's not. Are there cases of over-prescribing or inappropriate prescribing? Of course there are. There always have been, and there always will be. But marginalizing these patients, stigmatizing them, denying them medications depending on the circumstances, of course, that's not helping them. I would advise, talk to your patients with compassion, counsel them, be aware of local resources. If you're able to do so, develop relationships with local facilities that treat patients with substance use disorder. Connect your patients with those places. SAMHSA has a helpline with a lot of resources that you can always refer patients to. I think the first step is not perpetuating the stigma that these patients face so frequently in the medical community that turns them away from seeking care in the first place and sends them back into a very, very dangerous environment.

PT: What are the current treatment approaches for benzodiazepine use disorder?

Anderson: So unlike OUD, there are currently no FDA approved medications for the treatment of benzodiazepine use disorder (BUD), so there's no long-term Suboxone or methadone-like (Methadose; Mallinckrodt Pharmaceuticals) option for patients with BUD. Rather, the treatment approach is a medically supervised, gradual taper with a long-acting benzodiazepine, generally chlordiazepoxide (Librium; Roche) or diazepam (Valium; Roche) with adjunctive psychosocial treatment. Benzodiazepines should almost always be tapered, unless they've only been used for a few days or sporadically on a “pro re nata” (PRN) dose or at a lower dose. But for patients who have been using higher doses for long periods of times, the taper rate is a gradual reduction of the dose, generally 25-to-50% every 1-to-2 weeks over a period of usually 6-to-10 weeks, you may go even slower. You could do a reduction of 10-to-20% every 1-to-2 weeks. It really depends on the patient and their condition. How long have they been using the benzodiazepine, and at what dose? Which specific drug are we talking about, and what is its pharmacokinetic profile? What is the patient's capacity to tolerate withdrawal symptoms? Longer durations of use are associated with a higher likelihood of more severe symptoms during the taper. Those subjective benzodiazepine withdrawal symptoms during a taper can worsen as the reduced dose reaches about 25% of the initial dose that they were taking, and then start to improve as the dose reaches zero. But broadly speaking, a gradual, slow taper is the initial approach.

Now, preventing recurrent use really consists of non-pharmacological methods like counseling, behavioral therapies, managing co-occurring disorders, and avoiding benzodiazepines in favor of other alternatives. There are other pharmacological alternatives for treating most of the conditions that they're indicated for. Just to make the point, managing those co-occurring disorders is a very important point, I think. If you recall the common reasons why people are misusing these drugs in the first place, in most cases, they're addressing an under-treated medical condition, like anxiety disorders or insomnia. Or they're using them as part of some drug cocktail with other drugs like opioids or alcohol. Treating the underlying anxiety, insomnia, depression, OUD, alcohol use disorder, or whatever the underlying condition is, or underlying conditions are, that may have been fueling the benzodiazepine misuse in the first place, that's really key to treatment.

PT: How can pharmacists be aware of the illicit use and safe of benzodiazepines and counterfeit medication?

Anderson: I would say, educate your patients and be aware of the dangerous climate that's out there. Take care of your families. Make sure your loved ones are aware of how dangerous the situation is out there right now regarding these illicit drugs. I believe the DEA has a public health campaign going on right now called “1 pill can kill,” and this can certainly be the case for many people, especially kids who are exposed to these drugs and are opioid-naive. Again, as I mentioned, there are a lot of people in this country with OUD, substance use disorder, who know what they're taking, and they seek these drugs out. We should be treating these patients with compassion and doing our best to connect them with proper care whenever they're ready to accept that, or harm reduction resources and harm reduction counseling and advice if they're not quite ready to stop using these substances entirely. But for those who may not be aware, I would just argue that education and spreading awareness is the best preventative tool that we have. In addition, being familiar with the laws around naloxone, spreading awareness of the availability of naloxone now, and making sure that patients have access to the medications they need.