Carl Salzman, MD
Professor of Psychiatry at Harvard Medical School and past chairman of the American Psychiatric Association Benzodiazepine Task Force. Interview by Marcia L. Zuckerman, MD. Board member of The Carlat Psychiatry Report; outpatient psychiatrist, Hallmark Health, Medford, MA; clinical assistant professor in psychiatry, Tufts School of Medicine. Edited by Chris Aiken, MD. Editor-in-Chief of TCPR; practicing psychiatrist, Winston-Salem, NC.
Drs. Salzman, Zuckerman, and Aiken have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.
TCPR: Benzodiazepines were the most commonly prescribed drug—of all drugs—in the 1970s. Are they still that popular?
Dr. Salzman: I think benzodiazepines are still widely used, both appropriately and inappropriately. The SSRIs were supposed to replace the benzos for long-term treatment of anxiety, but while the use of these antidepressants has increased in anxiety disorders, the use of benzos has barely fallen.
TCPR: Why is that?
Dr. Salzman: I’m speculating, but one reason is that the benzos are more potent anxiolytics. In generalized anxiety disorder, their effect size is in the medium range (0.5) compared to SSRIs, which have a small effect size of 0.3 (Gomez AF et al, Expert Opin Pharmacother 2018;19(8):883–894). The second reason is the benzos work faster. Finally, they are helpful for sleep. They may not always be the best drugs for sleep, but they are reliable.
TCPR: On the other hand, physicians seem to have more negative attitudes about benzos today than they did in the 1970s.
Dr. Salzman: Yes. I call it “benzo hysteria.” It’s very hard to get a doctor to prescribe a benzodiazepine, though on their own they are almost never fatal in overdose. Some benzo use is inappropriate: the wrong patient, the wrong dose, the wrong duration, or the wrong interaction with other drugs like alcohol, opioids, or other sedative-hypnotics. But if you take away those situations and just look at the legitimate medical use of benzos, these are good drugs and they are effective. We know the pharmacology. We know how they work in the brain. They are sedative-hypnotics and can cause dependence, but that depends on the dose and duration.
TCPR: What do you consider the appropriate dose and duration for benzodiazepines?
Dr. Salzman: Once you’re above 3 mg/day of clonazepam, you begin to think, “Why does this person need more? Am I missing something?” Or when their dose keeps increasing and you’re getting calls saying, “I’m still anxious and can’t sleep.” We don’t like to use benzodiazepines long term, but there are many people who suffer from serious chronic anxiety that is not well managed by antidepressants but is well managed by modest doses of a benzo. Benzos are also useful for short-term control of agitation, and they are very good for panic disorder and phobias. Two are FDA approved in panic disorder—alprazolam and clonazepam—and we have the best data supporting their use in panic disorder.
TCPR: Do you see tolerance with long-term use?
Dr. Salzman: Tolerance develops to the sedative effect, but usually not to the anxiolytic effect. It depends on the patient. If the patient regularly uses alcohol or any other sedative-hypnotic, you want to be very careful. I don’t recommend long-term benzos for patients who drink on a daily basis, but if they have a drink on Saturday night at dinner, that’s not a prohibition—though it depends how much they drink on Saturday night.
TCPR: What would be too much for you?
Dr. Salzman: More than one cocktail or a glass or two of wine a day for most people, unless they are elderly or in poor health—then any alcohol would be too much. I would ask if they ever mixed the two and what happened, and I would warn about the interaction with alcohol. At high levels the two can be fatal in overdose, and at moderate levels both of them increase the risk of car accidents.
TCPR: Are there any other populations where benzodiazepines would give you pause?
Dr. Salzman: Yes, I would try not to prescribe in borderline and antisocial personality disorders. Elderly patients and those with chronic obstructive pulmonary disorder are also high risk. I would avoid in patients with substance use disorders, even when they are in recovery. A history of an opioid use disorder or of accidental overdose on opioids would be a red flag. Opioids and benzos are risky together, but it isn’t that people who are taking benzos then add opioids. Instead, it’s the other way around: People who are taking opioids add the benzos. This is because sedative-hypnotics increase the high of an opioid, which is well known. Any sedative-hypnotic will do it, and barbiturates will do it as well.
TCPR: What if they are legitimately taking a benzodiazepine for anxiety, and then have an acute pain situation that requires an opioid? Or if they have chronic pain from rheumatoid arthritis or a congenital deformity, along with social anxiety?
Dr. Salzman: That’s still a risk. If benzodiazepine therapy is appropriate, I’d want the pain doctor to prescribe both in those cases. I’d call the doctor and explain, “The patient needs some benzodiazepines. Could one doctor prescribe both drugs so that you can keep track of dosing and whether there’s potential abuse?”
TCPR: What about patients with a history of alcohol use disorder?
Dr. Salzman: I do prescribe to some patients who have a distant history of an alcohol use disorder and are active in AA. We don’t have a lot of data in this group, but an outpatient psychiatric clinic followed people with past alcohol abuse who were prescribed benzos for up to 12 years and found no problems with tolerance or relapse (Mueller TI et al, Alcohol Clin Exp Res 2005;29(8):1411–1418).
TCPR: They didn’t tend to relapse into alcohol or benzo use?
Dr. Salzman: Right. Now, I should warn you about another group of patients. As benzos and opioids have come under more regulatory scrutiny, we’re seeing more patients referred by primary care physicians who no longer feel comfortable prescribing benzodiazepines to those patients. I know one psychiatrist whose office got flooded with these cases, and sometimes the patients were very loud and even threatening. Some of the prescribing was appropriate, but many of the patients were just angry and unhappy about their lives, and they were demanding Klonopin. They abused alcohol; they had bad marriages; they were out of work. He put up a sign in his waiting room that said, “This doctor does not prescribe Klonopin for any reason.” Over the next couple of weeks, the office emptied out, and the people who remained were legitimate patients for benzodiazepines.
TCPR: A lot of people are stressed out and unhappy. They may not have a genuine psychiatric disorder, but what is the harm if a benzo makes them feel better?
Dr. Salzman: Well, it might make them feel better, but then they start to increase the dose, and pretty soon you have somebody taking 10 mg/day of clonazepam. That person needs help managing their stress, and a benzodiazepine won’t do that.
TCPR: What are the risks in the elderly?
Dr. Salzman: Older patients are more susceptible to falls, traffic accidents, and respiratory suppression on benzos. Whether benzos raise the dementia risk is less clear.
TCPR: Why are you less worried about the dementia risk?
Dr. Salzman: There were studies showing an association, but that doesn’t prove causality, and more recent studies have cast doubt. In a prospective follow-up study with 3434 patients, the risk of dementia actually went down as the dose exposure went up (Gray SL et al, BMJ 2016;352:i90). Another study with 616,256 patients found the same risk of dementia in people taking benzodiazepines as in those on antidepressants, suggesting that these meds are just a marker for another variable, like having a psychiatric disorder (Baek YH et al, J Am Med Dir Assoc 2020;21(2):201–211.e2). In the early phases, dementia can present with anxiety and depression, and that can confound the association. Recently a Danish group tried to get around that by removing patients from their study who developed dementia within the first two years of starting the benzo, as those were more likely to be cases where early signs of dementia were misdiagnosed as anxiety or depression. They found no association between benzos and dementia (n = 235,465; Osler M and Jørgensen MB, Am J Psychiatry 2020;177(6):497–505).
TCPR: How do you take people off benzodiazepines?
Dr. Salzman: A slow taper is important. If the patient is taking 2 mg/day of clonazepam, you would go down by, say, 0.25 mg per week until you get to 1 mg. Then at 1 mg you’ve got to go even slower. The reason is that the receptors where benzos work are beginning to upregulate and are becoming more sensitive to the withdrawal of the drug. The brain makes benzodiazepines, and it stops doing so when you start prescribing, so you’ve got to give the brain a chance to reestablish its normal benzodiazepine level while you’re tapering. So taper slowly.
TCPR: Are you saying the brain produces benzodiazepines on its own?
Dr. Salzman: Yes, the term for these is “endozepines.” We don’t know exactly what they are, but several compounds have been put forth as candidate endozepines that modulate the benzodiazepine receptor (Tonon MC et al, Pharmacol Ther 2020;208:107386).
TCPR: Back to withdrawal. What do you do when you need to lower by smaller increments than you can get to by cutting the pill in half?
Dr. Salzman: Alprazolam, diazepam, and lorazepam are available as liquids. For others, like clonazepam, patients can grind the 0.5 mg tablet into a fine powder with a mortar and pestle, or just spill out the contents for benzos that come as capsules. Next, they dissolve the solids into a measured amount of water—say, four ounces. You’d need to guide them with the ratio of pills to liquid to get the right dose, then use that to continue a very slow taper, adjusting as you evaluate how tolerable the withdrawal symptoms are.
TCPR: Do you ever use other medications to help with benzo withdrawal?
Dr. Salzman: They aren’t very helpful, but sometimes I use propranolol. It reduced the severity of withdrawal symptoms in a double-blind study (60–120 mg/day). Some people use gabapentin (Neurontin), though there’s not much literature on that, but pregabalin (Lyrica) improved sleep in a controlled trial of benzodiazepine withdrawal (200–400 mg/night). There are also small controlled studies supporting carbamazepine at doses of 200–800 mg/day (Tyrer P et al, Lancet 1981;1(8219):520–522; Rubio G et al, Eur Addict Res 2011;17(5):262–270; Di Costanzo E et al, Minerva Psichiatr 1992;33(4):301–304).
TCPR: Do you have a go-to benzo?
Dr. Salzman: I don’t have a favorite. Some people do better on different benzos for reasons we don’t understand. I prefer lorazepam for sleep and for short-term use. I also prefer lorazepam in the elderly as it doesn’t have hepatic drug interactions and doesn’t accumulate metabolites. I’m less likely to use a benzodiazepine with a long half-life like clonazepam in an elderly patient, because that can raise the fall risk.
TCPR: What do you warn patients about before starting a benzo?
Dr. Salzman: I tell them that the drug can interfere with driving. It slows their reaction time, particularly when the serum levels peak, which is 30–60 minutes after taking it. That’s still true if they’ve been on a steady dose for a long time, so they wouldn’t want to drive when the level is at its peak, although there is also evidence that high anxiety can impair driving. Next, I say, “If you take this drug on a steady basis, you’re probably going to develop a physiologic dependence—not an addiction, a dependence—so you must never stop it abruptly unless there’s an emergency or under a doctor’s supervision. If you want to stop the drug, call me and we’ll work out a taper.” Finally, I warn them not to mix it with opioids, other sedative-hypnotics, or alcohol.
TCPR: Final thoughts?
Dr. Salzman: Don’t be afraid of benzos. They are among the safest drugs we have. Even in overdose, they are safer than most psychiatric medications, unless they are taken with another sedative-hypnotic like alcohol or an opiate or the patient has chronic obstructive pulmonary disorder.
TCPR: Thank you for your time, Dr. Salzman.
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